Volume49,
49,Suppl.
Suppl.
1, March 2013
Volume
4, November
2013
ISSN 0959-8049
EJC
EUROPEAN JOURNAL OF CANCER
5th Asian Oncology Summit
and 9th Annual
MarkersConference
in Cancer:
of the Organisation for
A joint meeting by ASCO, EORTC and NCI
Oncology and Translational Research
Abstract Book
March 22–24, 2013, Bangkok, Thailand
7–9 November 2013
Abstract
Book
Brussels,
Belgium
THE OFFICIAL JOURNAL OF
European Journal of Cancer
Editor-in-Chief:
Editors:
Basic and Preclinical Research:
Drug Development:
Early Breast Cancer:
Advanced Breast Cancer:
Gastrointestinal Cancers:
Genitourinary Cancers:
Lung Cancer:
Gynaecological Cancers:
Head and Neck Cancer:
Sarcomas:
Melanoma:
Neuro-oncology:
Epidemiology and Prevention:
Paediatric Oncology:
Founding Editor:
Past Editors:
Editorial Office:
Alexander M.M. Eggermont
Institut Gustave Roussy
Villejuif, France
Richard Marais, Manchester, UK
Giorgio Parmiani, Milan, Italy
Jean-Charles Soria, Villejuif, France
Kathleen I. Pritchard, Toronto, Canada
David Cameron, Edinburgh, UK
Eric Van Cutsem, Leuven, Belgium
Michel Ducreux, Villejuif, France
Cora Sternberg, Rome, Italy
Mary O’Brien, London, UK
Ignace Vergote, Leuven, Belgium
Kevin Harrington, London, UK
Jean-Yves Blay, Lyon, France
Dirk Schadendorf, Essen, Germany
Roger Stupp, Zurich, Switzerland
Jan Willem Coebergh, Rotterdam, The Netherlands
Rob Pieters, Rotterdam, The Netherlands
Henri Tagnon
Michael Peckham, London, UK; Hans-Jörg Senn, St Gallen, Switzerland; John Smyth, Edinburgh, UK
Elsevier, The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK
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EDITORIAL BOARD
CLINICAL ONCOLOGY
J.-P. Armand (France)
A. Ayhan (Japan)
R. Blamey (UK)
M. Bolla (France)
J. Boyages (Australia)
N. Brünner (Denmark)
F. Cardoso (Portugal)
J. Cassidy (UK)
M. Castiglione (Switzerland)
L. Cataliotti (Italy)
L. Cheng (USA)
H. Cody (USA)
R. Coleman (UK)
A. Costa (Italy)
J. De Bono (UK)
M.J.A. De Jong (The Netherlands)
E. de Vries (The Netherlands)
A. Dicker (USA)
R. Dummer (Switzerland)
F. Eisinger (France)
S. Erridge (UK)
G. Ferrandina (Italy)
H. Gabra (UK)
H. Gelderblom (The Netherlands)
B. Hasan (Belgium)
J.C. Horiot (Switzerland)
C. Huber (Germany)
R. Jakesz (Austria)
J. Jassem (Poland)
D. Jodrell (UK)
V.C. Jordan (USA)
A. Katz (Brazil)
M. Kaufmann (Germany)
I. Kunkler (UK)
L. Lindner (Germany)
P.E. Lønning (Norway)
P. Lorigan (UK)
K. McDonald (Australia)
R. Mertelsmann (UK)
F. Meunier (Belgium)
T. Mok (Hong Kong)
D. Nam (Korea)
P. O’Dwyer (USA)
J. Overgaard (Denmark)
N. Pavlidis (Greece)
J. Perry (Canada)
P. Price (UK)
D. Raghavan (USA)
J. Ringash (Canada)
J. Robert (France)
A. Rody (Germany)
D. Sargent (USA)
M. Schmidinger (Austria)
S. Sleijfer (The Netherlands)
P. Sonneveld (The Netherlands)
A. Sparreboom (USA)
M. van den Bent (The Netherlands)
M. Van Glabbeke (Belgium)
G. Velikova (UK)
U. Veronesi (Italy)
A. Vincent-Salomon (France)
A. Voogd (The Netherlands)
E. Winquist (Canada)
BASIC, PRECLINICAL AND TRANSLATIONAL RESEARCH
A. Albini (Italy)
P. Allavena (Italy)
F. Balkwill (UK)
M. Barbacid (Spain)
M. Broggini (Italy)
C. Catapano (Switzerland)
J. Collard (The Netherlands)
E. Garattini (Italy)
A. Gescher (UK)
R. Giavazzi (Italy)
I. Hart (UK)
W. Keith (UK)
L.A. Kiemeney (The Netherlands)
J. Lunec (UK)
D.R. Newell (UK)
G.J. Peters (The Netherlands)
A. Puisieux (France)
V. Rotter (Israel)
M. Schmitt (Germany)
C.G.J. Sweep (The Netherlands)
G. Taraboletti (Italy)
P. Vineis (UK)
N. Zaffaroni (Italy)
D. Forman (France)
A. Green (Australia)
K. Hemminki (Germany)
C. Johansen (Denmark)
L.A. Kiemeney (The Netherlands)
M. Maynadié (France)
H. Møller (UK)
P. Peeters (The Netherlands)
A.G. Renehan (UK)
S. Sanjose (Spain)
M.K. Schmidt (The Netherlands)
H. Storm (Denmark)
L.V. van de Poll-Franse (The Netherlands)
H.M. Verkooijen (The Netherlands)
R. Zanetti (Italy)
G. Chantada (Argentina)
F. Doz (France)
A. Ferrari (Italy)
M.A. Grootenhuis (The Netherlands)
K. Pritchard-Jones (UK)
L. Sung (Canada)
M. van den Heuvel-Eibrink (The Netherlands)
M. van Noesel (The Netherlands)
EPIDEMIOLOGY AND PREVENTION
B. Armstrong (Australia)
P. Autier (France)
J.M. Borras (Spain)
C. Bosetti (Italy)
H. Brenner (Germany)
L.E.M. Duijm (The Netherlands)
J. Faivre (France)
S. Franceschi (France)
PAEDIATRIC ONCOLOGY
C. Bergeron (France)
A. Biondi (Italy)
E. Bouffet (Canada)
M. Cairo (USA)
H. Caron (The Netherlands)
Volume 49, Supplement 4
November 2013
ISSN 0959-8049
European Journal of Cancer
Editor-in-Chief
Alexander M.M. Eggermont
Markers in Cancer:
A joint meeting by ASCO, EORTC and NCI
Abstract Book
7–9 November 2013
Brussels, Belgium
Amsterdam
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Boston
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London
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New York
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Oxford
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Paris
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Philadelphia
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San Diego
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St Louis
European Journal of Cancer
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iv
Acknowledgements
With the support of the Minister of Scientific Research of the Brussels Capital Region
Pharmaceutical Industries
Media partners for their valuable assistance in improving the visibility of this meeting
v
Table of Contents
Acknowledgements
iv
Foreword
vii
Faculty List
viii
Societies’ Profiles
x
Scientific Program
Scientific Program – Overview
xiii
Scientific Program – Details
xiv
Faculty’s Biosketches
xix
Speakers’ Presentations
S1
Topic 1: New trial concept and challenges for the future?
S1
Topic 2: Biology-driven clinical trials
Topic 3: Progress and implications of novel technology for clinical trials
S2
S3
Topic 4: Regulatory issues
Topic 5: Circulating / Imaging biomarkers
S4
S5
Topic 6: Predictive markers for immunotherapy
Topic 7: Pathway driven approaches
S5
S6
Topic 8: Genomics driven approaches
An EORTC Workshop on Biospecimen Pre-Analytical Stability and Diagnostics
S7
S8
Six Best Poster Abstracts – Oral Presentations
S11
Poster Presentations
S13
Author Index
S39
Disclosures
S43
Abstracts Index
S46
As a significant number of cancers in Europe can be attributed to smoking a strict no-smoking policy will be enforced
within all areas used by the conference.
Save the Date
Markers in Cancer
Diagnostic
Development Tutorial
May 5-6, 2014
Bethesda North Marriott Hotel and Conference Center
Bethesda, Maryland, USA
The 1 ½ day Diagnostic Development Tutorial will address issues
critical to understanding the advances, limitations, development,
and validation of molecular markers. This limited-attendance event
will feature didactic presentations and hands-on discussions of
real-life challenges. Working in small teams, participants will create
development plans for assays that will aid clinical decisions related
to choice of therapy. This format will encourage interaction and
reflective learning and provide ample opportunity for discussion and
faculty feedback. Attendance is limited to early-career oncologists.
This live activity has been approved for AMA PRA Category 1 Credit ™.
markersincancer.org
vii
Markers in Cancer: A joint meeting by ASCO, EORTC and NCI
7–9 November 2013, Brussels, Belgium
“Be ready for the next generation of cancer treatments”
Foreword
Dear Colleagues,
We cordially invite you to attend Markers in Cancer, a joint meeting by ASCO, EORTC & NCI which will be held
7–9 November 2013 in Brussels.
Next generation sequencing and high throughput screening technologies are revolutionizing our current molecular
understanding of cancer. In addition, molecular tumor profiles can now be established at affordable cost within a timeframe
compatible with clinical practice. It is anticipated, that in the coming decade biomarker-based patient selection will move
to the forefront of effective cancer treatment for the majority of patients.
This year’s program will address the challenges we face, the opportunities which await us, and focus on the relevance
and the feasibility of implementing emerging technologies in clinical practice. You will learn the ins and outs of current
biomarker research including next generation biomarker discovery as well as the development and quality control necessary
to turn next generation biomarkers into reliable diagnostics. Furthermore, it is likely that clinical trial design involving
multiplex biomarker testing and molecular imaging will have to be adapted to provide evidence of which (combination)
treatment is most effective for the heterogeneous and genetically diverse cancer patient population presenting in the clinic.
The meeting brings together clinicians, laboratory scientists, bio-informaticians, pathologists, statisticians, industry
representatives, healthcare providers, regulatory agencies, and patient advocates who together with an outstanding faculty
will deal with these emerging issues.
We are also pleased to announce that, for the first time, we will host a Workshop on “Biospecimen Pre-Analytical Stability
and Diagnostics: A joint NCI BRN/SPIDIA Workshop”!
A Diagnostic Development Tutorial will be held prior to the Main Meeting (5–7 November 2013) in order to address issues
critical to understanding the advances, development, limitations, and validation of molecular markers. This Diagnostic
Development Tutorial, “From Hypothesis to Product”, is open to a limited audience and will feature didactic presentations
and hands on discussion of real life challenges.
We look forward to welcoming you in Brussels for what promises to be a captivating and intellectually stimulating
meeting! After the meeting you will be ready for the new era of cancer care based on next generation guided therapy
selection.
Christophe LE TOURNEAU
Co-chair
John MARTENS
Co-chair
viii
Faculty List
Chairs: Christophe Le Tourneau & John Martens
Organizing Committee
ASCO
EORTC
NCI
James Abbruzzese
MD Anderson Cancer Center
Houston (US)
Christophe Le Tourneau
Institut Curie
Paris (FR)
Tracy Lively
National Cancer Institute
Rockville (US)
Lisa Carey
UNC – Chapel Hill
Chapel Hill (US)
John Martens
Erasmus MC
Rotterdam (NL)
Magdalena Thurin
National Cancer Institute
Rockville (US)
Scientific Committee
ASCO
EORTC
NCI
Janet Dancey
Ontario Institute for Cancer Research
Kingston (CA)
Nandita deSouza
Institute of Cancer Research & Royal
Marsden NHS Foundation Trust
Sutton (GB)
Shivaani Kummar
National Cancer Institute
Bethesda (US)
Francisco Esteva
NYU Cancer Institute
New York (US)
Patricia LoRusso
Karmanos Cancer Institute
Detroit (US)
David Sidransky
Johns Hopkins University
Baltimore (US)
Walter Stadler
University of Chicago
Chicago (US)
Christian Dittrich
Ludwig Boltzmann Institute for Applied
Cancer Research
Vienna (AT)
Jacqueline Hall
EORTC Headquarters
Brussels (BE)
Michail Ignatiadis
Institut Jules Bordet
Brussels (BE)
Roberto Salgado
Institut Jules Bordet
Brussels (BE)
Frank Lin
National Cancer Institute
Rockville (US)
Helen Moore
National Cancer Institute
Bethesda (US)
Eric Polley
National Cancer Institute
Bethesda (US)
John Welch
National Cancer Institute
Rockville (US)
Tutorial Planning Committee
ASCO
EORTC
NCI
Susan Hilsenbeck
Baylor College of Medicine
Houston (US)
Fred Sweep
UMC Radboud
Nijmegen (NL)
Mei Polley
National Cancer Institute
Bethesda (US)
Edward Kim
Levine Cancer Institute
Carolinas Healthcare System
Charlotte (US)
Sabine Tejpar
University Hospital Gasthuisberg
Leuven (BE)
Paul Williams
Frederick National Laboratory
for Cancer Research
Frederick (US)
Faculty List
ix
Other Faculty Members
Tommy Alain
McGill University and Goodman
Cancer Research Centre
Montreal (CA)
Udai Banerji
The Institute of Cancer Research & The
Royal Marsden
Sutton (GB)
Robert Becker
U.S. Food and Drug Administration
Silver Spring (US)
Jan Bogaerts
EORTC Headquarters
Brussels (BE)
David Chelsky
Caprion
Montreal (CA)
Nai-Kong Cheung
Memorial Sloan-Kettering Cancer Center
New York (US)
Elisabeth de Vries
University Medical Center Groningen
Groningen (NL)
Angela DeMichele
University of Pennsylvania School
of Medicine
Philadelphia (US)
Mitchell Dowsett
Royal Marsden Hospital
London (GB)
David Eberhard
University of North Carolina
Chapel Hill (US)
Iordanis Gravanis
European Medicines Agency
London (GB)
Kelly Oliner
Amgen, Inc.
Newbury Park (US)
Richard Grose
Barts Cancer Institute
London (GB)
Xavier Paoletti
Institut Curie
Paris (FR)
Juhl Hartmut
Indivumed GmbH
Hamburg (DE)
Mario Pazzagli
University of Florence
Florence (IT)
Monika Hegi
University Hospital Lausanne
Lausanne (CH)
Michael Postow
Memorial Sloan-Kettering Cancer Center
New York (US)
Manuel Hidalgo
Centro Integral Oncologico Clara
Campal
Madrid (ES)
Jordi Rodon
Vall d’Hebron Institute of Oncology
Barcelona (ES)
Stefanie Jeffrey
Stanford University
Standford (US)
Richard Kaplan
University College London, UCL
Hospital & NCRN Coordinating Centre
London (GB)
Shirin Khambata-Ford
Novartis Pharmaceuticals Corp
East Hanover (US)
Denis Lacombe
EORTC Headquarters
Brussels (BE)
Ultan McDermott
Wellcome Trust Sanger Institute
Cambridge (GB)
Philip Febbo
(US)
Federico Monzon
Baylor College of Medicine
Houston (US)
Thierry Gorlia
EORTC Headquarters
Brussels (BE)
Uwe Oelmueller
QIAGEN GmbH
Hilden (DE)
Nicolas Servant
Institut Curie
Paris (FR)
Steven Shak
Genomic Health Inc
Redwood City (US)
Frazer Symmans
UT MD Anderson Cancer Center
Houston (US)
Geraldine Thomas
Imperial College London
London (GB)
Fernando Ulloa Montoya
GSK Vaccines
Rixensart (BE)
Kurt Zatloukal
Institute of Pathology
Graz (AT)
x
Societies’ Profiles
The ASCO Mission and Vision
The American Society of Clinical Oncology (ASCO) is a professional oncology society committed to conquering cancer
through research, education, prevention and delivery of high quality patient care.
Vision Statements:
• All cancer patients will have lifelong access to high quality, effective, affordable and compassionate care;
• The most accurate cancer information will be available so that patients and physicians can make informed decisions
about cancer prevention and treatment;
• Information we learn from every patient will be used to accelerate progress against cancer;
• Resources will exist to attract the best clinicians and investigators to provide optimal patient care and to conduct
transformative research;
• ASCO will be recognized as the most trusted source of cancer information worldwide.
Membership
Our diverse network of more than 30,000 oncology professionals recognizes ASCO’s dedication to provide the highest
quality resources in education, policy, the pioneering of clinical research and above all, advancing the care for patients
with cancer. ASCO is unique in that we are the only organization that encompasses all oncology subspecialties, allowing
our members to grow from the professional and personal expertise of their colleagues worldwide and across disciplines.
International members make up approximately 30% of the Society’s total membership and represent more than 120
countries.
The ASCO Annual Meeting
The ASCO Annual Meeting brings together more than 30,000 oncology professionals from a broad range of specialties to
share the latest cancer research in the areas of basic and clinical science. The abstracts presented each year at the Annual
Meeting reflect the foremost research and strategies in oncology that will directly impact patient care.
To learn more, visit www.asco.org
Societies’ Profiles
xi
The European Organisation for Research and Treatment of Cancer (EORTC) brings together European cancer clinical
research experts from all disciplines to improve cancer care.
Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all
disciplines involved in cancer research and treatment in more than 300 hospitals in over 30 countries.
EORTC Headquarters, a unique pan European clinical research infrastructure based in Brussels, Belgium, handles some
30 protocols that are permanently open to patient entry, over 50,000 patients who are in follow-up, and a database of more
than 180,000 patients.
Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation
programs and medical practices.
EORTC studies have contributed to success stories in drugs development including the registration of several drugs by the
United States Food and Drug Administration and the European Medicines Agency. The EORTC has a proven track record
in establishing new standards, e.g. RECIST, QOL, etc., and in changing clinical practice.
Full clinical, scientific, operational, quality assurance, and regulatory support for clinical and translational research projects
is provided by the EORTC Headquarters staff who augment this support with strong expertise in biostatistics, clinical study
design and methodology, endpoint definition and analysis, and new initiatives in imaging and long term survivorship.
Through its scientific strategy, the EORTC aims to define the future of cancer therapy. It recognizes that the role of
pragmatic data and related methodology need to be developed within multi-stakeholder platforms, and with this goal in
mind, the EORTC participates in projects such as those put forth by the Innovative Medicines Initiative. Such activities
make the EORTC one of Europe’s leading players in transforming experimental discoveries into new treatments with a
significant clinical impact for the benefit of patients.
www.eortc.org
xii
Societies’ Profiles
The National Cancer Institute (NCI) is a component of the National Institutes of Health (NIH), one of eight agencies
that compose the Public Health Service (PHS) in the Department of Health and Human Services (DHHS). The NCI,
established under the National Cancer Act of 1937, is the Federal Government’s principal agency for cancer research and
training. The National Cancer Act of 1971 broadened the scope and responsibilities of the NCI and created the National
Cancer Program. Over the years, legislative amendments have maintained the NCI authorities and responsibilities and
added new information dissemination mandates as well as a requirement to assess the incorporation of state-of-the-art
cancer treatments into clinical practice.
The National Cancer Institute coordinates the National Cancer Program, which conducts and supports research, training,
health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment
of cancer, rehabilitation from cancer, and the continuing care of cancer patients and the families of cancer patients.
Specifically, the Institute:
• Supports and coordinates research projects conducted by universities, hospitals, research foundations, and businesses
throughout this country and abroad through research grants and cooperative agreements.
• Conducts research in its own laboratories and clinics.
• Supports education and training in fundamental sciences and clinical disciplines for participation in basic and clinical
research programs and treatment programs relating to cancer through career awards, training grants, and fellowships.
• Supports research projects in cancer control.
• Supports a national network of cancer centers.
• Collaborates with voluntary organizations and other national and foreign institutions engaged in cancer research and
training activities.
xiii
Scientific Program – Overview
Posters can be viewed in the Grand Hall 1 (Level-2):
From Thursday 7 November (12h30) to Saturday 9 November (11h00)
SESSION A – Thursday 7 November 2013 (Afternoon)
Personalized Medicine
12.30–13.30
13.30–15.15
Welcome Coffee
TOPIC 1: New Trial Concepts and Challenges for the Future
15.15–15.45
15.45–18.00
Coffee Break
TOPIC 2: Biology-Driven Clinical Trials
18.00–20.30
Posters viewing & discussion (Buffet dinner)
SESSION B – Friday 8 November 2013 (Morning)
Challenges of Next Generation Cancer Therapy
08.00–10.00
10.00–10.30
TOPIC 3: Progress and Implications of Novel Technology for Clinical Trials
Coffee Break
10.30–12.30
TOPIC 4: Regulatory Issues
12.30–13.30
Lunch
SESSION C – Friday 8 November 2013 (Afternoon)
NonInvasive Biomarkers
13.30–15.30
TOPIC 5: Circulating / Imaging Biomarkers
15.30–16.00
16.00–17.45
Coffee Break
TOPIC 6: Predictive Markers for Immunotherapy
SESSION D – Saturday 9 November 2013 (Morning)
Markers for Cancer Therapy
08.00–10.00
TOPIC 7: Pathway Driven Approaches
10.00–10.30
10.30–12.15
Coffee Break
TOPIC 8: Genomics Driven Approaches
12.15–13.30
Lunch
An EORTC Workshop on Biospecimen Pre-Analytical Stability and Diagnostics
Saturday 9 November 2013 (Afternoon)
13.30–14.30
14.30–15.30
Opening and Introduction
SESSION I: Preanalytical Variation Affecting Analysis of Proteins, RNA, and Free Circulating
15.30–16.00
DNA in blood
Coffee Break
16.00–17.30
SESSION II: Preanalytical Variation Affecting Analysis of Proteins, RNA, and Morphology in
Post-Surgical Tissues
17.30–18.30
SESSION III: Development of Evidence-Based Biospecimen Standards
xiv
Scientific Program – Details
SESSION A
Personalized Medicine
Thursday 7 November 2013 (Afternoon)
Chairs: Christophe Le Tourneau (EU) & Tracy Lively (US)
TOPIC 1 (13h30 – 15h15)
NEW TRIAL CONCEPT AND CHALLENGES FOR THE FUTURE
Biostatistical challenges for the design of biology-driven trials
(X. Paoletti)
Bioinformatics analysis for real-time applications
(N. Servant)
Pathology challenges for biology-driven trials: The Ki67 experience
(M. Dowsett)
Selected abstract for oral presentation (abstract # MC13-0049):
Two-stage adaptive cutoff design for building and validating a prognostic biomarker signature
(M. Polley)
TOPIC 2 (15h45 – 18h00)
BIOLOGY-DRIVEN CLINICAL TRIALS
Rationale of the design of the WINTHER trial
(J. Rodon)
Rationale of the design of the I-SPY trial
(A. DeMichele)
Rationale of the design of the SHIVA trial
(C. Le Tourneau)
Molecular profiling based assignment of cancer therapy (MPACT)
(S. Kummar)
Selected abstract for oral presentation (abstract # MC13-0075):
Rapid assessment of TORC1 suppression as a functional biomarker predicting responsiveness to RAF
and MEK inhibitors in BRAF-mutant melanoma patients
(R.B. Corcoran)
Scientific Program – Details
xv
SESSION B
Challenges of Next Generation Cancer Therapy
Friday 8 November 2013 (Morning)
Chairs: John Martens (EU) & Lisa Carey (US)
TOPIC 3 (08h00 – 10h00)
PROGRESS AND IMPLICATIONS OF NOVEL TECHNOLOGY FOR CLINICAL TRIALS
Clinical reporting of NGS data
(D. Eberhard)
Selected abstract for oral presentation (abstract # MC13-0060):
Analytical validation of the MPACT assay, a targeted next generation sequencing
clinical assay for cancer patient treatment selection
(C. Lih)
Are we ready for genomes in the clinic?
(U. McDermott)
Application of next generation sequence for retrospective biomarker analyses
in tumors samples from Phase II/III clinical trials
(S. Khambata-Ford)
Discussion / Q&A (All)
TOPIC 4 (10h30 – 12h30)
REGULATORY ISSUES
Translational scientists – Overview of process of taking an assay from the lab to the clinic
(J. Martens)
EMA perspective on approval issues
(I. Gravanis)
FDA view on approval issues and new guidelines
(R. Becker)
R&D’s view on obstacles to development of diagnostics for clinical development
(S. Shak)
Clinician’s view
(TBC)
Statistical issues on biomarker ascertainment and power to detect interactions
(J. Bogaerts)
Discussion / Q&A (All)
xvi
Scientific Program – Details
SESSION C
NonInvasive Biomarkers
Friday 8 November 2013 (Afternoon)
Chairs: Michail Ignatiadis (EU) & Magdalena Thurin (US)
TOPIC 5 (13h30 – 15h30)
CIRCULATING / IMAGING BIOMARKERS
Circulating tumor cells (CTCs) and circulating DNA to monitor tumor heterogeneity
in clinical trials
(S. Jeffrey)
PET imaging to monitor tumor heterogeneity in clinical trials
(E. de Vries)
Selected abstract for oral presentation (abstract # MC13-0026):
KRAS mutated plasma DNA as predictor of outcome from irinotecan monotherapy in
metastatic colorectal cancer
(K. Spindler)
Panel Discussion: What is the role of “liquid biopsy” and functional imaging to interrogate
tumor evolution in clinical trials
(All)
TOPIC 6 (16h00 – 17h45)
PREDICTIVE MARKERS FOR IMMUNOTHERAPY
Monitoring response to anti CTLA-4 therapy
(M. Postow)
Predictive gene signature (GS) in MAGE-A3 antigen-specific cancer immunotherapy
(F. Ulloa Montoya)
Bone marrow minimal residual disease (MRD) was the strongest predictor of survival from high risk
metastatic neuroblastoma (NB) following anti-GD2 immunotherapy, when tested in multivariate models that
include FcR polymorphism and missing ligand for inhibitory killer-immunoglobulin-like receptor (KIR)
(N. Cheung)
Selected abstract for oral presentation (abstract # MC13-0071):
Immune response against non-targeted tumor antigens after treatment with sipuleucel-T
and its association with improved clinical outcome
(D. Guhathakurta)
Scientific Program – Details
xvii
SESSION D
Markers for Cancer Therapy
Saturday 9 November 2013 (Morning)
Chairs: Christian Dittrich (EU) & Francisco Esteva (US)
TOPIC 7 (08h00 – 10h00)
PATHWAY DRIVEN APPROACHES
Challenges and opportunities for molecular screening platforms:
The EORTC SPECTA program
(D. Lacombe)
Pathways triggered by FGF and other growth factors
(R. Grose)
Prediction of the efficacy of mTOR targeted therapies
(T. Alain)
Genotype-based combinations of RAS/RAF and PI3K pathway inhibitors
(U. Banerji)
TOPIC 8 (10h30 – 12h15)
GENOMICS DRIVEN APPROACHES
Genomic wide biomarker discovery in personalized patient derived xenografts
(M. Hidalgo)
RAS mutations as markers of resistance for colorectal cancer patients treated with
the anti-EGFR monoclonal antibody panitumumab
(K. Oliner)
Epigenetic markers in cancer
(M. Hegi)
Selected abstract for oral presentation (abstract # MC13-0079):
Prospective mutational characterization of Japanese patients with non-small cell lung cancer using
surgically resected tumor specimens by next-generation sequencing
(Y. Koh)
xviii
Scientific Program – Details
An EORTC Workshop on
Biospecimen Pre-Analytical Stability and Diagnostics
Saturday 9 November 2013 (Afternoon)
Chairs: Roberto Salgado (EU) & Helen Moore (US)
OPENING AND INTRODUCTION (13h30 – 14h30)
Opening remarks from the co-chairs
(H. Moore & R. Salgado)
Keynote address: Overcoming the challenges of biospecimen collection for R&D, clinical trials and
biobanking
(G. Thomas)
Overview of biospecimen science in the BRN and SPIDIA programs
(H. Moore & U. Oelmueller)
SESSION I (14h30 – 15h30)
Preanalytical Variation Affecting Analysis of Proteins, RNA, and Free Circulating DNA in blood
A controlled assessment of pre-analytical variables and their impact on the proteome
in the collection and storage of plasma and serum
(D. Chelsky)
Evidence-based guidelines for the pre-analytical phase of DNA, RNA and cell-free
DNA testing in blood samples
(M. Pazzagli)
SESSION II (16h00 – 17h30)
Preanalytical Variation Affecting Analysis of Proteins, RNA, and Morphology in Post-Surgical Tissues
Effects of intrasurgical and postsurgical variables on stability of signaling molecules in cancer tissues
(J. Hartmut)
Evaluation of novel alternatives to formalin fixation for companion diagnostics
(K. Zatloukal)
Preanalytical variation affecting detection of RNA in breast cancer tissues
(F. Symmans)
SESSION III (17h30 – 18h30)
Development of Evidence-Based Biospecimen Standards
NCI biospecimen evidence-based practices
(H. Moore)
SPIDIA – Dissemination of results into CEN technical specifications for biospecimen handling
(U. Oelmueller)
Elements of a Global Action Plan for Harmonization of Biospecimen Handling
(R. Salgado)
xix
Faculty’s Biosketches
James Abbruzzese
James L. Abbruzzese, MD, FACP is the Waun Ki Hong
Distinguished Chair and Chairman of the Department of
Gastrointestinal Medical Oncology at the University of
Texas M.D. Anderson Cancer Center in Houston, Texas.
Dr. Abbruzzese has published over 400 peer-reviewed articles, numerous chapters and reviews. In 2001 Dr. Abbruzzese served as a co-chair for the American Association
for Cancer Research Program Committee and he was the
Program Chairman for the American Society of Clinical
Oncology Annual Meeting in 2007. He has recently served
as a member of the AACR Board of Directors and currently serves on the ASCO Board of Directors. He is a past
member of the AACR Research Fellowships Committee,
the ASCO Grant Awards and Nominating Committees, and
currently serves as chairman of National Cancer Institute
Clinical Trials and Translational Research Advisory Committee. He is a Deputy Editor of Clinical Cancer Research,
and member of several other editorial boards including past
service for the Journal of Clinical Oncology. His scholarly
interests center on clinical and translational research for
pancreatic cancer.
Tommy Alain
Tommy Alain received his PhD at the University of
Calgary under the mentorship of Dr. Peter Forsyth and Dr.
Patrick Lee. He trained in oncology, cell biology, and virology while studying the oncolytic potencies of reovirus,
vesicular stomatitis virus, and myxoma virus in various
cancers. During his post-doctoral studies at McGill University in the laboratory of Dr. Nahum Sonenberg, he pursued
work on the control of translation initiation and the mammalian target of rapamycin (mTOR) signaling pathway for
oncology research, in particular on the roles that the translation initiation factor eIF4E, and its repressors 4E-BPs,
play in modulating the efficacy of anti-cancer therapeutics.
Currently a research associate in the laboratory of Dr. Sonenberg at McGill University, he will begin in the new year
his new position as a Scientist and Assistant Professor at
the Children’s Hospital of Eastern Ontario and the University of Ottawa. Dr. Alain has expertise in cell based assays,
generating cell models of cancer, and developing virology
and translation strategies to target malignancies.
Udai Banerji
Dr. Udai Banerji obtained his MD in India at the University of Bombay in 1994. He started as a research fellow
at the Institute of Cancer Research, obtaining his PhD
in 2005 while completing his medical oncology training
at The Royal Marsden. In April 2007, he was appointed
as a Senior Lecturer and Honorary Consultant in Medical Oncology at The ICR and The Royal Marsden; he
is now a Cancer Research UK Clinical Senior Lecturer.
The portfolio of the Phase I unit at The Royal Marsden
includes over 30 phase I trials. Dr. Banerji is the Deputy
Director of the Drug Development Unit and is involved
in running a number of these trials. He is interested in
the discovery and applications of HSP90, PI3K, AKT
and mTOR inhibitors and has been involved in phase I
studies of HSP90 inhibitors such as 17-AAG, 17-DMAG,
CNF204 and AUY922. In addition to Phase 1 trials, his
independent laboratory research interests include the use of
pharmacodynamic (PD) biomarkers; examples include the
use of HSP70, CRAF and CDK4 as PD biomarkers and
HSP90 inhibitors. Other interests include quantifying signalling output to design combinations of signalling agents
to reverse resistance to anti-cancer drugs.
Robert Becker
Robert Becker is Chief Medical Officer for the Office of
In Vitro Diagnostics and Radiological Health (OIR), Center
for Devices and Radiological Health (CDRH), FDA, with
special attention to inter-office coordination on regulation
of newly emerging genetic/genomic IVD’s. Dr. Becker previously served as Director, Division of Hematology and
Immunology Devices, in OIR (then named OIVD). He
is experienced in regulation of IVD’s aimed at cell- and
tissue-based specimens (e.g. classical hematology, flow cytometry, cytology, histopathology), plus blood coagulation
tests, and immunoserologic tests.
Dr. Becker earned his MD and PhD in Immunology at
Duke University, and he is board certified in anatomic and
clinical pathology. He served in the United States Air Force
as a pathologist at the Armed Forces Institute of Pathology, Washington, DC from 1983 to 2004, specializing in
urologic pathology and with research and clinical service
applying image analysis and flow cytometry to diagnostic
pathology.
Jan Bogaerts
Jan Bogaerts earned his degree (1986) and PhD (1993)
in mathematics at the Free University of Brussels (VUB).
In 1988 he earned a degree in management (VUB). From
1986 to 1993 he worked as assistant in mathematics and
statistics at the faculties of Economic, Social and Political
Sciences at VUB. In 1993 he joined BMS as statistician,
and was promoted Associate Director Statistics. He worked
on the development of several drugs in oncology, including FDA and EMEA submissions. In 2004 he joined the
EORTC as statistician of the EORTC Breast Cancer Group.
xx
In 2006 he was appointed senior statistician and in 2010
Head of the Statistics department. In 2012 he was appointed Methodology Vice Director. He contributed to the
development of version 1.1 of RECIST and is on the RECIST Steering Committee. He represents EORTC as course
director of the Flims workshop. He is also the statistician
of the EORTC MINDACT trial. Statistical interests include
the use of methodological issues around Progression Free
Survival, alternative ways to use changes in tumor measurements as predictive markers, and the correct evaluation
of the contribution of new markers to existing prognostic
risk evaluation.
Lisa Carey
Lisa A. Carey, MD is the Richardson and Marilyn
Jacobs Preyer Distinguished Professor of Breast Cancer
Research in the UNC Department of Medicine, Division of
Hematology/Oncology. In 2012 she became the Division
Chief of Hematology/Oncology, as well as the Physicianin-Chief of the North Carolina Cancer Hospital. At UNCLinberger she is the Medical Director fo the Breast Center,
and in 2010 became the Cancer Center’s Associate Director for Clinical Research. Dr. Carey has a longstanding
research interest in the clinical applications of laboratory
findings in breast cancer, with a particular interest in the
clinical implications of different molecular subtypes of
breast cancer. She designs and leads clinical trials of novel
drugs and approaches, and is a close collaborator with several laboratory investigators and epidemiologists.She was
awarded a Doris Duke Clinician Scientist Award in 1999,
a Career Development Award from the NCI in 2000, and
was inducted into the Johns Hopkins Society of Scholars in
2008. In 2011, Dr. Carey was awarded the NCI Director’s
Service Award.
David Chelsky
No information received
Nai-Kong Cheung
Nai-Kong V. Cheung received his MD and PhD (Immunology) from Harvard Medical School. Following specialty training in Pediatric Hematology/Oncology at Stanford University, he became interested in the immunotherapy of cancer, developing monoclonal antibodies targeting
tumor antigens in metastatic neuroblastoma, including antibody 3F8 against ganglioside GD2 and 8H9 against B7-H3.
These antibodies were successfully tested in the setting of
minimal residual disease (MRD) where myeloid effectors
and natural killer cells play critical roles. In order to measure MRD accurately, he exploited genome-wide screens
to develop panels of molecular markers. He holds the Enid
A. Haupt Chair in Pediatric Oncology, heads the neuroblastoma program and directs the Robert Steel Laboratory
at Memorial Sloan-Kettering Cancer Center in New York.
There he has established an active translational program
Faculty’s Biosketches
to explore novel genetically engineered antibodies and to
bring them to pediatric patients diagnosed with metastatic
cancers.
http://www.mskcc.org/prg/prg/bios/203.cfm and http://
www.mskcc.org/mskcc/html/55349.cfm
Janet Dancey
Dr. Dancey is Program Leader for High Impact Clinical Trials, Ontario Institute for Cancer Research, Director,
Clinical Translational Research and Physician Coordinator, Melanoma Disease Site Committee for NCIC Clinical
Trials Group, Chair, Cancer Care Ontario Experimental
Therapeutics Network and Professor, Department of Oncology, Queen’s University. Previously, she was Associate
Chief in the Investigational Drug Branch of the Cancer
Therapy Evaluation Program of the National Cancer Institute. She completed medical school at the University
of Ottawa in 1988. She received certifications in internal
medicine and medical oncology. In her current position Dr.
Dancey is responsible for development of strong translational research programs within NCIC CTG clinical trials
and OICR High Impact Clinical Trial Program. Her clinical
focus is on melanoma and gastrointestinal malignancies.
Key accomplishments include establishment of the High
Impact Clinical Trial Program following successful international peer review, and development of novel trials to
evaluate investigational drugs in rare tumour settings, to
evaluate next-generation sequencing technologies in cancer
patient management.
Elisabeth de Vries
Prof. Dr. E.G. Elisabeth de Vries, MD, PhD is Professor of Medical Oncology, and head of the Department
of Medical Oncology at the University Medical Center
Groningen, Groningen, the Netherlands. She is involved in
patient care, teaching, and research. Her research lines are
aimed at increasing the sensitivity of tumors to anticancer
drugs, and she uses imaging techniques to support this.
Apart from laboratory studies, she performs and coordinates clinical trials. She has received numerous grants
and is PI of CTMM (Center for Translational and Molecular Medicine) grant MAMMOTH ,of ERC advanced grant
OnQview and of Alpe d’HuZes grant IMPACT. She is currently chairperson of the committee for the new RECIST
2.0 version on behalf of the EORTC.
In 2002, she was appointed as a member of the Royal
Academy of Arts and Sciences (KNAW). She received the
European Society of Medical Oncology (ESMO) award in
2009. She is Fellow of the European Academy of Cancer
Sciences and member of the Governing Body European
Academy of Cancer Sciences since 2010. She was awarded
a Royal Netherlands Academy of Sciences professorship in
2011.
Faculty’s Biosketches
Angela DeMichele
Dr. DeMichele is an Associate Professor of Medicine
and Epidemiology at the University of Pennsylvania and
Senior Scholar in the Center for Clinical Epidemiology
and Biostatistics. She received a BS in Biochemistry from
Brown University, and MD from Washington University
and an MS in Clinical Epidemiology from the University
of Pennsylvania, where she also received clinical training
in Internal Medicine and Hematology/Oncology. She is
currently Co-Leader of the Breast Cancer Research Program and Co-Director of the 2-PREVENT Breast Cancer
Translational Center of Excellence at the Abramson Cancer
Center. Her research focuses on developing breast cancer
biomarkers and novel therapeutics through numerous clinical trials and epidemiologic studies supported by the NIH,
Pharma and Komen Foundation. She is a past recipient
of an ASCO YIA, a Career Development Award from the
American Cancer Society and an NIH K23 award. She
directed Penn’s Doris Duke Clinical Research Fellowship
Program and has served on the American Board of Internal
Medicine Oncology Subspecialty Board, the ASCO Education Committee and numerous editorial boards, including
the Journal of Clinical Oncology.
Nandita deSouza
Nandita M. deSouza, Professor of Translational Imaging
and Co-Director of the MRI Unit, Institute of Cancer Research, UK. Main interests: Oncological imaging with particular emphasis on gynaecological, prostate and breast tumours, using functional imaging techniques to understand
biology, improve staging and monitor treatment response.
Nandita holds a Cancer Research UK Imaging Centre grant
in MRI as Co-Principal Investigator and has several project
and studentship grants. She currently chairs the EORTC
Imaging Group. Publications: ∼130 peer-reviewed articles,
several book chapters and editor of a multi-author book on
Endocavitary MRI of the pelvis.
Christian Dittrich
Christian Dittrich, MD, Professor of Medicine at the
Vienna University School of Medicine, is head of the 3rd
Medical Department Centre for Oncology and Hematology
at the Kaiser Franz Josef-Spital in Vienna and director
of the Ludwig Boltzmann Institute for Applied Cancer
Research (LBI-ACR VIEnna). Recently, he became coordinator of the ESMO Faculty for Principles of Clinical
Trials and Systemic Therapy. He serves as member of the
EORTC Protocol Review Committee (PRC) and Scientific
Audit Committee (SAC). He is a representative of the
EORTC Network of Core Institutions (NOCI) and serves
actually as chair of the EORTC New Drug Advisory Committee (NDAC) and as member of the EORTC Board.
Representing ESMO, he is faculty member of the Clinical
Trials Workshops of Flims and Saudi Arabia. He has been
running a CME-initiative in trials’ methodology in German
xxi
language under the patronage of ESO-d/DESO since 1998.
He has research interests in clinical trials’ methodology,
new drug development and translational research, focused
on solid tumors. He has been acting as principal or coinvestigator in numerous clinical trials from phase I (first
in human) to phase III.
Mitchell Dowsett
No information received.
David Eberhard
David A. Eberhard MD, PhD is Associate Professor
in the Departments of Pathology and Pharmacology at
the University of North Carolina at Chapel Hill. Areas
of research interest include: molecular pathology and genomics of solid tumors; oncology companion diagnostics;
preclinical and clinical development of novel assays and
therapeutics for personalized medicine in oncology; digital
pathology and image analysis of solid tumors. Dr. Eberhard
directs the Pre-Clinical Molecular Pathology Laboratory in
the Lineberger Cancer Center at UNC, providing molecular pathology support for translational research efforts in
cancer genomics including Next-Generation Sequencing of
tumor and non-tumor human biosamples. Previously, he
served as Director of Clinical Trials Pathology Services
at LabCorp, as a pathologist-scientist at Genentech Inc.
and as Assistant Research Professor at the University of
Virginia.
Francisco Esteva
Dr. Francisco J. Esteva is Professor of Medicine at New
York University School of Medicine, Associate Director
of Clinical Investigation of the NYU Cancer Institute,
Director of the Breast Medical Oncology Program and
co-Director of the Phase I Program at NYU. Dr. Esteva received his medical and doctoral degrees from the
University of Zaragoza in Spain. He completed a residency in internal medicine at Cooper Hospital University
Medical Center (Camden, NJ) and a fellowship in medical oncology at Georgetown University Medical Center
(Washington, DC). He was a faculty member at MD Anderson Cancer Center (Houston, Texas) from 1997 to 2013.
He received the K23 patient-oriented research career development award from the US National Cancer Institute and
multiple research awards. He is a member of the American
Society for Clinical Investigation. He is an author of more
than 100 publications in the area of breast cancer research
and treatment. Dr. Esteva is dedicated to the clinical development of novel therapies for breast cancer, with a passion
for improving the survival and quality of life of cancer
patients through innovative research and compassionate
patient care.
Philip Febbo
No information received.
xxii
Thierry Gorlia
Thierry Gorlia is a member of the team allocated by
the EORTC Headquarters to provide scientific and logistic
support to EORTC Brain Tumor Group and Translational
Research (TR) Unit in the conduct of cancer clinical trials
and TR projects. He reports to the Head of Biostatistics
Unit and work in close cooperation with the other members of his teams (coordinating physician, data manager,
etc.), and with other units of the Headquarter for particular
projects. Thierry Gorlia has focused his research on the
prognosis and diagnosis of Brain tumors in clinical trials.
He has been involved in the development of disease specific quality of life modules (Gastric), health economics
studies within clinical trials (brain, ovarian cancer). He has
developed expertise in the statistical design of TR projects
and their analyses. In particular, when microarrays are
involved.
Iordanis Gravanis
I studied medicine at the University of Ioannina, in
Greece between 1992 and 1998. I then worked for three
years (1998–2001) as primary care physician in Greece,
half of it as conscript in the Greek army. From January
2002 until April 2007, I studied towards a PhD in Molecular and Cellular Pharmacology at Stony Brook University,
NY, working on mouse models of neurodegeneration. I
joined the European Medicines Agency in August 2008
where I have been managing oncology drug authorisations
and post-authorisation drug lifecycle as well as providing
scientific secretarial support to working parties developing
regulatory guidance for medicines.
Richard Grose
1999 University College London, PhD in Cell Biology
1999–2001 Postdoctoral Fellow, Institute of Cell Biology,
ETH Zurich, Switzerland
2001–2004 Postdoctoral Fellow, Cancer Research UK London Research Institute
2004–2010 Lecturer in Cell Biology, Barts Cancer Institute
2010–present Senior Lecturer in Cell Biology, Barts Cancer Institute
My group is interested in understanding how Fibroblast
Growth Factors (FGFs) and their receptors (FGFRs), which
play critical roles during development, are hijacked by cancer cells to drive tumourigenesis. FGFR signalling can
be a positive driving force for cell proliferation, survival
and migration but is kept under tight control via feedback
loops. In cancer, these controls can be bypassed by a variety of mechanisms and we are investigating how this
happens. We are focusing currently on breast, pancreatic
and endometrial cancer, using 2D and 3D cell based models to investigate how cellular behaviour changes when
FGFR signalling is perturbed. We collaborate with clinical
Faculty’s Biosketches
colleagues to determine the clinical significance of our
findings through analysis of patient samples.
Jacqueline Hall
Dr. Hall joined the EORTC (Belgium) Translational Research Unit in May 2009 after 8 years of research and
training in multidisciplinary environments. She completed
a bioinformatics PhD at Glasgow University where she
worked alongside Epigenomics AG (Berlin) and Orion
Genomics Inc (St Louis) investigating DNA methylation
markers. After her PhD she joined McGill University
(Montreal) for a post-doc in breast cancer at the McGill
Center for Bioinformatics, Rosalind and Morris Goodman
Cancer Centre. At the EORTC HQ she now focuses on
infrastructure development and integration of translational
research activities into EORTC clinical studies. This involves the implementation of human biological material
collection and biobanking, developing and implementing
quality assurance principles for biomarker assays in trials
as well as managing processes for review and implementation of translational research in EORTC clinical trials.
Dr. Hall also has a keen interest in bioinformatics and data
sharing. She is also a member of the EORTC PathoBiology
Group (PBG) and EORTC Pharmacology and Molecular
Mechanisms Group (PAMM).
Juhl Hartmut
Founder and Chief Executive Officer of Indivumed
GmbH and Inostics GmbH in Hamburg. Hartmut Juhl
studied medicine from 1979 to 1986 and received his
doctorate of medicine in 1989. From 1987 to 1992 he
worked as a research associate at the Hamburg Eppendorf
Surgical University Clinic.In 1995 he became a specialist
in general surgery at the Christians Albrecht University
in Kiel and obtained his habilitation in 1996. From 1999
to 2002 he led a gastrointestinal cancer research group
as Associate Professor at the Lombardi Cancer Center
of Georgetown University in Washington DC. In 2002,
Hartmut Juhl became co-founder of Indivumed GmbH in
Hamburg. Indivumed is focused on individualizing cancer therapy based on a highly standardized tumor tissue
bank, a comprehensive clinical data collection and a broad
range of specialized research services. In 2008, Indivumed
GmbH and scientists from Johns Hopkins University, Baltimore/Maryland, founded the subsidiary Inostics GmbH
which is specialized in detection of cancer-specific somatic
DNA-changes. Hartmut Juhl holds an extraordinary professorship at the Hamburg University and is Adjunct Professor
at the Lombardi Cancer Center of Georgetown University.
Monika Hegi
Monika Hegi is associate professor for Experimental
and Translational Neuro-Oncology at the University Lausanne, Switzerland. After her PhD (Dr.sc. nat.) at the
ETH Zurich she pursued post-doctoral training in molecu-
Faculty’s Biosketches
lar toxicology and carcinogenesis at the National Institute
of Environmental Health Sciences (NIEHS), NIH, RTP,
NC, USA, and directs the laboratory of Brain Tumor
Biology and Genetics in the Department of Clinical Neurosciences since 1998.She works in close collaboration
with international cooperative groups, in particular the
EORTC Brain Tumor Group, for which she serves as coordinator for translational research. Analyzing molecular
profiles of gliomas from patients enrolled in trials, has
uncovered mechanisms of treatment resistance. Clinically
most relevant was the demonstration of a predictive value
for epigenetic silencing of the repair gene MGMT for
benefit from the alkylating agent temozolomide in trials
for glioblastoma. This has led to a paradigm change in
neuro-oncology: The MGMT methylation status is now
used as biomarker for stratification or patient selection in
glioma trials and guides treatment decisions in particular
for elderly glioblastoma patients.
Manuel Hidalgo
Manuel Hidalgo was born in Antequera, Malaga, in
1968. He received his MD from the Universidad de Navarra
in 1992 and his PhD from the Universidad Autonoma de
Madrid in 1997. Manuel specialized in Medical Oncology
at the Hospital Universitario 12 de Octubre, Madrid, obtaining his license in 1996. He completed his training in
drug development at the University of Texas Health Science Center, San Antonio (USA), where he briefly joined
as Faculty. He then moved to Johns Hopkins University in
2001 as Co-Director of the Drug Development and GI Programs.In 2009, he joined the CNIO to lead the GI Cancer
Clinical Research Unit. Manuel is a founding member of
the pancreatic cancer research team.He has published 180
papers in peer-reviewed journals and his work has been
funded by the NCI, AACR, and ASCO.In 2011, he was
named Vice Director of Translational Research at CNIO
with the mission to foster translational research.
Susan Hilsenbeck
Susan Hilsenbeck, PhD is a Professor of Medicine at
the Baylor College of Medicine in Houston TX, USA
and is Director of the Biostatistics and Informatics Shared
Resource of the Duncan Cancer Center at Baylor. She
is an internationally known biostatistician with particular
interests in prognostic and predictive markers in cancer,
especially breast cancer, and design and analysis of early
phase, translational clinical trials. She is the statistician of
record for a number of single and multi-center early phase
breast cancer trials. She also has a long-standing commitment to education of clinical investigators. Dr. Hilsenbeck
is a member of the Tutorial Committee for the Markers in
Cancer Diagnostic Development Tutorial.
xxiii
Michail Ignatiadis
Michail Ignatiadis, MD PhD is attending Physician
(Medical Oncologist) at the Medical Oncology Department, Jules Bordet Institute (IJB), Brussels, Belgium since
2007. He obtained his MD from the Aristotle University
of Thessaloniki Greece in 1996, his Medical Oncology
specialization from the University of Crete, Greece in 2006
and his PhD on circulating tumor cells in early breast
cancer from the University of Crete, Greece in 2008. Apart
from his clinical appointment in IJB he is also actively involved in translational and clinical research. Dr. Ignatiadis
is particularly interested in drug and biomarker development in breast cancer.
Stefanie Jeffrey
Stefanie Jeffrey, MD, is the John and Marva Warnock
Professor and Chief of Surgical Oncology Research in the
Department of Surgery at Stanford University School of
Medicine. She received her undergraduate degree in Chemistry and Physics and master’s degree in Chemistry from
Harvard University. She graduated from medical school
at University of California San Francisco (UCSF), where
she also completed her surgical residency. Professor Jeffrey was a key member of the Stanford/Norway team that
pioneered the use of DNA microarrays to classify breast
cancers by their molecular subtypes. She later led the Stanford team that invented the MagSweeper, a device that
captures rare cells, such as circulating tumor cells, live and
at extremely high purity for downstream single cell analyses. Using patient tissues obtained fresh from the operating
room, her laboratory generates patient-derived orthotopic
xenograft models of breast and colorectal cancer for use
in pre-clinical studies of circulating tumor cells (CTCs),
circulating tumor DNA (ctDNA), and other circulating
biomarkers during drug treatment.
Richard Kaplan
Pr. Kaplan is Senior Clinical Scientist and Chair at
the MRC Clinical Trials Unit at University College London, Consultant in Oncology at UCL Hospital, and Associate Director of the National Cancer Research Network
(NCRN) Coordinating Centre. He is a medical oncologist
and trialist, formerly Chief of the Clinical Investigations
Branch, National Cancer Institute (NCI),NIH, and Program
Director for the NCI’s national program of Cooperative
Groups and Consortia.He was responsible for scientific
coordination of the NCs portfolio of funded or sponsored
treatment trials in GI, GU and CNS malignancies. He has
served on advisory committees and panels for NCI, NIH,
FDA and EMA, as well as for other government agencies,
clinical trials organisations and specialty societies in North
America, Europe and Australia. In 2004 he came to the UK
to become Associate Director for Industry for NCRN and
Professor of Oncology in the Leeds Institute of Molecular
Medicine and has promoted collaborative research, both
xxiv
commercial and investigator-led, between the NHS and the
pharma and biotech industries. Since 2008 he has also led
clinical research in colorectal, prostate, and renal cancer at
MRC CTU.
Shirin Khambata-Ford
Dr. Shirin Khambata Ford is Global Head Correlative Sciences, Oncology Global Development, Novartis.
She leads a group focused on clinical biomarker development and translational research for full development
programs. Prior to this she was a Sr. Biomarker Experimental Medicine Leader, Roche where she led biomarker
work for early development oncology programs. She was
previously Director, Oncology Biomarkers, Bristol-Myers
Squibb where she led a group responsible for the discovery,
validation and implementation of clinical biomarkers for
the late stage portfolio. Her key accomplishments include
being the lead researcher on the team that discovered that
EGFR ligand expression and KRas mutation status are
predictive of benefit from cetuximab in metastatic CRC.
This resulted in a seminal publication in Journal of Clinical
Oncology. Her research has led to publications in journals such as New England Journal of Medicine, multiple
presentations at oncology conferences – ASCO, AACR,
ESMO and patent applications. As the Biomarker Lead
for cetuximab, she was a key participant in regulatory
and diagnostic activities in addition to providing scientific
leadership and expertise.
Edward Kim
Edward S. Kim, MD is Chair of Solid Tumor Oncology and Investigational Therapeutics and the Donald
S. Kim Distinguished Chair for Cancer Research at the
Levine Cancer Institute, Carolinas HealthCare System in
Charlotte, NC. He previously was Associate Professor and
Chief of the Section of Head and Neck Cancer at MD
Anderson Cancer Center. Dr. Kim studies novel targeted
agents in the treatment and prevention settings and has
expertise in lung, head and neck, as well as thymic cancers
and chaired BATTLE, the personalized medicine program
in lung cancer. Dr. Kim serves on the editorial boards of
JCO, CCR, and Clinical Lung Cancer. Dr. Kim is also
the recipient of several awards including the ASCO YIA
and the AACR Scholar in Training Award. He also served
as the PI of the MD Anderson SWOG U10 institutional
grant and is the recipient of a V Foundation Grant. Dr.
Kim is the author or coauthor of more than 100 published
articles, book chapters, reviews in journals such as Lancet,
Journal of Clinical Oncology, Cancer Discovery, Cancer,
and Cancer Prevention Research.
Shivaani Kummar
Dr. Shivaani Kummar received her medical degree from
Lady Hardinge Medical College, New Delhi, India and her
Internal Medicine Residency training from Emory Univer-
Faculty’s Biosketches
sity, Atlanta, Georgia. Upon completion of her fellowship
training in Medical Oncology and Hematology from the
National Institutes of Health, Bethesda, MD, she joined
Yale Cancer Center, Yale University, New Haven, Connecticut as an Assistant Professor in Medical Oncology. In
2004 she moved back to the National Cancer Institute to
pursue her work in early drug development in oncology. At
present, she is Head of Early Clinical Trials Developemnt,
Office of the Director, Division of Cancer Treatment and
Diagnosis, and head of the Developmental Therapeutics
Section, Medical Oncology Branch, National Cancer Institute. Dr. Kummar has published in major peer-reviewed
journals in the field of oncology, and serves of the scientific
program committee for the American Society of Clinical
Oncology (ASCO) annual meetings and is a member of
ASCO and the American Association for Cancer Research
(AACR).
Denis Lacombe
In 1988 Dr. Lacombe graduated as MD from the University of Marseilles (France). He was granted for a Master
Post-doctoral Fellowship at the Roswell Park Cancer Institute, Buffalo, NY, USA for Fundamental and Clinical
Pharmacokinetics from 1989 to 1991. From 1991 to 1993
he worked as Clinical Research Adviser in charge of the
development of a new drug in oncology in the pharmaceutical industry. From September 1993 to January 2013
he has been working as Clinical Research Physician at
the EORTC in Brussels for various Groups. Until 2007,
as Assistant Director Medical Affairs, he coordinated the
EORTC New Drug Development Team conducting new
drug development studies. Currently amongst his activities, he is responsible for the Early Project Optimization
Department dedicated to ensure EORTC studies being in
line with the EORTC strategy. Since November 2010, he
has been appointed as Director HQ of the EORTC with
main missions being to ensure that the functioning of the
EORTC HQ is in line with the decisions of the EORTC
Board and to develop and coordinate the future EORTC
Scientific Strategy in accordance with the evolving health
care ecosystems.
Christophe Le Tourneau
Christophe Le Tourneau has been appointed as a senior
Medical Oncologist at the Institut Curie in November 2009.
He is heading the Phase I Program as well as the Head
and Neck Clinic. He is also running a multicenter randomized personalized medicine trial (SHIVA). Christophe
Le Tourneau was certified in Medical Oncology in 2005
and got his PhD in Clinical Epidemiology in 2007. He
did a Clinical Research Fellowship at Princess Margaret
Hospital in Toronto, Canada, in the Drug Development
Program from November 2007 to November 2009 under
the supervision of Pr Lillian Siu. His main interests are oncology phase I clinical trials with a special attention at the
Faculty’s Biosketches
methodology to conduct these trials, as well as Head and
Neck oncology. Christophe Le Tourneau is the principal
investigator of several phase I trials, as well as of clinical
trials in Head and Neck oncology.
Frank Lin
Frank I. Lin, MD, is currently at the National Cancer
Institute (NCI) in the U.S. National Institutes of Health. Dr.
Lin is Board-certified in both Internal Medicine and in Nuclear Medicine, and completed his clinical imaging training
at Stanford University and at the University of California
UC Davis. Since joining the National Cancer Institute in
2010, Dr. Lin has served as the Medical Officer in the
Clinical Trials Branch of Cancer Imaging Program, where
he oversees all aspects of imaging trials from Phase 0 to
Phase III that are sponsored by the NCI. Dr. Lin’s research
interests involve the role of both functional and molecular
imaging in the diagnosis of cancer and evaluation of cancer
therapies.
Tracy Lively
Dr. Tracy Lively joined the NIH in 1996 as a program
director in the Cancer Diagnosis Program of the National
Cancer Institute. Prior to coming to the NIH she had been
an assistant professor in the Division of Biomedical Sciences at the University of California, Riverside, and had
completed post-doctoral fellowships in cancer biology and
human genetics. As a program director, and later as Deputy
Associate Director of the Cancer Diagnosis Program, Dr.
Lively has been responsible for the scientific oversight of
a portfolio of investigator-initiated research grants. She has
also developed and implemented targeted research initiatives for exploratory research, for technology development
and for patient-oriented research in cancer diagnostics. She
reviews the correlative science aspects of protocols for
NCI’s clinical trials program. She also organizes scientific
meetings and working groups with investigators outside the
NIH
Patricia LoRusso
Patricia LoRusso, D.O. is a Professor of Medicine in
Wayne State University School of Medicine’s Department
of Oncology, and Director of the Eisenberg Center for
Translational Therapeutics at the Karmanos Cancer Institute, Detroit, Michigan. Her primary interest is translational
therapeutics with a focus on phase I clinical research and
novel trial designs. She currently directs one of only 14
National Cancer Institute (NCI) U01-funded phase I sites
in North America.
Dr. LoRusso serves as co-chair of the NCI Cancer
Therapy Evaluation Program (CTEP) Investigational Drug
Steering Committee. She has also served on the education and scientific committees of the American Society of
Clinical Oncology (ASCO), the scientific committee of the
American Association for Cancer Research (AACR), and
xxv
as a parent member of the NCI’s Quick Trials Clinical Subcommittee. She has served either ad hoc or as an appointed
member on multiple study sections. She has also served
four years as a faculty member of the Methods in Clinical Cancer Research Workshop in Flims, Switzerland and
six years as a faculty member of the Methods in Clinical
Cancer Research Workshop in Vail. CO.
John Martens
John WM Martens is Associate Professor heading the
laboratory of Genomics and Proteomics of Breast Cancer
in the Dept. of Medical Oncology, Erasmus MC, Rotterdam, the Netherlands. He received his PhD (1994) in
Molecular Biology at Wageningen University (NL). After being a post-doc in Molecular Endocrinology at the
Erasmus MC, Rotterdam (NL) (1994–1998) and at UCSF
(1998–2001), he preceded his career in 2001 in translational breast cancer research at his current department. He
currently is chair of EORTC-Pathobiology group, member
of the Steering Committee of the Center for Personalised
Cancer Treatment, member of BCAC and various national
translational research advisory committees. The major aim
of his research is to determine by using a multitude of
state-of-the-art high-throughput genomics and proteomics
technologies which biological factors are associated with
disease progression and/or the development of resistance
to therapies in breast cancer.
Ultan McDermott
Ultan McDermott is a clinician scientist with an interest
in cancer genomes and how they impact on drug response
in the clinic. He is a Group Leader in the Wellcome
Trust Sanger Institute as well as a practicing Oncologist at
Addenbrooke’s Hospital in Cambridge.
He trained as a medical oncologist and obtained a PhD
in cancer biology at Queen’s University, Belfast. He was
accepted for a post-doctoral research position at Harvard
Medical School and Massachusetts General Hospital in
2005, where he established a high-throughput cancer cell
line drug screen to identify genomic alterations that could
be used in the clinic to stratify patients for treatment. His
research interests are in the area of predictive biomarkers to
cancer therapeutics and in vitro models of drug resistance
in human cancers.
He joined the Sanger Institute in 2009 as a clinical research fellow and was appointed to the faculty as a Group
Leader in 2010 with the award of a Cancer Research UK
fellowship. He was made a Fellow of the Royal College of
Physicians in 2011.
Federico Monzon
Dr. Monzon is board certified in anatomical/clinical
pathology and molecular genetic pathology by the American Board of Pathology. Dr. Monzon received his MD degree from the Universidad Nacional Autónoma de México
xxvi
and did his Pathology residency training at Thomas Jefferson University Hospital in Philadelphia and Molecular
Genetic Pathology subspecialty training at the University
of Pittsburgh Medical Center. He has a broad background
in molecular diagnostics and pathology informatics and
significant experience in the translation of novel technologies into clinical molecular tests. At the University
of Pittsburgh, he led genomics studies that validated a
microarray-based clinical assay for the diagnosis of tumors
of unknown origin. These studies were used to support
one of the first FDA cleared gene expression tests (Pathwork Tissue of Origin). Until recently, Dr. Monzon was
Director of Molecular Pathology at the Cancer Genetics
Laboratory of Baylor College of Medicine. Prior to Baylor,
he was Director of Molecular Pathology at The Methodist
Hospital in Houston, founder and head of the advisory
board for iKaryos Diagnostics, and Director of the Clinical
Genomics Facility at the University of Pittsburgh Cancer
Institute. He recently joined Invitae, a company specialized
in genetic testing.
Helen Moore
Dr. Helen Moore directs the National Cancer Institute’s
Biospecimen Research Network program (BRN) within
the Biorepositories and Biospecimen Research Branch
(BBRB). The BRN encompasses extramural research programs, a Web-based biospecimen literature database, and
community outreach activities including the annual BRN
Symposium, “Advancing Cancer Research Through Biospecimen Science”. Dr. Moore is a Molecular Biologist with a
broad background in research and development. She joined
the NCI in 2006 from Celera Genomics, where she led
and managed cross-functional teams to develop bioinformatics products focused on Comparative Genomics and
data visualization; developed new drug targets for complex diseases using multiple approaches including genetic
analysis of disease association study data, biological pathways analysis, literature mining, and genomic analysis; and
contributed to the assembly and annotation of the human
genome. Dr. Moore leads an NCI collaboration with the
EU SPIDIA program, is a member of the ISBER Science
Policy Committee, and is the Biospecimen Science section
editor for the journal Biopreservation and Biobanking.
Uwe Oelmueller
Dr. Uwe Oelmueller is the coordinator of the European
Collaborative Grant Project SPIDIA within the European
Commission FP7 program. The SPIDIA consortium is
working on the standardization and improvements of preanalytical tools and procedures for in vitro diagnostics.
It is build by 7 public research organizations, 8 research
companies and an official European standards organization. Dr. Oelmueller is a vice president RandD at QIAGEN
and a management committee co-chair at the QIAGEN
/ BD joint venture company PreAnalytiX. He is head-
Faculty’s Biosketches
ing the technology center "Diagnostic Sample Preparation"
within QIAGEN’s global MDx Development. The center
involves technology and product development projects for
clinical sample collection, preservation, storage, transport
and archiving, and the isolation and analysis of human and
pathogen nucleic acids. Prior to QIAGEN, Dr. Oelmueller
headed a research group at the Clinical Microbiology Center, University of Goettingen, Germany, working on the
AIDS disease stage relevant HIV RNA expression pattern. Dr. Oelmueller’s scientific work is presented in more
than 70 patents, patent applications, scientific papers and
abstracts.
Kelly Oliner
Kelly S. Oliner, PhD is currently a Scientific Director
in the Medical Sciences – In Vitro Diagnostic Group at
Amgen. Dr. Oliner has been involved in prospective testing of the KRAS predictive biomarker, next generation
sequencing analysis of a phase 3 study, a circulating tumor
DNA analysis aimed at describing mechanisms of acquired
resistance and the demonstration that MET IHC has the
potential to stratify gastric cancer patients who respond to
anti-HGF antibody treatment. Most recently she has completed studies on the predictive nature of the RAS (KRAS
and NRAS) biomarker.
Dr. Oliner received her BA from Smith College and
her PhD from the Johns Hopkins School of Medicine.
Her PhD thesis was focused on the molecular genetics
of colorectal cancer in the laboratory of Bert Vogelstein.
Two post-doctoral fellowships at Somatix Gene Therapy
and Chiron Corporation followed. Currently, Dr. Oliner
focuses on leading late stage oncology biomarker and in
vitro diagnostic development teams.
Xavier Paoletti
Xavier Paoletti, PhD, is senior statistician at the Institut Curie and co-head for the research team of clinical
biostatistics at INSERM U900. He is also the referent
statistician for the early clinical study group (GEP) of
the French federation of anti-cancer centers and for the
Innovative Therapies agains Cancer in Children European
network. He is in charge of the Statistical Training Applied
to Clinical Research (STARC) from the Paris VI Pierre &
Marie Curie University.
Xavier Paoletti developed expertises in statistical methods for early phase clinical trials with both methodological
and applied works. He has also been interested in the
validation of surrogate markers in gastric cancer while
conducting individual patient-based meta-analyses. Finally
he is closely involved in biomarkers-driven trials, such as
the SHIVA trial with Dr. C. Le Tourneau and is interested
in the statistical issue of detecting treatment variation in
patients’ subgroups based on intermediate endpoints.
Faculty’s Biosketches
xxvii
Mario Pazzagli
Full Professor of Clinical Biochemistry and Clinical
Molecular Biology, Faculty of Medicine, at the Dept of
Clinical and Experimental Biochemical Sciences, University of Florence, Italy. Former member of the Executive
Board of the EFLM, Former Chair of the IFCC-C-MD
commission, Advisor of the CLSI Committee on Molecular Methods; Chair of the Working Group on Personalized Laboratory Medicine of the EFLM, Co-ordinator
of the FP6 EU projects “Multi-National External Quality
Assay (EQA) Programmes in Clinical Molecular Diagnostics based on Performance and Interpretation of PCR
assay methods including dissemination and training” (contract LSH no. 504842), Member of the FP7 EU Project
SPIDIA: Standardisation and improvement of generic preanalytical tools and procedures for in vitro diagnostics
2008–2011 (Contract no. 222916). National representative
of the CEN/TC 140/WG 3 “Quality management in the
medical laboratory”. Editor of 7 books and author of about
150 publications in International peer reviewed journals.
Michael Postow
Dr. Michael Postow is a physician on the faculty at
Memorial Sloan-Kettering Cancer Center in the MelanomaSarcoma Oncology Service. He completed medical school
at New York University School of Medicine and internal
medicine residency training at Brigham and Women’s Hospital/Harvard Medical School. He then returned to New
York City to pursue a fellowship in Medical Oncology at
Memorial Sloan-Kettering Cancer Center where he served
as Chief Fellow. During fellowship, he conducted research
with Dr. Jedd Wolchok studying interactions between radiotherapy and immunotherapy (the abscopal effect) and
characterizing the absolute lymphocyte count as a pharmacodynamic biomarker for ipilimumab. He has organized
a prospective study to further evaluate the abscopal effect
and has been involved in a number of studies investigating promising immunotherapeutic approaches for patients
with advanced melanoma. Aside from medicine, he enjoys
playing music, snow skiing, and sailing in the New York
Harbor.
Eric Polley
Eric Polley, PhD, is a Mathematical Statistician in the
Biometric Research Branch of the Division of Cancer
Treatment and Diagnosis at the NCI. Dr. Polley received
his BAin Mathematics from Saint John’s University (MN),
a MS in Biostatistics from Columbia University, and a
PhD in Biostatistics from the University of California,
Berkeley in 2010. His primary research area involves the
development and evaluation of prediction models, statistical analysis of high-throughput genomic data and oncology
clinical trial design.
Jordi Rodon
Jordi Rodon is attending physician at the Medical Oncology Department of the Vall d’Hebron University Hospital and Clinical Coordinator of the Research Unit for
Molecular Therapy of Cancer (UITM) – “la Caixa”.
He obtained his specialization in Medical Oncology
from the Institut Catala d’Oncologia, Barcelona. He has
been a Research Fellow in the Advanced Drug Development Fellowship program at the Institute for Drug Development in San Antonio, Texas (USA), and Senior Research
Fellow at the Investigational Cancer Therapeutics Department at the MD Anderson Cancer Center in Houston,
Texas (USA). He joined the Medical Oncology Department of the Vall d’Hebron University Hospital in 2008
and has been Principal Investigator or Co-Investigator for
more than 80 Phase I clinical trials. He is also involved
in translational research derived from the clinical trials at
UITM, as well as projects in Personalized Oncology as
Principal Investigator of the BKM120 Stand-Up-to-Cancer
(SU2C) “Dream Team”, and member of the Worldwide
Innovative Networking in personalized cancer medicine
(WIN) Consortium.
Mei Polley
Dr. Mei-Yin “May” Polley received her doctoral degree
in Biostatistics from Columbia University. Her dissertation
was honored The Joseph L. Fleiss Memorial Prize in Biostatistics for an Outstanding Dissertation. Upon graduation,
she joined the biotechnology company Amgen as a Senior
Biostatistician. In 2007, she joined the faculty of the Department of Neurosurgery at the University of California
San Francisco as an Assistant Professor where she provided statistical expertise to support a broad array of brain
tumor research projects. In 2010, she moved to the Biometric Research Branch at the National Cancer Institute.
At present, she provides statistical leadership to both the
Cancer Diagnosis Program (CDP) and the Cancer Therapy
Evaluation Program (CTEP) through participation in reviews of protocols and grants involving correlative science
studies. She also serves as a statistical reviewer on several
correlative science committees. Her current research interests include biomarker trial designs, early phase trials and
assay reliability. Dr. Polley has published in many professional journals in the field of statistics and oncology. She is
an Associate Editor for Neurosurgery.
Roberto Salgado
Roberto Salgado, MD, PhD is board certified in Anatomic
Pathology since 2006, has obtained his medical training at
the University Hospital of Antwerp (Belgium) and the University Hospital in Leiden (The Netherlands). A PhD thesis
was obtained working with the Translational Cancer Research Group of the AZ Sint-Augustinus Hospital/Antwerp
and at the Department of Pathology at the University Hospital of Antwerp; studying the interactions of haemostasis
and angiogenesis in breast cancer. His training in Anatomic
Pathology and Molecular Pathology took place at the Uni-
xxviii
versity Hospital Antwerp, the University Hospital Leuven
and at the Jules Bordet Institute. Currently he works at
the Breast International Group (www.breastinternational
group.org) located in the Jules Bordet Institute and at the
Department of Pathology/Translational Cancer Research
Group/AZ Sint-Augustinus Hospital in Antwerp. He works
in close collaboration with the EORTC, having as main
tasks integrating tumorbanks and molecular testing laboratories in clinical trials. He is also an auditor on Molecular Pathology/Genetic laboratories for the Federal Belgian
Government.
Nicolas Servant
Nicolas Servant has a background in biological analysis
and computer science (M.Sc.) and a strong experience in
cancer bioinformatics and high-throughput analysis. In the
last few years, he was mainly involved in the analysis of
breast local recurrence in young women. Since 2012, he
leads the next-generation analysis team of the bioinformatics platform of the Institut Curie (Paris, France). His
team is today involved in the development of bioinformatics workflows for next-generation sequencing applications
and provides bioinformatics support to the research and
medical teams of the Institut Curie.
Steven Shak
Steven Shak, MD, is Executive VP Research and Development of Genomic Health, Inc, which is focused on
improving the quality of treatment decisions for cancer
patients. He and his colleagues have worked together with
leading oncology clinical research groups to develop and
commercialize the Oncotype DX® breast cancer, colon
cancer, and prostate cancer assays. Dr. Shak has previously served as Senior Director and Staff Clinical Scientist at Genentech, Inc. where he led the clinical team
that gained approval of trastuzumab (Herceptin®) and of
the companion diagnostic HercepTest for metastatic breast
cancer. In addition, Dr. Shak cloned and expressed the
therapeutic human enzyme human DNase I or dornase
alfa (Pulmozyme®), a mucus-dissolving enzyme that is
approved worldwide for the treatment of cystic fibrosis.
Dr. Shak previously held faculty positions in Medicine and
Pharmacology at New York University School of Medicine.
Dr. Shak has an undergraduate degree from Amherst College, an MD degree from New York University School
of Medicine, and post-graduate training in medicine and
research at Bellevue Hospital in New York City and the
University of California, San Francisco.
David Sidransky
Dr. Sidransky is a renowned oncologist and research
scientist named and profiled by TIME magazine in 2001 as
one of the top physicians and scientists in America, recognized for his work with early detection of cancer. Since
1994, Dr. Sidransky has been the Director of the Head
Faculty’s Biosketches
and Neck Cancer Research Division at Johns Hopkins University School of Medicine and Professor of Oncology,
Otolaryngology, Cellular & Molecular Medicine, Urology,
Genetics, and Pathology at John Hopkins University and
Hospital. Dr. Sidransky is one of the most highly cited
researchers in clinical and medical journals in the world,
in the field of oncology during the past decade, with over
450 peer-reviewed publications. He has contributed more
than 60 cancer reviews and chapters and has published
more than 30 articles on UCC and 150 on SCC cancers including seminal papers on genetic and epigenetic changes
in these tumor types. He has pioneered the detection of
various molecular alterations in human cancer and bodily
fluids. Dr. Sidransky is the recipient of a number of awards
and honors, including the 1997 Sarstedt International Prize
from the German Society of Clinical Chemistry, the 1998
Alton Ochsner Award Relating Smoking and Health by
the American College of Chest Physicians, and the 2004
Richard and Hinda Rosenthal Award from the American
Association of Cancer Research.
Walter Stadler
Walter Stadler, MD, is an expert in prostate, kidney,
bladder, and testicular cancers. He concentrates on the use
of chemotherapy, immunotherapy, anti-angiogenic therapy,
and molecularly targeted therapy for patients with locally
advanced or metastatic disease.
His research focuses on the development of new treatments for these urological cancers. Dr. Stadler’s recent
research includes development of molecular and imaging markers for predicting response to various anti-cancer
therapies.
Dr. Stadler has authored and co-authored more than 170
articles in medical journals such as Cancer Research and
the Journal of Clinical Oncology, in addition to more than
100 book chapters, reviews, letters, and editorials. He is
an active member of several committees and boards, including the NCI Investigational Drug Steering Committee,
the NCI Board of Scientific Counselors, medical advisory
boards of the Kidney Cancer Association and the Bladder
Cancer Advocacy Network, and the editorial boards of
Cancer and UpToDate in Oncology, an information source
for oncologists.
Fred Sweep
Fred Sweep (1959) is full professor of Chemical Endocrinology and head of the department of Laboratory
Medicine at the Radboud University Nijmegen Medical
Centre. He is board certified in Clinical Chemistry and
Endocrinology. He studied Medical Biology at the University of Utrecht, where he also obtained his PhD degree
(Pharmacology). He had his training as a clinical chemist
at the RUNMC. Fred Sweep has published over 365 papers
(Hirsch-index 43). Sweep is active member of many different national and international societies devoted to cancer
Faculty’s Biosketches
biomarkers. Presently, Sweep is elected president of the
SKML. Sweep’s department has developed EQA programs
for steroid hormone receptors and other biomarkers since
1975. His current research interests are focused on development of new antibody based assays for biomarkers
in oncology with emphasis on proteases and angiogenesis. The department of Laboratory Medicine harbours all
up-to-date laboratory facilities for Clinical Chemistry, Endocrinology, Haematology, (transplantation) Immunology,
Blood transfusion, Paediatrics and Neurology.
Frazer Symmans
Dr. Symmans is Professor of Pathology at The University of Texas MD Anderson Cancer Center where he
practices surgical pathology and co-directs the Breast Cancer Pharmacogenomics Program. Dr. Symmans received
his medical degree from the University of Auckland before
completing his residency training at Columbia University
College of Physicians and Surgeons and fellowship training at MD Anderson. Dr. Symmans joined the faculty of
MD Anderson in 2000. Dr. Symmans’ research is focused
on breast cancer, with specific emphasis on neoadjuvant
treatment trials for evaluation of chemo sensitivity and
development of diagnostic tests to select the most effective treatments for individuals with breast cancer. He has
adapted genomic technologies to clinical needle biopsies
of breast cancer in order to use gene expression profiling
to identify important genes for response to chemotherapy and, independently, to endocrine therapy; to validate
gene expression tests with clinical potential; and to establish their performance in the context of clinical testing.
He has published over 70 peer-reviewed articles, and has
been awarded several prestigious grants in breast cancer
pharmacogenomics.
Sabine Tejpar
Sabine Tejpar, MD, PhD is Associate Professor in the
Department of Oncology, University of Leuven, Belgium.
She works as a part time clinician treating GI malignancies, part time researcher (Senior Clinical Investigator of
the Fund for Scientific Research- Flanders (Belgium), with
a focus on basic and translational research in colorectal
cancer. Main projects involve molecular sub classification
of colorectal cancer, prognostic markers in adjuvant colorectal cancer and predictive markers for efficacy of EGFR
inhibition. She is a member of EORTC board and chair of
the EORTC Translational Research Advisory Committee
(TRAC).
Geraldine Thomas
Gerry Thomas is a serial biobanker. She established the
Chernobyl Tissue Bank (CTB: www.chernobyltissuebank.
com) in 1998 which provides a platform for a systems
biology approach to the mechanisms involved in radiation
induced thyroid cancer and supports tissue collection for
xxix
international epidemiology studies. She has also developed
two research tissue banks in the UK that are embedded
within the NHS. Gerry is the Scientific Director for the
Wales Cancer Bank (www.walescancerbank.com), which
opened in 2004, and since appointment to the Chair of
Molecular Pathology at Imperial College in 2008, she has
revamped the Imperial College Healthcare Tissue Bank
(www.imperial.ac.uk/tissuebank) to provide a flexible tissue resource to accommodate a varied portfolio of clinical
studies. She sits on a number of advisory boards for tissue
banking initiatives in Europe, and combines tissue banking
with research interests in the molecular pathology of breast
and thyroid cancer, and the effects of radiation exposure on
health.
Magdalena Thurin
Program Director at Cancer Diagnosis Program, NCI,
where her major focus has been on development of projects
in the area of biomarkers for clinical application in cancer. Her specific interest is on research programs in the
cutting-edge areas of molecular markers in melanoma and
the immune response for prognosis and prediction of response to treatment of cancer. Prior to joining NCI in 2001
she conducted research at The Wistar Institute of Anatomy
and Biology in Philadelphia focusing on characterization
of carbohydrate antigens, their function in cancer progression and cancer vaccines. Her research experience includes
structural and immunochemical approaches to study expression of carbohydrate structures including blood group
type antigens that correlate with tumor progression. After completing her PhD and MS degree in Biochemistry
at the University of Warsaw, Poland, she received postdoctoral training at the Wistar Institute in Philadelphia and
subsequently began an academic career at the same institution. She has published over 70 papers in peer-reviewed
journals, is an active member of many different societies
devoted to cancer biomarkers and is an editor for several
journals.
Fernando Ulloa Montoya
Fernando Ulloa Montoya, PhD, Senior Scientist, RandD,
Head of Molecular Biology in Cancer Immunotherapeutics,
GlaxoSmithKline (GSK) Biologicals, Rixensart, Belgium.
Dr. Ulloa Montoya received his Biochemical Engineering
degree from the National Polytechnic Institute in Mexico
in 1998, his MS degree in 2001 from Washington State
University and completed his PhD training in Chemical
Engineering at the University of Minnesota Twin Cities in
2006. During his post-doctoral training at the Katholieke
Universiteit Leuven, Belgium (2006–2008), he also held
the position of stem cell core facility leader; in which he
used transcriptional profiling for characterizing and predicting the functionality of adult stem cells. He joined
GlaxoSmithKline Biologicals in 2008 and has since led a
group working on discovery and development of transcrip-
xxx
tome based biomarkers to predict cancer patient’s response
to antigen specific cancer immunotherapy (ASCI).
John Welch
Jack Welch, MD, PhD, is Head of Gastrointestinal and
Thoracic Cancers Therapeutics in the Clinical Investigations Branch of the Cancer Therapy Evaluation Program
(CTEP), Division of Cancer Treatment and Diagnosis, at
the NCI. Dr. Welch came to CTEP from the European
Organisation for the Research and Treatment of Cancer
(EORTC), where he was a senior clinical research physician. Dr. Welch received his BS in Biology from Georgetown University, his MD degree from the State University
of New York at Buffalo, and his PhD in Pharmacology
from Roswell Park Cancer Institute. He completed a pediatric residency at Georgetown University, and subsequent
fellowship in Pediatric Hematology-Oncology at the Children’s Hospital of Philadelphia.
Paul Williams
The Molecular Characterization Laboratory was established to focus on development of state of the art genomic
Faculty’s Biosketches
technologies for clinical research. Laboratory goals are to
assist in the development and application of well characterized and validated clinical assays to support cancer patient
management. One of several ongoing pilot projects is the
development and implementation of massively parallel sequencing assays for selection of patients for early stage
clinical trials. He has been active in the use of molecular
technologies for drug target discovery. During 13 years at
Genentech, he developed novel assays to support clinical
studies and discover new therapeutic targets. He was the
author of the first quantitative “real-time” PCR papers and
contributed to the development of this powerful technology.
Prior to joining FNLCR, he was a senior research group
leader at Roche Molecular Diagnostics, where he led the
research effort and managed two large multi-national clinical assay studies: The Microarray Innovations in Leukemia
Study and collaborated with the Leukemia and Lymphoma
Molecular Profiling Project. He has published over 50
manuscripts and holds over 30 issued US Patents.
Kurt Zatloukal
No information received.
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SPECTAcolor
An innovative path to new colorectal cancer treatments
EORTC has connected over 30 leading clinical centers across
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dedicated to patients with advanced colorectal cancer (CRC).
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spectacolor.indd 1
17/09/2013 16:13:24
European Journal of Cancer (2013) 49, Supplement 4, S1–S38
Abstracts
Markers in Cancer: A joint meeting by ASCO, EORTC and NCI,
7–9 November 2013, Brussels, Belgium
Speakers’ Presentations
Topic 1: New trial concept and challenges for
the future
SP001
Biostatistical challenges for the design of biology-driven trials
X. Paoletti. Biostatistics, Curie, Paris, France
An important objective of early phase-trials (phase I and phase II) is to
understand the mechanisms of action of a new compound and to identify
potential activity that would justify going into larger trials. Biology then plays
a central role but using biological measurements to drive the design raise
numerous issues.
In this communication, we will focus on challenges of biology-driven early
phase trials. In phase I clinical trials, three main types of dose finding trials
that incorporate translational research can be identified. We will see what
is feasible and what type of information can be expected in each situation.
We will emphasize the importance of having reliable sensitive endpoints and
assays and highlight the risk of erroneous conclusions at this very early stage
of the clinical development.
We will then focus on proof of concept phase II designs and show that
randomization is a key component for evaluating the added value of biology
measures and to distinguish between prognostic factors and factors predictive
of the response to treatment. The SHIVA trial that compares standard practice
to the administration of targeted agent based on molecular profile of the
tumour, will serve as an illustration of the importance of an adequate design
to obtain reliable conclusions. We will review several possible designs for
such a trial and detail the strength and limits of each of them. In particular,
we will emphasize the importance of consolidating our knowledge on the
biomarkers in order to design powerful phase III trials. Multistep designs
appear as promising yet delicate design. We will also plead for simple
well-designed trials addressing well-defined objectives. Again, we will insist
on the importance of sensitive endpoints to detect variations of activity
according to biomarkers and to the necessary steps to go from an exploratory
research to a validated biomarker.
its tumour. The last decade witnessed the development of high-throughput
technologies such as microarrays, and more recently next-generation sequencing, which paved the way to personalized medicine in the field of
oncology. While the cost of these technologies decreases every day, we are
facing an exponential increase in the amount of data generated. Our ability
to quarry this genetic information in daily practice relies strongly upon the
availability of a performant bioinformatics system that assist in the translation
of knowledge from the bench to molecular targets and diagnosis.
Clinical trial and routine diagnosis constitutes different approaches in clinical
practice, yet they both require a bioinformatics environment, which ensures
the integration and the traceability of all samples’ information as well as
the processing and analyses of the genomic data, and which implements
well-defined procedures for workflow management and decision making. A
knowledge integration system was developed at the Institut Curie to facilitate
the integration of the clinical and pathological data, and to track in real-time
the processing of individual samples. Checkpoints from the biopsy, to the
technological platforms and to the final analysis results are also installed. In
addition, the bioinformatics environment must ensure secure storage of large
datafiles as well as access to high performance computing enabling rapid
analysis of data and secure results delivery within a few hours.
For the molecularly-based analysis or profiling, the bioinformatics challenges
include establishing validated computational pipelines for identifying reliably
genomic alterations and mutations, with adequate quality control. Currently,
several methods are available but no consensus on a standard computational
tool dedicated to such questions was reached yet. User-friendly interface
are also needed to allow physicians to control the analysis workflow and to
facilitate the interpretation of individual patient data.
Personalized medicine projects are now a reality. Thus, real-time medical
informatics systems that integrate clinical and genomic data, as well as
efficient sample traceability are today mandatory. Developing high-throughput
technologies like sequencing into validated diagnostics that can be used for
patient care is still a major challenge, which can be addressed by sharing
expertise in cancer genomics, bioinformatics, pathology and clinical genetics.
SP003
Pathology challenges for biology-driven trials: The Ki67 experience
SP002
Bioinformatics analysis for real-time applications
N. Servant 1 , P. Hupé 1 , M. Kamal 2 , C. LeTourneau 3 , E. Barillot 1 . 1 INSERM
U900 – Plateforme de Bioinformatique, Institut Curie, Paris, France;
2 Département de Transfert, Institut Curie, Paris, France; 3 Département de
Médecine oncologique, Institut Curie, Paris, France
Genetically guided medicine requires the delivery of individually adapted
medical care based on the genetic characteristics of each patient and of
0959-8049/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
M. Dowsett. Academic Department of Biochemistry, Royal Marsden Hospital,
London, United Kingdom
Ki67 is a highly favoured marker of proliferation in multiple malignant tissues
because of its ease of measurement by immunohistochemistry (IHC) and
general analytic ruggedness of the assay. It has been of particular interest in
breast cancer where it has multiple potential applications. Of greatest clinical
interest is its possible role in assessing prognosis and likelihood of benefit
from specific treatments. So far as prognosis is concerned we have shown
S2
that it is best assessed as part of a panel of other IHC markers including ER,
PgR and HER2 to form an index termed IHC4 and this is most appropriately
applied by integration with standard clinicopathological parameters. In the
research context Ki67 has been validated as a tool for assessing the
comparative efficacy of endocrine treatments in the presurgical context and
as such is being applied as a primary end-point in many biology-driven trials
particularly where proliferation is a direct target of the therapy. In addition, a
4,000 patient clinical trial called POETIC (PeriOperative Endocrine Therapy
for Individualised Care) in ER+ breast cancer is in follow-up in part to
determine whether measuring Ki67 during endocrine treatment is a better
index of long-term outcome than the conventional approach to measuring it
before treatment. Measurement of Ki67 during or at the end of neoadjuvant
therapy (endocrine or chemotherapy) is being employed to plan modified
treatment on the basis of the residual risk of recurrence.
All of these applications require a standardized approach to analysis and
scoring that is not currently present. To rectify this guidelines for harmonization
of methodology have been published (Dowsett et al., JNCI, 2011; 103:1–9)
and a series of interlaboratory studies has been designed. Until these report
valid between-laboratory comparisons of data are limited in value. Although
Ki67 remains a very helpful outcome measure within individual research
studies, the direct application of cut-offs for clinical management can be highly
misleading unless performed by laboratories who have their own reference
data or have cross-validated against the methodology of a group that has such
data. As we move forward it will be important to recognize that different levels
of precision and accuracy are demanded by the many potential uses of Ki67.
Topic 2: Biology-driven clinical trials
SP004
Rationale of the design of the WINTHER trial
J. Rodon. Vall d’Hebron Institute of Oncology, Barcelona, Spain
Recent advances in diagnostics and targeted therapies during the last decade
have changed how Oncology is viewed. Stratified Medicine has emerged
from the accumulated evidence garnered from matching targeted therapies
with tumor molecular aberrations. Concomitantly, current knowledge derived
from large-scale, massively parallel sequencing technologies, and global
research initiatives have illuminated the utility of understanding the molecular
basis of cancer through genome analysis. In addition, some pilot studies are
transforming the way we analyze tumor tissue molecular aberrations, the
design of clinical trials and the measurement of treatment efficacy. Taken
together, these pilot studies are paving the way for designing clinical trials
that empirically test the concept of Personalized Cancer Medicine.
The WinTHER is an innovative phase 2 clinical trial that will assess the
potential of selecting targeting therapies according to the tumor biology of
patients. The trial will explore a rational choice of therapeutics and their
efficacy beyond current limitations. From each patient’s biopsy of the tumor
(or metastasis) and normal tissue, a complete biological analysis of DNA,
RNA and microRNA will be undertaken. The choice of therapy will be
rationally guided either by matching actionable targets found in the tumor
analysis (matching drug and molecular alterations, arm A) or the tumor
gene expression and predicted sensitivity of the drug (matching differentially
expressed genes between tumor and normal tissue with drugs, arm B).
In this presentation, I will describe the trial design and methods and how
we incorporated many of the lessons learned from prior experiences in
Personalized Cancer Medicine.
SP005
Rationale of the design of the I-SPY trial
A. DeMichele 1 , D. Yee 2 , N. Hylton 3 , L. Vant’Veer 4 , W.F. Symmons 5 ,
J. Perlmutter 6 , J. Lyandres 7 , S. Davis 7 , M. Buxton 7 , D. Berry 8 ,
L. Esserman 9 . 1 Abramson Cancer Center, University of Pennsylvania,
Philadelphia, USA; 2 Masonic Cancer Center, University of Minnesota,
Minneapolis, USA; 3 Department of Radiology, University of California, San
Francisco, USA; 4 Helen Diller Cancer Center, University of California, San
Francisco, USA; 5 Department of Pathology, MD Anderson Cancer Center,
Houston, USA; 6 507 N. 5th Ave, Gemini Group, Ann Arbor, USA;
7 Department of Surgery, University of California, San Francisco, USA;
8 Department of Biostatistics, MD Anderson Cancer Center, Houston, USA;
9 Helen Diller Cancer Center, University of California, San Francisco, USA
New approaches to drug development are needed to lessen the time, cost and
Speakers’ Presentations
resources to identify and optimize active agents. Strategies to accelerate drug
development include testing drugs earlier in the disease process such as the
neoadjuvant setting, in which the surrogate short-term endpoint, pathological
response (pCR), may identify active agents and shorten the time to approval
of both efficacious drugs and biomarkers identifying patients most likely to
respond. I-SPY 2 is a multicenter, phase 2 trial using adaptive randomization
within biomarker subtypes to evaluate a series of novel agents/combinations
when added to standard neoadjuvant weekly paclitaxel (T) ×12 (with
trastuzumab if Her2+), followed by doxorubicin & cyclophosphamide (AC)
q2–3 wk ×4, for women with high-risk stage II/III breast cancer. The primary
endpoint is pathologic complete response (pCR) at surgery. Participation is
limited to patients with sufficiently poor prognosis (risk of early recurrence)
with standard therapy to justify exposure to investigational agents; thus
those with tumors <2.5 cm or hormone receptor (HR)+/MammaPrint (MP)
low biomarker profiles are not eligible. Agents selected for inclusion in
I-SPY2 must have adequate safety information from phase Ib studies in
combination with a taxane at a dose and schedule approximating the
I-SPY2 regimen. I-SPY2 safety data are collected electronically through a
web-based application (“TRANSCEND”) developed specifically for the trial in
collaboration with the NCICB. The I-SPY2 DSMB meets monthly to review
safety and outcome data, providing the opportunity to conduct frequent
monitoring for unexpected safety signals, and constantly re-evaluate the
risk/benefit ratio for a given drug or combination in the trial. The study is
designed to identify and “graduate” regimens that have ≥85% Bayesian
predictive probability of success (statistical significance) in a 300-patient
biomarker-linked Phase 3 neoadjuvant confirmatory trial defined by HR
& HER2 status & MP “signature”. Experimental regimens can “graduate”
in at least 1 of 10 possible signatures, with a maximum number of 120
patients enrolled per regimen. As of August 2013, over 400 women have
been enrolled to the trial and randomized to T/AC with or without one of
seven investigational therapies from five different pharmaceutical companies,
including veliparib/carboplatin, neratinib, AMG-386, ganitumab/metformin,
pertuzumab, pertuzumab/ado-trastuzumab emtansine (T-DM1) or MK-2206.
Whether any of these investigational therapies have been graduated or
dropped for futility has not been announced. The I-SPY3 TRIAL, currently in
development, will provide a platform for drugs graduating from I-SPY2 to be
definitively tested in a randomized phase 3 trial with primary endpoints of
both pCR and event-free survival.
SP006
Rationale of the design of the SHIVA trial
C. Le Tourneau 1 , M. Kamal 2 , E. Mitry 3 , A. Goncalves 4 , N. Isambert 5 ,
C. Gavoille 6 , O. Tredan 7 , J.P. Delord 8 , M. Campone 9 , X. Paoletti 10 .
1 Medical Oncology, Institut Curie, Paris, France; 2 Translational Research,
Institut Curie, Paris, France; 3 Medical Oncology, Institut Curie, Saint-Cloud,
France; 4 Medical Oncology, Institut Paoli Calmettes, Marseille, France;
5 Medical Oncology, Centre Georges-Francois Leclerc, Dijon, France;
6 Medical Oncology, Centre Alexis Vautrin, Nancy, France; 7 Medical
Oncology, Centre Leon Berard, Lyon, France; 8 Medical Oncology, Centre
Claudius Regaud, Toulouse, France; 9 Medical Oncology, Centre Rene
Gauducheau, Nantes, France; 10 Biostatistics, Institut Curie, Paris, France
Two recent studies suggest that a histology-independent approach consisting
in selecting molecularly targeted agents based on the molecular profile of
patients’ tumors, whatever the tumor location and histology are, improves
patients’ outcome [Von Hoff et al., 2010; Tsimberidou et al., 2012]. However,
the lack of randomization versus standard of care in these studies did not
allow drawing robust conclusions.
The SHIVA trial is a multicentric randomized proof-of-concept phase II trial
comparing molecularly targeted therapy based on tumor molecular profiling
versus conventional therapy in patients with any type of refractory cancer. The
primary endpoint is progression-free survival (PFS). The molecular profile
performed on a mandatory biopsy includes the assessment of (1) hot spots
mutations using the AmpliSeq cancer panel on Ion Torrent/PGM (Life Technologies), (2) gene copy number alterations using Cytoscan HD/Affymetrix,
and (3) expression of estrogen, progesterone and androgen receptors by
immunohistochemistry on formalin-fixed sample. The algorithm used by a
Molecular Biology Board (MBB) to guide treatment in the experimental arm
is presented in Table 1. The efficacy analysis will be performed on 200
randomized patients. Randomization is stratified according to the molecular
pathway selected for drug selection as well as on the patients’ prognosis
using the Royal Marsden Hospital score for phase I cancer patients. A
cross-over is proposed at disease progression. Feasibility results on the first
Speakers’ Presentations
S3
Abstract SP006 – Table 1
Molecular abnormalities
KIT, ABL, RET
PI3KCA, AKT1
AKT2,3, mTOR, RAPTOR, RICTOR
PTEN
STK11
BRAF
PDGFRA/B, FLT-3
EGFR
HER-2
SRC
EPHA2, LCK, YES
ER, PR
AR
Type of molecular abnormality
Molecularly targeted agents
Activating mutation or amplification
Activating mutation or amplification
Amplification
Inactivating mutation and LOH
Inactivating mutation and LOH
Activating mutation or amplification
Activating mutation or amplification
Activating mutation or amplification
Activating mutation or amplification
Activating mutation or amplification
Amplification
Protein expression >10%
Protein expression >10%
Imatinib
Everolimus
Everolimus
Everolimus
Everolimus
Vemurafenib
Sorafenib
Erlotinib
Lapatinib + Trastuzumab
Dasatinib
Dasatinib
Tamoxifen (or letrozole if contra-indication)
Abiraterone
ER = Estrogen receptor; PR = Progesterone receptor; AR = Androgen receptor; LOH = Loss of heterozygosity.
100 included patients were presented at the 2013 ESMO meeting. More than
300 patients have been included as of September 2013.
We present here the rationale for the design of the SHIVA trial and discuss its
advantages and drawbacks in the context of personalized cancer medicine.
SP007
Molecular profiling based assignment of cancer therapy (MPACT)
S. Kummar 1 , A. Chen 1 , J. Lih 2 , M. Williams 2 , L. Rubinstein 1 , B. Conley 1 ,
J.H. Doroshow 1 . 1 National Cancer Institute, Maryland, USA;
2 SAIC-NCI-Frederick National Laboratory for Cancer Research, Frederick,
MD, USA
Targeting unique aberrations within the tumor is the goal of personalized
medicine. Assignment of therapy based on underlying genetic aberrations
is guided by the hypothesis that patients with mutations in a given pathway
in their tumor are more likely to derive clinical benefit if treated with agents
that target that pathway than if treated with agents that do not. Multiple trials
and trial designs, the so-called umbrella and basket trial designs, have been
proposed based on this hypothesis. However, apart from a few examples
of successfully targeting such mutations, more data from randomized trials
is required to establish the role of molecular profiling based assignment of
cancer therapy for patients with refractory solid tumors.
The US National Cancer Institute (NCI) is initiating a randomized pilot trial
that aims to establish whether patients with advanced cancers who have no
treatment options with proven benefit, and with tumor mutations in one of 3
genetic pathways (DNA repair, PI3K, or RAS/RAF) are more likely to derive
clinical benefit if treated with agents targeting that pathway than if treated
with agents that do not. Each patient will be randomly assigned to receive the
recommended Phase II dose of either a study drug identified to work on their
tumor’s mutation in the given pathway, or an agent from the complementary
set not identified to work on the mutations of interest (MOIs). Patients
enrolled on study will have a tumor biopsy sequenced in a CLIA-certified
lab for specific MOIs in the DNA repair pathways, PI3K pathway, and the
RAS pathway. Therapy will be assigned based on defined criteria following
identification of an actionable mutation of interest. The objectives of the trial
are to compare the response rate (CR+PR) and progression-free survival
(PFS) for treatment with agents chosen based on the presence of specific
mutations in patient tumors with the response rate and PFS for treatment
with agents randomly chosen from the complementary set of agents not
identified to work on the MOIs. Patients will be randomized 2:1 in favor of the
target-directed arm; the trial will discriminate between tumor response rates
of 20% vs. 5% and median PFS of 3.6 vs. 2 months
Topic 3: Progress and implications of novel
technology for clinical trials
SP008
Clinical reporting of NGS data
D. Eberhard. Pathology Pharmacology and Lineberger Comprehenesive
Cancer Center, University of North Carolina, Chapel Hill, USA
Next-generation sequencing (NGS), also known as massively parallel sequencing, presents great opportunities for advancing a tumor genomics-based
approach to clinical tumor diagnostics, especially companion diagnostics and
clinical development of targeted therapeutics. The various technologies of
massively parallel sequencing potentially allow assessment of a variety of
genomic alterations across many genes or even an entire genome, at an
economic cost that is now competitive with other established clinical diagnostic tests. Medical research and diagnostic laboratories are now adopting
NGS platforms for various purposes ranging from preclinical research on
tumor genomics, through clinical research often related to targeted therapy
development, into clinical diagnostics and personalized medicine schemes.
Each of these settings have particular and differing needs that must be
considered in how to deliver NGS results that are relevant and useful. Various
professional and regulatory organizations are working on developing recommendations for the clinical implementation and reporting of NGS results. This
presentation will give a background review, describe our efforts at UNC to
implement a clinical research program using NGS (UNCseqTM), and present
new recommendations from an NCI working group group regarding the use
of “Omics”-based predictors in NCI-sponsored clinical trials.
SP009
Are we ready for genomes in the clinic?
U. McDermott. Cancer Genome Project, The Wellcome Trust Sanger
Institute, Cambs, United Kingdom
Cancer is a disease of the genome. Mutations in genes that confer a selective
advantage to the cancer cell are perpetuated through subsequent generations
of daughter cells and result in clonal expansion of that cell. In addition to
being responsible for tumourigenesis, it is also clear that in some cancers the
presence of specific gene mutations has major effect on treatment response
and survival in the clinic. The most celebrated recent example of this is the
V600E mutation in the BRAF oncogene. Melanoma tumours harbouring this
mutation are exquisitely sensitive to small molecule inhibitors of BRAF, and
patients are now routinely screened for this mutation in melanoma clinics
prior to treatment stratification. However, it is likely that mutations in other
genes within the same tumour will also play a role in treatment response and
multi-gene signatures will become increasingly important as predictive tools.
Analysis of the 10,000 tumours exome sequenced world-wide is enabling
us to define the cancer genes within each tumour type, and to restrict the
design of a targeted gene screen (TGS) to these “drivers”. Thus, today a
panel of 300–400 genes would encapsulate all genes recurrently mutated,
amplified or deleted in solid tumours and could be delivered at a fraction of the
cost of a whole genome. We have demonstrated that such a targeted gene
screen can deliver high depth NGS data from archived FFPE tissue samples
and using low amounts of DNA. Although there is a significant interest in
the application of whole genome sequencing in the clinic, we would argue
that there are technical, financial and logistical reasons why this is not the
best use of current healthcare resources and that a TGS approach adopted
systematically across all cancer patients would be truly transformative for
clinical practice.
SP010
Application of next generation sequence for retrospective biomarker
analyses in tumors samples from Phase II/III clinical trials
S. Khambata-Ford. Oncology Clinical Development, Novartis
Pharmaceuticals Corp, East Hanover, USA
Next Generation Sequencing (NGS) has been applied increasingly in cancer
S4
genomics research over the last seven years. Most of the reported results are
genetic landscapes generated on tumor samples collected outside clinical
trials or from early phase oncology trials. Application of this technology in
large global Phase 3 trials provides an excellent opportunity for advancing personalized healthcare by identifying potential predictive markers of therapeutic
benefit. This presentation showcases an exploratory retrospective biomarker
analysis in BOLERO-2, a Phase 3 study of everolimus (mTOR inhibitor,
Afinitor® ) in Hormone Receptor (HR) positive, Her2-negative advanced breast
cancer.
In BOLERO-2, EVE plus exemestane (EXE) more than doubled progressionfree survival (PFS) versus EXE alone, with consistent benefit in the
overall population and in all clinically defined subgroups. Potential predictive
biomarkers for EVE benefit were assessed in a panel of 182 cancer-related
genes using NGS. NGS data from formalin-fixed archival tumor specimens
were assessed for exon sequence and gene copy number variations.
Univariate and multivariate Cox models were used to evaluate correlations
with Progression Free Survival (PFS).
Patients with NGS data (>250× coverage; n=227; 157 in EVE+EXE; 70
in EXE alone) had comparable baseline characteristics and PFS outcomes
versus the overall trial population (hazard ratio for PFS=0.40 and 0.45, respectively). Treatment benefit with EVE was mostly maintained in subgroups
defined by a single altered gene such as PIK3CA, CCNDI, FGFR1 with a
>10% rate of alteration. Patients with no or only 1 genetic alteration in key
signaling (PI3K, FGFR) or cell cycle pathways had greater PFS benefit from
EVE than patients whose tumors contained multiple alterations.
This is the first global registration trial in which predictive biomarkers of
therapeutic benefit were explored by correlating broad genetic variations
with clinical efficacy. It demonstrated the feasibility of using NGS and the
power of large scale correlative analysis in a randomized Phase 3 trial. The
observations suggest the potential interplay of multiple oncogenic pathways in
determining optimal therapeutic benefit from EVE in HR+, HER2− advanced
breast cancer. These exploratory results also point to potential novel rational
targeted therapy combinations that will be further investigated.
Topic 4: Regulatory issues
SP011
Translational scientists – Overview of process of taking an assay fropm
the lab to the clinic
J. Martens. Medical Oncology, Erasmuc MC Cancer Institute, Rotterdam,
The Netherlands
Genomics research is expanding our understanding of cancer biology
in general as well as our insight in clinical relevant aspects of cancer
progression such as metastatic potential and therapeutic vulnerability. As a
results research on prognostic and predictive markers is a vivid field and
the number of diagnostic markers is rapidly expanding leading a multitude
of novel and potentially informative and clinically useful biomarkers. Rather
than measuring these as single markers in an uniplex assay, in the future
one or more multiplex assays will likely be used to guide clinical decisions.
In this session we will hear the experts view on the regulatory aspects of
the implementation of next generation diagnostics in the clinical arena. To
set the stage I will discuss the standard route a biomarker assay has to
travel before it can be used for clinical decisions. Aspects which mainly
involve providing solid evidence defined as Level Of Evidence (LOE) from
category 5 till 1 will be discussed as well as various aspects of proper
measuring such biomarker as we as to ensure that the standards of those
assays are maintained over a long period time. As examples I will use the
prognostic markers uPA/PAI-1 developed by the EORTC Pathobiology group.
This marker panel has travelled all the way from being discovered in a small
retrospective cohort to independent multicenter validation and prospective
testing and is now listed in the ASCO and St Gallen guidelines for the clinician
to guide them for taking decisions in patients visiting the clinic in the current
daily routine. Other examples being discussed include the current prognostic
gene expression signatures which are following or have travelled a similar
route towards clinical application. Also examples of predictive markers will be
given. In the end, and to set the stage for the discussion, the impact of NGS
is discussed likely leading to an explosion of informative markers moving
towards clinical application and how this might impact the current practice of
biomarker implementation. After this presentation, experts in the field which
include a clinician, a biologist, a representative from a regulatory body and
from a diagnostic company and a statistician will give their professional view
on the most critical issues, in their opinion, relevant for the rapid advancement
Speakers’ Presentations
of the plethora of potentially useful markers currently being discovered from
the bench to the bed-side.
SP012
EMA perspective on approval issues
I. Gravanis. European Medicines Agency
(Bio)Markers may serve a variety of functions in oncology drug development
and ultimately authorisation. The most prominent function is as a means
to determine patient populations expected to benefit or not benefit from
a new drug. This is commonly linked to the fact that novel drugs often
belong to the class of “targeted agents”, i.e. they act upon specific biological
pathways/functions implicated in cancer. However, the approval of numerous
targeted therapies in the recent years has not been granted in biomarkerdefined patient populations. This discrepancy is being attributed to the
relative non-specificity of targeted agents acting promiscuously on multiple
pathways, so that no single marker can be predictive of drug activity while the
development of a marker-signature involving multiple ones is challenging. At
the same time, disease biology is either complex or evolving in the course of
the disease, so that targeted agents are often not impressively effective or
resistance to them develops quickly. Systems approaches promise to address
this lack of understanding of the static or evolving disease, but concrete
examples of this have not reached drug regulatory authorities.
The latest EU regulatory guidance on anticancer drug evaluation
(EMA/CHMP/205/95/Rev.4) addresses the use of biomarkers in guiding
oncology drug development. It encourages the use of biomarkers in early
phases of drug development to inform PK/PD relationships and correlations.
It also assumes that, irrespective of pharmacological class, entrance into
clinical development of new molecule today is guided by translational
research. This means that in most cases there are hypotheses to be tested
and candidate biomarkers available. However, in practice this is not the case
so that the majority of drugs currently reaching not only confirmatory trials but
even approval do not have biomarkers defining their target population, while
historically such use of biomarkers has been necessitated by lack of adequate
efficacy in an unselected population. This is not meant to say that activity and
efficacy in the biomarker-negative population should be overlooked when this
exists and holds promise of benefit in these patients.
Use of biomarkers to define eligibility in confirmatory trials ultimately defines
the target population upon approval. However, retrospective biomarker analyses may also lead to restrictions to the target population when appropriate
and when the benefit/risk balance is not considered positive in the unselected
population. Determination of biomarker status is crucial and, although
approval of relevant diagnostics in the EU is separate from drug approval,
a diagnostic assay complying with the relevant EU legal requirements, as
appropriate, should be available at time of drug authorisation. Moreover, the
adequacy of the available diagnostic assays to correctly identify patients
eligible for treatment and the feasibility of its application in wide clinical
practice is taken into consideration when drug approval decisions are made.
Finally, EU guidance also opens the possibility towards biomarker-defined
authorisations across histologies, provided appropriate conditions are met.
SP013
FDA view on approval issues and new guidelines
R. Becker
No abstract presentation received.
SP014
R&D’s view on obstacles to development of diagnostics for clinical
development
S. Shak. Genomic Health Inc., Redwood City, USA
To develop and clinically validate a new HER2-specific monoclonal antibody
for breast cancer treatment, a rigorous multi-step drug development program
was required. Similarly, to develop and clinically validate a new quantitative
RT-PCR gene expression assay to guide breast cancer chemotherapy
treatment planning, it was necessary to bring the rigor of drug development
to the process for cancer diagnostic development. In both instances, it was
critical to optimize and standardize new technologies, antibody humanization
for trastuzumab and precise, reproducible RNA quantitation from tumor blocks
for Oncotype DX (detailed data on the performance characteristics of the
Speakers’ Presentations
Oncotype DX assay will be presented). In both instances, it was also equally
important that academia, industry, advocacy, and regulatory authorities
collaborate to ensure that the studies were well-designed and successfully
implemented. It requires a team with all accountable, and the skills, processes, and resources to perform the early exploratory studies and the later
controlled validation studies. Most importantly, tests must be “Fit for Purpose”
with evidence relevant to that specific purpose, with consistent results
across multiple well-designed studies and value beyond traditional measures.
Multiple well-designed clinical studies using a standardized quantitative assay
system can successfully provide the evidence required by physicians to use
the genomics of individual tumors to individualize cancer treatment.
SP015
Clinican’s view
TBC
No abstract presentation received.
SP016
Statistical issues on biomarker ascertainment and power to detect
interactions
J. Bogaerts. EORTC Headquarters, Brussels, Belgium
Biomarkers may be construed from different perspectives: diagnosis, prognosis, or various predictive purposes. Predictive biomarkers can identify
classes of patients that are specially sensitive to a particular treatment, or
the opposite, or that have no need for a (class of) treatment. They could also
identify classes of patients for whom currently no good treatment options are
available.
At the statistical level, prognostic analyses have better properties than
predictive questions. The latter, while conceptually not complex, do involve
interaction questions: a comparative treatment effect needs to be proven to be
different in one group as compared to the treatment effect in the other group.
Imprecision in biomarker assessment (i.e. assay performance) can lead to
frightening loss of effect size and power in such analyses.
We will discuss mathematical repercussions of various types of predictive
biomarker questions, and try to indicate settings where the full penalty of a
statistical interaction may not need to be endured.
From the statistical point of view, the key point in biomarker development is
its purpose and intended usage. This will drive the design of the trials to be
undertaken, and the analysis path to follow.
Topic 5: Circulating / Imaging biomarkers
SP017
Circulating tumor cells (CTCs) and circulating DNA to monitor tumor
heterogeneity in clinical trials
S. Jeffrey. Surgery, Stanford University, Stanford, USA
Dr. Jeffrey will discuss circulating tumor cells and circulating tumor DNA in the
context of intratumoral heterogeneity, single cell analysis, and applications
related to cancer monitoring and drug selection.
SP018
PET imaging to monitor tumor heterogeneity in clinical trials
E. de Vries, M. van Kruchten. Medical Oncology, UMCG, Groningen, The
Netherlands
Increasingly cancer patients are treated based on tumor characteristics.
Typically this is done through the use of tumor biopsies, which may be
performed on archival tissue that does not represent the contemporary status
of the tumor. Even with a recent tissue sample, there are still problems of
heterogeneity among lesions and within lesions. Heterogeneity plays a role in
limiting the efficacy of targeted therapy and is a barrier to precision medicine.
Given this heterogeneity, and the fact that often not all lesions can be
biopsied, other supporting techniques are required.
Molecular radionuclide imaging with positron emission tomography (PET) can
potentially fulfill this task. Most clinical molecular imaging data are gathered
on the visualization of general processes, such as glucose metabolism
with 18 F-fluorodeoxyglucose (FDG) and DNA synthesis with 18 F-fluoro-L-
S5
thymidine PET-imaging. But PET imaging can also visualize other important
tumor cell characteristics, like hormone receptors, growth factors and growth
factor receptors.
Visualization of the estrogen receptor (ER) with 18 F-fluoroestradiol (FES)
proved to be feasible in breast cancer patients. Heterogeneity of ERexpression is shown by both FES-positive and -negative lesions present
in 15–47% of patients with an ER-positive primary tumor. Furthermore, up
to a 6-fold difference in quantitative FES-uptake can be observed among
metastases within individual patients. Finally, dual imaging with FDG-PET
and FES-PET showed that FES/FDG ratios varied greatly across patients.
The androgen receptor (AR) was imaged with 18 F-fluoro-5α-dihydrotestosterone
(FDHT) in prostate cancer patients. FDHT-PET showed that MDV3100, an
AR antagonist, that blocks androgens from binding to the AR, substantially
reduced FDHT binding (Scher H et al. Lancet 2010).
HER2 can be visualized with 89Zr-trastuzumab-PET. In metastatic breast
cancer patients quantifiable tracer uptake in liver, bone and brain lesions was
seen. Within patients, higher 89Zr-trastuzumab uptake was observed in liver
lesions, compared to bone and brain lesions. Furthermore, tracer uptake of
liver, bone and brain lesions varied within and across patients.
With 89Zr-bevacizumab-PET, visualizing VEGF-expression, we showed in
renal cell carcinoma patients a wide range of 89Zr-bevacizumab uptake by
tumor lesions, a reduction in uptake by bevacizumab treatment and a wide
range in uptake changes upon sunitinib treatment. Also, for the anti-VEGF
antibody HuMV833 a heterogeneous distribution and clearance was observed
between and within tumors using 124 I-labeled HuMV833 (Jayson GC et al. J
Natl Cancer Inst. 2002).
Thus, new molecular imaging can identify the levels of a specific tumor
target across the entire body over time, can provide new mechanistic and
pharmacological insights and can contribute to distinguish patients most likely
to benefit from a specific treatment.
Topic 6: Predictive markers for
immunotherapy
SP019
Monitoring response to anti CTLA-4 therapy
M. Postow. Medicine, Memorial Sloan-Kettering Cancer Center, New York,
USA
Immunotherapy directed against cytotoxic T lymphocyte antigen-4 (CTLA-4)
has improved overall survival (OS) for patients with melanoma in two
randomized phase III trials and is being evaluated for additional malignancies.
Pre-treatment or on-treatment biomarkers, reflective of the mechanistic
activity of CTLA-4 blockade, are urgently needed to identify patients most
likely to benefit. The investigation of immunotherapeutic biomarkers is
conceptually distinct from investigations of biomarkers pertaining to targeted
agents which typically interact directly with intratumoral oncogenic pathways.
Since CTLA-4 blocking antibodies target lymphocytes, we have explored
the absolute lymphocyte count (ALC) as a pharmacodynamic biomarker for
ipilimumab. Immunosuppressive myeloid derived suppressor cells (MDSC)
inhibit lymphocytes, and additional data suggest MDSC quantity is also associated with CTLA-4 therapeutic outcomes. Other emerging, novel possible
biomarkers for CLTA-4 therapy will be discussed as will plans for prospective
evaluation.
SP020
Predictive gene signature (GS) in MAGE-A3 antigen-specific cancer
immunotherapy
F. Ulloa Montoya. R&D, GSK Vaccines, Rixensart, Belgium
Antigen-specific cancer immunotherapeutics aim at educating the immune
system to treat cancer. The candidate cancer immunotherapeutic used
here is a combination of the MAGE-A3 tumor-specific antigen with an
immunostimulant designed to enhance immune response. Two Phase II trials
yielded signs of activity for this cancer immunotherapeutic in metastatic
melanoma and NSCLC adjuvant setting (NCT00086866–NCT00290355).
Gene expression profiling by microarray analysis was performed on fresh
frozen tumor samples taken before treatment and used to identify biomarkers
potentially predictive of benefit from Antigen specific cancer immunotherapy
treatment. Such predictive biomarkers were initially identified in Phase II
melanoma patients and then tested in NSCLC Patients.
S6
In the metastatic melanoma patients, a set of 84 genes was identified whose
expression was potentially associated with improved clinical response. A
classifier based on gene-expression data was cross-validated and showed a
greater overall survival in the population of patients whose tumor presented
the GS: median OS was 16.2 months (95% CI, 9.0 to 20.0 months) in the
GS-negative population and 29.0 months (95% CI, 20.5 to 40.2 months) in the
GS-positive population. The genes identified were mainly immune-related,
involving interferon gamma pathways and specific chemokines, suggesting
that their pre-treatment expression may influence the tumor’s immune
microenvironment and the patient’s clinical benefit. The predictive value of
the melanoma signature in NSCLC was corroborated in samples from the
proof-of-concept Phase II study in adjuvant NSCLC patients. The disease-free
interval, primary endpoint of the Phase II study, for the overall population and
for the patients whose tumor presented the predictive “metastatic melanoma”
GS showed that the relative improvement in the risk of recurrence upon
treatment with the MAGE-A3 Cancer Immunotherapeutic was increased in
the patients with the predictive GS as compared to the overall population: HR
GS(+) patients = 0.42 (95% CI [0.17;1.03], HR GS(−) patients = 1.17 (95%
CI [0.59; 2.31]), while the respective HRs were 0.85 (95% CI [0.50; 1.43]) in
the 157 patients analyzed for GS and 0.78 (95% CI [0.49; 1.24]) in the entire
study population of 182 patients). Furthermore, this GS classification did not
show a difference in DFS between the GS+ and GS− patients in the placebo
group (HR=1.23 (95% CI: [0.51; 2.98], suggesting that this signature is not
prognostic in this patient population.
In conclusion, an 84-gene GS appeared associated with improved clinical
response to the MAGE-A3 immunotherapeutic in metastatic melanoma and in
resected NSCLC (primary tumor sampling). Phase III trials to confirm these
findings prospectively are ongoing.
Reference:
[1] Ulloa Montoya F, Louahed J, Dizier B, et al. Predictive gene signature
in MAGE-A3 antigen-specific cancer immunotherapy. J Clin Oncol 2013;
31(19):2388–95. doi: 10.1200/JCO.2012.44.3762. Epub 2013 May 28.
SP021
Bone marrow minimal residual disease (MRD) was the strongest
predictor of survival from high risk metastatic neuroblastoma (NB)
following anti-GD2 immunotherapy, when tested in multivariate models
that include FcR polymorphism and missing ligand for inhibitory
killer-immunoglobulin-like receptor (KIR)
N. Cheung, I. Cheung, D. Kuk, I. Ostrovnaya, S. Modak, K. Kramer,
B. Kushner. Department of Pediatrics, Epidemiology-Biostatistics, Memorial
Sloan-Kettering Cancer Center, New York, USA
Background: Immunotherapy using anti-GD2 antibody is now a standard of
care for children with high risk metastatic neuroblastoma. Identifying predictive markers of response and survival can provide a better understanding
of the underlying immunobiology and help optimize efficacy among patient
subgroups.
Methods: Prognostic markers were analyzed in 343 patients treated at
Memorial Sloan-Kettering under 4 protocols (NCI-V90-0023, NCT00002634,
NCT00002560, NCT00072358). All patients had stage 4 disease, diagnosed
at >18 m at diagnosis and/or with MYCN amplification. They were treated
with anti-GD2 antibody 3F8, without or with granulocyte-macrophage colonystimulating factor (GM-CSF), given either intravenously (iv) or subcutaneously
(sc). Group 1 (n=169) was first treated in first remission, group 2 (n=105)
had primary refractory disease, and group 3 (n=69) in > second complete
remissions (2nd CR). Immunotherapy cycles were given every 1–3 months
over 2 years if human anti-mouse antibody (HAMA) response was negative.
Progression-free survival (PFS) and overall survival (OS) were estimated
by Kaplan-Meier method; prognostic variables were tested using log-rank
test, and their independent significance was assessed by multivariate Cox
regression. Prognostic variables included tumor MYCN amplification, gene
polymorphism of Fc-receptors (FcgR2A and FcgR3A), missing inhibitory KIR
ligands for natural killers (NK), route of GM-CSF, pre-3F8 (pre-MRD) and the
2-month post-3F8 bone marrow MRD (post-MRD) using a 4-marker panel
(GD2 synthase, PHOX2B, CCND1 and ISL1) as measured by quantitative
RT-PCR, HAMA and other relevant treatment variables.
Results: For PFS, post-MRD and disease group were statistically significant
prognostic factors. For OS, HAMA, disease group, post-MRD, FCGR2A polymorphism, and missing KIR ligand were significant. In addition, interactions
between FCGR2A and disease group, as well as between post-MRD and
disease group were significant; FCGR2A being strongest among primary
refractory, and post-MRD strongest among 1st remission group.
Speakers’ Presentations
Table 1
Endpoint Prognostic Variable
HR Lower Upper p-value
Bound Bound
PFS
4.23
0.68
1.24
0.41
3.06
0.31
0.61
0.17
0.52
OS
postMRD (positive vs negative)
1st remission vs primary refractory
2nd remission vs primary refractory
HAMA (positive vs negative)
postMRD (positive vs negative)
FCGR2A (“HR or RR” vs “HH”)
Missing KIR ligand (favorable vs unfavorable)
1st remission vs primary refractory
2nd remission vs primary refractory
3.14
0.49
0.85
0.28
1.65
0.16
0.42
0.07
0.22
5.70
0.95
1.81
0.59
5.69
0.60
0.87
0.39
1.21
<0.001
0.023
0.270
<0.001
<0.001
0.001
0.006
<0.001
0.129
Conclusion: Marrow MRD determined after two cycles of immunotherapy
was the strongest predictor of outcome, irrespective of disease status at
the beginning of anti-GD2 immunotherapy. While the significance of missing
KIR ligand supports the role of NK-mediated cytotoxicity, the impact of
high affinity FCGR2A allele primarily among patients with primary refractory
chemo-resistant disease suggests a role of 3F8-mediated myeloid-dependent
anti-NB effect for metastasis in the bone marrow.
Topic 7: Pathway driven approaches
SP022
Challenges and opportunities for molecular screening platforms:
The EORTC SPECTA program
D. Lacombe 1 , S. Tejpar 2 , F. Cardoso 3 , R. Salgado 4 , J. Hall 1 ,
V. Golfinopoulos 1 . 1 EORTC, Brussels, Belgium; 2 University Hospitals
Leuven, Leuven, Belgium; 3 Champalimaud Cancer Center, Lisbon, Portugal;
4 Bordet Institute, Brussels Belgium
Newly developed targeted drugs are tested, through clinical trials, on
restricted groups of patients exhibiting specific biomarkers. When the
prevalence of those biomarkers is low, a high number of patients need
to be screened. Recruitment of patients in a biomarker-led clinical trial
requires significant effort due to the number of patients screened and the
complexity and cost of such screening. Moreover, when various clinical trials
are targeting the same population of patients, the availability of samples may
be restricted and patients may lose the opportunity to enter a potential clinical
trial. To avoid duplication of effort and guarantee efficient patient access
to clinical trials, the European Organization for Research and Treatment of
Cancer is building a program of collaborative molecular screening platforms,
for patients with various advanced tumor entities. The first platforms are
dedicated to colo-rectal, central nervous system tumors and melanoma.
SPECTA is the first European initiative intended to accelerate clinical trial
access by ensuring robust screening of markers that can potentially allow
patients to be enrolled in open clinical trials. Patients with predefined tumor
stages will be proposed to have their material centrally processed for
pathological examination and screening of cancer gene alterations. Common
cancer genes are investigated using respectively certified assays and next
generation sequencing technologies. By matching clinical, pathological and
molecular profiles of patients to eligibility criteria of available biomarker-led
clinical trials, SPECTA achieves a real-time identification of eligible patients
across Europe and patient-oriented parallel screening for multiple trials. In
this presentation, we will describe SPECTA as a new business model which
is based on currently active network of clinical centers, a central biobanking
and pathology facility, qualified assays laboratories, software to collect, trace
and secure the data and algorithms to match the patients in real time with
trials. We will also detail the model of partnership that has been developed to
engage all stakeholders in the project, including the patient organizations, the
European Society of Pathology, the Sanger Institute and our funders as well
as the pharmaceutical industry sector.
SP023
Pathways triggered by FGF and other growth factors
R. Grose. Centre for Tumour Biology, Barts Cancer Institute, London, United
Kingdom
Fibroblast Growth Factor Receptor (FGFR) plays critical roles during embryogenesis, homeostasis and repair but is kept under tight control in normal
tissues. A number of mechanisms have been used by cancers to co-opt
FGFR signalling; ligands or receptors can be amplified/over-expressed, fusion
Speakers’ Presentations
proteins can be generated, autocrine stimulation can occur, and novel nuclear
signalling pathways can be adopted.
FGFR signalling has been implicated in a number of different cancer types.
Genome wide association studies have identified key SNPs in FGFR2 that
associate significantly with risk of developing ER positive breast cancer and,
similarly, FGFR1 over-expression has been associated with poor prognosis in
ER positive breast cancer. Activating mutations have been reported in several
cancer types and, recently, we have identified a role for nuclear FGFRs in
regulating cancer cell behaviour.
I will discuss the current status of FGFs and FGFRs as markers in cancer and
the mechanisms by which they are being targeted therapeutically.
SP024
Prediction of the efficacy of mTOR targeted therapies
T. Alain. McGill Cancer Centre, Montréal, Québec, Canada
mRNA translation is dysregulated in cancer. This is caused by altered expression of translation factors and the hyperactivated oncogenic pathways that
promote protein synthesis (e.g. the mammalian target of rapamycin (mTOR)).
Consequently, the loss of translational control results in increased expression
of proteins with proliferative, survival, and angiogenic functions. Active-site
mTOR inhibitors (asTORi) hold great promise for targeting dysregulated
mTOR signaling in cancer. However, because of the multifaceted nature of
mTORC1 signaling, identification of reliable biomarkers for the sensitivity of
tumors to asTORi is imperative for their clinical implementation. We found
that cancer cells acquire resistance to asTORi by downregulating eukaryotic
translation initiation factor (eIF4E)-binding proteins (4E-BPs). Loss of 4E-BPs
or overexpression of eIF4E renders neoplastic growth and translation of
tumor-promoting mRNAs refractory to mTOR inhibition. Conversely, moderate
depletion of eIF4E augments the anti-neoplastic effects of asTORi. The
anti-proliferative effect of these inhibitors in vitro and in vivo is therefore significantly influenced by perturbations in eIF4E/4E-BP stoichiometry, whereby
an increase in the eIF4E/4E-BP ratio dramatically limits the sensitivity of
cancer cells to asTORi. We propose that the eIF4E/4E-BP ratio, rather than
their individual protein levels or solely their phosphorylation status, should
be considered as a paramount predictive marker for forecasting the clinical
therapeutic response to mTOR inhibitors.
SP025
Genotype-based combinations of RAS/RAF and PI3K pathway
inhibitors
U. Banerji. Division of Cancer Therapeutics & Division of Clinical Studies,
Institute of Cancer Research & The Royal Marsden, Sutton, United Kingdom
Background: There are currently multiple inhibitors targeting the RAS/RAF
and PI3K pathways (BRAF, MEK PI3K, AKT and m-TOR inhibitors) in
development. Each class of drugs have shown clinical activity in single agent
studies and are active in relatively small, defined subsets of tumours which
harbour specific mutations. It is hypothesized that combinatorial inhibition of
both signalling networks could broaden range of tumours where these drugs
could be used in. Our aims included; a) To define tumours which were most
likely to respond to the combination compared to each single agent alone b)
To define the degree of target inhibition needed to achieve maximal growth
inhibition (as it may not be possible to clinically deliver full doses of both drugs
in a combination due to overlapping toxicity).
Materials and Methods: We used two tool compounds (MEK inhibitor
PD0325901 and AKT inhibitor AKT1/2 inhibitor) in an attempt to answer these
questions. We exposed a panel of cell lines (4 BRAF mutant, 5 PIK3CA
mutant 3 KRAS mutant and 5 cell lines with no mutation in BRAF, PIK3CA
or KRAS) to the MEK and AKT inhibitor separately for 24 hours. We then
calculated the concentration of the MEK inhibitor required to reduce the
phosphorylation of ERK by 25, 50, 75 and 100% of and the concentration of
the AKT inhibitor required to reduce phosphorylation of S6 by 25, 50, 75 and
100%. We then exposed the panel of cell lines to various concentrations of
the combinations of the MEK and AKT inhibitors known to inhibit pre-defined
degrees of signalling output for 96 hours and studied growth inhibition using
sulforhodamine assays.
Results: In 4/4 BRAF mutant cells, there was significantly more growth
inhibition caused by maximal inhibition of MEK as compared to maximal
inhibition of AKT and in 5/5 PIK3CA mutant cells, there was significantly
more growth inhibition caused by maximal inhibition of AKT as compared
to maximal inhibition of MEK. Interestingly, in 4/5 cell lines with no BRAF,
S7
PIK3CA or KRAS mutations, cells were significantly more susceptible to AKT
inhibition compare to MEK inhibition and 1/5 of these cell lines were equally
susceptible to AKT and MEK inhibition. Further 1/3 cell lines with KRAS
mutations were more sensitive to MEK inhibition, 1/3 more susceptible to AKT
Inhibition and 1/3 were equally sensitive to maximal MEK or AKT Inhibition.
Further experiments are being conducted to expand the cell line panel to 20
and study the inhibition of different combinations of MEK and AKT inhibitors
known to inhibit MEK and AKT by different degrees. This will help to define
the cells most likely to respond to the combination and further define the
degree of target inhibition needed while designing these combinations.
Conclusion: Combinations of MEK and AKT inhibitors are likely to be more
effective than single agents only in defined subsets of cancers and this
information is crucial to the design of clinical trials evaluating the efficacy of
these combinations.
Topic 8: Genomics driven approaches
SP026
Genomic wide biomarker discovery in personalized patient derived
xenografts
M. Hidalgo. Centro Integtral Oncologico Clara Campal, Madrid, Spain
Pancreatic cancer (PDAC) remains one of the most deadly cancers. Over
the last few years, the genomic landscape of pancreatic cancer as well as
precursor pancreatic cancer lesions have been deciphered in great depth.
These studies show that PDAC develops as the consequence of accumulation
of mutations in key oncogenes and tumour suppressor genes. The disease,
once established, is characterized by high complexity, heterogeneity and
genomic instability. Despite this facts, some patients harbour actionable
mutations which targeting has resulted in significant clinical benefit. Indeed,
one of the most active areas of research in PDAC is the development of
strategies and approaches to personalize the treatment of patients. This is
a complex field that can be tackle from many complementary angles. Our
group has been interested in using patient derive xenogaft (PDX) models,
aka Avatar mouse models, to guide cancer treatment. A piece of freshly
collected tumour is implanted in immunodeficient mouse models, expanded,
treated with different anticancer agents alone and in combination to select
the most effective drug/regimen to treat the patient cancer. Our data show
that the approach is highly predicted but, because of complexity and cost
issues, not widely applicable to clinical practice at the present stage. To
solve some of these limitations we are working on different aspects. One
area is technological development to increase the take rate of tumours and
to speed time to engraftment and expansion time. Currently, these figures are
approximately 60–80% and 5–7 months. Studies are in progress to optimize
this aspect. Another key question is the selection of agents, both alone and
in combination, to be tested in the model. In this regard, it is important
to integrate biomarker assessment in the tumour to pre-select a series of
treatment candidates that can then be tested in the PDX models. To this
end, we have now integrated next generation sequencing and assessment of
copy number variation in patient’s tumour. These studies provide us with an
unbiased overview of the tumour genomic landscape. From this data, using
different bioinformatics and biological methods we extract the most relevant
drug targets that are then bench tested against the patient Avatar mouse
model to select the most effective treatment.
SP027
RAS mutations as markers of resistance for colorectal cancer patients
treated with the anti-EGFR monoclonal antibody panitumumab
K. Oliner. Medical Sciences – In Vitro Diagnostics, Amgen Inc., Thousand
Oaks, USA
Panitumumab (pmab) is an anti-EGFR antibody that is now indicated in
the EU for the treatment of adult patients with WT RAS (KRAS and
NRAS) metastatic colorectal cancer. Data will be presented from analyses of
tumor RAS mutations from three randomized pmab studies. The hypothesis
generating study was a multigene analysis of the phase 3 monotherapy study
of Pmab vs. best supportive care. Final RAS result ascertainment of this study
employing a combination of next-generation sequencing, Sanger sequencing
and WAVE-based SURVEYOR® analysis was 75%. This study suggested
that RAS mutations beyond the most commonly tested KRAS codons 12 &
13 might be predictive of lack of response to Pmab therapy (Peeters, 2013
and Patterson, 2013). This led to two prespecified analyses of the RAS
S8
biomarker, a prospective analysis of the phase 2 PEAK study of Pmab plus
FOLFOX vs. bevicuzumab plus FOLFOX and the prospective-retrospective
analysis of the phase 3 PRIME study of Pmab plus FOLFOX vs. FOLFOX
alone. Banked patient tumor specimens, that were previously found to be WT
KRAS exon 2 by the Therascreen® assay, were subjected to parallel Sanger
sequencing and WAVE-based SURVEYOR® analysis of KRAS exons 3 & 4
and NRAS exons 2, 3 & 4. RAS result ascertainment was 80% and 90% in
PEAK and PRIME, respectively. In the larger PRIME study 17% of tumors
that were previously designated WT KRAS were found to harbor mutations in
this expanded RAS analysis. In the pmab + FOLFOX studies, the additional
RAS mutations were associated with an inferior PFS and OS in the pmab
arm, consistent with previous findings for the KRAS exon 2 mutations. No
new safety signals were found. Clinically, these randomized studies clearly
demonstrate that expanded RAS analysis leads to the selection of patients
who have increased PFS and OS compared to selection of patients who are
wild-type for KRAS exon 2 alone (Oliner, 2013 and Schwartzberg, 2013) when
treated with pmab. Most strikingly, the median OS benefit in the PRIME study
was increased to 5.8 months from previously reported 4.2 month benefit when
testing KRAS exon 2 alone. By selecting patients whose tumors do not harbor
these additional RAS mutations there is a clinically meaningfully increase
in the benefit:risk profile of panitumumab. This presentation will focus on
how exploratory hypothesis generation testing followed by a prospective
retrospective analysis led to the rigorous demonstration of RAS as a primary
resistance biomarker.
SP028
Epigenetic markers in cancer
M. Hegi. Clinical Neurosciences, University Hospital Lausanne, Lausanne,
Switzerland
Epigenetic alterations have been recognized as important mechanisms in
neoplastic transformation, malignant progression of cancer, and response
to therapy. Efforts using high through put sequencing in diverse tumor
types has identified a growing number of mutations in epigenetic modifier
genes (e.g. MLL family member genes or TET2), histone genes (H3F3A),
or in genes indirectly affecting epigenetic modifiers such as mutations in
IDH1 and 2. These mutant proteins can have more generalized effects
on DNA methylation through distinct mechanisms, resulting e.g. in a CpG
island methylator phenotype (CIMP, IDH1 or 2 mutations, TET2), or a
CpG island hypomethylator phenotype (CHOP, H3F3A-mt G34) deregulating
expression of large numbers of genes, but also of regulatory non-coding
RNAs. Epigenetic silencing by aberrant methylation of CpGs in the gene
promoter region affects diverse cancer relevant pathways leading to activation
of oncogenic pathways such as the WNT pathway, mediated by silencing of
WNT antagonists, or by inactivation of tumor suppressing pathways, including
DNA repair (MLH1, MGMT). Most interestingly, some of these epigenetic
alterations can be converted into the “Achilles heel” of the affected tumors
upon treatment with certain classes of anti-cancer agents. In fact, we have
shown previously for glioblastoma that promoter methylation of the MGMT
gene that encodes a DNA repair enzyme, confers a benefit to treatment
with the alkylating agent temozolomide. Hence, the methylation status of the
MGMT promoter has become the first predictive biomarker in this tumor type
and is used in the clinic. Aberrant DNA methylation patterns have tumor
type specific characteristics that are also distinct from respective normal
tissue. Hence DNA methylation in characteristic genes can also serve as
biomarkers for early detection of neoplastic cells, such as methylation of
GSTP1 in prostate cancer or SEPT9 in colon cancer. For some tumor types
non-invasive tests using plasma-derived DNA are in development.
Taken together, development of markers for epigenetic alterations is a growing
field and will inform on many questions, ranging from early tumor detection,
tumor classification, prognostication, detection of treatment targets, or as
predictive factors. Hence, beside mutation analysis of epigenetic modifier
genes, reliable and validated tests for detection of aberrantly methylated gene
promoters will be required.
Speakers’ Presentations
An EORTC Workshop on Biospecimen
Pre-Analytical Stability and Diagnostics
SP029
Keynote address: Overcoming the challenges of biospecimen
collection for R&D, clinical trials and biobanking
G. Thomas. Surgery and Cancer, Imperial College London, London, United
Kingdom
Risk analysis is a useful tool in designing protocols to address the challenges
of biospecimen collection. An assessment of risk is based on the answers to
three questions – What can go wrong?, How likely is it to happen? and, if it
does happen, what are the consequences?
In order to answer these questions, a detailed understanding of all the
steps involved in biospecimen acquisition is needed. This includes how the
multidisciplinary team interacts during a clinical procedure which leads to the
acquisition of the biospecimen of interest. The second step then involves
identifying the weak links in the chain of custody for the biospecimen, and the
final step requires a detailed understanding of biospecimen science.
For samples obtained from operative material, the chain from removal of
tissue from a patient to stabilization of the material either by fixation and
processing to paraffin or freezing can be complicated, dependent on the
interaction of staff in the operating theatre and pathology staff and their
relative locations within a hospital. Protocols that are to be used in multi-centre
studies should identify areas of difference in procedure between sites that
are most likely to lead to significant changes in specimen quality and provide
information on how these effects may be mitigated.
A biospecimen is only useful for research if it is fit for purpose. In reality,
the majority of researchers will not have identified which of the pre-analytical
variables that can occur during a chain of custody affect the suitability of that
specimen for their specific analysis. It therefore becomes the responsibility
of the protocol author to identify key steps in the chain from acquisition
to use that are likely to result in degradation of the analyte within the
sample. Procedures can then be put in place to decrease the likelihood of
these events occurring. Acquisition of samples in the clinical setting is not a
simple procedure, but an approach using risk analysis to design protocols for
procurement is a useful tool in improving sample quality, and hence reducing
noise due to pre-analytical variables in the final analysis.
SP030
A controlled assessment of pre-analytical variables and their impact on
the proteome in the collection and storage of plasma and serum
David Chelsky
No abstract presentation received.
SP031
Evidence-based guidelines for the pre-analytical phase of DNA, RNA
and cell-free DNA testing in blood samples
M. Pazzagli 1 , F. Malentacchi 1 , R. Wyrich 2 , C.C. Hartmann 2 , P. Verderio 3 ,
S. Pizzamiglio 3 , C.M. Ciniselli 3 , M. Kubista 4 , S. Weisbuch 5 , S. Gelmini 1 .
1 Dept. of Experimental and Clinical Biomedical Sciences, University of
Florence, Florence, Italy; 2 Qiagen GmbH, Qiagen GmbH, Hilden, Germany;
3 Unit of Medical Statistics and Biometry, IRCCS Istituto Nazionale dei
Tumori, Milan, Italy; 4 TATAA Biocenter AB, TATAA Biocenter AB, Gothenburg,
Sweden; 5 Immunid, Immunid, Grenoble, France
Molecular diagnostics have allowed for great progress in medicine, but
its full potential is hampered by the lack of guidelines for the collection,
handling, stabilisation and storage of the biosamples. The development of
evidence-based quality guidelines for blood samples require identification of
the critical steps in the pre-analytical procedure that need to be controlled
and possibly further developed.
To reach this goal, within the FP7 EU Granted Project “Standardisation
and Improvement of generic pre-analytical tools and procedures for in
vitro diagnostics” (SPIDIA; Grant Agreement no. 222916, www.spidia.eu),
pan-European external quality assurance schemes (EQAS), specifically
designated for the monitoring of the performance of the pre-analytical phase
of DNA, cell-free DNA and RNA testing in blood samples, have been
executed.
With the support of the European Federation for Clinical Chemistry and
Speakers’ Presentations
Laboratory Medicine (www. efcclm.org) more than 320 applications from 220
laboratories representing 30 European countries were obtained. The participants received the same sample/s (whole blood, plasma) and performed, in
two separated runs, sample extractions using their own standard protocol
and reagents. Participants then sent back the extracted DNA/RNA to the
SPIDIA laboratories for analysis, providing also details about the reagents
and protocols used for the extraction.
At the SPIDIA laboratories the extracted samples were tested for quality/quantity/integrity and stability. Each participant received a specific report
with a summary of its performance obtained by considering the results of all
the other participants.
From the SPIDIA-EQAs, the most critical steps in the pre analytical procedure
were identified. The results of these studies will enable the development of
several European Technical Specifications (CEN/TS) currently under evaluation by the European Committee for Standardization (CEN; www.CEN.eu).
SP032
Effects of intrasurgical and postsurgical variables on stability of
signaling molecules in cancer tissues
J. Hartmut. Indivumed, Hamburg, Germany
Surgical biospecimens are the main source for cancer research and
tissue diagnosis. With rapidly increasing numbers of targeted therapies the
understanding of tumor biology in patients becomes important for patient
stratification and prediction of drug response. Therefore, it is extremely
important to understand variables that affect expression of genes and
proteins and their phosphorylation status in tissues during surgery and
postsurgical processing.
Indivumed together with three partner clinics in Hamburg, Germany (Israelitisches Krankenhaus, Agaplesion and University Clinic Hamburg-Eppendorf)
performed a study, funded by the NCI, to analyze the impact of surgical
procedures and postsurgical processing of tissue with respect to gene
expression, the expression of cancer therapy relevant proteins and the
phosphorylation of key proteins regulating cancer pathway activity in primary
and metastatic colorectal cancer tissue. The ultimate goal has been to define
genes and proteins which are stable and, thus, can be regarded to be
uncritical for research and diagnostic purposes as well to identify potential
markers that can serve as quality markers for tissue testing.
Tissue samples from the tumor and adjacent normal tissue were collected
from 80 patients with colorectal cancer at different time points before and after
tumor resection. They were subjected to an analysis of defined proteins of the
EGFR-family and the related Akt and MAPK signaling pathway. In addition,
gene expression was analyzed in total RNA samples using whole genome
chips.
Our data show that there is a significant difference in the molecular composition of tissue specimens that were collected after tumor resection compared
to those tissue specimens that were collected before tumor resection. This
difference is larger than the difference between various post-resection times
between 10 and 45 minutes. The observed effect is either due to warm- and
cold ischemia, or is caused by a combination of the surgical manipulation
of the tissue, length of warm ischemia, drug application and other individual
variables. Postsurgery the processing time is the most important variable for
preserving molecular composition.
This study presents an important contribution to the understanding of
molecular changes that are being introduced into tissue samples during the
preanalytical phase, i.e. by the tissue collection procedure itself.
SP033
Evaluation of novel alternatives to formalin fixation for companion
diagnostics
K. Zatloukal 1 , K.F. Becker 2 , D. Groelz 3 , S. Guendisch 2 , M. Kap 4 ,
M. Kruhoffer 5 , P.H.J. Riegman 4 , P. Turano 6 , C. Viertler 1 , R. Wyrich 3 .
1 Medical University of Graz, Institute of Pathology, Graz, Austria; 2 Technical
University, Institute of Pathology, Munich, Germany; 3 Qiagen GmbH,
Research and Development, Hilden, Germany; 4 Department of Pathology,
Josephine Nefkens Institute, Rotterdam, The Netherlands; 5 Aros Applied
Biotechnology A/S, Science Park Skejby, Aarhus, Denmark; 6 University of
Florence, Magnetic Resonance Center and Department of Chemistry,
Florence, Italy
The efficacy of targeted therapies mostly relies on the selection of the
appropriate patients to treat. This requires the analysis of the status of
S9
the drug target and affected downstream biological mechanisms. Therefore,
the application of companion diagnostics based on different types of
molecular biomarkers related to DNA, RNA, proteins or metabolites on
tissues becomes increasingly important. It is know that these biomolecules
are markedly modified by the formalin fixation procedure which limits their
analysis in tissue specimens collected for histopathological examination. A
novel non-formalin based fixative (PAXgeneR, Qiagen) has been extensively
tested within the large integrated project “Standardisation and improvement
of generic pre-analytical tools and procedures for in-vitro diagnostics”
(SPIDIA; www.SPIDIA.eu) which was funded by the 7th European framework
programme.
Data obtained showed that PAXgene preserved DNA and RNA almost as
good as snap freezing in liquid nitrogen. The efficiency and accuracy of
next generation DNA sequencing was comparable to snap frozen tissues.
PAXgene revealed far less gene-to-gene variations as compared to formalin
fixation and resulted in up to 100-fold increased sensitivity of qRT-PCR based
assays. Furthermore, proteins including phospho-proteins could be recovered
well from PAXgene-fixed paraffin-embedded tissue samples. Epitopes were
well preserved. However immunohistochemistry protocols required optimization for some of the antibodies tested. Morphologic features and diagnostic
criteria could be well reproduced as compared the classical formalin-fixed
tissues. Safety evaluation showed similar pathogen inactivation capacity as
formalin.
These findings suggest that PAXgene is a promising new fixative that would
allow state-of-the-art histopathological analysis and application of a broad
range of molecular biomarkers from the same tissue sample without the need
of different sample processing workflows (e.g., formalin fixation and snap
freezing). This would markedly improve the feasibility of application of novel
companion diagnostics in drug development and routine health care.
The work was funded by the 7th European Union Framework Programme
under grant agreement no. 222916.
SP034
Preanalytical variation affecting detection of RNA in breast cancer
tissues
F. Symmans
No abstract presentation received.
SP035
NCI biospecimen evidence-based practices
H. Moore, K.B. Engel. Biorepositories and Biospecimen Research Branch –
Cancer Diagnosis Program Division of Cancer Treatment and Diagnosis,
National Cancer Institute, USA
The U.S. National Cancer Institute’s BRN (Biospecimen Research Network)
program focuses on the systematic study of different biospecimen collection,
processing, and storage parameters and their effects on downstream
analyses. The BRN supports new research and maintains an online literature
resource, the Biospecimen Research Database, which catalogs and describes
the published literature in Biospecimen Science. Together, these resources
help to build a much-needed knowledge base in Biospecimen Science. A
remaining challenge is the translation of this knowledge to improved biospecimen practices, with the ultimate goal of improving the quality of scientific
research and development. To address this challenge the NCI has developed
the concept of Biospecimen Evidence-based Practices. This concept will be
elaborated in the presentation. The Biospecimen Evidence-based Practices
can be used to support and speed the development of evidence-based
Standard Operating Procedures for biospecimen collections that are integral
to basic research and clinical trials.
S10
SP036
SPIDIA – Dissemination of results into CEN technical specifications for
biospecimen handling
U. Oelmueller 1 , K.F. Becker 2 , M. Heinrich 3 , L. Krieger 3 , M. Kubista 4 ,
M. Pazzagli 5 , P. Riegman 6 , P. Turano 7 , C. Viertler 8 , K. Zatloukal 8 . 1 MDx
Development, QIAGEN GmbH, Hilden, Germany; 2 Department of Pathology,
Technical University of Munich, München, Germany; 3 DIN Institute, DIN
Deutsches Institut für Normung e. V., Berlin, Germany; 4 TATAA Biocenter
AB, TATAA Biocenter AB, Goeteborg, Sweden; 5 Dept. of Experimental and
Clinical Biomedical Sciences, University of Florence, Florence, Italy;
6 Department of Pathology, Erasmus Medcial Center, Rotterdam,
Netherlands Antilles; 7 Magnetic Resonance Center (CERM), University of
Florence, Florence, Italy; 8 Institute of Pathology, Medical University of Graz,
Graz, Austria
Molecular in vitro diagnostics and biomedical research have allowed great
progress in medicine. Further progress is expected by new technologies
analyzing cellular biomolecule profiles such as nucleic acids, proteins, and
metabolites. New biomarkers based on these biomolecule classes including
disease specific biosignatures will be key value drivers for future personalized
medicine and improved health care. Studies have demonstrated that profiles
of these molecules as well as their qualities can change significantly during
Speakers’ Presentations
sample collection, processing, transport, storage, archiving and biomolecule
isolation thus making diagnostics or research unreliable or even impossible. High quality clinical samples with preserved bioanalyte profiles are
therefore critical to diagnostics, research, and biobanking. Developing new
pre-analytical technologies and tools as well as standardizing pre-analytical
workflows is therefore of high importance. The large-scale integrating
research project SPIDIA within the European Union FP7 program is one of
the major contributors to these efforts (grant no. 222916, www.spidia.eu). The
project is supported by 7 private research and diagnostic companies, 8 public
research organizations, and the European Committee for Standardization
CEN. The consortium is working on the standardisation and improvement of
generic pre-analytical tools and procedures for in vitro diagnostics. SPIDIA’s
research has focused on analyzing and improving pre-analytical workflows
for blood, tissues, and body fluids. The project results serve as important
evidence for developing new standards. In October 2012 the European
Committee CEN/TC 140 “In vitro diagnostic medical devices” accepted the
SPIDIA consortium’s proposal for a first Technical Specification Document
“Molecular in-vitro diagnostic procedures – specifications for pre-analytical
workflows for selected sample types”. Up to 16 Technical Specifications
for different individual sample types and bioanalytes such as RNA, DNA,
proteins, metabolites are currently being developed within a dedicated
CEN/TC 140 working group.
S11
Six Best Poster Abstracts – Oral Presentations
MC13-0026
KRAS mutated plasma DNA as predictor of outcome from irinotecan
monotherapy in metastatic colorectal cancer
K. Spindler 1 , A.L. Appelt 1 , N. Pallisgaard 2 , R.F. Andersen 2 , A. Jakobsen 1 .
1 Oncology, Vejle Hospital, Vejle, Denmark; 2 Biochemistry, Vejle Hospital,
Vejle, Denmark
Background: A major proportion of colorectal tumors harbour KRAS
mutations, a negative predictive marker for outcome of EGFR targeted
therapies combined with irinotecan. The role of mutation status for outcome
of chemotherapy alone has only been sparsely investigated and with negative
results.
Purpose/Objective: We investigated the clinical implications of KRAS
mutations in patients treated with irinotecan monotherapy when detected in
archival tumor tissue and plasma cell free DNA.
Materials and Methods: Patients were included in a prospective nonrandomised phase II and biomarker study (Protocol ID S-20090114).
Inclusion criteria were; histopathologically verified mCRC, measurable disease according to RECIST, indication for secondline irinotecan monotherapy
according to local guidelines, informed consent to therapy and biobank
collection and age ≥18. Patients received irinotecan 350 mg/m2 q3w.
Response was evaluated according to RECIST v 1.1. Plasma was obtained
from a pre-treatment EDTA blood-sample, and KRAS mutations detected in
tumor and plasma using an in-house qPCR.
Results: The median number of cycles was 4 (range 1–15), response rate
(RR) 13%, and disease control rate (DCR) 57%. Median PFS was 4.6 mo
(95% CI 3.7–5.8) and OS 9.5 mo (95% CI 8.4–11.8). Ninety-two patients
had matching tumor and blood samples and concordance between tumor
and plasma KRAS status (pKRAS) was 82% (69/84). Mutation status in
archival tumor tissue did not correlate to efficacy, but none of the patients
with mutations detectable in plasma responded to therapy (RR=0). The RR in
pKRAS wt patients was 19%, (p=0.014). DCR in pKRAS wt patients was 66%,
and 37% in the patients with pKRAS mutations (p=0.01). Tumor mutation
status was associated with OS but not PFS, whereas pKRAS had a strong
influence on both parameters. Median OS was 13.0 mo (95% CI 9.5–15.1) in
pKRAS wt patients, and 7.8 mo (4.6–8.4), in patients with pKRAS mutations,
HR 2.26 (95% CI 1.31–3.90), p<0.0001. PFS was 4.6 mo (95% CI 3.3–6.4)
and 2.7 mo (95% CI 2.1–4.5), respectively, HR 1.69 (95% CI 1.03–2.77),
p=0.01. Cox regression analysis confirmed an independent prognostic value
of pKRAS status, but not KRAS tumor status.
Conclusions: This study indicates that tumor KRAS has minor clinical impact
in patients treated with irinotecan monotherapy compared to plasma KRAS
which seems to hold important predictive and prognostic information. These
data call for reconsideration of the role of KRAS in mCRC and for validation in
a randomised trial.
MC13-0049
Two-stage adaptive cutoff design for building and validating a
prognostic biomarker signature
M. Polley, E. Polley, E. Huang, B. Freidlin, R. Simon. Biometric Research
Branch, National Cancer Institute, Bethesda MD, USA
Background: The scientific community has committed expansive resources
during the last decade to identify useful biomarkers for clinical use.
Purpose/Objective: Cancer biomarkers are frequently evaluated using
archived specimens. Routine collection of high quality specimens is an
expensive and time-consuming process. Therefore, care should be taken to
preserve these precious and scarce resources. Here we propose a novel
statistical design to allow efficient evaluation of a panel of biomarkers while
making economic use of available resources.
Materials and Methods: Motivated by the use of futility monitoring for a
treatment effect in clinical trials, here we propose a Two-Stage Adaptive
Cutoff (TACO) design that affords the possibility to stop performing biomarker
assays if an early evaluation of the model performance indicates that
the hypothesized biomarker effect will not be confirmed. Our study design
includes four components: (a) signature building with a statistically valid test of
the model performance based on data in stage 1; (b) an early futility stopping
if the model performance in stage 1 is unsatisfactory; (c) a completely
locked-down biomarker signature in stage 1 with a properly cross-validated
cutoff to classify patient status; and (d) an independent validation of the
locked-down biomarker signature (including the cutoff) in stage 2.
Results: We give an example based on a publicly available dataset to
illustrate the use of the procedure. Simulation studies are presented to
evaluate the operating characteristics of the design. We demonstrate that
with the proposed design, substantial savings in specimens is possible under
the null hypothesis when the model performance is undesirable. The practical
aspects of the proposed design are discussed.
Conclusions: In this work, we propose a statistical design useful for developing and validating a biomarkers signature which includes a stopping rule for
futility in the event of poor model performance. Novel statistical designs like
this are needed to allow conservation of precious tissue specimens for future
research.
MC13-0060
Analytical validation of the MPACT assay, a targeted next generation
sequencing clinical assay for cancer patient treatment selection
C. Lih 1 , D. Sims 1 , E. Polley 2 , Y. Zhao 2 , M. Mehaffey 1 , T. Forbes 1 ,
R. Harrington 1 , W. Walsh 1 , P. McGregor 1 , R. Simon 2 , B. Conley 3 ,
S. Kummar 4 , J. Doroshow 4 , P.M. Williams 1 . 1 Molecular Characterization
Laboratory, Frederick National Laboratory for Cancer Research, Frederick,
USA; 2 Biometric Research Branch, National Cancer Institute, Shady Grove,
USA; 3 Cancer Diagnosis Program, National Cancer Institute, Shady Grove,
USA; 4 Division of Cancer Treatment and Diagnosis, National Cancer
Institute, Bethesda, USA
Background: Robust and analytically validated assays are essential for
development of targeted cancer therapies. MPACT (Molecular Profiling
based Assignment of Cancer Therapeutics) is a proposed clinical trial that
randomizes patients who failed standard treatment to therapy targeted or not
to their own tumor’s molecular abnormalities.
Purpose/Objective: Using next generation sequencing, we developed a
multi-analyte somatic variant assay to support the treatment selection for
MPACT trial. Here we report the results from analytical validation study.
Materials and Methods: The MPACT assay interrogates a total of 59,150 bp
that represents minimally, 392 variant loci with reported actionable value to
guide treatment decisions. In this analytical validation study, we assessed the
sensitivity, specificity, and reproducibility for 5 classes of sequence variants,
single nucleotide variant (SNV), insertion and deletion (Indel, 3bp or less),
large indel (greater than 3bp), SNV at homopolymeric region (HP, greater
than 2 identical bases in a row), and Indel at HP.
Results: Using DNA samples derived from a hapmap normal cell-line
(CEPH, NA12878) with 27 spiked positive control plasmids and from cultured
cancer cell-lines or FFPE xenografts derived from cells harboring known
variants, we found that the sensitivity is 99.3% in SNVs, 91.1% in SNVs
at HP, 100% in Indels, 66.7% in Indels at HP, and 88.9% at large Indels.
Reproducibility analysis in a subset of DNA samples revealed that the interand intra-operator concordances are 95.1% and 98.3% respectively, with
greater than 0.99 R square values in allele frequency for detected variants.
Sanger sequencing of 22 loci in 5 xenograft samples demonstrated 100%
accuracy with MPACT assay results. By sequencing three hapmap normal
cell-lines (CEPH, Yoruban, Chinese female) multiple times, we showed that
the MPACT assay achieved 100% specificity in reportable range for all
5 classes of variants. In addition, we blindly tested 10 unknown tumor
specimens that were genotyped previously by a CLIA assay in another
lab and found that the MPACT assay reported accurately all 9 previously
identified variants at near identical frequency. Finally, we compared the data
from MPACT assay and exome capture sequencing using Hiseq for 5 pairs of
clinical tumor specimen and matched blood samples. The high concordance
confirmed that the MPACT assay results are validated by an independent
NGS platform.
Conclusions: This validation study demonstrated that the MPACT assay was
well-suited for the intended clinical use.
S12
MC13-0071
Immune response against non-targeted tumor antigens after treatment
with sipuleucel-T and its association with improved clinical outcome
D. Guhathakurta, L.Q. Fan, T. Vu, N.A. Sheikh, J.B. Trager. Research,
Dendreon Corporation, Seattle, USA
Background: The development of immunotherapies targeting cancer provides a unique challenge in biomarker development [1]. Clinical benefits of
immunotherapy are often not observed with the typical measures used to
assess tumor progression (such as the RECIST or WHO criteria). Therefore,
the identification of novel post-treatment biomarkers associated with clinical
benefit is important for cancer immunotherapy development as well as patient
care management. One consequence of an effective immunotherapy may
be epitope spread or antigen spread [2]: tumor cell death during the initial
response to an immunotherapy may lead to the release of tumor-associated
antigens and the priming of self-reactive T and/or B lymphocytes specific to
these antigens [2]. Antigen spread may subsequently promote more efficient
tumor killing and may occur with a higher frequency in clinical responders [2],
therefore providing avenues for the identification of novel, mechanism-based,
biomarkers of clinical outcome.
Purpose/Objective: Sipuleucel-T, an FDA approved immunotherapy for the
treatment of symptomatic or minimally symptomatic, metastatic castrateresistant prostate cancer [3], is designed to elicit immune responses to the
prostate-specific protein, Prostatic Acid Phosphatase (PAP). We have sought
to determine if antigen spread occurs in response to sipuleucel-T.
Materials and Methods: Using high-content protein microarrays, followed by
independent technical validations, we have evaluated antigen spread in patients after sipuleucel-T treatment in IMPACT, a controlled phase 3 clinical
study.
Results: Subjects treated with sipuleucel-T consistently mounted an elevated
IgG responses against a range of cancer antigens, whereas subjects in the
control arm did not. Responses were observed against targets aberrantly
expressed in prostate tumors as well as targets in pathways involved in
prostate cancer progression. IgG responses to specific cancer or prostate
antigens were technically validated using Luminex xMAP, and were also
observed in an independent clinical trial. Importantly, these responses were
associated with improved clinical outcome (overall survival).
Conclusions: This study provides further insight into the mechanism of action
of sipuleucel-T and potential biomarkers to assess clinical outcome after treatment. The methods and results presented here may benefit the development
of biomarkers of clinical outcome for other cancer immunotherapies.
References:
[1] Topalian, SL, et al. Cancer immunotherapy comes of age. J Clin Oncol
2011;29:4828–36.
[2] Ribas A, et al. Determinant spreading and tumor responses after
peptide-based cancer immunotherapy. Trends Immunol 2003;24:58–61.
[3] Kantoff PW, et al. Sipuleucel-T immunotherapy for castration-resistant
prostate cancer. N Engl J Med 2010;363:411–22.
MC13-0075
Rapid assessment of TORC1 suppression as a functional biomarker
predicting responsiveness to RAF and MEK inhibitors in BRAF-mutant
melanoma patients
R.B. Corcoran 1 , S.M. Rothenberg 1 , A. Piris 1 , R.M. Nazarian 1 ,
S. Maheswaran 1 , J. Settleman 2 , J.A. Wargo 1 , K.T. Flaherty 1 , D.A. Haber 1 ,
J.A. Engelman 1 . 1 Cancer Center, Massachusetts General Hospital,
Boston, USA; 2 Discovery Oncology, Genentech, South San Francisco,
USA
Background: Selective RAF and MEK inhibitors have transformed the
treatment of BRAF -mutant melanoma. Still, a substantial percentage of
patients fail to respond to therapy, and most responses are partial and
short-lived. Presently, there are no clinically useful biomarkers to guide the
treatment of BRAF -mutant melanoma.
Purpose/Objective: To identify effective biomarkers to predict which BRAFmutant melanoma patients are more or less likely to benefit from RAF or MEK
inhibitors.
Materials and Methods: BRAF-mutant melanoma cell lines were characterized before and after treatment with RAF or MEK inhibitors in vitro and in
xenografts. Paired biopsies obtained from BRAF-mutant melanoma patients
before and ∼2 wks after initiation of RAF inhibitor therapy were assessed
by IHC for a change in phosphorylation of ribosomal protein S6 (P-S6).
Serial fine-needle aspiration (FNA) biopsies were obtained prospectively from
Best Poster Abstracts – Oral Presentations
patients before and after initiation of therapy, and P-S6 was assessed by
quantitative immunofluorescence microscopy.
Results: Suppression of TORC1 activity in response to RAF or MEK
inhibitors, as measured by decreased P-S6 levels, effectively predicted
sensitivity in BRAF -mutant melanoma cell lines in vitro and in mouse tumor
xenografts. In sensitive melanomas, TORC1 and P-S6 were suppressed in
response to RAF or MEK inhibitors, but in resistant melanomas, TORC1
activity was maintained, in some cases despite robust suppression of MAPK
signaling by these inhibitors. In paired biopsies obtained from patients
with BRAF -mutant melanoma before treatment and after initiation of RAF
inhibitor therapy, P-S6 suppression was associated with significantly improved
PFS [HR=0.19, 95% CI 0.01–0.84, p=0.03]. In serial FNA biopsies obtained
prospectively from patients before and during the first 2 weeks of RAF inhibitor
therapy, a change in P-S6 in patients’ tumor cells could be readily monitored
in real-time by multiplexed, quantitative immunofluorescence microscopy. A
decrease in P-S6 correlated with tumor response, providing a rapid and
minimally-invasive potential means to monitor the efficacy of treatment, before
changes in tumor volume are apparent by traditional radiographic imaging.
Conclusions: These results establish suppression of P-S6 after initiation of
RAF inhibitor therapy as a robust potential functional biomarker to guide the
treatment of BRAF -mutant melanoma, and present a powerful methodology
for monitoring changes in potentially any signaling pathway in response to
targeted therapies in patients.
MC13-0079
Prospective mutational characterization of Japanese patients with
non-small cell lung cancer using surgically resected tumor specimens
by next-generation sequencing
Y. Koh 1 , H. Kenmotsu 2 , M. Serizawa 1 , M. Isaka 3 , K. Mori 4 , T. Takahashi 2 ,
M. Endo 5 , T. Nakajima 6 , Y. Ohde 3 , N. Yamamoto 2 . 1 Drug Discovery and
Development, 2 Thoracic Oncology, 3 Thoracic Surgery, 4 Clinical Trial
Coordination Office, 5 Diagnostic Radiology, 6 Diagnostic Pathology, Shizuoka
Cancer Center, Sunto-gun, Japan
Background: Detection of tumor genetic alterations is critically needed for
lung cancer clinic as well as for the development of molecular targeted
therapeutics.
Purpose/Objective: Here we report the results of a broad spectrum of
genetic alterations identified in Japanese non-small cell lung cancer (NSCLC)
patients by ultra-deep targeted sequencing.
Materials and Methods: Highly multiplexed amplicon sequencing was performed using genomic DNA extracted from snap-frozen tumor specimens.
TruSeq amplicon cancer panel was used for the detection of somatic
mutations in 48 cancer related genes followed by ultra-deep sequencing
(Illumina) at an average coverage of approximately 3,400×. ALK, ROS1
and RET translocations and EGFR, MET, PIK3CA, FGFR1 and FGFR2
amplifications were also detected by multiplex RT-PCR and quantitative PCR,
respectively.
Results: The demographics of 279 consecutive patients enrolled in this
prospective study at Shizuoka Cancer Center between July 2011 and March
2013: median age 69 years (range: 38–92); male 66%; never smoker 25.8%;
histology: adenocarcinoma 70.6%, squamous cell carcinoma (SQ) 25.1%,
others 4.3%; tumor stage: I 58.1%, II 22.6%, III 15.4%, IV 3.9%. TP53
mutation was most frequently detected (35.9%) in all patients, particularly in
SQ (59.2%). Mutations in genes such as CTNNB1 (4.0%), SMAD4 (1.5%),
GNAS (1.0%), STK11 (1.0%), HRAS (0.5%) and PTPN11 (0.5%) were also
detected in addition to major mutations in genes such as EGFR (44.8%),
KRAS (18.4%) and PIK3CA (4.5%) in adenocarcinoma. PIK3CA (19.7%),
HRAS (2.8%), APC (1.4%), FGFR2 (1.4%), FGFR3 (1.4%) and SMAD4
(1.4%) mutations were identified in SQ and notably, 40.9% of SQ patients
harbored concurrent gene mutations, suggesting the genetic complexity of
this histological subset. FGFR1 amplification was found in 7.0% of SQ,
suggesting lower frequency in East Asian population than in Caucasian
population. As for PIK3CA mutation, the majority (92.8% of all PIK3CA
mutant SQ cases) was detected in exon 9 (residues E542 and E545) in
SQ but in contrast, mutations in exon 1 and 20 (residues G106 and H1047,
respectively) were more frequently detected (33.3% combined of all PIK3CA
mutant adenocarcinoma cases) in adenocarcinoma.
Conclusions: We managed to detect a wide range of genetic alterations and
to identify additional actionable mutations along with popular driver mutations
in NSCLC by next-generation sequencing technology. These data should
be incorporated into lung cancer clinic to implement personalized cancer
medicine.
S13
Poster Presentations
MC13-0001
Validation of a new tissue acqusition tool for molecular biology in
oncology
J. Janssens 1 , M. Verjans 2 , A. Cornelis 3 , M. Deleu 4 , J.P. Bogers 5 .
1 Oncology, University Hasselt, Hasselt, Belgium; 2 Gynecology, Regional
Hospital Tienen, Tienen, Belgium; 3 Pathology, Regional Hospital Tienen,
Tienen, Belgium; 4 Oncology, Regional Hospital Tienen, Tienen, Belgium;
5 Pathology, University Antwerp, Antwerp, Belgium
Background: Histological and molecular examinations are a prerequisite to
understand cancer, determine optimal individualized care, and identify targets
for potential novel therapies. Despite this key role of tissue based research,
the act of biopsy still remains troublesome.
Purpose/Objective: New direct and frontal biopsy technologies have
emerged with the aim to alleviate the bottleneck of inappropriate tissue
acquisitions from minimal invasive interventions. This study was undertaken
to validate the Spirotome type of instruments to harvest high quality tumor
tissue in sufficient quantity.
Materials and Methods: The new Spirotome instruments for minimal invasive
biopsy procedures were evaluated in a population of 750 patients at risk
or suffering from various types of cancer in the period 2004 to 2012. All
patients were given informed consent according to institutional requirements.
The biopsy specimen, harvested under direct imaging in various parts of the
human body, was evaluated to provide enough high quality tissue for omic
research in comparison to diagnostic surgery. Only when the pathological
and molecular data were considered complete and comparable to surgery or
in line with follow-up and with sufficient patient comfort, the procedure was
defined as successful.
Results: In all 750 patients tissues could be harvested. In less than 2%
the tissue was considered non contributive to a complete diagnosis. Sample
sizes were between 100 and 300 mg. Patient comfort was excellent as
less than 5% of the patients experienced significant pain or hematoma that
needed medication or intervention. Pneumothorax for lung applications was
less than 10%. In only two cases hospitalization was needed or prolonged
(pneumothorax). 53 cases had diagnosis when surgery was not possible. The
cost of the materials was less than 200 Euro per procedure.
Conclusions: New biopsy procedures are increasingly more patient friendly
with appropriate comfort and safety. The new macrobiopsies are less
expensive, making molecular biology at reach for every oncological patient,
company and health care provider. Direct and frontal macrobiopsies open
new avenues for future bio-banking, pharmacogenomics, omic research and
personalized medicine. It is anticipated that drug discovery and clinical
implementation of targeted therapies will be highly facilitated and that clinical
research time for multicenter trials will be significantly shortened
MC13-0004
Prognostic significance of MGMT and IDH1 in patients with secondary
glioblastoma
L. Bie, X. Zhang, M. Li. Neurosurgery, The First Hospital of Jilin University,
Changchun, China
Background: Several studies have observed a change in MGMT silencing
and IDH1 mutation in secondary glioblastomas (sGBMs). However, reports
about the prognostic value of promoter methylation of the MGMT gene and
IDH1 mutations in secondary glioblastomas (sGBMs) are few in number.
Purpose/Objective: In our research, pts with sGBM and IDH1 mutation had
a significantly improved outcome. Moreover, MGMT methylation is also a
powerful prognostic marker in sGBM pts.
Materials and Methods: The study involved primary and secondary tumor
tissue samples from 89 GBMs pts (P/S: 42/47) diagnosed and treated within
the First Hospital of Jilin University from Jan 2006 to Nov 2011. After surgical
treatment, all GBM pts were subjected to radiotherapy with concomitant
administration of TMZ. Pts with GBM were screened for promoter status of
MGMT gene, by the methylation-specific polymerase chain reaction (MSP),
and, for IDH1 mutations by direct sequencing.
Results: A total of 42 of 89 pts (47.2%) had primary GBMs (pGBMs)
(Group 1), while 47 pts (52.8%) had secondary GBMs (Group 2). In Group
2, 23 pts (21/47, 44.7%) developed a sGBM through progression from a
low grade glioma (LGG) WHO grade II and a secondary anaplastic gliomas
(sAG) (Group 2a), whereas 26 pts (26/47, 55.3%) showed a direct malignant
transformation from a LGG to a sGBM (Group 2b). MGMT methylation was
observed in 38 (42.7%) GBMs, with a higher frequency in sGBMs than
pGBMs (24/14, 51.1 vs. 33.3%; p=0.008). MGMT methylation status was
associated with increased median survival time in pGBMs and sGBMs pts.
IDH1 mutations are present in the majority of sGBMs but rare in pGBMs
(31/5, 66.0 vs. 11.9%; p<0.001). Group 2a had a higher frequency with IDH1
mutation than group 2b (18/12, 78.3 vs. 46.2%; p<0.01). The median survival
time after malignant progression of all sGBMs pts with an IDH1 mutation was
longer than in pts with wild-type IDH1 (3.2 vs. 1.1 ys; p<0.01). IDH1 mutation
had an improved outcome in group2a, which is compared with group 2b (3.9
ys vs. 2.1 ys; p<0.05).
Conclusions: In our population, pts with sGBM and IDH1 mutation had
a significantly improved outcome. In addition, MGMT methylation is also a
powerful prognostic marker in sGBM pts.
MC13-0005
An integrated molecular genetic profiling of low-grade gliomas
identifies clinically relevant mRNA genes
L. Bie, Y. Li. Neurosurgery, The First Hospital of Jilin University, Changchun,
China
Background: Most low-grade gliomas patients the prognosis is good, but the
small number of patients can progress to high-grade gliomas. Less biomarker
for prognosis of the patient clinical urgent need for new effective prognostic
markers.
Purpose/Objective: WHO Grade II glioma (G2G) is a pre-malignant brain
tumor and continuous growth, migration along the white matter tracts and
unavoidable malignant transformation. Thus we have identified an mRNA
expression signature that can predict G2G patient survival.
Materials and Methods: To identify an mRNA expression signature that can
predict G2G patient survival, we analyzed the mRNA expression data of
GBM patients (n=91) derived from The Cancer Genome Atlas (TCGA) and
GEO microarray datasets by WebArrayDB software. We divided the patients
randomly into training (n=46) sets and testing sets (n=45) with equal number
in each group.
Results: We identified 8 significant mRNAs using Cox regression analysis
on the training set and formulated a risk score based on the expression
signature of these mRNAs that segregated the patients into high and low
risk groups with significantly different survival times (hazard ratio [HR] = 3.2;
95% CI: 2.1–6.7; p<0.001). This signature was independently validated in
the testing set (HR=1.2; 95% CI: 0.5–2.7; p<0.01). G2G patients with high
risk scores had overall poor survival compared to the patients with low risk
scores. Cox multivariate analysis with patient age as a covariate on the entire
patient set identified risk score based on the 8 mRNA expression signature to
be an independent predictor of patient survival (HR=1.3; 95% CI: 0.47–3.12;
p=0.02).
Conclusions: Thus we have identified an mRNA expression signature that
can predict G2G patient survival.These findings may have implications in
the understanding of gliomagenesis, development of targeted therapy and
selection of high risk G2G patients for adjuvant therapy.
MC13-0006
Cell-free circulating DNA can be used as a noninvasive approach for
detection of genetic/epigenetic alterations in brain tumors
L. Bie, Y. Li, X. Hong. Neurosurgery, The First Hospital of Jilin University,
Changchun, China
Background: Intracranial meningioma tumors, the majority of patients with
good prognosis, but some patients relapse, progression to malignancy.The
blood markers tumors to assess patient prognosis in meningiomas has not
been carried out.
S14
Poster Presentations
Purpose/Objective: We evaluated whether cell-free circulating DNA can be
used as a noninvasive approach for detection of genetic/epigenetic alterations
in brain tumors during the course of the disease.
Materials and Methods: Paired tumor-serum samples from 37 primary patients with glioblastoma and 21 primary benign meningiomas were analyzed.
19 non-cancer individuals serum were used as control. The median interval
between surgery and serum sampling was 1.5 month. The methylation status
of O6 -methyl guanine methyltransferase (MGMT) was studied by methylationspecific PCR. The mRNA expression of CCNB1 was studied by qRT-PCR.
Promoter hypermethylation in MGMT was detected at high frequencies in
paraffin-embedded (FFPE) tumor sections and serum in glioblastoma.
Results: Statistically significant tumor-serum concordance was found for
MGMT methylation in patients (r =0.87, p<0.01). None of the control serum
showed aberrant methylation. Hypermethylation in serum DNA was all
accompanied with methylation in the corresponding tumor tissues with 100%
specificity. Highly elevated MGMT methylation levels in serum were the
sole independent factors predicting inferior overall survival in this cohort.
Over-expression of CCNB1 was also detected in FFPE and serum in
meningioma patients. None of the control serum showed over-express.
CCNB1 expression was significantly higher in patients with tumor recurrence
(p<0.01).
Conclusions: CCNB1 serum mRNA was a potential prognostic factor
predicting meningioma recurrence.
glioblastoma could provide important information for the progression and host
responses of glioblastoma.
Purpose/Objective: We studied a panel of 120 cytokines and growth factors
and investigated their prognostic values for glioblastoma.
Materials and Methods: A protein antibody array was first performed to
study the prognostic significance of 120 cytokines in the plasma samples
of 45 glioblastoma patients prior to craniotomy or biopsy procedure. An
independent set of plasma samples from 100 patients with glioblastoma with
complete clinicopathologic data and follow-ups were used for validation.
Results: Ten cytokines were identified by Significance Analysis of Microarray
(SAM), in which four were associated with poor prognosis (IL-15, MCP-1,
GDNF, IL-1R4/ST2), and six were associated with good prognosis (IGFBP-6,
MIP-1δ, ICAM-3, IL-7, MIP-3β, and sgp130) of the glioblastoma patients.
Moreover, a 4-cytokine panel composed of IL-7, IL1R4/ST2, sgp130 and
MCP-1 showed significant correlation with overall survival of the glioblastoma
patients (HR: 2.068; 95% CI: 1.357–3.153; p=0.001). In the validation set, the
cytokine panel was significantly correlated with overall survival (HR 1.753;
95% CI 1.502–2.255, p<0.001).
Conclusions: This panel of four cytokines: IL-7, IL1R4/ST2, sgp130, and
MCP-1 can serve as a prognostic marker for patients with glioblastoma.
MC13-0007
Metabolomic profile of multiple myeloma patients
P.C. Boutros 1 , E. Lalonde 1 , A.S. Ishkanian 2 , J. Sykes 2 , N. Moon 1 ,
G. Zafarana 2 , J. Thoms 2 , C.L. Have 2 , C. Malloff 3 , V.R. Ramnarine 2 ,
A. Meng 2 , D.F.Y. Mak 1 , J. Squire 4 , I. Jurisica 2 , M. Pintilie 2 , A. Dal Pra 2 ,
T. van der Kwast 2 , W.L. Lam 3 , M. Milosevic 2 , R.G. Bristow 2 . 2 Ontario
Cancer Institute, University Health Network, Toronto, Canada; 3 Integrative
Oncology, British Columbia Cancer Research Centre, Vancouver, Canada;
4 Pathology and Oncology, Queen’s University, Kingston, Canada
L. Puchades-Carrasco 1 , R. Lecumberri 2 , J. Martínez-López 3 ,
J.J. Lahuerta 3 , M.V. Mateos 4 , F. Prósper 5 , J.F. San Miguel 4 ,
A. Pineda-Lucena 1 . 1 Structural Biochemistry Laboratory, Centro de
Investigación Príncipe Felipe, Valencia, Spain; 2 Hematology Service, Clínica
Universidad de Navarra, Pamplona, Spain; 3 Hematology Service, Hospital
12 de Octubre, Madrid, Spain; 4 Hematology Service, Hospital Universitario
de Salamanca, Salamanca, Spain; 5 Hematology and Cell Therapy Area,
Clínica Universidad de Navarra, Pamplona, Spain
Background: Multiple myeloma (MM) remains an incurable disease. New
approaches to develop better tools for improving patient prognostication as
well as monitoring treatment efficacy are very much needed.
Purpose/Objective: In this study, the capability of metabolomics by 1 H-NMR
to characterize the metabolic profile of MM patients was evaluated.
Materials and Methods: Serum metabolic profiles from MM patients at
diagnosis (n=27) and after achieving complete remission of the disease
(n=23) were acquired using 1 H-NMR. A matched control set of 31 serum
samples from healthy individuals was also included.
Results: Multivariable statistical modeling of the data showed that MM
patients exhibit a specific serum metabolic profile (R2 =0.686; Q2 =0.462)
characterized by lower concentrations of different lipids and some amino
acids. A similar analysis performed in MM patients after achieving complete
remission indicated that some of these changes are partially reverted upon
responding to treatment (R2 =0.710; Q2 =0.358), thus reflecting that the
metabolic profile of a MM patient gets closer to that of a healthy individual
after the disappearance of major disease manifestations. Overall, the analysis
of the variations in the metabolites found to play an important role in the
discrimination between the groups included in this study revealed three
different behaviours that could be related to disease progression, treatment
response and achievement of complete remission.
Conclusions: Our results highlight the potential of metabolomics by 1 H-NMR
for identifying MM biomarkers that could be used to objectively discriminate
individuals with and without MM, and monitor response to treatment. Furthermore, the results associated with the response to treatment are particularly
relevant because, if validated in prospective studies, they could represent a
starting point in the individualization of the therapeutic regimes for different
patient groups.
MC13-0008
A panel of four cytokines predict the prognosis of patients with
glioblastoma
Y. Lin 1 , Y. Wang 1 , T.A.O. Jiang 2 , Z. Guozhen 2 , J.I.N.G. Zhang 2 .
1st Hospital of China Medical University, Shenyang, China;
2 Neurosurgery, Beijing Neurosurgical Institute, Beijing, China
1 Neurosurgery,
Background: A comprehensive evaluation of cytokine levels in patients with
MC13-0009
A prognostic CNA signature sub-stratifies intermediate-risk prostate
cancer
Background: Men with prostate cancer (CaP) are stratified into low, intermediate and high risk groups based on clinical factors such as pre-treatment
prostate-specific antigen (PSA) levels, tumour grade and tumour stage.
Intermediate-risk patients vary widely in clinical outcome, with a 20–40%
recurrence rate, as measured by a rise in post-treatment PSA concentration
(biochemical recurrence).
Purpose/Objective: In practice, there is no way to accurately identify the
intermediate-risk patients that derive benefit from therapy. To address this
issue, we developed prognostic signatures to further stratify these patients
into sub-groups with distinct risk-profiles by applying machine learning to
gene copy number profiles from intermediate risk patients.
Materials and Methods: rray comparative genomic hybridization (aCGH)
was applied to frozen biopsies from 126 intermediate-risk CaP patients
prior to image-guided radiotherapy. Copy number aberrations (CNAs) were
extracted and used to develop signatures which were then evaluated in an
independent cohort of 129 low to intermediate risk patients treated by radical
prostatectomy. Unsupervised and supervised machine-learning techniques
were applied to identify disease subtypes and to develop a prognostic
signature.
Results: With unsupervised hierarchical clustering, we identified four distinct
patient clusters within the radiotherapy cohort. Patients from the surgery
cohort were matched to these clusters and the resulting clusters have
statistically different biochemical recurrence rates. We also used a supervised
learning approach with RandomForests to develop a CNA-signature. This
signature is effective at identifying patients at risk of biochemical recurrence,
while accounting for clinical covariates (HR=8.77, p=1.08×10−5 ). Finally,
we found that including a measure of genomic instability in both models
maintained the prognostic effects, suggesting that these measures contain
independent prognostic information.
Conclusions: We have recapitulated known genomic heterogeneity and
shown that there are prognostic genomic subtypes within the intermediate-risk
group. We also developed a clinically-relevant CNA-signature which stratifies
intermediate-risk patients into two refined risk groups, independent of clinical
features and genomic instability. The higher risk sub-group could be triaged
to more aggressive systemic therapies given their rapid failure after local
therapy alone. The lower risk sub-group may be over-treated, suggesting
novel hypotheses for future clinical trials. In conclusion, we have identified a
genomic biomarker which is promising in improving clinical management of
intermediate-risk CaP patients.
Poster Presentations
MC13-0010
HLA and cytokinic markers in cervical cancer
S. Zidi 1 , A.M.E.L. Mezlini 2 , H. Verdi 3 , Y. Yilmaz-Yalcin 3 , A. Yazici 4 , F. Atac 3 ,
B.Y. Loueslati 1 . 1 Biology, Faculty of Sciences of Tunis, ElManar, Tunisia;
2 Oncology, Salah Azeiz Oncology Institute, Tunis, Tunisia; 3 Medical Biology,
Faculty of Medicine, Ankara, Turkey; 4 Biostatistics, Faculty of Medicine,
Ankara, Turkey
Background: It is increasingly evident that the variability in host immunogenetic background, especially in human major histocompatibility genes
and pro-inflammatory cytokines, may modulate the susceptibility to Human
Papilloma Virus infection and cervical cancer.
Purpose/Objective: We have conducted a case-control study in Tunisian
women to examine the effect of genetic variation in HLA class II DRB1 and
DQB1, Interleukin (IL) 10, Interferon (INF)-γ, IL1-α, IL-1β and tumour necrosis
factor (TNF)-α gene polymorphisms in cervical cancer susceptibility.
Materials and Methods: Blood samples were collected from histopathologically confirmed patients of cervical cancer and unrelated healthy female
controls of similar ethnicity. HLA genotyping was performed by PCR sequence
specific primers technique. The IL 10-1082, and INFγ +874 polymorphisms
were typed by Amplified Refractory Mutation Sequence PCR and the
IL1-α +4845, IL-1β −511 polymorphisms were analyzed by PCR Restriction
Fragment Length Polymorphism.
Results: The data revealed significant positive and negative associations,
suggesting either predisposing or protective effects of these genes in the
disease outcome. DRB1*15, alone or linked to DQB1*06, was associated with
a 2.7 and 3.5 fold increase in risk for cervical cancer, respectively. DRB1*13DQB1*03 showed a similar 3.5 risk effect. In contrast, only one haplotype
– DRB1*13-DQB1*06 – provides evidence for a weak protection (about 0.3
fold reduction) of cervical cancer. At the polymorphic nucleotide 1082 of
the IL-10 promoter and the IL1-α +4845 polymorphism, no differences were
found between patients and control subjects. Women carrying IFN-γ+874 T/T
genotype were at lesser risk of cervical cancer (about 0.5 fold reduction).
However, IL-1β −511 the C/C genotype was associated with 2.3 increased
risk for cervical cancer.
Conclusions: Our results demonstrate a possible increased risk for cervical
cancer associated with the DRB1*15 allele, DRB1*13-DQB1*03 haplotype
and homozygote genotype IL-1β −511C/C and a possible protective effect
with the DRB1*13-DQB1*06 haplotype and homozygote genotype IFN-γ
+874 T/T.
MC13-0012
Vitamin D downregulates biomarkers in the prostaglandin pathway
E. Sauter, W.Q. Qin, C.S. Smith. Surgery, University of Texas HSC, Tyler,
USA
Background: Epidemiologic evidence suggests that women with higher
circulating levels of vitamin (vit)D have a lower breast cancer risk, and
preclinical studies suggest that vitD mediates growth inhibition through
prostaglandin (PG) inhibition. Celecoxib, in clinical use to treat arthritis,
inhibits PGs through a mechanism different than vitD.
Purpose/Objective: Our objective was to determine if there was synergy
between vitD and celecoxib in the cancer promoting PG pathway reduction in
healthy women.
Materials and Methods: 36 healthy women of normal cancer risk were
randomized to receive daily for one month or one menstrual cycle one of
four treatments: placebo, 400 international units (IU) vitD3, 2000 IU vitD3,
or 2000 IU vitD3 + 400 mg celecoxib. Serum, plasma, nipple aspriate fluid
(NAF), +/− mammary duct (MD) samples were collected. Serum and NAF
were analyzed for PGE2 , serum for vitD3, plasma for celecoxib, and MD RNA
for cyclooxygenase (COX)-2.
Results: vitD3 levels increased in women receiving 2000 IU daily vitD (with or
without celecoxib), but not in the other groups (p<0.01). Celecoxib increased
(p<0.01) after treatment only in participants receiving the agent. PGE2
decreased in the breast after treatment with 2000 IU vitD3, but not in the
other groups (p=0.01), and 2000 IU vitD3 worked better at lowering PGE2
than 2000 IU vitD3 + celecoxib (p=0.018). COX-2 decreased in the breasts of
women taking 2000 IU vitD3, but not in the other groups.
Conclusions: vitD3 alters the PG pathway in the breasts of healthy women
in a dose dependent fasion. Adding celecoxib does not provide synergy.
S15
MC13-0014
Cost-effectiveness of FDG-PET/CT for cytologically indeterminate
thyroid nodules
D. Vriens 1 , E.M.M. Adang 2 , R.T. Netea-Maier 3 , J.W.A. Smit 3 , J.H.W. de
Wilt 4 , W.J.G. Oyen 1 , L.F. de Geus-Oei 1 . 1 Nuclear Medicine, Radboud
University Nijmegen Medical Center, Nijmegen, The Netherlands; 2 Health
Evidence, Radboud University Nijmegen Medical Center, Nijmegen, The
Netherlands; 3 Medical Endocrinology, Radboud University Nijmegen Medical
Center, Nijmegen, The Netherlands; 4 Oncological Surgery, Radboud
University Nijmegen Medical Center, Nijmegen, The Netherlands
Background: Screening for malignancy in thyroid nodules (TNs) is performed
using fine-needle aspiration cytology (FNAC). In approximately 25% of
patients FNAC is inconclusive, mostly due to follicular neoplasia or cellular
atypia, and diagnostic (hemi)thyroidectomy is proposed. This strategy results
in futile surgery in 75% of these patients as histology reveals a benign TN.
Our recent meta-analysis reported a high negative predictive value of 96%
for FDG-PET/CT in this category of patients. As over a third of patients
do have a negative FDG-PET/CT, we hypothesized that its routine use in
FNAC-indeterminate TNs leads to better and more cost-effective patient
care. In a decisionanalytic approach we set out to calculate the efficacy and
economical value of FDG-PET/CT in order to support implementation.
Purpose/Objective: In a decision analytic approach we set out to calculate
the efficacy and economical value of FDG-PET/CT in order to support
implementation.
Materials and Methods: We developed an 8-state Markov decision model.
Based on literature, reimbursement schedules of diagnosis/treatment combinations and expert panel opinion, we attributed distributions to the transition
probabilities, costs and utility scores. Analysis of the model was performed
by probabilistic sensitivity analysis for hypothetical adult patients with
FNAC-indeterminate TNs over a duration of 5 years. Means and confidence
intervals of discounted costs and QALYs were determined. Efficiency of
FDG-PET/CT was presented by the incremental cost effectiveness ratio
(ICER) in thousand euros per QALY gained (k€/QALY). One-way sensitivity
analysis was performed over a plausible range for all variables.
Results: Modifying current practice with routine use of FDG-PET/CT resulted
in 47.9% fewer surgeries for benign nodules. Compared to surgery in all
patients, the fraction of untreated cancers was 1.3%, similar as reported in literature. Over 5 years, mean discounted cost estimates were €8,934 (95% CI:
€8,902–€8,965) for current practice and €8,102 (95% CI: €8,063–€8,140)
with the routine use of FDG-PET/CT. Current practice and FDG-PET/CT
produced no significantly difference in QALYs (4.56 and 4.60 QALY, respectively). FDG-PET/CT therefore saved €832 per 0.04 QALY gained (ICER:
−25 k€/QALY): i.e. the dominant alternative. Only the utility attributed to
observation after a negative FDG-PET/CT could lead to a negative effect on
QALYs. At the minimum value tested (0.90), a FDG-PET/CT-driven approach
would lead to 0.1 less QALYs over 5 years (ICER: +9 k€/QALY) compared to
conventional work-up (utility of post-surgery surveillance: 0.99).
Conclusions: Markov decision modeling showed the potential costeffectiveness of FDG-PET/CT in TN patients with inconclusive FNAC. A
prospective randomized study is necessary to confirm these observations.
MC13-0015
p14ARF methylation is a common event in the pathogenesis and
progression of mixoid and pleomorphic liposarcoma
J. Sopta 1 , R. Davidovic 2 , R. Kovacevic 1 , N. Lujic 3 , D. Ristic 4 . 1 Faculty of
Medicine, Institute of Pathology, Belgrade, Serbia; 2 Faculty of Medicine,
Institute Vinca, Belgrade, Serbia; 3 Faculty of Medicine, Institute Banjica,
Belgrade, Serbia; 4 Faculty of Medicine, Institute for Cancer, Belgrade, Serbia
Background: Liposarcoma represents the most abundant group of soft tissue
sarcomas. The group can be divided into three different classes: differentiated/undifferentiated (WDLPS/DDLPS), mixoid/round cell (MLPS/RCLPS)
and pleomorphic liposarcoma (PLS). It has become apparent that p53–p14
and Rb–p16 pathways play important roles in the pathogenesis of various
sarcoma types. Molecular studies of the genes involved in these two pathways
showed wide variations between the liposarcoma subtypes or even within the
same subtype.
Purpose/Objective: We sought to examine mutational status of p53 and
methylation status of p16INK4a /p14ARF genes in primary and recurrent
liposarcoma tumors. In order to follow mutational and epigenetic status of the
selected genes eighteen primary and recurrent tumor tissue samples were
selected.
S16
Materials and Methods: In order to follow mutational and epigenetic status
of the selected genes eighteen formalin fixed paraffin embedded (FFPE)
primary and recurrent tumor tissue samples were selected. Eleven samples
had pure mixoid histology, one was mixoid with <5% of round cell component
and the others were PLS.
Results: Immunohistochemical analysis revealed that p53 protein was
overexpressed in 3/12 MLPS (25%) and 6/6 PLS (100%). Mutational analysis
showed that two out of eleven MLPS (2/11, 18.2%) and two out of six PLS
(2/6, 33.3%) contained mutated p53 gene. However, the frequencies of the
p14ARF gene methylation were 83.3% (10/12) and 50% (3/6) in mixoid and
pleomorphic group, respectively. Overall, 15 out of 18 (83.3%) samples had
either p53 mutation or methylated p14ARF .
Conclusions: The results from the current study suggest paramount importance of the p14ARF gene methylation in the pathogenesis and progression of
mixoid and to a lesser extent pleomorphic liposarcoma.
MC13-0017
Upregulation of TRF1 and TRF2 (telomere repeat binding factors)
protein contributes to telomere shortening in renal cell carcinoma
D. Pal 1 , U. Sharma 1 , R. Khajuria 1 , S.K. Singh 2 , N. Kakkar 3 , R. Prasad 1 .
PGIMER, Chandigarh, India; 2 Urology, PGIMER,
Chandigarh, India; 3 Histopathology, PGIMER, Chandigarh, India
1 Biochemistry,
Background: TRF1 and TRF2 are telomere repeat binding proteins that
are exclusively found at the telomeres. Both TRF proteins have a Myb-like
helix-turn-helix domain in their carboxyterminus and a central conserved
domain that includes sequences responsible for the formation of homodimers.
The two proteins do not heterodimerize, and they differ substantially at the N
terminus which is acidic in TRF1 but basic in TRF2. The protection of human
telomeres crucially depends on these factors and it is reasonable to assume
that the requirement for TTAGGG repeats at chromosome ends reflects the
need for TRF1 and TRF2 binding. Telomere dysfunction is believed to be the
significant factor in carcinogenesis.
Purpose/Objective: To elucidate the carcinogenesis mechanism, the expression of TRF1, TRF2 and change in telomere length were investigated in
renal cell carcinoma (RCC).
Materials and Methods: Total 80 cases of RCC treated by surgery under
advanced Urology services of Nehru Hospital, at Postgraduate Institute of
Medical Education and Research, Chandigarh were included in the present
study. For comparison, normal renal cortex samples were taken in each case.
Transcriptional expression of TRF1 and TRF2 were estimated by real time
PCR. Whereas Protein levels were detected by using immunohistochemical
and immunofluorscence method. The mean telomere length was determined
by southern blotting followed by hybridization.
Results: The expression of TRF1 and TRF2 were significantly higher in
the tumor tissue in comparison with normal renal parenchyma. The mean
telomere length in RCC tissue was significantly shorter than that in normal
renal parenchyma. The mean telomere length in all tissue samples were
inversely correlated with the level of TRF1 and TRF2 expression.
Conclusions: Our result suggests that the upregulation of TRF 1 and TRF2
may work to reduce the telomere length in RCC and could contribute to the
carcinogenesis of renal cell carcinoma.
MC13-0018
Circulating miRNA-148a as a predictive biomarker for early relapse of
UICC stage II and III colorectal cancer patients following curative
resection
J.Y. Wang, H.L. Tsai. Cancer Center and Surgery, Kaohsiung Medical
University and Hospital, Kaohsiung, Taiwan
Background: The recurrence of colorectal cancer (CRC) is frequent within
the first year of curative resection surgery and may be unavoidable.
MicroRNA-148a is proven to be an oncomiRNA or a tumor suppressor miRNA
in various cancers.
Purpose/Objective: We recently identified microRNA-148 (miRNA-148) as
a predictor of early recurrence in CRC. In the present study, we further
investigated the function and serum level of miRNA-148 in relation to early
recurrence of CRC.
Materials and Methods: First we further confirmed overexpression of
miRNA-148 in non-early relapse subjects. Gain-of-function in vitro studies
were used to evaluate the effect of miRNA-148 on cell proliferation, migration,
invasion, and cell cycle progression. The colon cancer cell line Caco2 and
Poster Presentations
a stable clone overexpressing miRNA-148 were xenografted to evaluate the
in vivo effect of miRNA-148 in null mice. Finally, circulating miRNA-148 was
investigated as a potential biomarker for identifying early relapse.
Results: The results demonstrate that miRNA-148a overexpression is related
to early relapse of CRC through suppression of cell proliferation, migration,
and accumulation in the G2 phase but also to a better disease-free survival
and overall survival. The serum miRNA-148 increased significantly in early
relapsed patients compared to non-early elapsed patients (P =0.015).
Conclusions: miRNA-148 shows anti-tumorigenesis activity, and preoperative circulating miRNA-148 levels can be used to predict postoperative early
relapse of CRC.
MC13-0019
Tumor microenvironment of metastasis: An imaging based marker of
risk for distant metastasis of breast cancer
J. Jones 1 , X. Xue 2 , H. Lin 3 , M. Oktay 1 , B. Robinson 4 , F. Gertler 5 ,
A. Glass 6 , J. Sparano 7 , J. Condeelis 8 , T. Rohan 2 . 1 Pathology, Albert
Einstein College of Medicine, Bronx, USA; 2 Epidemiology and Population
Health, Albert Einstein College of Medicine, Bronx, USA; 3 Health Evidence
and Policy, Mount Sinai School of Medicine, New York, USA; 4 Pathology and
Laboratory Medicine, Weill Cornell Medical College, New York, USA; 5 Koch
Institute, Massachusetts Institute of Technology, Boston, USA; 6 Health
Research, Kaiser Permanente Northwest, Portland, USA; 7 Oncology,
Montefiore Medical Center, Bronx, USA; 8 Anatomy and Structural Biology,
Albert Einstein College of Medicine, Bronx, USA
Background: Hematogenous metastasis is the principal cause of death in
breast cancer. Intravital imaging in mouse models has identified intravasation
sites called TMEM (Tumor MicroEnvironment of Metastasis). Previously, we
confirmed TMEMs in human breast cancer samples and observed that
increased TMEMs are associated with increased metastatic risk.
Purpose/Objective: The purpose of this study was to assess TMEM as a
marker of metastatic risk in a large cohort study of breast cancer patients, and
to compare TMEM with IHC4, a score that provides prognostic information
comparable to that provided by Oncotype DX® .
Materials and Methods: TMEM is a microanatomic structure in which there
is the direct contact of an endothelial cell, a perivascular macrophage, and
an invasive tumor cell. TMEMs are assessed in whole tissue sections by
a sequential triple immunostain for the 3 cell types: macrophages (CD68),
endothelial cells (CD31), and invasive tumor cells (pan-Mena). IHC4 (ER, PR,
Her2, and Ki67) was assessed using standard methods. Stained slides were
read by pathologists blinded to outcome.
The population for this study was a nested case-control study of 259
case-control pairs diagnosed between 1980 and 2000, chosen from a total
cohort of 3760 invasive ductal carcinomas, and followed through 2010. Cases
were women who ultimately developed distant metastasis; controls, women
who did not.
Odds ratios (OR) (95% CI) for the association of metastasis with TMEM
were estimated overall and for 3 subgroups (ER+/Her2−, Her2+, and triple
negative). The ORs for TMEM were compared with those for IHC4. Where
TMEM was significantly associated with risk we performed a receiver
operating characteristic analysis (ROC) and computed the area under the
curve (AUC).
Results: TMEM was associated with an almost 3 fold increased risk of
metastasis in ER+/Her2− tumors (multivariate OR (95% CI)high vs. low tertile =
2.70 (1.39–5.26), Ptrend = 0.004), whereas IHC4 had a borderline positive
association with risk (OR10 unit increase = 1.06 (1.00–1.13)). The association
for TMEM persisted after adjustment for IHC4. There were no significant
associations with the other two subgroups.
Conclusions: TMEM score is a novel, mechanism-based assay that is
positively associated with risk of distant metastasis in women with ER+/Her2−
breast cancer and provides prognostic information that is complementary
to IHC4 and other clinicopathologic risk factors. Strategies for automating
TMEM scoring, and additional validation studies, including assessment of
clinical utility, are underway.
Poster Presentations
MC13-0020
Targeted next-generation sequencing (NGS) of circulating tumor cells
(CTCs) and matched primary tumors
S.V. Liu 1 , P.W. Dempsey 2 , W. Strauss 2 , Y. Xu 1 , T. Xu 1 , T.J. Triche 3 ,
D.I. Quinn 1 , A. Goldkorn 1 . 1 Internal Medicine/Genitourinary Oncology,
University of Southern California, Los Angeles, USA; 2 Bioengineering R&D,
Cynvenio Biosystems, Westlake Village, USA; 3 CHLA Genomics Core
Facility, University of Southern California, Los Angeles, USA
Background: Personalizing cancer care relies on accurate detection of
actionable genomic aberrations in tumor cells. Conventionally, this strategy
relies on analysis of primary tumor samples, which are often temporally and
biologically distinct from recurrent, metastatic or treatment-resistant disease.
As an alternative, CTCs offer real-time cancer tissue for analysis that may
more accurately represent the current state of a patient’s disease.
Purpose/Objective: In this pilot, we used CTCs as source material for
targeted NGS across a range of malignancies.
Materials and Methods: Under IRB approval, blood samples from patients
with advanced cancer were labeled with EpCAM ferrofluid and placed into the
LiquidBiopsy® platform (Cynvenio Biosystems, Inc.), an immunoaffinity-based
microfluidic device tailored to query genomic events. CTCs were identified
by CK, CD45 and DAPI expression. A matched WBC pellet served as a
control representing germline sequence. Amplicon libraries were generated
using Life Technologies AmpliSeq 2.0 and sequenced with an Ion Torrent
sequencer. When available, matched formalin fixed paraffin embedded
(FFPE) primary tumor tissue from the same patient was analyzed in parallel.
Somatic single nucleotide variants (SNV) present in CTCs or FFPE samples
but not in WBC were identified.
Results: CTCs were detected in 18 of 19 patients with advanced prostate
(8), breast (6), renal cell (2), bladder (1), lung (1) and rectal (1) cancer
(CTC median 54, range 15–421). Germline SNPs were consistently detected
across WBC, CTC and FFPE samples. Significant SNVs (occurring in >1%
of DNA in a sample) were found in 6 of 18 patient CTC samples (range 1–6
SNVs/sample, frequency 1.1–11.9% with 620X–14,422X sequence coverage
depth). Numerous SNVs were identified in all 9 matched primary tumor FFPE
specimens but did not correlate with the SNVs identified in the CTCs.
Conclusions: This pilot demonstrates the feasibility of using CTCs as a
real-time disease relevant substrate for NGS to identify personalized genomic
targets. A high number of CTCs were detectable across malignancies,
and CTC germline variants correlated with matched WBC controls. Cancer
relevant SNVs were detected in a third of patients even using the relatively
narrow primary tumor derived AmpliSeq platform. The FFPE specimens
generated a high number of SNVs but did not correlate with CTC profiles,
likely reflecting biological disparity between early localized tumors and
advanced metastatic disease, as well as genomic artifacts introduced into
primary tumor specimens by FFPE preservation. These data demonstrate
the feasibility and potential biological and technical advantages of CTCs over
traditional FFPE samples for genomic analysis in the pursuit of personalized
cancer medicine.
MC13-0021
Impact of post-protocol anti-epidermal growth factor receptor therapy
on survival in wild-type KRAS/NRAS metastatic colorectal cancer: Data
from the PRIME study
M. Peeters 1 , J.Y. Douillard 2 , S. Siena 3 , T. Price 4 , J. Tabernero 5 , R. Sidhu 6 ,
S. Braun 7 , A. Rong 8 . 1 Department of Oncology, University Hospital Antwerp
(UZA), Antwerp, Belgium; 2 Department of Medical Oncology, Centre René
Gauducheau, Nantes, France; 3 Department of Haematology and Oncology,
Ospedale Niguarda Cà Granda, Milan, Italy; 4 Haematology/Medical
Oncology Unit, Queen Elizabeth Hospital and University of Adelaide,
Woodville, Australia; 5 Department of Medical Oncology, Vall d’Hebron
University Hospital, Barcelona, Spain; 6 Department of Clinical Development,
Amgen Inc., Thousand Oaks, USA; 7 Department of Medical Development –
Oncology, Amgen GmbH, Zug, Switzerland; 8 Department of Biostatistics,
Amgen Inc., Thousand Oaks, USA
Background: Updated intent-to-treat (ITT) overall survival (OS) results with
longer follow-up and higher OS event attainment from the phase III, 1st-line
PRIME study demonstrated improved OS in patients with wild-type (WT)
KRAS ( exon 2) metastatic colorectal cancer (mCRC) receiving panitumumab
(pmab) + FOLFOX4 vs FOLFOX4 alone (23.8 vs 19.4 months, respectively,
hazard ratio [HR] 0.83; p=0.03 [Douillard et al. J Clin Oncol 2013; 31{Suppl;
abstract 3620}). New data from this trial suggest that mCRC patients with
S17
mutations in KRAS or NRAS beyond KRAS exon 2 may not respond to pmab
treatment (Oliner et al, J Clin Oncol 2013;31(Suppl): abstract 3511).
Purpose/Objective: To assess the OS impact of crossover to post-protocol
anti-epidermal growth factor receptor (EGFR) therapy in the control arm
of PRIME for patients with wild-type (WT) KRAS/NRAS exons 2–4 (RAS )
mCRC.
Materials and Methods: In PRIME, patients with no prior chemotherapy
for mCRC were randomised 1:1 to pmab 6.0 mg/kg Q2W + FOLFOX4 or
FOLFOX4. ITT OS analyses and inverse probability-of-censoring weighted
(IPCW) analyses were performed. IPCW censors patients at the time of
subsequent anti-EGFR therapy use and estimates HRs that are valid in the
presence of informative censoring, enabling imputation of OS for crossover
patients using OS data from those who did not crossover. Data from a
post-hoc OS update conducted when ≥80% of patients had an OS event
were analysed for the WT RAS population overall and in the subgroup of
patients with an Eastern Cooperative Oncology Group (ECOG) score of 0/1
(stratification factor).
Results: See table.
OS update (WT RAS )
Pmab + FOLFOX4
FOLFOX4
Number of patients
259
253
ITT analysis of OS; median, months (95% CI)
Overall
25.8 (21.7–29.7)
20.2 (17.6–23.6)
0.77 (0.64–0.94); 0.009
HR (95% CI); p-valuea
ECOG 0/1
25.4 (21.4–28.7)
20.5 (18.1–23.2)
HR (95% CI); p-valuea
0.79 (0.66–0.94); 0.0089
IPCWb–d analysis of impact of post-protocol anti-EGFR therapy, HR (95% CI); p-value
Overall
0.69 (0.50–0.95); 0.024
ECOG 0/1
0.60 (0.43–0.84); 0.031
a
Descriptive p-value; b Rimawi & Hilsenbeck, J Clin Oncol 2012; c Colleoni et al, J Clin
Oncol 2011; d Robins & Finkelstein, Biometrics 2000. CI = confidence interval.
Conclusions: To improve outcomes in mCRC, it is important to continue
to refine the optimum patient population by assessing the OS impact of
new biomarkers. IPCW may also be particularly suited for detecting OS
benefits beyond those detected with an ITT approach that ignores selective
crossover/drop-in bias.
MC13-0022
Resection rates and survival in patients with wild-type KRAS/NRAS
metastatic colorectal cancer and liver metastases: Data from the
PRIME study
M. Peeters 1 , J. Tabernero 2 , J.Y. Douillard 3 , S. Siena 4 , C. Davison 5 ,
S. Braun 6 , R. Sidhu 7 , K. Öhrling 8 . 1 Department of Oncology, University
Hospital Antwerp (UZA), Antwerp, Belgium; 2 Department of Medical
Oncology, Vall d’Hebron University Hospital, Barcelona, Spain; 3 Department
of Medical Oncology, Centre René Gauducheau, Nantes, France;
4 Department of Haematology and Oncology, Ospedale Niguarda Cà
Granda, Milan, Italy; 5 Department of Biostatistics, Amgen Ltd, Cambridge,
United Kingdom; 6 Department of Medical Development – Oncology, Amgen
GmbH, Zug, Switzerland; 7 Department of Clinical Development, Amgen Inc.,
Thousand Oaks, USA; 8 Department of Medical Development – Oncology,
Amgen AB, Solna, Sweden
Background: Hepatic resection has become a standard treatment option for
patients with metastatic colorectal cancer (mCRC) and colorectal cancer liver
metastases (CLM). Data are required on the proportion of mCRC patients
identified using refined molecular staging (e.g. wild-type [WT] KRAS/NRAS
[RAS ] status) and treated with aggressive 1st-line therapy (e.g. panitumumab
[pmab] + FOLFOX4) who become eligible for potentially curative hepatic
resection. Data on the rate of successful conversion from unresectable to
resectable CLM (e.g. by achieving early tumour shrinkage by week 8) could
help guide multidisciplinary treatment decisions for patients with mCRC and
CLM.
Purpose/Objective: To evaluate resection rates and overall survival (OS)
outcomes for all patients with WT RAS mCRC and CLM who were treated in
the PRIME study.
Materials and Methods: In PRIME, patients with no prior chemotherapy for
mCRC and unresectable disease at baseline were randomised 1:1 to pmab
6.0 mg/kg Q2W + FOLFOX4 or FOLFOX4. Using data from an exploratory
analysis conducted when ≥80% of patients had an OS event, the proportion
of patients achieving ≥30% tumour shrinkage/response by week 8 and
S18
Poster Presentations
rates of metastasectomy/complete resection were analysed in CLM patients
with WT RAS (KRAS/NRAS exons 2–4 assessed) mCRC. Median OS and
3-year OS rates for WT RAS CLM patients receiving each treatment were
also evaluated. The data were summarised descriptively and tested for
significance using Cox’s proportional hazards models.
Results: Baseline characteristics were generally similar between treatment
groups. For efficacy results, see table.
WT RAS CLM patients (n=89)
Pmab+FOLFOX4
(n=48)
≥30% tumour shrinkage at week 8, n (%)
Metastasectomy, n (%)
Complete resection, n (%)
Median OS, months
Hazard ratio (95% confidence intervals)
3-year OS rate, %
P-valuec
FOLFOX4
(n=41)
34 (79)*a
18 (51)*b
15 (31)
9 (22)
14 (29)
7 (17)
40.7
33.4
0.71 (0.43–1.16)
55
44
0.015
0.349
0.216
0.174
*Patients assessed at baseline and Wk 8; a N=43; b N=35; c Descriptive p-value.
Conclusions: In this post-hoc analysis from PRIME including 1st-line mCRC
patients with initially unresectable WT RAS CLM, there was a greater
reduction in tumour burden for pmab+FOLFOX4 vs FOLFOX4 at week 8
as well as numerically higher rates of metastasectomy, complete resection
and 3-year OS. Pmab+FOLFOX4 treatment resulted in conversion of almost
one-third of initially unresectable CLM patients, enabling metastasectomy in
31% and complete resection in 29%.
MC13-0023
Revisiting TFF1 and TFF3 as biomarkers in breast cancers: A 246
cases study
S. Delpous 1 , N. Reix 2 , A. Welsh 3 , C. Wendling 1 , F. Alpy 1 , J.M. Lessinger 2 ,
M.P. Chenard 3 , M.C. Rio 1 , C. Tomasetto 1 , C. Mathelin 4 . 1 Functional
Genomics and Cancer, IGBMC, Illkirch, France; 2 Biochemistry, CHU,
Strasbourg, France; 3 Pathology, CHU, Strasbourg, France; 4 Senology, CHU,
Strasbourg, France
Background: A better knowledge of mammary tumorigenesis allows the development of personalized patient care. For example, adjuvant chemotherapy
is not justified for all patients. While it is beneficial for those at high risk of
relapse, it might be detrimental for other patients. This therapeutic decision
is based on several criteria and can be difficult in some cases. Therefore,
it is necessary to develop new tools predicting risk of recurrence in early
stage breast cancer. TFF1 and TFF3 proteins represent potential biomarkers.
Indeed, TFF1 and TFF3 are two related proteins induced by estradiol, and
expressed at high levels in some breast cancers. Studied in isolation, their
value as prognostic markers remains controversial.
Purpose/Objective: Our objective is to evaluate the prognostic potential
value of combined TFF1 and TFF3 dosages.
Materials and Methods: We analyzed by Western Blot (WB) both TFF1
and TFF3 expression in a prospective cohort of 246 human invasive breast
carcinomas. In parallel, TFF1 and TFF3 expression was measured by
ImmunoHistoChemistry (IHC) in 109 of them. An immunoscore for WB and a
histoscore for IHC were established. Associations between TFF1 and TFF3
expressions with various clinico-pathological features were determined using
GraphPad software.
Results: Immunoscores and histoscores were significantly correlated both for
TFF1 and for TFF3. Both methods appear complementary since IHC is highly
sensitive and WB is highly specific. Unexpectedly, there is not a complete
overlap between TFF1 and TFF3 expression in breast cancers. Tumors
double positive for TFF1 and TFF3 were associated with lympho-vascular
invasion and lymph node involvement compared to TFF1 or TFF3 simple
positive tumors.
Conclusions: In contrast with previous published reports, TFF1 and TFF3
can be expressed independently from each other. Of interest, this study
indicates that TFF1 and TFF3 may distinguish subtypes within the luminal
group. Recent functional data showed TFF1 and TFF3 are involved in cell
migration and invasion. In addition, a microarray study showed TFF1 and
TFF3 were in a five-gene signature predicting bone metastasis. Along the
same line, our results show TFF1 and TFF3 expression are associated with
some poor prognostic indicators. Taken together, these data suggest the
TFF1 and TFF3 double positive tumors should be considered for adjuvant
chemotherapy. They definitively show TFF1 and TFF3 expression in breast
cancer merits further investigation on larger cohorts.
MC13-0024
Impact of post-progression anti-vascular endothelial growth
factor-containing therapy on survival in patients with metastatic
colorectal cancer: Data from the PRIME study
M. Peeters 1 , J.Y. Douillard 2 , S. Siena 3 , T. Price 4 , J. Tabernero 5 , R. Sidhu 6 ,
S. Braun 7 , C. Davison 8 . 1 Department of Oncology, University Hospital
Antwerp (UZA), Antwerp, Belgium; 2 Department of Medical Oncology,
Centre René Gauducheau, Nantes, France; 3 Department of Haematology
and Oncology, Ospedale Niguarda Cà Granda, Milan, Italy;
4 Haematology/Medical Oncology Unit, Queen Elizabeth Hospital and
University of Adelaide, Woodville, Australia; 5 Department of Medical
Oncology, Vall d’Hebron University Hospital, Barcelona, Spain; 6 Department
of Clinical Development, Amgen Inc., Thousand Oaks, USA; 7 Department of
Medical Development – Oncology, Amgen GmbH, Zug, Switzerland;
8 Department of Biostatistics, Amgen Ltd, Cambridge, United Kingdom
Background: Refining the identification of eligible patients (pts) for treatment
with agents targeting EGFR and VEGF pathways and the optimum sequencing of biologic agents combined with chemotherapy remain relevant for the
treatment of metastatic colorectal cancer (mCRC). Continuing anti-VEGF
therapy from 1st-line through 2nd-line therapy resulted in median overall
survival (OS) of 23.9 months in unselected mCRC pts (Bennouna et al Lancet
Oncol 2012).
Purpose/Objective: To explore OS outcomes for pts in the PRIME study who
had been identified as having wild-type KRAS/NRAS (WT RAS ) mCRC and
received 2nd-line therapy that did/did not include an anti-VEGF agent.
Materials and Methods: In PRIME, 1183 pts with no prior chemotherapy
for mCRC were randomised to panitumumab (pmab) 6.0 mg/kg Q2W +
FOLFOX4 or FOLFOX4. Using data from an exploratory analysis conducted
when ≥80% of pts had an OS event, median OS from start of 1st-line therapy
was calculated for pts with WT RAS (KRAS/NRAS exons 2–4 assessed)
mCRC who did/did not receive post-progression (PD) anti-VEGF therapy.
Data were summarised descriptively and tested for significance using Cox’s
proportional hazards models.
Results: Overall, 505 pts had WT RAS mCRC and 346 also received
post-PD therapy. Of these, 100 (29%) received post-PD anti-VEGF therapy
and 246 (71%) did not; median OS was longer for those receiving subsequent
anti-VEGF therapy (38.1 vs 23.6 months, respectively; HR 0.63 [95% CI
0.48–0.81]; p<0.0004). Similar results were found irrespective of 1st-line
treatment received, but median OS was longer when anti-VEGF agents were
used after 1st-line pmab+FOLFOX4 treatment (table).
Pmab+FOLFOX4
Post-PD anti-VEGF therapy
Yes
No
FOLFOX4
Yes
No
Pts, n
55
114
45
132
Median OS, months
40.0
26.0
36.2
20.6
Yes vs no anti-VEGF therapy
HR (95% CI)
0.64 (0.44–0.94)
0.62 (0.44–0.89)
Descriptive p-value
0.0211
0.0101
Pmab+FOLFOX4 vs FOLFOX4 – with post-PD anti VEGF
HR (95% CI)
0.64 (0.41–1.00)
Descriptive p-value
0.0494
Pmab+FOLFOX4 vs FOLFOX4 – without post-PD anti VEGF
HR (95% CI)
0.69 (0.53–0.92)
Descriptive p-value
0.0096
Conclusions: Treatment of WT RAS mCRC pts with pmab+FOLFOX4 followed by an anti-VEGF agent produced a median OS of 40 months in these exploratory analyses. We acknowledge bias in our results since, pts were not randomised to 2nd-line treatment and, in accordance with Bennouna et al, deaths
and dropouts prior to 1st-line PD are not considered. However, prospective
confirmation of this treatment strategy may be of value to clinical practice.
MC13-0025
TP53 gene polymorphism and its Pro/Pro variant is potentially
contributing to cancer susceptibility in epithelial ovarian carcinoma
patients from North Indian population
R. Mir, Z. Mariyam, D. Sagar, A. Imtiyaz, R. Prakash, G. Gauri, N. Khurani,
Y. Prasant, J. Jamsheed, F. Shazia, S. Alpana. Cancer Genetics Lab,
Maulana Azad Medical College and Associated Hospitals, New Delhi, India
Background: Ovarian cancer is the leading cause of death from gynecological malignancies. The early stages of this disease are asymptomatic
Poster Presentations
and more than 75% of the cases are diagnosed with regional or distant
metastases. P53 is a tumor suppressor gene and is involved in the etiology
of ovarian cancer. Studies investigating the associations between the p53
codon 72 polymorphism and ovarian cancer risk showed conflicting results.
A polymorphism at codon 72 of the human tumour-suppressor gene, p53,
results in translation to either arginine or proline.
Purpose/Objective: To investigate the association of p53 codon 72 polymorphism with susceptibility to epithelial ovarian cancer in North Indian women
and to correlate them with clinicopathological characteristics of disease.
Materials and Methods: The study was conducted on 100 epithelial ovarian
cancer patients and 100 healthy controls. Genotyping of p53 codon 72
polymorphism was examined by PCR with allele-specific primers.
Results: The proportions of individuals homozygous for the arginine allele,
homozygous for the proline allele, and heterozygous for the two alleles were
33%, 17%, and 50% among women screened for ovarian cancer; 62%,
6%, and 32% among the control group. A significant correlation was found
between the Arg/Pro (p<0.0004) and Pro/Pro (p<0.0006) genotypes with
respect to the Arg/Arg genotype. Pro/Pro genotype emerged as the risk factor
with an OR of 5.3 and a RR of 2.5.
Conclusions: Our study suggests that Pro/Pro genotype of 72 codon
polymorphism could be an independent susceptibility marker in northern
Indian women with ovarian carcinomas.
MC13-0027
Deregulation of cell polarity protein Lgl2 correlates with gastric cancer
progression and loss of E-cadherin
K. Nam 1 , M.A. Kim 2 , G. Choe 1 , W.H. Kim 2 , H.S. Lee 1 . 1 Pathology, Seoul
National University Bundang Hospital, Seongnam-si, Korea; 2 Pathology,
Seoul National University Hospital, Seoul, Korea
Background: Lethal giant larvae 2 (Lgl2) is a tumor suppressor that
regulate epithelial cell polarity and proliferation at the basolateral domain.
The role of Lgl2 on cancer progression has been suggested with relation to
epithelial-mesenchymal transition (EMT) in epithelial cancers.
Purpose/Objective: The present study aimed to evaluate the clinical and
prognostic significance of Lgl2 expression in gastric cancer and its correlation
with EMT marker expression. Additionally, we have evaluated Lgl2 expression
in non-neoplastic lesions including normal, active gastritis and intestinal
metaplasia to whether Lgl2 may be involve in gastric carcinogenesis.
Materials and Methods: To investigate the clinical implication of Lgl2 in
gastric cancer, 409 cases of surgically resected gastric cancers and 154
cases of endoscopically removed neoplastic or preneoplastic lesions were
examined. Immunohistochemistry of Lgl2, E-cadherin, β-catenin, MMP2,
S100A4, Snail-1, vimentin and ZEB-1 was performed. The expression of Lgl2
mRNA was examined using RNA in situ hybridization method.
Results: Loss of membranous Lgl2 staining was correlated with diffuse type,
lymph node metastasis and advanced pTNM stage (p<0.05). Furthermore,
loss of membranous Lgl2 expression in adenocarcinoma was associated with
reduced E-cadherin expression (p<0.001). Among EMT markers, S100A4,
MMP2 and Lgl2 expression was associated with poor survival (p<0.05). In
addition, combined analysis of Lgl2, S100A4 and MMP2 allows more precise
estimation of prognosis in gastric cancer. During gastric carcinogenesis,
membranous expression of Lgl2 was progressively lost in 4% of normal mucosa, 75% of intestinal metaplasia, 58% of gastric dysplasia, 69% of intestinal
type gastric cancer and 96% of diffuse type gastric cancer. The expression
of Lgl2 protein was concordant with mRNA expression status (p<0.001).
Conclusions: Our data suggest that Lgl2 might function as a tumor
suppressor in gastric cancer and its mislocalization could be important in
carcinogenesis and cancer progression.
S19
role in cancer invasion and metastases. It degrades the extracellular matrix, allowing cancer cells to invade the surrounding tissue. The uPA receptor, uPAR,
is a three domain protein anchored to the surface of cells. Soluble cleaved
and intact forms of uPAR are continuously released into circulation. Previous
studies have shown that the forms of soluble uPAR (suPAR) have prognostic
value in a number of different malignancies, but none has investigated the
prognostic value of suPAR in patients with cholangiocarcinoma.
Purpose/Objective: To investigate the prognostic value of suPAR’s different
forms in patients with cholangiocarcinoma recieving chemotherapy.
Materials and Methods: A cohort of consecutive patients with inoperable
cholangiocarcinoma was established retrospectively from two separate institutions using exact similar treatment guidelines. Serum samples from the
patients were collected from a common biobank. The suPAR forms were
measured by the use of three time-resolved fluorescence immunoassays
(TR-FIAs) in serum samples taken before start of chemotherapy. A multivariable Cox regression analysis of overall survival (OS) was done including
the suPAR forms, CA19-9, age, gender, locally advanced/metastatic disease,
performance status and institution.
Results: One hundred and sixty-eight patients treated with chemotherapy
and with a baseline serum sample were identified. Seventy percent had
WHO performance status 0 +1. The median age was 64.5 (range 24.1–78.7).
Patients received a median of six cycles of chemotherapy (range 0.5–20).
The levels of intact+cleaved suPAR forms (suPAR(I–III)+(II–III)) at baseline
(entered as a continuous variable log transformed base 2) was an independent predictor of survival (HR 1.93 (95% CI; 1.41–2.64), p<0.0001) in a
Cox multivariable regression model. In a multivariable model not including
suPAR(I–III)+(II–III), uPAR(I) was an independent predictor of OS (HR=1.25,
95% CI: 1.06–1.47, p=0.007) and similarly for suPAR(I–III) (HR=1.32, 95% CI:
1.01–1.73, p=0.040). The inclusion of CA19-9 (n=114) at baseline, showed
CA19-9 to also be a predictor of OS (HR=1.10 (95% CI: 1.01–1.19) p=0.023)
independent of suPAR(I–III)+(II–III).
Conclusions: Intact + cleaved serum suPAR (suPAR(I–III)+(II–III)) is an
independent prognostic marker for OS in patients with inoperable cholangiocarcinoma. The other uPAR forms were also significant predictors of OS but
were not independent of suPAR(I–III)+(II–III). Our results warrant validation in
an independent cholangiocarcinoma patient cohort.
MC13-0029
Diffusion Weighted Imaging (DWI) as a biomarker for evaluation of
neoadjuvant treatement in localy advanced breast cancer
S. Drisis, M. Ignatiadis, K. Stathopoulos, S.L. Chao, M. Lemort. Radiology,
Institut Jules Bordet, Brussels, Belgium
Background: The use of preoperative chemotherapy is nowadays the
standard treatment not only for locally advanced but also for operable breast
cancer with tumour size ≥2 cm. Since the field of new drug development is
under continuous improvement, surrogate markers that would predict or early
assess the response to treatment became essential.
Purpose/Objective: To examine if diffusion weighed imaging (DWI) could
MC13-0028
Prognostic significance of serum levels of intact and cleaved forms of
urokinase plasminogen activator receptor (suPAR) in patients with
inoperable cholangiocarcinoma
M. Grunnet 1 , I.J. Christensen 2 , U. Lassen 1 , L.H. Jensen 3 , M. Lydolph 4 ,
I.K. Lund 2 , G. Hoyer-Hansen 2 , N. Brünner 5 , M. Sorensen 1 . 1 Oncology,
Rigshospitalet, Copenhagen, Denmark; 2 Finsen Laboratory, Rigshospitalet,
Copenhagen, Denmark; 3 Oncology, Lillebaelt Hospital, Vejle, Denmark;
4 Biochemistry and immunology, SSI, Copenhagen, Denmark; 5 Veterinary
Pathobiology, University of Copenhagen, Copenhagen, Denmark
Background: The urokinase plasminogen activator (uPA) system plays a vital
Figure 1. Subtraction image (A) and diffusion weighted image (DWI) (B) at EX1 for a
responder. At EX2 no enhancement is detected in subtraction image (C) and the ADC
value is increased at DWI (D).
S20
serve as a biomarker for evaluation of neoadjuvant chemotherapy (NAC) in
localy advanced breast cancer.
Materials and Methods: A retrospective study was performed, including 29
patients who received NAC and underwent two MRI examinations, one before
(EX1) and one during NAC (EX2). The apparent diffusion coefficient (ADC)
was measured at both examinations. Postoperative pathological examination
was used as the golden standard for the evaluation of tumour response with a
binary model: responders and non-responders according to the presence of
residual vital tumour. Statistical analysis was performed using Wilcoxon rank
sum test.
Results: From the 29 patients 21 were non-responders (72.5%) and 8
showed complete pathological response (27.5%). There was no significant
difference between responders and non-responders for EX1 (p=0.96) but a
significant difference (p=0.004) was found for EX2 between the two response
groups. After treatment, responders (mean ADC = 0.865) showed higher
values than non-responders (mean ADC = 0.414) indicating higher cellularity
in the non-responders group. Moreover, the relative difference of ADC values
between the two time points was statistically different for the two response
groups showing more important increase of the ADC value for the responder
group.
Conclusions: DWI-MRI could have a potential monitoring role in neoadjuvant
treatment for locally advanced breast cancer. Responders showed higher
ADC values than non-responders at EX2 and more important increase of the
ADC value between EX1 and EX2.
MC13-0030
Regulation of hepatocyte growth factor-mediated cell proliferation and
apoptosis through high-motility group A1 in stomach cancer cells
H. Lee 1 , K.H. Lee 2 . 1 Division of Hematology and Oncology Department of
Internal Medicine, Dongnam Institute of Radiological and Medical Sciences,
Busan, Korea; 2 Division of Hematology and Oncology Department of
Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
Background: High-motility group A (HMGA) genes are frequently reactivated
in many types of human cancers, and over-expression of HMGA proteins
is linked to malignant transformation and progression in human cancers.
However, the molecular mechanisms by which HMGA1 participates in gastric
carcinogenesis needs to be further analyzed.
Purpose/Objective: In this study, the role of HMGA1 in invasion and
metastasis was investigated and the mechanisms of action were elucidated.
Materials and Methods: HMGA1 upregulation by hepatocyte growth factor
(HGF) was further confirmed in NUGC3 and MKN28 gastric cancer cells by
RT-PCR and Western blotting. To determine the role of HMGA1 in HGFmediated cell proliferation, cell invasion and apoptosis, stable HMGA1-shRNA
cells and the control cells were prepared and treated with or without HGF.
Results: HMGA1 knockdown decreased a decrease in HGF-mediated cell
proliferation and invasion, but increased apoptotic cell death. HMGA1-shRNA
cells showed higher level of p53 protein and lower level of Bcl-2 protein
than the control cells. HMGA1 knockdown abolished HGF-mediated HMGA1
binding to the Bcl-2 promoter and thus the activation of Bcl-2 promoter by
HGF. HMGA1 knockdown also inhibited HGF-mediated Akt phosphorylation.
Conclusions: The results suggest that HGF-mediated upregulation of
HMGA1 might be involved in cell growth, cell invasion, and apoptosis in
gastric cancer through the regulation of p53, Bcl-2 and Akt activation and
therefore, HMGA1 might be the potential therapeutic target for gastric cancer
treatment.
MC13-0031
Tumour miR-210 expression is elevated in malignant pleural
mesothelioma patients with shorter survival undergoing extrapleural
pneumonectomy
M.B. Kirschner 1 , Y.Y. Cheng 1 , S.C. Kao 1 , B.C. McCaughan 2 , N. van
Zandwijk 1 , G. Reid 1 . 1 Asbestos Diseases Research Institute, Asbestos
Diseases Research Institute, Sydney, Australia; 2 Cardiothoracic Surgical
Unit, Royal Prince Alfred Hospital, Sydney, Australia
Background: Malignant pleural mesothelioma (MPM) is an aggressive
cancer with a median survival of around one year. A selected group of
patients with a potentially resectable tumour mass may be considered for
extrapleural pneumonectomy (EPP), however the results of this form of
treatment are variable.
Purpose/Objective: In the present study we used microarray profiling to
Poster Presentations
identify microRNAs which might have the potential to serve as a prognostic
biomarker in patients eligible for EPP.
Materials and Methods: The study used 60 formalin-fixed paraffin embedded
(FFPE) tumour tissues from MPM patients who underwent EPP and had
sufficient tumour for RNA extraction, a series which had been previously used
to assess the prognostic value of the NLR. MicroRNA microarray profiling
was performed on the 8 patients with longest (median: 53.7 months) and the
8 patients with shortest (median: 6.4 months) survival. Candidate microRNAs
were independently validated using TaqMan assay-based microRNA-specific
RT-qPCR. Levels of validated candidates were then assessed by RT-qPCR
in 44 additional tumour samples. The median relative expression level of
each candidate was used as cut-off to determine high and low expression for
examination using the Kaplan-Meier method. Individually significant (p<0.05)
variables were entered into a multivariate model together with the established
risk factors age, gender, histological subtype, NLR.
Results: Microarray profiling identified 16 microRNAs with differential expression between long-term and short-term survivors RT-qPCR validation found
levels of miRs-30e, -93, -106b, -210, and -222 to be significantly different
between long-term and short-term survivors. Expression of miR-30e and
miR-210 showed a significant association with survival. MiR-30e: median
OS of 24.2 months for low expression vs 13.3 months for high expression
(p=0.03); miR-210: median OS of 24.2 months for low expression vs 13.7
months for high expression (p=0.008). Multivariate analysis with age, gender,
histological subtype, NLR and microRNA expression included as variables
revealed that miR-210 was the only factor remaining significant (p=0.006;
hazard ratio: 0.41; 95% CI: 0.2–0.85).
Conclusions: This study has identified expression of miR-210 as a potential
new prognostic factor for patients undergoing EPP. Further validation is
needed, but this marker has the potential to assist in better selection of MPM
patients eligible for radical surgery.
MC13-0032
Validation of 1 H-NMR-spectroscopy based metabolomics as a tool to
detect lung cancer via a simple blood sample
E. Louis 1 , L. Mesotten 2 , M. Thomeer 3 , K. Vanhove 4 , K. Vandeurzen 5 ,
K. Darquennes 6 , G. Reekmans 7 , P. Adriaensens 7 . 1 Faculty of Medicine and
Life Sciences, Hasselt University, Diepenbeek, Belgium; 2 Nuclear Medicine,
Ziekenhuis Oost-Limburg, Genk, Belgium; 3 Lung Diseases, Ziekenhuis
Oost-Limburg, Genk, Belgium; 4 Faculty of Medicine and Life Scienes,
Hasselt University, Diepenbeek, Belgium; 5 Lung Diseases, Mariaziekenhuis
Noord-Limburg, Overpelt, Belgium; 6 Lung Diseases, Ziekenhuis Maas en
Kempen, Maaseik, Belgium; 7 Institute of Material Research, Hasselt
University, Diepenbeek, Belgium
Background: Lung cancer is the leading cause of cancer death worldwide.
Until today no effective methods permit the early detection of lung cancer.
Therefore, detection methods with an improved specificity and sensitivity
are urgently needed. Over the past decade, accumulating evidence has
shown that the metabolism of cancer cells differs from that of normal cells.
Metabolites are the end products of cellular metabolism and disturbances
in biochemical pathways which occur during the development of cancer
consequently provoke changes in the metabolic phenotype. Recently, our
research group has built a statistical classifier (i.e. a metabolic phenotype)
using multivariate orthogonal partial least squares-discriminant analysis
(OPLS-DA). After removing the outliers (original dataset: 78 lung cancer
patients and 78 control subjects), this classifier allows to discriminate between
lung cancer patients and control subjects with a sensitivity of 83% (62 out of
75) and a specificity of 96% (71 out of 74).
Purpose/Objective: The present study aims to validate these promising
results in an independent study population of 80 patients with anatomopathologically confirmed lung cancer (before any treatment) and 80 control
subjects.
Materials and Methods: Fasting venous blood samples are collected and
analyzed by 1 H-NMR spectroscopy. Subsequently, the constructed classifier
is used to predict this independent group of lung cancer patients and control
subjects.
Results: By using the constructed classifier, 64 out of 80 (80%) lung cancer
patients and 55 out of 80 (69%) control subjects are correctly classified.
Conclusions: The constructed classifier allows to classify the majority of the
lung cancer patients and control subjects correctly. Once we have collected
sufficient samples to validate this method, we want to investigate at random
whether it allows to detect lung cancer in a population with a low prevalence,
actually whether it can be used as a valid screening tool.
Poster Presentations
MC13-0033
Prognostic value of CD109+ circulating endothelial cells in recurrent
glioblastomas treated with bevacizumab and irinotecan
M. Eoli 1 , A. Calleri 2 , M.G. Bruzzone 3 , E. Anghileri 4 , S. Pellegatta 4 ,
P. Mancuso 5 , A. Di Stefano 6 , F. Bertolini 5 , L. Cuppini 4 , G. Finocchiaro 4 .
1 Neuro-Oncology, Fondazione IRCCS Istituto Neurologico C. Besta, Milan,
Italy; 2 Laboratory of Hematology-Oncology, European Institute of Oncology,
Milan, Italy; 3 Neuro-Radiology, Fondazione IRCCS Istituto Neurologico C.
Besta, Milan, Italy; 4 Neuro-Oncology, Fondazione IRCCS Istituto
Neurologico C. Besta, Milan, Italy; 5 Laboratory of Hematology-Oncology,
European Institute of Oncology, Milan, Italy; 6 Neurology, Ondazione IRCCS
Istituto Neurologico Nazionale C. Mondino, Pavia, Italy
Background: Data suggest that circulating endothelial and progenitor cells
(CECs and CEPs,respectively) may have predictive potential in cancer patients treated with bevacizumab, the antibody recognizing vascular endothelial
growth factor (VEGF).
Purpose/Objective: Here we report on CECs and CEPs investigated in 68
patients affected by recurrent glioblastoma (rGBM) treated with bevacizumab
and irinotecan and two Independent Datasets of rGBM patients respectively
treated with bevacizumab alone (n=32, independent dataset A: IDA) and
classical antiblastic chemotherapy (n=14, independent dataset B: IDB).
Materials and Methods: rGBM patients with KPS >50 were treated until
progression, as defined by MRI with RANO criteria. CECs expressing CD109,
a marker of tumor endothelial cells, as well as other CEC and CEP subtypes,
were investigated by six-color flow cytometry.
Results: A baseline count of CD109+ CEC higher than 41.1/ml (1st quartile)
was associated with increased progression free survival (PFS; 20 versus 9
weeks, P=0.008) and overall survival (OS; 32 versus 23 weeks, P=0.03).
Longer PFS (25 versus 8 weeks, P=0.02) and OS (27 versus 17 weeks,
P=0.03) were also confirmed in IDA with CD109+ CECs higher than
41.1/ml but not in IDB. Patients treated with bevacizumab with or without
irinotecan that were free from MRI progression after two months of treatment
had significant decrease of CD109+ CECs: median PFS was 19 weeks;
median OS 29 weeks. The presence of two non-contiguous lesions (distant
disease) at baseline was an independent predictor of shorter PFS and OS
(P<0.001).
Conclusions: Data encourage further studies on the predictive potential of
CD109+ CECs in GBM patients treated with bevacizumab.
MC13-0034
Prognostic factors of biochemical recurrence after radical
prostatectomy for localized and locally-advanced prostate cancer
V. Chernyaev 1 , V.B. Matveev 1 , M.I. Volkova 1 , Z.N. Nikiforova 2 ,
V.E. Shevchenko 2 . 1 Department of Urology, N.N. Blokhin Cancer Research
Center, Moscow, Russia; 2 Oncoproteomics Laboratory Research Institute of
Cancerogenesis, N.N. Blokhin Cancer Research Center, Moscow, Russia
Background: to reveal prognostic factors of PSA-failure following radical
prostatectomy in patients with localized and locally-advanced prostate cancer.
Purpose/Objective: to reveal prognostic factors of PSA-failure following
radical prostatectomy in patients with localized and locally-advanced prostate
cancer.
Materials and Methods: medical data of 386 consecutive patients with
localized and locally-advanced prostate cancer who underwent radical
prostatectomy from 1997 to 2011 were analyzed. Median age was 61.0
years. Median PSA before surgery – 10.3 ng/ml. Plasma levels of VEGF,
VEGFR2, VEGFR3, TGF-β1, CD105, IL-6 were measured using Enzyme
Linked-Immuno-Sorbent Assay (ELISA) before radical prostatectomy in 77
patients. Postoperatively the tumours were categorized as pT2 in 288
(59.1%), pT3 – in 144 (37.3%), pT4 – in 14 (3.6); pN+ – in 34 (8.8%)
cases. Gleason score <7 was present in 254 (65.8%), ≥7 – in 132 (34.2%)
specimens. Perineural invasion was identified in 188 (48.7%), angiolymphatic
invasion – in 126 (32.6) cases.
Results: Biochemical recurrence occurred in 64 (16.6%) out of 386 patients
at a median follow-up of 30.5 (12–164) months. Independent predictors of biochemical recurrence were PSA (HR 0.161 (95% CI: 0.058–0.449); p=0.001),
Gleason sum in surgical specimens (HR 0.496 (95% CI: 0.268–0.917);
p=0.025), pN (HR 0.415 (95% CI: 0.181–0.955); p=0.039). The patients were
divided into 3 prognostic groups: good (0 factor), intermediate (1 factor), poor
(2 factors) and very poor (3 factors) (AUC – 0.720 (95% CI: 0.656–0.784)).
High preoperative levels VEGF (≥67 pg/ml) (p=0.005), VEGFR2 (≥3149
pg/ml) (p=0.036), VEGFR3 (≥2268 pg/ml) (p=0.001), TGF-β1 (≥14473 pg/ml)
S21
(p=0.052) were identified as unfavorable prognostic factors for survival without
PSA-failure.
Conclusions: Independent prognostic factors of biochemical recurrence after
prostatectomy were PSA, Gleason sum and pN. Joint effect of the factors
allows to predict PSA-relapse with accuracy 0.720. Preoperative serum levels
VEGF, VEGFR2, VEGFR3, TGF-β1 potentially are perspective markers for
PSA-failure after surgical treatment prostate cancer, further trials are needed.
MC13-0035
Generation and (genetic) characterization of pre-clinical glioma models
for “targeted therapies”
B. Tops 1 , A. Navis 1 , A. Van Raaij 1 , K. Verrijp 1 , H. Petersen-Baltussen 2 ,
M. Ter Laan 2 , P. Wesseling 1 , W. Leenders 1 . 1 Pathology, Radboud University
Nijmegen Medical Center, Nijmegen, The Netherlands; 2 Neuro-surgery,
Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Background: Currently, few effective therapeutic options are available for
patients with gliomas, i.e. the most frequent primary tumors of the brain. Due
to the diffuse growth pattern of the tumor cells into the normal brain tissue,
gliomas are impossible to remove surgically. Treatment with radiotherapy
and/or chemotherapy is also never curative. The average survival of patients
with a glioblastoma is little more than 1 year.
In recent years an increasing number of so-called “personalized cancer
treatments” have been made available for several tumor types, “personalized”
meaning that the treatment is tailored to the molecular changes in the patient’s
tumor. Examples of successful treatments are the tyrosine kinase inhibitors
crizotinib, targeting ALK in non-small cell lung carcinoma, and vemurafenib,
targeting a mutated form of BRAF in melanoma.
Purpose/Objective: We aim to identify novel and rational therapeutic strategies for individual glioma patients. The approach in this project is twofold; (1)
genetic profiling of gliomas to identify possible therapeutic targets and (2) the
generation of pre-clinical models (cell culture and intra-cerebral xenografts)
from the same gliomas, which can then be used to validate therapies,
rationally designed based on the outcome of 1). Especially intra-cerebral
mouse models are invaluable, since the diffuse infiltrative growth of glioma
cells into the normal brain parenchyma, often with intact blood brain barrier,
are difficult to mimic using in vitro systems. These characteristics of glioma
biogenesis are important as these may hamper therapeutic efficacy.
Materials and Methods: To generate pre-clinical models, freshly resected
tumor tissue is processed for in vitro cell culture and the remaining cell
suspension is aliquoted and stored for the generation of intra-cerebral
xenograft models at a later time point. Parallel to the creation of pre-clinical
models, the tumor tissue is genetically profiled by massive parallel sequencing
(IonPGM) using the comprehensive cancer panel from Life Technologies
(containing 409 cancer-related genes).
Results: We are currently in the process of generating and characterising the
first glioma models.
Conclusions: Here we will present the first (genetic) data regarding the
tumors and models we created so far, and discuss potential therapeutic
targets.
MC13-0036
Dynamics of IGF-1R expression during endocrine breast cancer
treatment
S. Heskamp 1 , O.C. Boerman 1 , J.D.M. Molkenboer-Kuenen 1 , W.J.G. Oyen 1 ,
W.T.A. van der Graaf 2 , H.W.M. van Laarhoven 3 . 1 Department of Nuclear
Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The
Netherlands; 2 Department of Medical Oncology, Radboud University
Nijmegen Medical Centre, Nijmegen, The Netherlands; 3 Department of
Medical Oncology, Amsterdam Medical Center, Amsterdam, The
Netherlands
Background: The insulin-like growth factor 1 receptor (IGF-1R) is a potential
new target for breast cancer treatment. IGF-1R may be involved in the development of resistance against conventional systemic anti-cancer treatment.
So far, the effect of neoadjuvant therapy on IGF-1R expression in breast
cancer patients is unknown.
Purpose/Objective: The aim of our study was to assess changes in IGF-1R
expression in breast cancer after neoadjuvant treatment and to study whether
these changes were associated with survival.
Materials and Methods: Retrospectively, paraffin embedded tumor material
was collected from pretreatment biopsies and surgical resections of 64 breast
S22
cancer patients who were treated between 1989 and 2010 with neoadjuvant
chemotherapy (CMF, anthracycline-based or taxane-based schedule) or
endocrine therapy. ER, PR, HER2, and IGF-1R expression were determined
immunohistochemically. IGF-1R expression was scored by two independent
readers as negative (0), incomplete weak (1+), complete weak to moderate
(2+), and strong (3+) membranous staining. IGF-1R expression before and
after chemotherapy was compared. The correlation between changes in
IGF-1R expression and survival was analyzed by Kaplan-Meier (log-rank
test).
Results: At time of diagnosis, 12 (19%), 18 (28%), 27 (42%), and 5 (11%)
tumors were scored 0, 1+, 2+, and 3+ for IGF-1R expression, respectively.
High IGF-1R expression (2+ or 3+) at diagnosis correlated significantly
with ER positivity, low tumor stage (stage I/II) and longer overall survival
(p<0.05). After neoadjuvant treatment, IGF-1R expression remained the
same in 42 (66%) patients, was upregulated in 11 (17%) patients and
downregulated in 11 (17%) patients. Upregulation in IGF-1R expression was
significantly associated with high tumor stage (stage III/IV) at diagnosis. Most
importantly, changes in IGF-1R expression were significantly associated with
overall survival (p=0.007, Fig. 1). Mean overall survival time for upregulation,
no change, and downregulation in IGF-1R expression was 2.7±0.4 years,
6.9±0.9 years and 14.7±2.0 years, respectively.
Poster Presentations
generated by a typical gradient-echo sequence. Each time-intensity curves
were assigned to a sixteenth division of the phantom image, thus repeating
this allocation for each time points, we obtained the dynamic series images
stack (Fig. 1). Afterwards, variable experimental conditions that could affect
the performance of the processing software are incorporated.
Figure 1
Figure 1. Kaplan-Meier survival curve estimates of overall survival for patients with
a tumor showing no change, a decrease or an increase in IGF-1R expression after
neoadjuvant breast cancer treatment.
Conclusions: Neoadjuvant treatment can induce changes in IGF-1R expression of breast tumors. Upregulation of IGF-1R expression was associated
with a short overall survival, while a downregulation was associated with
a long overall survival. Patients whose tumors showed increased IGF-1R
expression may potentially benefit from IGF-1R targeted therapy.
MC13-0037
A synthetic phantom for quality assessment of DCE-MRI quantification
S.L. Chao. MRI, Institut Jules Bordet, Brussels, Belgium
Background: In the recent last years, the development of novel antiangiogenic and antivascular cancer therapies has led to important considerations regarding the potentiality for DCE-MRI measurement to be used as an
imaging biomarker of drug efficacy in clinical trials of angiogenesis inhibitors.
Purpose/Objective: Quantitative results are not comparable across sites for
lack of standardization in data acquisition protocols and analysis tools. The
purpose of this work is to synthetize a DCE-MRI test object from known values
of kinetic parameters so that it could be analyzed by multiple software tools to
compare their performance, and may provide prerequisites for standardization
procedure and sites/systems certification in multi-center trials.
Materials and Methods: We reused the simulated data obtained by Buckley
(MRM Vol. 47 March 2002) with 1 s resolution time, consisting in a vascular
input function and 13 tissues response curves. These data were generated by
MMID4 (http://nsr.bioeng.washington.edu) using different combination of parameters Ktrans , νe and vp . We extended this parameter space by 2 additional
curves. The concentration data are first converted to MR signal intensities as
The final phantom can include images for T1 mapping and provides customizable extend towards the image noise, the tissue native T1 , the overall onset
time, the time delay between arterial input and tissue vasculature, and the
measurement protocol (sampling time, repetition time, echo time, flip angle).
The phantom was tested by using in-house analysis software regarding the
robustness of its algorithms in fitting the commonly accepted general pharmacokinetic model. Parameter estimates obtained from 2 usual optimization
approaches, in time and frequency domains, were compared with the value
used in simulations.
Results: Regarding the robustness, tests on noisy data showed no error
during the software execution.
Ktrans was systematically overestimated, this was concomitant with an
under-estimation of vp : the % deviations from simulation values were much
more prominent in time domain (2–76, mean 26%) than in frequency domain
(0–13, mean 3%).
Estimations for νe were close to the simulation values along the parameters
space.
Conclusions: The single test performed here has demonstrated that the
optimization approach affects the comparison of results, yet this indication is
not always referred in pubished data. For developers, the phantom provide
ways to define acceptance criteria for software. Irrespective of the actual
QA/QC requirements for imaging, running on common test data should be
considered for any multi-centric study which requires a quantification process.
MC13-0038
Detection of circulating tumor cells-related biomarkers for predicting
early relapse of colorectal cancer by weighted enzymatic chip array
method
S. Lin 1 , H. Liu 2 . 1 Division of Medical Research, Fooyin University Hospital,
Ping Tung County, Taiwan; 2 Division of Laboratory Medicine, Fooyin
University Hospital, Ping Tung County, Taiwan
Background: Colorectal cancer (CRC) is a significant public health problem.
In Taiwan, it is estimated that over 10,000 new cases of CRC were
diagnosed in 2006, and over 4,100 patients died of CRC that year. It
is important to note that as many as 25–40% of patients who undergo
curative resection subsequently develop metastatic disease, suggesting that
undetected micrometastases exist, and may play a key role in relapse.
Purpose/Objective: The aim of this study was to detect the circulating tumor
cells (CTCs)related multiple biomarkers for predicting early relapse of CRC
patients by a weighted enzymatic chip array (WEnCA) method.
Materials and Methods: We selected 15 CTC associated candidate genes
including five genes demonstrated to correlated with cancer prognosis.
The expression level of 15 candidate genes of all 105 postoperative CRC
patients were detected by WEnCA platform and the correlation between the
experimental data and patients’ clinical pathological features was statistically
analysis using spss software.
Poster Presentations
Results: Postoperative relapse was significantly correlated with overexpression of four genes including EVI2B (P=0.001, OR=4.622), ATP2A2 (P=0.006,
OR=4.688), S100B (P=0.001, OR=11.521), TM4SF3 (P=0.001, OR=6.756),
and OLFM4 (P=0.008, OR=3.545). Sensitivity, specificity, and accuracy of
WENCA operation platform were 94.7%, 93.5%, and 97%, respectively.
Conclusions: Detection of CTC-related multiple biomarkers by WEnCA
operation platform can significantly improve the early prediction rate of
postoperative CRC relapse.
MC13-0039
Id1/IGF2/IGF1R/PI3K/AKT signaling cascade as functional markers and
therapeutic targets in esophageal cancer
B. Li 1 , G. Tsao 1 , K. Chan 2 , A. Cheung 1 . 1 Department of Anatomy,
2 Department of Pathology, The University of Hong Kong, Hong Kong, China
Background: Mounting evidence suggests that growth factors secreted by
cancer cells play important roles in cancer progression. Id1 is commonly
overexpressed in solid tumors including esophageal squamous cell carcinoma
(ESCC).
Purpose/Objective: We aim to determine if the functions of Id1 in promoting
cancer progression and chemoresistance are mediated by growth factors,
investigate the autocrine/endocrine effects of the key Id1-induced growth
factor, and evaluate the treatment efficiency of relevant anticancer therapeutic
strategies.
Materials and Methods: Antibody array-based screening was used to
identify differentially secreted growth factors from Id1-overexpressing ESCC
cells. In vitro and in vivo assays were performed to confirm the induction of
IGF2 by Id1, and to study the autocrine and endocrine effects of IGF2 in
promoting ESCC progression. Human ESCC tissue microarray was analyzed
for overexpression of IGF2 and its correlation with that of Id1 and p-AKT.
Fluorouracil (5-FU)-resistant ESCC sublines were established by treating
cells with increasing doses of 5-FU, and gene expression profiles were
compared with the parental cells by cDNA microarray. The anti-tumor and
anti-metastatic efficacies of IGF2 antibody and PI3K inhibitor wortmannin
were evaluated using tumor xenograft and experimental metastasis models.
Results: Id1 overexpression induced IGF2 secretion which promoted cancer
cell proliferation, survival and invasion by activating AKT in an autocrine
manner. IGF2 secreted by Id1-overexpressing ESCC xenograft could instigate
the growth of distant esophageal tumors, as well as promote metastasis
of circulating cancer cells in an endocrine manner. Tissue microarray data
showed overexpression of IGF2 in 21/35 (60%) human ESCC tissues which
was associated with up-regulation of Id1 and p-AKT. Moreover, Id1 was
identified by cDNA microarray analysis as being up-regulated in 5-FUresistant ESCC sublines; gain- and loss-of-function experiments confirmed
its importance in increasing chemoresistance. We found that IGF2 antibody
and wortmannin treatment significantly suppressed tumor growth, metastasis,
and chemoresistance in mouse models.
Conclusions: Our study demonstrated that the Id1/IGF2/PI3K/AKT signaling
cascade plays an important role in esophageal cancer progression and
chemoresistance. Blockade of IGF2/PI3K/AKT signaling has therapeutic
potential in the management of esophageal cancer.
This study is supported by General Research Fund (HKU 762610M) and
HKU Seed Funding Programme for Basic Research (201111159198).
MC13-0040
A novel HER3-V855A driver mutation homologous to EGFR-L858R in
lung cancer
I. Umelo 1 , A. Noeparast 1 , G. Chen 1 , M. Renard 2 , C. Geers 3 ,
J. Vansteenkiste 4 , E. Teugels 1 , J. De Greve 1 . 1 Medical and Molecular
Oncology, Vrije Universiteit Brussel, Brussels, Belgium; 2 Pediatric
Hemato-Oncology, UZ Leuven, Leuven, Belgium; 3 Pathology, UZ Brussel,
Brussels, Belgium; 4 Pneumology, UZ Leuven, Leuven, Belgium
Background: Somatic mutations found within the tyrosine kinase (TK)
domain of the human epidermal growth factor (HER or ErbB) family of
transmembrane receptors have been implicated in the development and progression of non-small cell lung cancer. These mutations have been identified
in the EGFR (epidermal growth factor receptor [HER1; ErbB1), HER2 (ErbB2)
and HER4 (ErbB4) genes, but no NSCLC associated functional mutations
have been described to date in the kinase inactive HER3 (ErbB3) gene.
Here, we report the case of an adolescent patient with advanced NSCLC
where DNA sequence analysis of all 4 HER family genes in his tumor biopsy
S23
specimen identified a novel V855A somatic mutation located in exon 21 of the
HER3 TK domain. Remarkably, the mutation maps at a position homologous
to the frequently described EGFR tyrosine kinase inhibitor (TKI)-sensitive
L858R activating mutation located in exon 21 of the EGFR TK domain.
Purpose/Objective: The aim of this study was to characterize the biological
effects of the novel HER3-V855A mutation in an in vitro mammalian cellular
system and to further investigate its potential as a possible therapeutic target
in NSCLC.
Materials and Methods: To examine functional differences we characterized
HER3-V855A alone or combined with its HER2, dimerization partner in a null
Ba/F3 model. Stable transfectants were subjected to MTS analysis in order to
assess cellular proliferation with HER-specific ligands as well as the growth
inhibitory effects of HER-specific inhibitors. Similarly, western blot analysis
evaluated the effect of growth factor stimulation and drug inhibition on the
HER signalling pathway. In addition, Annexin V/7-AAD analysis assessed the
effect of HER-specific inhibitors on apoptosis.
Results: In vitro functional analysis in a null Ba/F3 background reveals
that HER3-V855A when combined with its HER2 dimerization partner
leads to enhanced neuregulin 1β-induced receptor activation and transforms
interleukin-3 (IL-3) dependent Ba/F3 cells to neuregulin 1β-dependent growth.
Afatinib, a small molecule ErbB family inhibitor, has anti-proliferative and
pro-apoptotic effects on the HER3-V855A: wild-type HER2 Ba/F3 derivative
that is logarithmically higher than the effect obtained in the wild-type HER3:
wild-type HER2 combination.
Conclusions: Together, our findings demonstrate that kinase impaired
HER3 can be activated and that the HER3-V855A mutation confers a gain-offunction phenotype that is associated with sensitivity to afatinib. This finding
could be relevant for the treatment of NSCLC or other cancers carrying such
mutations.
MC13-0041
Is the prognostic role of serum CXCR4 in metastatic or recurrent
colorectal cancer?
S. Kim, Y. Choi, Y. Kim. Medicine, Korea University, Seoul, Korea
Background: The CXCR4 is involved in several aspects of tumor progression
including angiogenesis, metastasis, and survival. However, whether serum
CXCR4 level in metastatic or recurrent colorectal cancer (CRC) has a
prognostic role has been not evaluated.
Purpose/Objective: The purpose of this study is to investigate the role of
serum CXCR4 level for the prognosis of metastatic or recurrent CRC
Materials and Methods: We analyzed serum samples from 55 patients with
advanced CRC diagnosed between March 2008 and July 2011. Blood was
collected before beginning systemic chemotherapy and serum CXCR4 levels
were quantified by commercially available ELISA kit.
Results: The median age of the 55 patients was 62 years (range: 39–82)
and all patients received systemic chemotherapy of 2 or more line. The
median serum CXCR4 level was 0.8425 pg/ml. Patients with 2 or more of
metastatic sites, liver metastasis, or over more normal level of CA 19-9 (37
<) showed significantly higher level of serum CXCR4 than patients without.
The median overall survival of all patients was 19.53 months. There was
significant difference for OS between patients with CXCR4 ≤ 0.766 and
0.766 < (p=0.046). Univariate analysis showed that liver metastasis, no
debulking operation and higher level of CXCR4 (0.766 <) had significantly
poor prognostic value regarding OS (p<0.05).
Conclusions: Serum CXCR4 level was positively correlated with disease
burden (2 or more of metastatic sites, liver metastasis, or over more normal
level of CA 19-9). And there was significant difference for OS according to the
level of CXCR4. These findings suggested that CXCR4 might be useful as
surrogate marker of clinical outcome in metastatic or recurrent CRC.
MC13-0044
Impact of pre-analytical sample handling on metabolomic studies
R. Vettukattil, S. Lamichhane, T.H. Haukaas, S.A. Moestue, T.F. Bathen.
Circulation and Medical Imaging, Norwegian University of Science and
Technology, Trondheim, Norway
Background: Metabolomics offers a powerful tool to study the variations in
metabolites in various clinical conditions. Magnetic resonance spectroscopy
(MRS) is an analytical tool used in metabolomic studies, which allows
rapid and non-targeted exploration of metabolites in biological samples. As
metabolic profiling is gaining popularity in clinical research, it is important to
S24
Poster Presentations
Abstract MC13-0044 – Figure 1
assess the susceptibility of these techniques to systematic variations resulting
from sample handling and analysis.
Purpose/Objective: In this study we systematically investigated the effect
of post-surgical delay prior to sample freezing on metabolomics studies of
patient derived breast cancer xenograft tissue samples using high resolution
magic angle spinning (HR MAS) MRS.
Materials and Methods: Tissue samples were obtained from mouse
xenograft models representing luminal-like (n=3) and basal-like (n=3) molecular subtypes. After dissection, tumor tissue was snap frozen in liquid nitrogen
at 0, 15, 30, 60, 90, and 120 minutes after surgery. In total 8 samples
were collected from each tumor, which includes a replicate at 15 minutes
and a sample which was analyzed immediately after surgery, without any
freezing. All samples were analyzed by HR MAS MRS on a Bruker Avance
III 600 MHz/54 mm US at 4°C. Multivariate analysis of the spectral data was
performed in the form of unsupervised principal component (PC) analysis
using PLS-Toolbox 5.8 for MATLAB© . All procedures and experiments
involving animals were approved by the European Animal Research Authority.
Results: Multivariate analysis of the samples showed that individual
metabolite variation had a higher impact on the metabolic profile than the
post-surgical delay. The overall metabolic profile was fairly robust to variation
in sample processing (Fig. 1). Basal and luminal xenografts were separated
along first PC (accounting for 80.5% of overall variability) despite the wide
variation in sample freezing times.
Conclusions: MR spectroscopic metabolite profiles of tumor tissue samples
are more reproducible and robust to variation in post-surgical delay prior to
freezing than variation introduced by their biological differences. However, the
degree of variation in metabolites differs based on the type and molecular
heterogeneity of tumors. The need for stability analysis in every clinical
metabolomic study is warranted.
MC13-0045
Genes from the TP53 network and their role in ovarian cancer
prognosis and response to chemotherapy
A. Podgorska, L. Szafron, A. Felisiak-Golabek, J. Kupryjanczyk. Department
of Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute
of Oncology, Warsaw, Poland
Background: The TP53 gene is one of the most frequently mutated genes
in human cancers and is thought to play a crucial role in malignant transformation. The key role of TP53 as a tumour suppressor is to block cell cycle
progression and/or to induce apoptosis in response to cellular stresses. Within
the TP53 pathway there are different up/downstream effectors regulating its
stability and activity.
Purpose/Objective: The aim of this study was to evaluate clinical significance
of the expression of 5 different TP53-related genes (MDM2, MDM4, HUWE1,
GADD45A and CDKN2A) in advanced ovarian cancers, with respect to the
TP53 status.
Materials and Methods: Ovarian carcinomas from 106 patients treated with
taxane-platinum (TP, n=74) or platinum-cyclophosphamide (PC/PAC, n=32)
were chosen for real-time PCR analysis. mRNA expression levels of 5 genes
were screened using TaqMan® Gene Expression Assays (Life Technologies).
Data were analysed using the relative quantitation method with HGPRT
as a reference gene. Univariate and multivariate statistical analyses (Cox
proportional hazards model and logistic regression model) were performed to
evaluate overall survival, disease-free survival and response to chemotherapy. Analyses were made in the entire group, as well as in subgroups of
tumours with (TP53+) and without TP53 accumulation (TP53−).
Results: Within the TP-treated group of ovarian cancer patients elevated
expression of MDM2, MDM4, HUWE1 and GADD45A mRNA was associated
with enhanced risk of death in the TP53− subgroup (HR 1.30, p=0.002;
HR 1.83, p=0.005; HR 6.27, p=0.001; HR 5.44, p=0.028; respectively).
High GADD45A mRNA expression increased also the risk of recurrence
in the TP53+ subgroup (HR 3.49, p=0.048). Elevated MDM4 mRNA levels
decreased the probability of complete remission in the TP53− subgroup (OR
0.33, p=0.046). High expression of HUWE1 might have also an influence on
platinum sensitivity in the TP53− subgroup (OR 0.024, p=0.052). CDKN2A
mRNA expression did not show any statistically significant effect on clinical
endpoints. In the PC/PAC treated group none of the analysed gene expression
levels had an influence on clinical outcome.
Conclusions: In the present study we have demonstrated the clinical
importance of the expression of 4 TP53-related genes. Our results suggest
that high mRNA levels of MDM2, MDM4, HUWE1 and GADD45A are
negative predictive and/or prognostic factors in ovarian cancers treated with
taxane-platinum agents.
Poster Presentations
S25
MC13-0046
Volatile organic compounds as an early diagnostic tool for malignant
pleural mesothelioma
K. Lamote 1 , J. Van Cleemput 2 , K. Nackaerts 3 , J.P. van Meerbeeck 4 .
1 Respiratory Medicine, Ghent University Hospital, Ghent, Belgium;
2 Occupational Health Service, Eternit N.V., Kapelle-op-den-Bos, Belgium;
3 Respiratory Medicine, University Hospital Gasthuisberg, Leuven, Belgium;
4 Thoracic Oncology/MOCA, Antwerp University Hospital, Antwerp, Belgium
Background: Early diagnosis of malignant pleural mesothelioma (MPM) can
improve patients’ outcome but is hampered by non-specific symptoms and
investigations, which delay diagnosis and result in advanced stage disease
[van Meerbeeck JP, 2011]. An accurate non-invasive test allowing early stage
diagnosis in asbestos-exposed persons is lacking.
Purpose/Objective: Breathomics aims at a non-invasive analysis of volatile
organic compounds (VOCs) reflecting the cells’ metabolism. The breathogram
obtained by the electronic nose does however, not allow identification of
MPM-related VOCs [Chapman EA 2009, Dragonieri S 2011]. Ion mobility
spectrometry (IMS) combines the advantages of online direct sampling
with the possibility of VOC identification and linking to MPM pathogenesis
[Baumbach JI 2009]. We investigated which VOCs could play a role in MPM
pathogenesis in order to build a possible diagnostic MPM tool.
Materials and Methods: 10 MPM patients and 10 healthy professionally
asbestos-exposed individuals were included after refraining from eating,
drinking and smoking for at least 2 hours before sampling. They breathed
tidally for 3 minutes through a mouthpiece connected to a bacteria filter.
Ten ml alveolar air was sampled via a CO2 -controlled ultrasonic sensor and
analyzed using the BioScout Multicapillary Column/Ion Mobility Spectrometer
(MCC/IMS, B&S Analytik, Dortmund, Germany) [Westhoff M 2009], by using
N2 as a carrier gas. Per subject a background sample was taken. Peaks
of interest were visually selected and their intensity (V) was analyzed and
compared between background and breath samples via on-board VisualNow
3.2 software and SPSS v21 (IBM) using Mann-Whitney-U tests.
Results: Out of 41 peaks of interest, three show a significantly higher intensity
in the exhaled breath of MPM patients than healthy controls [Table]. The high
AUCROC of resp. P12 (0.877) and P24 (0.863) suggests a possible role of
these associated VOCs in MPM pathogenesis and as a diagnostic marker in
discriminating MPM patients from asbestos-exposed healthy controls.
Peak
MPM Intensity (V)*
AEx Intensity (V)*
p-value
AUCROC
P6
P9
P11
P12
P19
P20
P24
P26
P27
P33
P36
0.018 [0.013–0.027]
0.106 [0.085–0.124]
0.089 [0.068–0.120]
0.078 [0.054–0.168]
0.044 [0.038–0.048]
0.044 [0.029–0.059]
0.102 [0.085–0.123]
0.010 [0.007–0.016]
0.012 [0.008–0.021]
0.006 [0.004–0.007]
0.012 [0.009–0.016]
0.026 [0.019–0.031]
0.116 [0.104–0.145]
0.082 [0.064–0.093]
0.027 [0.022–0.060]
0.045 [0.042–0.055]
0.072 [0.043–0.078]
0.079 [0.069–0.089]
0.011 [0.006–0.013]
0.013 [0.010–0.052]
0.010 [0.007–0.019]
0.012 [0.009–0.016]
0.41
0.17
0.45
<0.01
0.76
0.17
0.03
0.76
0.60
0.03
0.82
0.490
0.763
0.750
0.877
0.777
0.620
0.863
0.567
0.618
0.237
0.517
*Median [IQR]. 1/K0 : inversed reduced ion mobility. AEx: healthy asbestos exposed individual. AUCROC : Area under the receiver operator characteristic curve (accuracy in
diagnosing MPM). MPM: Malignant Pleural Mesothelioma patient. RT: retention time.
Conclusions: Several VOCs of interest were obtained in the breath of
MPM patients. Two peaks were significantly discriminating between both
populations. GC-MS analysis and further large cohort studies are ongoing in
order to validate the accuracy of IMS as a diagnostic tool for MPM.
MC13-0047
Serum and tissue biomarkers for cancer biospecimen integrity
L. Agrawal, H. Moore, J. Vaught. BBRB Cancer Diagnosis Program, National
Cancer Institute, Rockville, USA
Background: High quality cancer biospecimens with appropriate clinical
annotation are critical in the era of biomarker discovery in personalized
medicine. Numerous pre-analytical factors affect human biospecimen integrity
for biomarker research in cancer. This situation is applicable to a variety
of biospecimens including plasma/serum and fixed cancer tissues used for
biomarker analysis.
Purpose/Objective: The purpose of the current work performed via Biospecimen Research Network (BRN) is to enable research to provide the foundation
for evidence-based practices and to develop serum and tissue biomarkers
for human biospecimen integrity. BRN is a program eastablished by the U.S.
National Cancer Institute (NCI) Biorepositories and Biospecimen Research
Branch (BBRB) to coordinate NCI’s biospecimen resource activities and
address those issues that affect access to the high quality specimens for
biomarker research.
Materials and Methods: We summarize here the development of assays
and identification of biomarkers that may be used as sentinel markers
of plasma/tissue stability in biobanks using mass-spectroscopy proteomics,
analysis of circulating miRNA, and immunostaining of FFPE tissues (AQUA
technology).
Results: In one of the projects, identification of protein biomarkers using
mass-spectrometry and Illumina arrays in serum obtained from breast cancer
and matched normal subjects has led to development of potential biomarker
panel for serum/plasma integrity and these biomarkers are currently being
validated. A second project studied effects of pre-analytical variables on circulating miRNA and identified and validated new and improved housekeeping
miRNA and biomarkers associated with breast cancer. In another study, a
series of biomarkers have been validated by construction of tissue microarray
(TMA) from 93 breast cancer specimens with known time to fixation as a
pre-analytical variable. A tissue quality index (TQI) model was generated
to predict the time to fixation and tissue quality by studying a subset of
biomarker proteins in breast cancer tissues using AQUA scores.
Conclusions: This presentation will outline the progressive efforts taken by
BRN investigator-led projects to identify and validate biomarkers for cancer
biospecimen integrity and help establish standards for serum and cancer
tissue quality for clinical trials and biomarker assay development.
MC13-0048
Disruption of CD9 affects adhesion, migration and actin polymerization
in ETV6/RUNX1 pre-B lymphocytes
M.P. Arnaud 1 , A. Vallee 1 , G. Robert 1 , E. Dondi 2 , B. Jacinthe 3 , C. Leroy 2 ,
N. Varin-Blank 2 , M.D. Galibert 1 , M.B. Troadec 1 , V. Gandemer 1 . 1 CNRS
UMR6290, Institut de Génétique et Développement de Rennes, Rennes,
France; 2 Université Paris 13, UMR978 INSERM, Rennes, France; 3 Unité
d’Hémato-pédiatrie, Centre Hospitalier Universitaire, Rennes, France
Background: CD9, a membrane protein member of the tetraspanin family, is
implicated in hematopoietic stem cell engraftment. Moreover CD9 expression
has been correlated with the risk of metastasis and is associated with a poor
clinical outcome in various types of cancer. Notably, CD9 is under expressed
in the ETV6/RUNX1 pre-B acute lymphoblastic leukaemia (ALL).
Purpose/Objective: The purpose of our study is to investigate the effect of
CD9 expression on the motility process in vitro and to identify the regulation
pathways related to CD9.
Materials and Methods: The CD9-positive REH cell line (from an
ETV6/RUNX1 ALL relapse) was used. By lentiviral transduction of shRNA
targeting CD9 mRNA, we generated REH cells depleted in CD9. We also
used an anti-CD9 antibody. Ability of cells to adhere on fibronectin and to
migrate in response to CXCL12 were measured in vitro. The activation of
PI3K/AKT pathway according to CD9 expression was studied by western
blotting. We also investigated the presence of membrane villi on cell surface
by scanning electron microscopy. Finally F-actin polymerization after CXCL12
stimulation was measured by rhodamin-phalloidin labelling and localization of
CD9 and CXCR4 was observed by immunofluorescence.
Results: We demonstrated a higher adhesion on fibronectin in CD9 overexpressing cells and with anti-CD9 antibody. Western Blot analysis revealed
that AKT activation positively correlate with cell’s adhesion rate. Preliminary
results with AKT inhibitors reinforced PI3K/AKT pathway role in adhesion of
REH. As well, the more CD9 is expressed, the more the migration rate in
response to CXCL12 is high. Migration rate is also increased with anti-CD9
antibody. By immunofluorescence we showed first that CD9 and CXCR4
are colocalized on cell membrane and secondly co-capped with actin in the
presence of anti-CD9 antibody. Without any stimulation, CD9-positive REH
had longer villi than ShCD9 transducted cell lines. After CXCL12 stimulation
F-actin polymerization is increased in CD9-positive cells.
Conclusions: Our data show that CD9 is a key actor in pre-B lymphoblasts
adhesion and CXCL12 dependant migration. CD9 expression interacts with
actin remodelling. We are now investigating a potential link between CD9
and RAC1 known to be activated in response to CXCL12.Therefore, the
expression level of CD9 could impact leukemic blasts abilities to spread and
be a major actor of relapses.
S26
MC13-0050
Proteomic markers in early buccal mucosa squamous cell cancers
S. Nair 1 , S. Malgundkar 2 , A. Patil 3 , S. Kane 3 , K. Sadhana 4 , A. D’Cruz 1 ,
S. Zingde 2 . 1 Head and Neck Service, Tata Memorial Center, Mumbai, India;
2 Zingde lab, ACTREC TMC, Mumbai, India; 3 Pathology, Tata Memorial
Center, Mumbai, India; 4 Bio-Statistics, ACTREC TMC, Mumbai, India
Background: Carcinoma of buccal mucosa is common in South Asia due
to large-scale usage of chewable tobacco. However, clinically these cancers
behave similar to tongue cancers, which are common in western countries.
Like any other head and neck squamous cell cancers (HNSCC), their
prognosis is affected by established clinical factors like nodal metastasis and
T stage. Presence of regional lymph node metastasis is one of the important
factors for poor clinical outcome and nodal status of the neck plays a decisive
role in the choice of treatment. An assessment of the cervical lymph node
metastatic status in oral cavity cancer not only helps to predict the prognosis
of patients, but also helps surgeons to choose the appropriate treatment.
About 70% of patients in T1 (<2 cm) and 30% in T4 primary tumour stage
may not have lymphatic metastasis at the time of treatment. Similarly, even
after using all the available technologies to detect lymph nodes in the neck,
the rate of occult metastasis is significantly high in OSCC. Many literature
reports points to several molecular markers expressed by the primary tumour
in predicting its metastasising nature. It is important that these markers should
be such that their use can be effectively translated into easy to implement
techniques in any molecular pathology laboratory. While gene expression
profiles are increasingly used for prognostication, their relative costs and time
requirements make them difficult for routine use in clinical service. Proteomic
markers can be detected using IHC and will be easier to use clinically.
Purpose/Objective: This study aims in developing a set of markers in
early buccal mucosa cancers using previously established set of proteomic
markers differentially expressed in buccal mucosa cancers.
Materials and Methods: We have analyzed formalin fixed paraffin embedded
blocks from 90 patients with early stage (T1/T2) buccal mucosa cancers
treated surgically at Tata Memorial Hospital, Mumbai. All patients were
clinically node negative at the time of surgery. Tissue microarrays was
prepared and the sectons stained with antibodies for 19 markers. The stained
slides were graded and quantified based on the localization, extent of staining
and intensity of staining.
Results: Median expressions of P53 and EGFR between node negative
and positive tumors were not significant. However, we observed significant
differences in the expression of the following markers among node negative
versus node positive tumor samples.
1. Higher expression of SFN is associated with lower risk of nodal metastasis
(p 0.03),
2. Higher expression of TCTP is associated with lower risk of nodal
metastasis (p 0.003). These markers along with 14-3-3-zeta also showed
significant differences in expression between well differentiated tumors
and others.
Conclusions: Proteomic markers have potential to predict nodal metastasis
in early stage buccal mucosa cancers.
MC13-0051
Molecular characterization of anaplastic astrocytoma and glioblastoma
multiforme: PTEN loss in conjunction with EGFR alterations predicts
response to therapy
M. Donovan 1 , A. Colomer 2 , P. Puig 2 , N. Erill 2 , I. Alarcon 2 , N. Vidal 3 ,
I. Ferrer 3 . 1 Pathology, Mt. Sinai Medical Center, New York, USA; 2 Pathology,
Althia Health S.L., 3 Pathology, Bellvitge Hospital, Baracelona, Spain
Background: Anaplastic Astrocytoma (AA) and Glioblastoma multiforme
(GBM) represent the most common and malignant of adult brain tumors.
Despite best standard of care including surgical resection, radiation and
chemotherapy (e.g. temozolomide), the median survival remains approximately 12–15 months, with fewer than 25% of patients surviving up to 2 years
and fewer than 10% of patients surviving up to 5 years. Previously we had
observed that EGFR amplification/polysomy in conjunction with PTEN LOH
by FISH was associated with improved outcome in patients with GBM.
Purpose/Objective: We sought to confirm and validate these initial findings
by expanding the patient cohort size, examining the protein levels of the
individual genes and to determine if AA patients have a similar predicted
phenotype.
Materials and Methods: Tissue microarrays (TMAs) with up to 4 cores/tumor
specimen from 174 patients (124 GBM and 50 AA) with a median follow up of
Poster Presentations
8 years were evaluated using dual-color DNA FISH for both PTEN and EGFR
amplification (AMP) and or high polysomy (POLY). In parallel, TMA arrays
were interrogated with a previously described multispectral immunofluorescent (IF) assay (Cordon-Cardo et al., 2007) which included: GFAP, EGFR,
PTEN and Ki67. Feature performance was univariately assessed using the
concordance index and Kaplan-Meier survival curves, individually controlled
for age and type of surgery (i.e. biopsy vs resection).
Results: The median survival for AA patients was 377 days vs. 175 days
for the GBM patients (p<0.001), median age of AA was 52 years and GBM,
62 years (P≤0.001). By IF, tumor specific KI67 was not predictive whereas
high levels of EGFR (p=0.014) and low PTEN (p=0.008) were associated
with poor outcome in the AA only group. In contrast, higher levels of PTEN
in the GBM cohort were associated with poor outcome (p=0.022). EGFR
AMP but not EGFR POLY was consistently associated with poor survival and
this finding was most significant when PTEN LOH was <40% for either AA
(p=0.001) or GBM (p=0.002), respectively. By comparison, the combination
of PTEN LOH >40% and EGFR polysomy in GBM when controlled for
surgical type, was associated with improved survival (p-value 0.002), while
those rare GBM patients with both EGFR AMP and PTEN LOH >40% also
had improved survival (p=0.012). The data supports a role for accurately
assessing both PTEN loss and EGFR status when predicting response to
treatment, especially for patients with EGFR POLY.
Conclusions: The incorporation of EGFR/PTEN DNA FISH and quantitative
IF is useful for developing a biologic baseline for understanding disease
course and response to treatment in malignant gliomas. PTEN LOH and
EGFR polysomy/amplification in GBM suggests a mechanism for favorable response and should help guide subsequent multi-modal treatment
regimens.
MC13-0052
Accuracy evaluation of a novel companion diagnostic method for
BRAF V600E/V600K identification in GSK clinical trials
L. O’Donnell 1 , W. Sweet 1 , X. Lu 1 , F. Meynier 2 , A. Derome 3 , L. Ganee 4 ,
F. Poyet-Gelas 3 , A. Martin 5 , M. Casey 6 , N. Kertesz 7 . 1 Clinical Affairs,
BioMerieux Inc., Durham, USA; 2 BioMath, BioMerieux Inc., Grenoble,
France; 3 V & V, BioMerieux Inc., Grenoble, France; 4 Product Design &
Development, BioMerieux Inc., Grenoble, France; 5 Oncology, GSK,
Collegeville, USA; 6 Statistics, GSK, Collegeville, USA; 7 Pharmaceutical
Liaison Manager, Response Genetics Inc., Los Angeles, USA
Background: The THxID™ BRAF kit is an in vitro diagnostic device intended
for the qualitative detection of the BRAF V600E and V600K mutations
in DNA samples extracted from formalin-fixed paraffin embedded (FFPE)
human melanoma tissue. The THxID™ BRAF kit is a real-time PCR test
on the ABI 7500 Fast Dx system and is intended to be used as an aid in
selecting melanoma patients whose tumors carry the BRAF V600E mutation
for treatment with dabrafenib [Tafinlar® ] and as an aid in selecting melanoma
patients whose tumors carry the BRAF V600E or V600K mutation for
treatment with trametinib [Mekinist™].
Purpose/Objective: The purpose of this study is to evaluate the accuracy
of the THxID™ BRAF assay using retrospective samples from three GSK
clinical trials
Materials and Methods: A total of 882 specimens from subjects in GSK
clinical trials BRF113710, BRF113929 and MEK114267 were retrospectively
tested with the THxID™ BRAF assay. Specimens had been screened
previously using an investigational use only (IUO) assay from Response
Genetics Inc. (RGI). After THxID™ testing, the remaining DNA eluates were
then sent to RGI for bidirectional Sanger sequencing. The accuracy of the
THxID™ BRAF assay was presented as the concordance with bidirectional
Sanger sequencing.
Results: For all the specimens combined as a group for samples with valid
results, the overall Positive Percent Agreement (PPA) and Negative Percent
Agreement (NPA) were 98.1% (403/411) (95% CI [96.2%; 99.0%]) and 93.9%
(417/444) (95% CI, [91.3%; 95.8%]), respectively. The PPA for V600E and
V600K were 98.0% (341/348) (95% CI, [95.9%; 99.0%]) and 93.7% (59/63)
(95% CI, [84.8%; 97.5%]), respectively. No specimen was detected for both
V600E and V600K.
The overall invalid rate for the THxID™ BRAF assay was 3.1% (27/882) with
the following identification by bidirectional Sanger sequencing: 6 samples as
V600E (0.7%), 1 samples as V600K (0.1%), and 20 samples as WT (2.3%).
Conclusions: The PPA and NPA results, as compared to the bidirectional
Sanger sequencing method, indicated a high accuracy of the THxID™ BRAF
assay for the identification of BRAF V600E/V600K. The THxID™ BRAF assay
Poster Presentations
has been demonstrated as an accurate and reliable method to aid in selection
of a population with BRAF V600E/V600K mutation for targeted therapy.
MC13-0053
High analytical concordance between a novel companion diagnostic
assay and an IUO assay for BRAF V600E/V600K detection in melanoma
L. O’Donnell 1 , W. Sweet 1 , X. Lu 1 , F. Meynier 2 , A. Derome 3 , L. Ganee 4 ,
F. Poyet-Gelas 3 , A. Martin 5 , M. Casey 6 , N. Kertesz 7 . 1 Clinical Affairs,
BioMerieux Inc., Durham, USA; 2 BioMath, BioMerieux Inc., Grenoble,
France; 3 V & V, BioMerieux Inc., Grenoble, France; 4 Product Design &
Development, BioMerieux Inc., Grenoble, France; 5 Oncology, GSK,
Collegeville, USA; 6 Statistics, GSK, Collegeville, USA; 7 Pharmaceutical
Liaison Manager, Response Genetics Inc., Los Angeles, USA
Background: The THxID™ BRAF kit is an in vitro diagnostic device intended
for the qualitative detection of the BRAF V600E and V600K mutations in DNA
samples extracted from formalin-fixed paraffin embedded (FFPE) human
melanoma tissue. The THxID™ BRAF kit is a real-time PCR test on the ABI
7500 Fast Dx system intended to be used as an aid in selecting melanoma
patients whose tumors carry the BRAF V600E mutation for treatment with
dabrafenib [Tafinlar® ] and as an aid in selecting melanoma patients whose
tumors carry the BRAF V600E or V600K mutation for treatment with trametinib
[Mekinist™].
Purpose/Objective: The objective of the study is to assess the analytical
concordance between THxID BRAF assay and an investigational use only
(IUO) assay from Response Genetics, Inc. (RGI).
Materials and Methods: A total of 926 samples from GSK clinical trials
BRF113710, BRF113929 and BRF113683 with results from the RGI IUO
were tested with THxID™ BRAF. Analytical concordance between THxID™
BRAF and RGI IUO was assessed using the test results and reported as
Positive Percent Agreements (PPA), Negative Percent Agreements (NPA),
and Overall Percentage Agreements (OPA). Discordants were tested by
bidirectional Sanger sequencing.
Results: The PPA between THxID™ BRAF and RGI IUO was 96.2% for
V600E, 97.8% for V600K, and OPA was 95.4%. The NPA between the two
assays was 96.5%. The same variables excluding the invalid samples were:
98.2%, 97.8%, 97.8%, and 97.5%, respectively.
A total of 16 discordant samples (1.7%, 16/926) with valid results from both
assays were tested with bidirectional Sanger sequencing. 4 instances were
shown as correctly identified by THxID™ BRAF, 9 instances by RGI IUO, and
3 instances were discordant to both assays.
There were 22 samples with invalid results reported from both assays, 13
samples reported invalid from THxID™ BRAF and valid from RGI IUO, and
11 samples reported invalid from RGI IUO but valid from THxID™ BRAF. The
total invalid rate from THxID™ BRAF and RGI IUO were 3.8% (35/926) and
3.6% (33/926) respectively.
Conclusions: THxID™ BRAF assay and RGI IUO assay showed a very
high concordance rate, indicating that the prospective clinical outcome with
RGI IUO assay can be transposed retrospectively to THxID™ BRAF assay,
enabling the selection of patients with BRAF V600E and /or V600K mutation
in melanoma tumors for targeted therapy.
MC13-0054
High precision of a novel companion diagnostic assay for the detection
of BRAF V600E/V600K in formalin-fixed paraffin-embedded melanoma
samples
L. O’Donnell 1 , W. Sweet 1 , X. Lu 1 , F. Meynier 2 , A. Derome 3 , L. Ganee 4 ,
F. Poyet-Gelas 3 , A. Martin 5 , M. Casey 6 , N. Kertesz 7 . 1 Clinical Affairs,
BioMerieux Inc., Durham, USA; 2 BioMath, BioMerieux Inc., Grenoble,
France; 3 V & V, BioMerieux Inc., Grenoble, France; 4 Product Design &
Development, BioMerieux Inc., Grenoble, France; 5 Oncology, GSK,
Collegeville, USA; 6 Statistics, GSK, Collegeville, USA; 7 Pharmaceutical
Liaison Manager, Response Genetics Inc., Los Angeles, USA
Background: The THxID™ BRAF kit is an in vitro diagnostic device intended
for the qualitative detection of the BRAF V600E and V600K mutations in DNA
samples extracted from formalin-fixed paraffin embedded (FFPE) human
melanoma tissue. The THxID™ BRAF kit is a real-time PCR test on the ABI
7500 Fast Dx system intended to be used as an aid in selecting melanoma
patients whose tumors carry the BRAF V600E mutation for treatment with
dabrafenib [Tafinlar® ] and as an aid in selecting melanoma patients whose
S27
tumors carry the BRAF V600E or V600K mutation for treatment with trametinib
[Mekinist™].
Purpose/Objective: The purpose of this study is to evaluate the precision of
the THxID BRAF assay by using a 15-member panel.
Materials and Methods: A 15-member panel was formulated to include 3
genotypes [wild type (WT), V600E, V600K], 3 mutant DNA concentrations
(LoD claim, Med-High positive, High Melanin content), and 2 tissue types
(Skin, Lymph node). The V600E and V600K samples were reconstituted
respectively by mixing DNA eluates of mutant and WT samples. The panel
was tested at three sites on three lots for three weeks, with each panel
member in duplicate.
The precision was determined by the percentage of correct identifications of
the samples’ mutation status, with the corresponding two-sided 95% score
confidence interval (CI).
Results: The results showed 100% correct identification of the sample mutation status for fourteen panel members, and 83.3% correct identification for
one panel member carrying V600E mutation with mutant DNA concentration
close to limit of detection (LoD) claim, in which the low mutation content of
the panel member was confirmed by pyrosequencing. The overall combined
percentage of correct identification is 98.9%.
For one panel member carrying V600K mutation with high melanin content,
100% correct identification was yielded with the diluted samples following the
Instructions For Use (IFU) specifications for repeating. The remaining panel
members with high melanin content were 100% correctly identified from
original DNA extracts.
Conclusions: The study demonstrates high precision of the THxID™ BRAF
Assay for the detection of BRAF V600E/V600K mutations in FFPE samples
from melanoma patients, indicating the assay can be used to aid in the
selection of a population with BRAF V600E/V600K mutations for targeted
therapy.
MC13-0055
Development of a companion diagnostic for pegylated recombinant
human PH20
L. Jadin, L. Huang, Q. Zhao, G. Wei, H.M. Shepard, A.B. Gelb, P. Jiang.
Research, Halozyme Therapeutics Inc., San Diego, USA
Background: The polysaccharide hyaluronan (HA) is a normal constituent
of the extracellular matrix. Up-regulation of HA production by tumor and/or
associated stromal cells often correlates with tumor progression. A pegylated
recombinant human hyaluronidase (PEGPH20) has been shown to deplete
tumor HA and lead to increased tumor perfusion, thereby enhancing the
activity of anticancer agents in preclinical models. A phase 1b study of
gemcitabine plus PEGPH20 in patients with stage IV previously untreated
pancreatic ductal adenocarcinoma (PDAC) showed efficacy, particularly
when intratumoral HA content was high in pretreatment samples. Therefore,
developing a companion diagnostic is important to select patients likely to
benefit from therapy by assessing pretreatment biopsies and monitoring the
effects of treatment.
Purpose/Objective: To evaluate a pseudo-immunohistochemical (IHC)
method for the detection of HA in malignancies as a companion diagnostic for
PEGPH20 therapy.
Materials and Methods: Pseudo-IHC was performed using a biotinylated
recombinant protein consisting of a modified human TSG-6 HA-binding
domain fused with the Fc fragment of human IgG1a (HTI-601). Quantitative
image analysis was performed to determine the percentage of pixels
above a defined intensity threshold relative to the total pixels stained and
counterstained. The specificity of staining was assessed by pre-incubation of
tissues with an HA-degrading enzyme, either Streptomyces hyaluronidase or
recombinant human PH20, depending on the specimen type.
Results: HTI-601 displayed high binding affinity, with a Kd of approximately
1E−10 M for 150 kDa HA. It proved very sensitive and specific for HA detection
in formalin-fixed, paraffin-embedded (FFPE) human normal tissues, human
cancers and xenograft tumors by pseudo-IHC. The method was able to
detect a significant reduction in HA content of PC3 human prostate cancer
and BxPC3 human pancreatic cancer xenograft tumors following PEGPH20
treatment.
Conclusions: This study demonstrates that pseudo-IHC using HTI-601 is a
specific, sensitive and accurate method for evaluating HA content in FFPE
human normal tissues and neoplasms. The value of this method as a
companion diagnostic for PEGPH20 is currently under investigation in Phase
2 clinical trials of PDAC.
S28
MC13-0057
A comprehensive IT platform to support GTEx operation
C. Shive 1 , L. Qi 1 , D. Tabor 1 , P. Hariharan 1 , S. Wu 1 , K.S. Um 1 , J. McLean 1 ,
N. Lockhart 2 , P. Guan 3 . 1 BBRB Support Program, SAIC-F, Bethesda, USA;
2 Division of Genomics & Society, National Human Genome Research
Institute, Bethesda, USA; 3 BBRB/CDP/DCTD, National Cancer Institute,
Bethesda, USA
Background: Designed to build upon Genome Wide Association Study
(GWAS) findings, the NIH Common Fund’s Genotype-Tissue Expression
(GTEx) project aims to study gene expression and regulation across multiple
human tissues (30+ tissue types) from approximately 1000 healthy normal
donors. It is expected to provide valuable insights into gene regulation and its
tissue specificity, identify correlation between genetic variations and variations
in gene expression levels as expression quantitative trait loci (eQTLs), and
help to understand inherited susceptibility to diseases.
Purpose/Objective: To meet the challenge of GTEx requirements for collecting and tracking high quality biospecimen samples, a custom-built software
system named Comprehensive Data Resources (CDR) was developed to
support sample collection work flow, clinical data entry, case management,
and review and curation of study data.
Materials and Methods: CDR is built with combination of technologies from
Grails, Oracle, Groovy, jQuery, Apache Solr.
Results: The CDR provides secure user access to case and sample data
based on pre-defined roles and privileges. Personally Identifiable Information
(PII) and Protected Health Information (PHI) are restricted to a limited data set
(LDS) and to authorized users through dynamic content redaction. Intuitive
graphic user interfaces for the Biopecimen Source Sites (BSS) streamline
data entry workflow by strictly following SOPs for sample collection and
processing. Contextual automated data checks and business rule validations
confirm data integrity and SOP adherence simultaneously. Web services APIs
allow the Pathology Resource Center to access digital imaging data from
tissue slides housed remotely at the Comprehensive Biospecimen Resource
(CBR). API’s connect to CBR’s LIMS systems for real-time sample inventory
data. De-identified GTEx data is provided via a private API with the Broad
Institute (LDACC) before the final release into dbGaP. The reporting and
analytics module supports data analysis and aggregation, report generation
and real-time operational data snapshots.
Conclusions: CDR is a distributed web-based system designed to support
GTEx operation from pilot phase to full scale-up stage. It manages and
maintains multi-dimensional data models around each donor case (average
500+ data elements/case). As an efficient case management tool capable of
connecting to various remote informatics systems, CDR could be adapted to
the broader biobanking community with the flexibility of building user-defined
work flows in the system.
MC13-0058
Inflammation-mediated epigenetic background for switching from
normal program to cancer growth
V. Halytskiy. Molecular Immunology Department, Palladin Institute of
Biochemistry of the National Academy of Sciences of Ukraine, Kiev, Ukraine
Background: Although inflammation is closely associated with tumor growth,
molecular basis of this interrelation remains unclear, especially when
pathogens do not damage the DNA. However, the inflammation entails
regular changes in the expression of cell microRNAs (miRNAs). Expression of
miRNAs miR-155, miR-21, miR-146a, miR-125b, miR-31, miR-34c, miR-200,
miR-203 and miR-205 is usually up-regulated whereas expression of miRNAs
miR-7a/b, miR-34a, miR-143, miR-145, miR-320a, miR-375, miR-379 and
miR-434-3p is down-regulated.
Purpose/Objective: This investigation aims to identify in what way the shifts
in miRNA expression pattern contribute to the cell transformation and tumor
growth.
Materials and Methods: miRNA targets within gene transcripts were
predicted in silico using TargetScan software.
Results: miRNA miR-143 can silence abl2, bcl-2, erbB3 and MYST2
genes. miR-145 targets E2F3, RASA1/2, CDK6, erbB3/B4, ESR1, ACTB/G1,
KDM1B/2B and Elp3 genes. miR-320 suppresses E2F1/3/7, RASA1, CDK6,
p57, ESR1, ITGB5, KDM1B and KAT6B genes. Down-regulation of these
miRNAs causes derepression of genes encoding histone acetyltransferases,
histone demethylases, key elements of proliferative and antiapoptotic signal
pathways as well as genes responsible for cell motility and abnormal
adhesion. Up-regulated miRNA miR-155 silences HDAC2/4/9, SIRT1, EZH1,
Poster Presentations
SETD7, CLDN1, CGN, OCLN, F11R (JAM-A) and TGFBR2 genes and genes
coding α-actinins. miR-21 can target DNMT3B, HDAC2, SIRT5, SETD6/8,
SUV39H2, CLDN1, CGN, CADM1, VCL and TGFBR2 genes.
Conclusions: Inflammation is associated with miRNA expression shifts that
lead to increasing of cell proliferation and survival as well as to silencing of
antiproliferative and proapoptotic genes. Also, up-regulated miRNAs suppress
genes encoding components of cytoskeleton and intercellular junctions. This
results in alterations in cell–cell adhesion, impairs contact inhibition, facilitates
cell motility and migration. Furthermore, up-regulated miRNAs silence genes
encoding the histone deacetylases, histone methyltransferases and de novo
DNA methyltransferase. This causes increasing of overall level of chromatin
acetylation and expression and, therefore, makes possible the reactivation
of silent oncogenes as well as transposons, which can rapidly lead to
dramatic increase of DNA damage level and genome destabilization. Thus,
inflammation creates epigenetic background for cell transformation as well as
for tumor promotion and metastatic spread.
MC13-0059
T-cell infiltration (TCI) observed on whole liver colorectal metastases
(LCM) resected after preoperative treatment is a prognostic survival
factor
M. Van den Eynde 1 , B. Mlecnik 2 , J.P. Machiels 3 , D. Debetancourt 4 ,
A. Mourin 5 , J.F. Gigot 6 , N. Haicheur 7 , F. Marliot 7 , F. Pagès 7 , J. Galon 2 .
1 Oncology, Université catholique de Louvain, Brussels, Belgium; 2 Cancer
immunology, Centre de Recherche des Cordeliers, Paris, France; 3 Oncology,
4 Centre du Cancer, 5 Pathology, 6 Digestive Surgery, Université Catholique de
Louvain, Brussels, Belgium; 7 Immunology, Hopital Européen Georges
Pompidou, Paris, France
Background: Colorectal cancer TCI is a strong prognostic factor for survival
after primary tumor resection. Curative surgery of LCM is the only hope for
cure of metastatic patients (pts). Nevertheless, 70% of them will relapse.
Purpose/Objective: TCI analysis of LCM is poorly characterized and could
be a prognostic factor as in primary tumor.
Materials and Methods: Pts engaged for curative liver surgery after preoperative treatment with available FFPE blocks for all resected LCM, were
included. An immunoscore (IS), defined by the TCI in the center (CT) and
the invasive margin (IM) for each LCM was determined using whole-slide
quantitative immunohistochemistry (markers: CD3, CD8, CD45RO). The
mean value of the 3 most infiltrated fields (0.8 mm2 ) for each markers was
defined in the CT and IM for all LCM. The total number of high densities (Hi,
above the cut-off at the median density) in CT and IM for each marker was
used to stratify pts for the IS. The markers were combined 2 by 2 in CT and
IM (CD3-CD8, CD3-CD45RO, CD8-CD45RO) and finally regrouped to an IS
of 0–2 Hi (IS0–2: low TCI) or 3–4 Hi (IS3–4: high TCI). For pts with multiple
LCM; the median value of all densities, the least and the most infiltrated
LCM/pt were analyzed. Cumulative DFS/OS analyses were performed using
the Kaplan-Meier estimator. OS/DFS analyses were made using univariate
Cox regression and compared by log-rank tests (IS0–2 vs 3–4).
Results: 59 patients (M/F 1.1, 203 LCM, mean 3.4/pt, synchr/metachr
5.4) were included. IS3–4 in the least infiltrated metastasis is significantly
associated with OS and DFS for all markers combinations.
LCM/pt
Median of all
Markers
Survival
CD3-CD8
DFS
OS
DFS
OS
DFS
OS
DFS
OS
DFS
OS
DFS
OS
DFS
OS
DFS
OS
DFS
OS
CD3-CD45RO
CD8-CD45RO
Least infiltrated
CD3-CD8
CD3-CD45RO
CD8-CD45RO
Most infiltrated
CD3-CD8
CD3-CD45RO
CD8-CD45RO
HR
Log-rank
Months
(IS0–2 vs 3–4; p-value (IS0–2 vs 3–4)
95% CI)
1.2 (0.7–2.3)
2.4 (0.7–7.3)
1.5 (0.8–2.9)
2.2 (0.8–5.9)
1.0 (0.6–2.0)
1.0 (0.4–2.9)
1.8 (1.0–3.4)
8.8 (2.0–39.1)
2.5 (1.3–4.9)
4.0 (1.2–14.2)
2.0 (1.0–3.7)
2.6 (0.9–7.6)
1.0 (0.6–1.9)
2.1 (0.7–6.6)
1.7 (0.9–3.2)
3.7 (0.8–16.2)
1.6 (0.8–3.2)
2.4 (0.7–8.4)
0.48
0.12
0.16
0.11
0.87
0.17
0.05
0.0007
0.004
0.01
0.03
0.06
0.93
0.17
0.12
0.06
0.16
0.16
8.0 vs 14.9
27.9 vs NR
8.0 vs 17.0
31.8 vs NR
8.4 vs 16.0
Poster Presentations
Conclusions: The TCI score (IS0–2 vs 3–4) determined in the least infiltrated
LCM/pt is a prognostic factor.
MC13-0062
Glioblastoma patients with arterio-venous normalization during
anti-angiogenic therapy have prolonged survival
K. Emblem 1 , T.T. Batchelor 2 , E.R. Gerstner 2 , D.G. Duda 3 , M.C. Pinho 1 ,
M. Ancukiewicz 3 , P.Y. Wen 4 , B.R. Rosen 1 , A.G. Sorensen 5 , R.K. Jain 3 .
1 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts
General Hospital, Boston, USA; 2 Department of Neurology, Massachusetts
General Hospital, Boston, USA; 3 Department of Radiation Oncology,
Massachusetts General Hospital, Boston, USA; 4 Center for Neuro-Oncology,
Dana-Farber Cancer Institute, Boston, USA; 5 Siemens Healthcare North
America, Siemens, Boston, USA
Background: Vessel architectural imaging (VAI) is a new paradigm in
magnetic resonance imaging (MRI) of cancer for assessment of vessel type
and relative oxygen saturation (SO2 ) levels [1].
Purpose/Objective: We used VAI to monitor vascular remodeling in newly
diagnosed glioblastoma (nGBM) patients treated with the anti-angiogenic
agent cediranib and chemo-radiation.
Materials and Methods: In this IRB-approved phase I/II study of cediranib
(NCT00662506), an oral pan-VEGF inhibitor [2], 40 patients with nGBM were
imaged weekly for 6 weeks during therapy and then monthly thereafter. Our
MRI protocol included a gradient-echo and spin-echo perfusion sequence for
VAI [1]. Here, a temporal shift in the gradient-echo signal relative to that of
spin-echo is used to assess in vivo information on vessel type (fast-inflow
arterioles or slow-inflow venules) and SO2 levels. As a control group, we
included 14 patients with nGBM enrolled in a parallel study at the same
S29
institution (NCT00756106). These patients underwent identical MRI and
chemo-radiation, but without cediranib.
Results: Twenty-one patients were identified as responders by the tumor
arterio-venous ratios overlapping that of reference tissue at a minimum of
two time points during therapy (Fig. 1). Responding patients had prolonged
overall survival (OS) compared to 19 non-responding patients (median OS
= 696 d vs. 381 d, Cox; P <0.01, corrected for MGMT methylation status).
At day +21, the median SO2 level of non-responders was 20% higher than
pre-treatment, compared to −10% for responders (Mann-Whitney; P <0.05),
indicating more hypoxia in non-responding tumors.
Conclusions: Using VAI we show for the first time in humans that antiangiogenic therapy induce vascular normalization in nGBM by arterio-venous
remodeling and improved oxygenation. Patients who responded to therapy by
mimicking the vessel architecture of normal tissue had prolonged survival.
References:
[1] Emblem KE, et al. Nature Med 2013; in press.
[2] Batchelor TT, et al. J Clin Oncol 2010;28:2817–23.
MC13-0063
MicroRNA-mRNA networks for identification of biomarkers for breast
cancer
A.F. Evangelista, T. Macedo, R.J.S. Oliveira, M.M.C. Marques. Molecular
Oncology Research Center, Research and Teaching Institute, Barretos
Cancer Hospital, Barretos, Brazil
Background: MicroRNAs (miRNAs) are highly conserved small noncoding molecules (∼22 nt) involved in post-transcriptional regulation. These
molecules are playing important role in a range of disease, especially in
cancer. Considering the importance of miRNAs as non-invasive biomarkers,
the identification of mRNA targets is important to elucidate molecular
mechanisms for future target therapies.
Purpose/Objective: Our aim was to identify microRNAs biomarkers by integration of mRNA and miRNAs expression profiles using bioinformatics tools.
Materials and Methods: In this study we performed mRNA and miRNA
Agilent microarrays of breast cancer cell lines, classified in different molecular
subtypes, such as luminal (T47D, MCF-7 and MCF-7/AZ), Her2 overexpression (SK-BR3 and BT-20), triple negative (MDA-MB-231 and Hs578T)
and normal phenotype (HB4A). All the microarray data analyses were
performed using the R environment. The anti correlated expression profiles of
differentially expressed miRNAs and mRNAs were considered and integrated
networks were constructed using GenMiR algorithm. The targets identified
were compared with those predicted by miRDip tool and functional analyses
were performed using DAVID and Panther databases.
Results: Unsupervised analysis revealed separation according to molecular
subtype in both mRNA and miRNA expression profiles. It was constructed
miRNA-mRNA networks for each one of the 70 miRNAs differentially
expressed, identified according to ANOVA p<0.01 bonferroni-corrected,
some of them previously associated with breast cancer progression, such
as miR-10, miR-21 miR-31, miR-221/222 and let7a. Their targets could be
grouped according to biological mechanisms, pathways in cancer and breast
cancer molecular subtype.
Conclusions: In conclusion, the present study identified several miRNA
biomarkers and targets of interest in miRNA-mRNA networks. Financial
support: FAPESP.
MC13-0064
Identification of a putative precursor lesion of papillary thyroid
carcinoma by cyclin D1 overexpression and p38 MAPK
phosphorylation
M. Lamba Saini 1 , B. Weynand 1 , J. Rahier 1 , M. Mourad 2 , M. Hamoir 3 ,
E. Marbaix 1 . 1 Pathology, Université catholique de Louvain, Brussels,
Belgium; 2 Surgery, Université catholique de Louvain, Brussels, Belgium;
3 Otorhinolaryngology, Université catholique de Louvain, Brussels, Belgium
Figure 1. Vessel architectural imaging. (A) Pre-treatment MRI including VAI for identification of vessel type. (B) Corresponding MRI during therapy. Note the change in
the arterio-venus ratio compared to pre-treatment. (C) Average arterio-venous ratios
for responding and non-responding patients. Responders mimic the arterio-venous ratios of healthy tissue during therapy. Similar to non-responders, a collective vascular
normalization is not observed in the control study. (D) Patients with arterio-venous normalization have prolonged OS.
Background: Papillary thyroid cancer (PTC) is the commonest endocrine
malignancy. Though significant progress has been made to understand the
pathways involved in the tumorigenesis of PTC, no precursor lesion has been
identified yet.
Purpose/Objective: The present study aims to identify and understand the
precursor lesion of PTC and its molecular markers.
Materials and Methods: Thirteen cases of metastatic PTC, papillary microcarcinoma and follicular variant of PTC (FVPTC) were identified from
S30
a histological review of 510 cases. In addition, 13 cases of a subset of
follicular adenomatoid nodules with focal areas showing nuclear features
characteristic of PTC, identified as putative PTC precursor lesion, were also
analyzed. Immunohistochemical analysis of galectin-3, HBME-1, CK 19 and
the proliferation markers Ki 67 and cyclin D1 was performed. Lesions were
analyzed for cyclin D1 gene amplification by fluorescent in situ hybridization.
PTC also frequently carries several genetic alterations in genes coding
for proteins that activate the mitogen-activated protein kinases (MAPK)
signaling pathway, which plays a key role in the regulation of cell growth and
differentiation. The role of MAPK pathway activity in PTC was investigated by
immunohistochemical labelling of phosphorylated ERK, JNK and p38.
Results: All putative precursor lesions showed immunolabelling of cyclin D1
and Ki 67; 11/13 cases showed immunolabelling of CK 19; 10/13 cases
showed immunolabelling of HBME-1 and 4/13 cases showed immunolabelling
of galectin-3. Surrounding adenomatoid areas showed no to faint focal
staining of cyclin D1, HBME-1 and galectin-3 in all thirteen cases. A low
rate of cyclin D1 gene amplification (Figure) was identified in a significant
proportion of cells in the putative precursor lesion as compared to surrounding
benign adenomatoid areas.
ERK and JNK activation was seen in 50 and 35 percent of PTC cases with immunolabelling in less than 10 percent of cells. p38 MAPK phosphorylation was
seen as abundant cytoplasmic immunolabelling in 55% of PTC cases and 60%
of putative precursor lesion cases. A one way ANOVA test showed significant
difference between the ERK, JNK and p38 phosphorylation (p<0.01).
Poster Presentations
(GEP) to sub-classify patients and predict outcome. Although promising,
these assays require fresh frozen tissue and for most health centers remain
prohibitively out of reach due to cost.
Purpose/Objective: We sought to confirm our original observation that
increasing levels of VEGF and BCL6 were associated with reduced outcome
using an expanded patient cohort evaluated with quantitative immunofluorescence (QIF). In addition, we wanted to assess whether QIF, using biomarkers
currently employed in the Colomo and Hans algorithm, is comparable to GEP
data, for risk stratification.
Materials and Methods: Complete clinical and QIF data for 118 patients from
three different sites in Spain were evaluated to predict response to standard
R-CHOP. Multiplex QIF with CRI Nuance imaging software was performed for
selected markers including: MUM1, CD10, CD20, BCL6, BCL2, VEGF, and
CMYC. The Colomo and Hans algorithm’s using QIF were compared with
previously obtained GEP data on 36 patients classified as either ABC (n=14)
or GCB (n=22). Kaplan-Meier survival function curves, concordance index
(CoI) and multivariate models were employed to associate marker expression
with OS and PFS.
Results: For all three cohorts, both low IPI and female gender predicted good
overall survival (p<0.001, respectively). We validated our previous VEGF cutpoint and confirmed high levels were associated with poor PFS (0.042). We
then re-calibrated the VEGF cut-point on 118 patients and further improved
this association for both OS (p=0.003) and PFS (p=0.004). We also validated
our prior BCL6 cut-point and confirmed high levels were associated with poor
PFS (p=0.001) and after re-calibration the results were even more significant
(OS, p=0.008; PFS, p=0.001). In addition, increasing amounts of CMYC were
associated with poor PFS and OS, respectively (p=0.014, 0.021). Mum1
by QIF alone was able to risk stratify patients classified by GEP (p<0.05)
suggesting a role for IF and other markers in future algorithms. Best multivariate model to predict OS or PFS included the IPI score and BCL6. Clinical
heterogeneity impacted on selected marker performance between cohorts.
Conclusions: VEGF and BCL6 may be useful markers for predicting likely
patient-specific response to current therapies. QIF with additional biomarkers
and integrated with clinical data should be comparable with GEP to risk
stratify patients in the future.
MC13-0066
ORILAB a functional and molecular imaging corelab for cancer
research
Figure 1. Amplification of cyclin D1 gene seen in the putative precursor lesion using
FISH. Cyclin D1 gene appears in red whereas chromosome centromeric repeat region
is green (bar = 20 μm).
Conclusions: Increased expression of cyclin D1 and amplification of its gene
along with immunolabelling of HBME-1 and p38 phosphorylation in areas
showing cytological features of PTC within follicular adenomatoid nodules
suggest that these areas could correspond to a precursor lesion of follicular
variant of PTC. Increased expression of p38-MAPK cascade in PTC variants
indicate that it is functional in PTC. p38-MAPK hyper-expression in the
precursor lesion can act as a potential complementary marker. However, its
role in the tumorigenesis of PTC needs to elucidated.
MC13-0065
Quantitative assessment of VEGF, BCL6 and CMYC predicts outcome
in patients with DLBCL treated with R-CHOP: Implications for guiding
future treatment selection
M. Donovan 1 , N. Erill 2 , P. Puig 2 , A. Colomer 2 , L. Colomo 3 , E. Campo 4 .
1 Pathology, Mt. Sinai Medical Center, New York, USA; 2 Pathology, Althia
Health S.L., Barcelona, Spain; 3 Pathology, Hospital Clinic, Barcelona, Spain;
4 Pathology, Hospital Clinic, University of Barcelona, Barcelona, Spain
Background: The pathogenesis of DLBCL is both complex and heterogeneous, and pathogenetic mechanisms remain largely unknown. Although
the addition of Rituximab (R) to CHOP has significantly improved outcome,
approximately 30–40% of patients ultimately die of their disease supporting
the need to improve risk stratification and understand response to therapy.
The international prognostic index (IPI) remains the “gold standard” for
progression free survival (PFS) and overall survival (OS); however, more
recently, several groups have reported the utility of gene expression profiles
L. Belenguer-Querol 1 , T. Guiot 2 , C. Garcia 2 , S. Chao 3 , S. Drisis 3 ,
M. Lemort 3 , P. Flamen 2 . 1 Oncology Related Imaging coreLAB, Institut Jules
Bordet, Brussels, Belgium; 2 Nuclear Medicine, Institut Jules Bordet,
Brussels, Belgium; 3 Radiology, Institut Jules Bordet, Brussels, Belgium
Background: Functional and molecular imaging techniques allow the identification of additional cancer imaging biomarkers for prognosis or prediction
of patient response to a specific treatment. Biomarkers technical feasibility
and diagnostic accuracy are available yet, however large scale multicentric
trials are required to validate them before implementation in clinical routine.
Setting up these studies involving functional and molecular imaging becomes
cumbersome due to image acquisition intra and inter-center variability and
differences in image quality and analysis.
Purpose/Objective: An Oncology Related Imaging coreLAB platform, ORILAB has been established within a university dedicated cancer hospital
environment to facilitate the use of imaging biomarkers in multicentric studies
through standardization and harmonization of imaging data acquisition,
analysis and storage.
Materials and Methods: ORILAB exploits available in-house academic
resources from multiple disciplines including physicists, engineers and
physicians. The platform entails definition of imaging protocols, a Clinical
Data Management System (CDMS) to electronically capture imaging trial
data from participating sites or from image reviewers, a Quality Management
System (QMS) to assure quality of source data and a centralized review
(CR) for image interpretation. The CR is constituted by Nuclear Medicine
and Radiology physicians with extensive experience in the development
of new cancer biomarkers and with a special interest in translating these
imaging procedures into clinical trials which demands greater standardization
endeavors.
Results: Imaging protocols describe guidelines for standardized acquisition
and transmission of imaging data reducing intra and inter-center variability.
Electronic encoding of imaging trial data results in faster and more reliable
input of trial data in multicentric studies by an earlier detection of noncompliance and queries. The QMS allows the adaptation of the CDMS workflow to
Poster Presentations
imaging data characteristics, such as automatic extraction of relevant imaging
information and visualization of trial images. New analysis tools developed
using accepted algorithms and models from the literature but absent on
commercial platforms allow more efficient and reproducible extraction of
relevant imaging parameters. Imaging data analyzed with identical tools and
in a centralized review approach diminishes inter-observer variability.
Conclusions: Regardless of generalization of morphology-based response
evaluation criteria, a large panel of other functional and molecular imaging
techniques for evaluating new drugs in oncology is underused due to a lack
of standardization. We created a qualified multidisciplinary team to manage
all clinical trial stages involving imaging data under strict standardization
and quality procedures, reducing intermediaries and contributing to a faster
adoption of innovative image biomarkers in multicentric trials.
MC13-0067
Association between Kras mutation in circulating cell-free tumor DNA
and clinical progression of colorectal cancer in patients receiving
cetuximab
M. Del Re 1 , P. Ulivi 2 , F. Belcari 1 , A. Passardi 2 , W. Zoli 2 , D. Amadori 2 ,
R. Danesi 1 . 1 Clinical and Experimental Medicine, University of Pisa, Pisa,
Italy; 2 Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e
la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
Background: Cell-free tumor DNA (cftDNA) is released into the circulation
and its recovery from plasma is a minimally invasive alternative to tumor
biopsy for selection of appropriate treatments based on molecular profiling.
The periodic monitoring of cftDNA for the identification of molecular changes
associated with resistance to target-specific treatments is a potentially
powerful approach to the optimization of drug sequences based on the
evolving mutational status of the tumor.
Purpose/Objective: Since Kras-mutated cell clones may arise under the
selective pressure exerted by cetuximab on a wild type tumor, the present
study screened Kras mutations in a small cohort of patients resistant to
cetuximab treatment.
Materials and Methods: Three Kras wild-type patients at diagnosis with
radiologic evidence of disease progression (PD) while on cetuximab were
screened for the developent of Kras mutations as a mechanism of secondary
resistance. Primary tumor at diagnosis and peripheral blood samples (6
ml) were drawn from patients at pre-cetuximab time-point (baseline) and
at PD during cetuximab treatment. DNA was extracted from plasma with
QIAamp Circulating Nucleic Acid Kit to recover DNA fragments of ≤1000
bp. PCR amplification was carried out with a QX100™ ddPCR™ System
(Bio-Rad) on 20-μL samples containing cftDNA and TaqMan probes for
KRAS G12D (35G>A) and G12V (35G>T) labeled with FAM/VIC. Samples
were then loaded into a droplet reader, which discriminates the difference in
fluorescence amplitudes on the basis of target gene amplification.
Results: Testing of the cftDNA samples at PD in patient 1 and 2 showed the
presence of the Kras mutation G12V and the G12D in patient 3. Interestingly,
pre-cetuximab cftDNA was positive for patients 2 and 3, but was not sufficient
to test the mutational status of Kras in patient 1.
Conclusions: ddPCR is a third-generation PCR technique for highly sensitive
detection of DNA fragments. Detection of mutations in cftDNA by advanced
technological platforms has important applications in the monitoring of
patients for the occurrence of secondary mutations that render their tumors
resistant to target-specific anticancer agents.
Acknowledgments: This study was funded in part by MIUR/PRIN 2011-2012
(Rome, Italy).
MC13-0068
National Cancer Institute (US) clinical assay development program
B. Conley 1 , B.A. Conley 1 , T.G. Lively 1 , J. Rohan 2 , S. Bharti 1 ,
M.M. Cavenagh 1 , C. Lih 2 , P.M. Williams 2 . 1 DCDT/CDP, National Cancer
Institute, Bethesda, MD, USA; 2 DCTD/FNLCR, National Cancer Institute,
Bethesda, MD, USA
Background: Discoverers of predictive or prognostic molecular features for
cancer often do not have the resources to analytically validate a “locked
down” assay.
Purpose/Objective: The Clinical Assay Development Program (CADP) was
created in 2011 to provide accessible resources to assay developers to
transition promising markers/signatures into validated assays for use in
clinical trials (http://cadp.cancer.gov/).
S31
Materials and Methods: Clinical (CLIA accredited) laboratory services are
provided through the Clinical Assay Development Network of 8 conracted
laboratories and/or by a research and CLIA accredited laboratory at FNLCR.
Tissue resources are also provided. Applicants from academia, industry
or government are eligible and must provide one intended clinical use, a
prototype assay, and relevant marker prevalence information. Applicants must
also describe the clinical need, the current state of the assay, and future plans
for assay development (e.g., use in a clinical trial). Examples of services
provided include platform migration, standard operating procedure (SOP)
development, cutpoint validation, statistical assistance, etc. Applications
recommened after evaluation by a panel of outside experts are reviewed
internally to ensure availability of appropriate resources. The successful
application is overseen by a project management team: project manager,
National Cancer Institute subject matter experts, expertise from contracted
resources and the assay submitter. Intellectual property remains with the
assay submitter. After validation, assay perfomance specifics and SOPs are
returned to the assay submitter.
Results: To date, two assays have been validated (in a 14 month time frame
for both) and 5 are in project management. Platforms include gene expression
analysis, ELISA, IHC/IFA, DNA sequencing, FISH, PCR. The success rate for
applications is about 25%. Additional applicants have used the advice of the
CADP team to improve development strategy.
Conclusions: There is continued need for education and assistance in assay
development for assays intended for use in clinical trials. Each assay presents
unique challenges and solutions. Creativity is needed in finding appropriate
specimens for assay validation. To date, the initial results of CADP are
promising.
MC13-0069
Obtaining maximal information from limited FFPE tissue specimens:
Development and validation of a 4-gene custom NGS panel for a GIST
clinical trial
P. Fang 1 , Z. Yan 1 , J. Kristof 1 , J. Staha 1 , K. Pelak 1 , M.R. Palmer 2 ,
C. Tribouley 3 , C. Spittle 1 , C. Galderisi 1 , J. Li 1 . 1 Assay Development,
MolecularMD Corp, Portland, USA; 2 Oncology Translational Medicine,
Novartis Pharmaceuticals Corporation, Cambridge, USA; 3 Oncology
Correlative Sciences, Novartis Pharmaceuticals Corporation, Florham Park,
USA
Background: Limited tissue availability and FFPE sample quality present
challenges for cancer mutation profiling, particularly for solid tumors such
as GIST. Maximizing the data from specimens requires advanced profiling
techniques; focused NGS panels provide higher sensitivity and more comprehensive sequence coverage than other methods and enable multiplexed
examination of several genes related to a given therapy.
Purpose/Objective: A custom GIST panel was designed to profile 4 drug
pathway related genes using minimal DNA from FFPE tissue, which may aid
in the interpretation of drug responses.
Materials and Methods: The region of interest (ROI) includes 20 exons
across c-KIT, PTEN, PIK3CA and PDGFRα, a total of 2.1 kb. Primers were
designed using Ion AmpliSeq Designer and MolecularMD’s proprietary primer
design method. 28 FFPE specimens representing primarily GI tumors were
analyzed. Sequencing was performed on the Ion PGM, and Data were
analyzed with Torrent Suite 3.4.2 and the MolecularMD analysis pipeline.
Results: Assay Specificity: No critical variants (non-synonymous and nonintronic) were detected in 6 normal FFPE DNA samples. LOD: The LOD
of the assay is 5% for SBS and indels, as determined by sequencing cell
line dilutions. Precision: 100% of the critical variants in the DNA used in the
precision study were reproducibly detected in 3/3 runs. Accuracy: 47 critical
variants with frequencies ranging from 7% to 79% (28 SBS, 11 deletions, 3
deletions with insertions, and 5 insertions) were detected in 28 tumor FFPE
samples. The maximum observed deletion and insertion sizes were 51 bp
and 45 kb, respectively. Variants were observed in all 4 of the targeted genes.
All variants with sufficient DNA quantity (n=46) were confirmed by direct
Sanger sequencing (variants with frequency >10%) or Sanger sequencing
following mutation enrichment (variants with frequency <10%).
Conclusions: This validation study demonstrates that with only 30 ng DNA
input, the KIT-PDGFRα-PIK3CA-PTEN custom NGS Panel is capable of
accurately detecting mutations, including SBS and small indels, in 20 exons
across 4 genes. This custom panel is tailored to the demands of a targeted
drug trial, and was designed to identify mutations in genes and regions
most relevant to the interpretation of trial results. A custom NGS panel is
scalable, in terms of ROI size and number of samples to be tested, and
S32
can be employed to maximize the breadth and depth of profiling information
generated from a given tissue specimen.
MC13-0070
Whole blood RNA signature as prognostic and predictive biomarker in
genitourinary malignancies
W. Oh 1 , U. Chippada Venkata 1 , L. Wang 2 , E. Reese 1 , T. Yee 1 ,
T. Kochukoshy 1 , C. Tsao 1 , M. Galsky 1 , J. Zhu 2 , Y. Gong 1 .
1 Hematology/Medical Oncology, Mt. Sinai Medical Center, New York, USA;
2 Genetics and Genomic Sciences, Mt. Sinai Medical Center, New York, USA
Background: We developed a whole-blood RNA transcript-based 6-gene signature (consisting of ABL2, SEMA4D, ITGAL, and C1QA, TIMP1, CDKN1A)
which separated patients into high and low risk survival groups in castration
resistant prostate cancer (CRPC) (Ross et al. Lancet Oncology, 2012).
Purpose/Objective: In this study, we validate the prognostic signature on
an updated qPCR platform and examine dynamic changes in the signature
during disease progression and with treatment. The application of the
signature across other genitourinary malignancies is also explored.
Materials and Methods: Whole blood was collected in PAX gene RNA tubes
from prostate (n=53), bladder (n=18) and renal (n=13) cancer patients in
different stages of the disease and on various treatment regimens. A subset
of patients had serial blood draws at multiple time points. Pre and post
treatment blood was also drawn from CRPC patients on an oral satraplatin
clinical trial (NCT01289067; PI: Oh). The 6-gene survival score for each blood
draw was derived as previously described.
Results: The 6-gene score generated on a new qPCR platform is highly
reproducible (CV <3% between triplicates). The signature remains highly
prognostic, separating CRPC patients into high and low risk groups of death
(p-value of logrank test <0.001). Interestingly, patients in earlier disease
stages had significantly lower scores compared to patients with CRPC
(p-value of t-test = 0.036). Patients (n=15) who had serial blood draws showed
different trends of scores with time, with a subset of patients demonstrating
rises preceding death. In a pilot study to determine the impact of treatment
on the prognostic score, we observed that 2 satraplatin responders showed
stable scores over the course of one year of therapy, whereas 2 progressing
non-responders showed significantly increased scores after 2 and 4 months
of treatment, indicating the potential use of the signature to assess treatment
outcome. Further, preliminary analysis showed that the 6-gene signature may
have prognostic value in bladder and renal cancers, which will be confirmed
in a larger cohort.
Conclusions: Our results suggest that the 6-gene whole blood RNA
signature has compelling prognostic ability independent of platform, provides
crucial prognostic information and is possibly indicative of an individual’s
response to disease progression and therapy.
MC13-0072
Tumor perfusion during bevacizumab and irinotecan in recurrent
glioblastoma: A multimodal approach
M. Eoli 1 , A. Di Stefano 2 , D. Aquino 3 , A. Scotti 3 , E. Anghileri 1 , L. Cuppini 1 ,
E. Prodi 3 , G. Finocchiaro 1 , M.G. Bruzzone 3 . 1 Neuro-Oncology, Fondazione
IRCCS Istituto Neurologico C. Besta, Milan; 2 General Neurology, Fondazione IRCCS Istituto Neurologico Nazionale C. Mondino, Pavia; 3 NeuroRadiology, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
Background: Angiogenesis is a requirement for progression of glioblastoma
(GBM) and Bevacizumab (Bev), an antibody directed to vascular endothelial
growth factor (VEGF), was recently used to treat GBM.
However in vivo modifications induced by treatment are under active
investigation.
Purpose/Objective: To analyze tumor changes induced by Irinotecan (Ir)
and Bev, we use two different methodologies: relative CBV variation (rCBV)
and Difference Perfusion Maps (DPMs).
Materials and Methods: 42 recurrent GBM patients underwent Bev (10
mg/kg) and Ir (125 or 340 mg/m2 ) every 2 weeks and were followed up with
a radiological protocol, including Dynamic Susceptibility Contrast MRI every
8 weeks. Radiological responses were assessed based on RANO criteria
(Wen et al, 2012). Two methods were used to assess perfusion changes. In
method A, relative CBV variation after 8 weeks of treatment was calculated
through semi-automatic ROI placement in the same anatomic region as in
baseline. In method B, relative CBV variations with respect to baseline values
were calculated into the evolving tumor region by voxel-by-voxel difference.
Poster Presentations
DPMs were created showing where rCBV significantly increased, decreased
or remained unchanged.
Results: Method A showed a significant decrease of rCBV in patients with
stable disease or partial response after 8 weeks of treatment (p=0.01) while
patients with tumor progression maintained elevated levels of rCBV (p=0.38).
Method B, based on DPMs, showed rCBV was increased in 35% (±16%) of
tumor volume (8 week-increased blood volume, 8w-IBV) and was decreased
in 17% (±14%) (8 week-decreased blood volume, 8w-DBV).
Patients presenting 8w-IBV higher than 18% (first quartile) showed a significantly longer PFS (p=0.045) and OS (p=0.016). Using DPM we observed that
early increase in global perfusion is related to better survival.
Conclusions: Further studies will be necessary to confirm the potential of
DPMs in predicting response to antiangiogenic therapy.
MC13-0073
MiR-183 and miR-494 as risk biomarkers for breast cancer development
T. Macedo, A.F. Evangelista, A.F.L. Marino, R.A.C. Vieira, A.F. Longatto,
V.A.O. Silva, D.O. Vidal, M.M.C. Marques. Molecular Oncology Research
Center, Research and Teaching Institute, Barretos Cancer Hospital,
Barretos, Brazil
Background: MicroRNAs (miRNAs) are small non-coding molecules (∼22 nt)
considered as new important biomarkers due to their stability and distribution
in virtually all tissues. Recent studies have suggested that microRNAs
(miRNAs) are involved in breast cancer initiation and progression by silencing
the expression of their target genes. However, miRNAs deregulation during
breast cancer development is poorly understood.
Purpose/Objective: Our aim was to identify miRNA biomarkers for breast
cancer development.
Materials and Methods: We performed Agilent miRNA microarray (∼866
human miRNAs) from 64 non-metastatic vs. metastatic patients. All the
microarray data analyses were done in R statistical environment. ROC and
relative risk curve were applied to miRNA expression values identifying two
important biomarkers, miR-183 and miR-494. To evaluate the role of these microRNAs, we performed in vitro functional assays in metastatic breast cancer
cell lines. Overexpression and silencing interventions were used to evaluate
the role of miRNAs miR-183 and miR-494 in MDA-MB-468, MDA-MB-231 and
MCF7 breast carcinoma cell lines. Cellular behavior (proliferation, migration
and invasion) was tested by XCelligence system. Finally, target prediction
was done using nine different bioinformatics algorithms and the technics of
real-time PCR and Western blot were applied to confirm the identified targets.
Results: The initial miRNA screening in breast cancer patients pointed
two important biomarkers for breast cancer development, miR-183 and
miR-494. The expression of these miRNAs were confirmed by real-time PCR.
Further functional assays confirmed their role in breast cancer, especially
by their influence in cell behavior (proliferation, invasion and migration).
It was identified several targets by bioinformatics tools and we confirmed
the regulation of targets of importance, such as PTEN and specific matrix
metalloproteinases.
Conclusions: We identified two miRNAs, miR-183 and miR-494, as important miRNA biomarkers for breast cancer development. Financial support:
FAPESP.
MC13-0074
Correlation between p53 immunohistochemistry and mutational status
in human melanoma tumors
M. Palmer, K. Horrigan, Y. Wang, Y. Yu, D.A. Sirko-Osadsa, B.H. Lee. OTM,
Novartis Institutes for BioMedical Research Inc., Cambridge, USA
Background: Oncogenic p53 alterations can affect the efficacy of novel
therapeutic molecules that target genes including HDM2 which negatively
regulate normal p53 function. Therefore, proper characterization of p53 status
in tumor samples is important for appropriate patient selection and clinical
trial enrollment for these novel therapies.
Purpose/Objective: This study examines the utility of an IHC H-score for
p53 for identifying TP53 mutations in human melanoma samples. By direct
comparison of these technologies we hope to determine the fraction of
mutation positive melanoma that can be detected by IHC.
Materials and Methods: Here we characterized a set of human primary
melanoma tumors using both immunohistochemistry (IHC) for p53 protein
expression and full gene sequencing. An IHC H-score, calculated for each
tumor, was correlated to mutational status.
Poster Presentations
Results: Tumors with p53 mutations were found to have H-scores of 120 or
greater, except for truncating p53 mutations which had H-scores of 0. Tumors
with no detectable p53 mutations had H-scores ranging from 0 to 120.
Conclusions: The findings support that segregation of p53 mutant versus
wild-type melanomas is possible by p53 IHC, although careful consideration
must be made for tumors that harbor p53 truncating mutations, which may be
completely negative for p53 expression by IHC.
MC13-0076
CHFR silencing and microsatellite instability as predictors of
sensitivity to docetaxel and gemcitabine in colorectal cancer
L. Pelosof 1 , S. Yerram 2 , N. Ahuja 1 , A. Delmas 2 , L. Danilova 3 , J. Herman 1 ,
N. Azad 4 . 1 Cancer Biology Program, 2 Gastrointestinal Cancer Program,
3 Bioinformatics, 4 Gastrointestinal Cancer Program and Chemical
Therapeutics Program, Johns Hopkins University, Baltimore, USA
Background: It is increasingly recognized that even within a particular tumor
type there is heterogeneity and that epigenetic differences likely contribute to
the varying responses to standard treatment observed among patients. By
combining tumors’ epigenetic alterations with existing knowledge of drugs’
mechanisms, DNA methylation alterations can serve as predictive biomarkers
for the efficacy of particular chemotherapeutic agents which can direct
patients’ treatment. CHFR methylation is associated with taxane sensitivity
in multiple tumor types while microsatellite instability (MSI) as a predictive
marker for therapeutic effect has had conflicting results though it is possibly
associated with gemcitabine sensitivity.
Purpose/Objective: To examine CHFR methylation and MSI as predictors of
chemotherapy sensitivity to docetaxel and gemcitabine in colorectal cancer
(CRC).
Materials and Methods: Five MSI cell lines and five MSS cell lines were
assessed for their CHFR methylation status and CHFR mRNA expression
levels. Growth curves were used to assess these lines’ sensitivity or
resistance to increasing concentrations of docetaxal and gemcitabine. To
assess if CHFR re-expression results in decreased sensitivity to docetaxel,
multiple cell lines were treated with the demethylating agent 5-azacitidine and
then exposed to increasing concentrations of docetaxel. In vivo treatment of
human xenografts of RKO, CACO2, and COLO205 were also examined for
their sensitivity to gemcitabine, docetaxel, and the combination.
Results: We observed increased sensitivity to gemcitabine in cell lines with
MSI and to docetaxel in cell lines with CHFR inactivation via DNA methylation.
Cells lines with silenced CHFR that demonstrated CHFR re-expression
with 5-azacitidine treatment showed decreased sensitivity to docetaxel. Cell
lines with silenced CHFR that did not have significant CHFR re-expression
showed no change in sensitivity to docetaxel. In the xenograft model, the
MSI-High/CHFR -methylated line RKO had tumor growth inhibition to each
agent, and at least additive tumor growth inhibition with combination therapy.
The MSS-CHFR-unmethylated line, CACO2, was resistant to single and
combination therapy.
Conclusions: CHFR methylation in CRC cell lines predicted for sensitivity in
vitro and in vivo to docetaxel, while MSI-High cell lines were more sensitive
to gemcitabine. These data suggest that a subset of CRC patients may
be selectively sensitive to the combination of gemcitabine and docetaxel,
and are the basis for an ongoing clinical trial of this combination in a
biomarker-selected patient population.
MC13-0077
Array CGH analysis of paired metastatic biopsies obtained
pre-treatment and at resistance to FOLFOX-bevacizumab in metastatic
CRC patients
Z. Diaz 1 , E. Przybytkowski 2 , C. Lan 2 , S. McNamara 3 , A. Aguilar-Mahecha 2 ,
E. Camlioglu 4 , A. Gologan 5 , G. Batist 2 , M. Basik 6 . 1 Q-CROC, Jewish
General Hospital, Montreal, Canada; 2 Department of Oncology, Jewish
General Hospital, Montreal, Canada; 3 Translational Research Program,
Quebec Clinical Research Organization in Cancer, Montreal, Canada;
4 Department of Radiology, Jewish General Hospital, Montreal, Canada;
5 Department of Pathology, Jewish General Hospital, Montreal, Canada;
6 Department of Oncology and Surgery, Jewish General Hospital, Montreal,
Canada
Background: Biopsy-driven clinical trials are essential to develop personalized therapeutics, since many critical questions are best addressed in
the tumor tissue being treated. Currently, first-line treatment regimen for
S33
metastatic colorectal cancer (CRC) consists of either FOLFOX or FOLFIRI in
combination with bevacizumab. However, there are no known biomarkers to
predict which patients are likely to respond or be resistant to either treatment.
Purpose/Objective: Our objective was to identify biomarkers of clinical
resistance to FOLFOX-bevacizumab. To do so, we designed a prospective
biopsy-driven study in patients with metastatic CRC (NCT00984048) receiving
first-line treatment with FOLFOX-bevacizumab.
Materials and Methods: Eligible patients had confirmed metastatic CRC,
measurable disease, and consented to tumor biopsy (three needle-core
biopsies (NCBs) of a non-resectable liver metastasis) before treatment and
at resistance. This study was approved at several Canadian hospitals, and
recruitment is still ongoing. Patient biopsy samples were analyzed for DNA
copy number alterations using the 244K Agilent platform.
Results: Thus far, sixty patients agreed to partake in this ongoing multicenter trial and to provide NCBs from liver metastases. Using standard
operating procedures developed for this trial, we were able to both preserve
morphology and obtain high-quality genomic material from biopsy tissue.
Histology was verified on every biopsy. Of the patients recruited to the
study, 3% withdrew consent before the first biopsy procedure, 3% of
biopsies were non-neoplastic, 3% were neuroendocrine, and 5% were mixed
neuroendocrine/adenocarcinoma. Not all patients agreed to, or were eligible
for a biopsy at acquired resistance to treatment. Some patients remain on
FOLFOX-bevacizumab and have not yet developed resistance. There were
10 paired biopsies that met our criteria (>60% neoplastic cells and <20%
necrosis) for downstream molecular profiling. We have already demonstrated
in a previous pilot study that the biopsies are suitable for DNA analysis (array
comparative genomic hybridization, methylation profiling) and RNA analysis
(gene expression profiling, splicing isoforms variants and micro RNA profiling). Here we report on array CGH analysis from 10 paired liver metastatic
biopsies obtained pre-treatment and at resistance to FOLFOX-bevacizumab
in metastatic colorectal cancer patients.
Conclusions: We conclude that obtaining serial liver NCBs is challenging,
but safe and feasible in metastatic CRC patients with unresectable liver
disease. This study will provide insight on the relevance of metastatic tissue
to identify genomic markers of clinical resistance.
MC13-0078
PARP1 variants associated with response to Temozolomide in
metastatic melanoma patients
A. Sedgewick 1 , M. Romkes 2 , S. Buch 2 , L. Villaruz 2 , I. Abecassis 3 ,
M. Saul 3 , J.M. Kirkwood 3 , P.V. Benos 4 , H. Tawbi 3 . 1 Joint Carnegie Mellon
University-University of Pittsburgh Program in Computational Biology,
University of Pittsburgh, Pittsburgh, USA; 2 University of Pittsburgh Cancer
Institute, University of Pittsburgh, Pittsburgh, USA; 3 University of Pittsburgh
Cancer Institute – Melanoma Program, University of Pittsburgh, Pittsburgh,
USA; 4 Department of Computational & Systems Biology, University of
Pittsburgh, Pittsburgh, USA
Background: Temozolomide (TMZ), an alkylating agent, is used in treatment
of metastatic melanoma. Response rates from TMZ alone vary (<20%) and
there are no known predictive biomarkers for response.
Purpose/Objective: We aimed to identify candidate biomarkers (SNP,
methylation and mRNA and miRNA expression) for response to TMZ in
patients with metastatic melanoma.
Materials and Methods: A selected SNP panel and whole-genome
mRNA/miRNA expression, and methylation microarray data were collected from tissues from 69 patients with metastatic melanoma treated with
TMZ. Patients were labeled as responder (n=22) or non-responder (n=47)
based on radiographic assessments. Potential biomarkers were identified
using a variety of methods including penalized regression, Mann Whitney
U test, and pairwise Markov random fields. We used data from the NCI
Developmental Therapeutics Program to find additional support for candidate
SNP markers.
Results: We identified SNPs in PARP1 (rs1805407) and PIK3R1 (rs251402)
by multiple feature selection tests as markers for response to TMZ. There
were no responders in the group of 21 patients with one or more variant
PARP1 alleles (p=5.4e−5). We examined the NCI-60 cell lines and identified
additional PARP1 SNPs that were in linkage disequilibrium with our candidate
SNP. Cell lines that had the variant were more resistant to alkylating agents.
Cyclophosphamide and Carmustine, were among the agents with the most
differential sensitivity scores between groups with and without the variant
(uncorrected p=0.014 and 0.021 respectively). Interestingly, this SNP was
also associated with increased PARP inhibitor sensitivity.
S34
Poster Presentations
Conclusions: The role of PARP1 in chemotherapy resistance is well
established and PARP inhibitors have been extensively utilized in clinical trials
to improve chemotherapy response. Our findings suggest that the PARP1
SNP rs1805407 is linked to a potentially more active form of PARP1 that
increases resistance to TMZ. This was supported by findings from the NCI-60
cell lines. We are validating those results in appropriate cell line models. The
PIK3R1 SNP highlights the role of altered signaling pathways in melanoma
and its functional role is being examined. The PARP1 SNP rs1805407 may
serve as a biomarker for response to TMZ chemotherapy and potentially
PARP inhibitor sensitivity in metastatic melanoma.
MC13-0080
Somatic mutations of the EGFR, KRAS and BRAF genes: Heterogeneity
in circulating epithalial tumor cells (CETC) as determined using the
Cobas® Z 480 analyzer
K. Pachmann, M. Pizon, D. Zimon, E.L. Stein. Transfusion Center,
Transfusion Center, Bayreuth, Germany
Background: Targeted therapies directed specifically against somatic mutations enhancing the activity of signalling pathways have been shown to
improve outcome compared with cytotoxic chemotherapies in patients with
advanced tumors carrying the respective mutations.
Purpose/Objective: This requires tests to identify such mutations which are
mainly performed on formalin fixed material from the primary tumor. However,
such material is not always available and, even more importantly, properties
of cells with metastatic potential may change during the course of disease.
In contrast, using maintrac® , a nondissipative approach avoiding enrichment
steps, CETC be detected and individually isolated in almost all patients
with lung and colon cancer and melanoma at different times of disease
and therefore can provide a liquid biopsy to monitor the course of disease.
We, here, report on the successful analysis of such isolated cells for gene
mutations in tumor driver genes EGFR, KRAS and BRAF.
Materials and Methods: Blood from patients with non-small cell lung cancer,
colon cancer and malignant melanoma was analyzed for cells positive for
epithelial antigen (EpCAM) using the maintrac® approach, which avoids cell
selection, and an image anlysis system or laser scanning cytometry for detection. Between 8 and 20 EpCAM positive cells from each patient were isolated
individually using a semiautomated capillary approach and deposited one by
one into micro cups. The DNA was subsequently amplified by whole genome
amplification and assayed using either the cobas® EGFR Mutation Test, the
cobas® KRAS Mutation Test or the cobas® BRAF V600 Mutation Test.
Results: DNA could be amplified from all indiviually isolated cells. An EGFR
mutation was detected in 12% of isolated tumor cells from a patient with
non-small cell lung cancer, the KRAS Mutation was detectable in 28% of cells
from a patient with colon cancer and the BRAF Mutation in 100% of evaluable
cells from a patient with melanoma.
Conclusions: Individually isolating epithelial tumor cells from the peripheral
blood from patients with non-small cell lung cancer, colon cancer and
melanoma allows not only detect driver mutations in circulating tumor cells
but also to determine the frequency of mutated cells. This proves, that at least
part of the CETC from the tumor. They can, in the future, be used as markers
of response to the action of drugs and contribute insight into how resistance
may be acquired.
MC13-0081
Cell cycle regulatory proteins in pancreatic cancer
Z. Simtniece 1 , I. Strumfa 1 , A. Abolins 1 , A. Vanags 2 , M. Pavars 2 , E. Vasko 1 ,
J. Gardovskis 2 . 1 Department of Pathology, Riga Stradins University, Riga,
Latvia; 2 Department of Surgery, Riga Stradins University, Riga, Latvia
Background: Pancreatic ductal carcinoma (PDAC) is one of the most aggressive cancers. Mutations or epigenetic alterations in the tumour suppressor
or cell cycle regulatory genes readjust cellular homeostasis and ability of
apoptosis (Lang et al., 1998; Angela et al., 2013). Detection of p53, p21,
p27 and cyclin D1 are described with predicting value of radiosensitivity and
chemosensitivity (Fu et al., 1998; Wang et al., 2012).
Purpose/Objective: The aim of this study was to determine the affected cell
cycle regulatory proteins and correlation of them with Ki-67 in PDAC.
Materials and Methods: Sixty-six consecutive cases of surgically treated
PDAC were evaluated retrospectively. The cases were characterised by
patient’s age, tumour TNM, stage, histological grade (G1-3), resection
margins (R0-1). Expression of Ki-67, p53, p21, p27 and cyclin D1 was
detected by immunohistochemistry (IHC) in PDAC and benign pancreatic
ducts (BPD). Descriptive statistics was performed by SPSS, version 20. The
study was approved by Committee of Ethics.
Results: In the whole group, the mean age was 63.5 years [95% confidence
interval CI: 60.6–66.0]. The most frequent tumour characteristics were: size
>2 cm: 93.9% [83.4–97.8]; T3: 93.9% [85.2–97.5]; N1: 68.8% [56.6–78.8];
stage IIA: 26.6% [17.3–38.5]; stage IIB: 64.1% [51.8–74.7]; G2: 58.5%
[46.3–69.7]; R1: 56.5% [44.0–68.1]. The main IHC data are shown in Table
1. Correlation was found between Ki-67 and p21 (p=0.01), p53 and p21
(p=0.01), p53 and p27 (p=0.00), p21 and p27 (p=0.05) expression.
Conclusions: Morphologically, pancreatic cancer is characterized by aggressive growth. The expression of the analysed cell cycle regulatory proteins
p53, p21 and cyclin D1 is frequently affected in pancreatic carcinogenesis
suggesting possible benefit from targeted treatment. The proliferation activity
shows direct correlation with p21, but the mutual association between p53,
p27 and p21 can involve more complex mechanisms.
MC13-0082
Salivary gland cancer in two male BRCA gene mutation carriers
P. Bossi 1 , C.B. Ripamonti 2 , S. Manoukian 2 , M. Colombo 2 , B. Peissel 2 ,
D. Zaffaroni 2 , L.D. Locati 1 , L. Licitra 1 , M.L. Carcangiu 3 , P. Radice 2 .
1 Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale
dei Tumori, Milan, Italy; 2 Department of Preventive and Predictive Medicine,
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 3 Department
of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Background: Germ-line mutations in BRCA genes predispose to breast and
ovarian cancers in women. In males, BRCA1 and BRCA2 mutations carriers
have a lifetime risk of breast cancer of 2% and 7% respectively and they
also exhibit an increased risk for prostate cancers. However, involvement of
BRCA mutations in other malignancies is still under investigation. No data are
available about the correlation between BRCA mutations and increased risk
of salivary gland cancers (SGC).
Purpose/Objective: To assess SGC in a cohort of patients undergoing
genetic cancer risk assessment.
Materials and Methods: We reviewed all the cases evaluated in our
Institution, for whom BRCA mutations assessment was available. Patients
with malignant SGC were retrieved.
Results: We evaluated 2260 families registered in our Institutional databases
from 1996 to 2012; 637 families were BRCA mutation positive, whereas 1623
index cases tested negative for BRCA mutations. Within mutated families, we
identified 801 carriers of BRCA1 mutation, 456 carriers of BRCA2 mutation
and 2 carriers with mutations in both genes. The review revealed two males
with SGC among the BRCA mutation carriers and no case in the non-mutated
group.
A 56 year-old BRCA1 mutation carrier developed an high-grade mucoepidermoid carcinoma of the parotid gland. He was treated with surgery and postoperative radiochemotherapy, and died 4 years later for distant metastases.
A 66-year-old BRCA2 mutation carrier developed a submandibular salivary
gland papillary cistoadenocarcinoma treated with surgery and radiation.
At 68 years, a sovraclavear node recurrence appeared and was treated
with radiotherapy, followed by parapharyngeal relapse with no treatment
opportunities. At the same age, he developed a ductal breast cancer.
Abstract MC13-0081 – Table 1. Expression of Ki-67, p53, p21, p27, cyclin D1 in PDAC and BPD
Parameter
Target
Ki-67
p53
p21
p27
Cyclin D1
Positive cases (%)
PDAC
BPD
PDAC
BPD
PDAC
BPD
100 [94.3–100]
21.8 [12.9–34.4]
1–55
0–4
20.8 [17.7–24.4]
0.4 [0.2–0.7]
69.4 [56.9–79.4]
14.0 [7.3–25.4]
0–97
0-10
30.8 [22.8–39.1]
0.65 [0.2–1.2]
93.6 [84.5–97.4]
37.5 [25.9–50.7]
0–65
0–13
23.4 [18.9–27.9]
1.5 [0.8–2.4]
100 [94.3–100]
100 [94.3–100]
6–82
26–90
34.7 [30.6–39.2]
51.5 [47.3–55.6]
80.9 [69.5–88.7]
18.6 [10.8–30.4]
0–65
0–16
19.9 [16.1–23.7]
0.9 [0.3–1.6]
Range of positive cells (%)
Mean count of positive cells (%)
Poster Presentations
Loss of heterozygosity (LOH) in tumor DNA extracted from paraffin-embedded
tissues of SGC was assessed by comparison with constitutional DNA from
matched peripheral blood leukocytes, using polymorphic markers linked to
BRCA1 and BRCA2 loci. We detected BRCA1 allele loss for the BRCA1
carrier and BRCA2 loss for the BRCA2 carrier. By sequencing analysis, we
defined that the losses affected the wild-type alleles in both cases. This
indicated somatic bi-allelic inactivation of BRCA genes, a well-documented
mechanism of cancer progression in cancers from BRCA mutation carriers.
Conclusions: BRCA1 and BRCA2 mutations carriers seem to have an
increased risk of SGC in comparison with BRCA negative cases. Further
confirmation is needed in larger cohorts.
MC13-0084
Tumor-specific DNA methylation in high-risk prostate cancer
K. Litovkin 1 , E. Lerut 2 , S. Joniau 3 , O. Geveart 4 , S. Isebaert 5 , M. Spahn 6 ,
B. Kneitz 7 , K. Haustermans 5 , A. Van Eynde 1 , M. Bollen 1 . 1 Cellular &
Molecular Medicine, KU Leuven, Leuven, Belgium; 2 Pathology University
Hospitals Leuven &, Department of Imaging and Pathology KU Leuven,
Leuven, Belgium; 3 Urology University Hospitals Leuven &, Department of
Development and Regeneration KU Leuven, Leuven, Belgium; 4 Stanford
Center for Cancer Systems Biology, Stanford University School of Medicine,
Stanford, USA; 5 Radiation Oncology University Hospitals Leuven &,
Department of Oncology KU Leuven, Leuven, Belgium; 6 University Hospital
Bern, Department of Urology, Bern, Switzerland; 7 Department of Urology
and Paediatric Urology, University Hospital Würzburg, Würzburg, Germany
S35
charide; however recent reports describe that paclitaxel could trigger the
TLR4 signalling pathway.
Purpose/Objective: Our aim was to evaluate influence of genes involved in
the TLR4 pathway in the distant-recurrence free survival in breast cancer
patients treated with neoadjuvant Taxane-Anthracycline chemotherapy.
Materials and Methods: We retrieved normalized gene expression data from
a public database (GSE25066) that includes 508 samples of breast cancer
patients profiled with the U133A microarray and treated with neoadjuvant
Taxane-Anthracycline chemotherapy. We choose randomly three cohorts
contained in that dataset as discovery group (I-SPY, LBJ/IN/GEI and MDACC
cohort1; n=244) and two cohorts as validation group (MDACC cohort2 and
USO; n=264). We screened the influence of the levels of expression of
the follow genes in the disease-free survival: TLR4, IRAK1, IRAK3, IRAK4,
TRAM, TRIF, TRAF3, TRAF6, IRF3, IRF7, SARM, SOCS3, SOCS1, DUBA,
SHP_2, PIN1, TAK1, TAB1, TAB2, NFKB1, NFKB2, IL-12P40, TNF, TTP, TAN,
TRIM38, CYLD, USP4, A20, NLRX1, IKKA, IKKB, NEMO, TRIM5, SHP-1,
SYK and CBL-B.
Results: Patients were grouped in tertiles according to the level of gene
expression for each cohort. In the discovery set, significant genes for
DFS were IRAK1 (P=0.005); IRAK4 (P=0.033); TRAF3 (P=0.032); USP4
(P<0.001); A20 (P=0.042); TRIM5 (P=0.042) and TNF (P=0.016). TLR4 was
not related to DFS. We assigned a score according to the level of expression
of each gene and its influence in the survival, (0, 0.5 and 1 according
to the tertile, where 1 was for the poorest prognostic group). An overall
score was obtained by the sum of all scores and patients were stratified in
three groups: Low-score (LS), intermediate-score (IS) and high score (HS).
Background: About a quarter of non-metastatic prostate cancers (PCa) are
classified as high-risk, based on preoperative prostate-specific antigen (PSA)
levels above 20 ng/ml, a biopsy Gleason score of 8–10 and/or an advanced
clinical stage (≥T3).
Purpose/Objective: The aim of this study was to evaluate promoter CpG
island hypermethylation in patients with high-risk PCa at five genes that have
previously been reported to be hypermethylated in PCa.
Materials and Methods: A two-step quantitative multiplex methylationspecific PCR (QM-MSP) was developed to assess methylation at the
promoters of APC, CCDN2, GSTP1, PTGS2 and RARB. Formalin-fixed
paraffin-embedded (FFPE) radical prostatectomy samples from 280 patients
with high-risk PCa, classified in two Belgian and one German cohort, were
analyzed. In addition, we examined non-cancerous FFPE prostate tissue
from 42 patients and lymph-node metastases from 16 patients. Our analysis
followed strategic steps: First, we assessed differential methylation patterns
between BPH, high-risk PCa and lymph node metastasis. Second, we studied
the associations between quantitative methylation and adverse pathological
features (pathological stage, Gleason score, biochemical recurrence and
clinical failure).
Results: We found that the combined DNA-methylation pattern of four genes
(APC, CCND2, GSTP1 and RARB loci) can distinguish high-risk PCa from
non-cancerous tissue with a specificity of 98% and a sensitivity of 96–100%.
Significant associations between RARB methylation and pathological stage,
and between GSTP1 methylation and tumor volume were found in two
cohorts. Univariate analysis revealed that the high methylation levels of
RARB and GSTP1 correlated with a higher risk for biochemical recurrence.
The hypermethylation of RARB was associated with a higher risk for clinical
failure. Interestingly, an increased methylation level at lymph node metastasis,
as compared to that of the primary tumor, was associated with a higher risk for
clinical failure. Finally, methylation levels of the selected markers were highly
correlated (Pearson correlation coefficients 0.45–0.82, P ≤0.001), hinting at a
common underlying mechanism.
Conclusions: DNA hypermethylation of APC, CCND2, GSTP1 and RARB
detected PCa with high sensitivity and specificity. Hypermethylation of RARB
and GSTP1 were associated with adverse pathological and clinical outcomes.
An increased DNA methylation in lymph-node metastatic sites, relative to that
of the primary tumor, was associated with a higher risk for clinical failure.
MC13-0085
Genes involved in TLR4 signal transduction as prognostic factors for
survival following Taxane-Anthracycline neoadjuvant chemotherapy for
invasive breast cancer
J. Pinto, P. Valdiviezo, A. Aguilar, C. Flores, R. Velazco, J. Suazo, C. Vallejos,
H. Gómez. Division de Investigación, Oncosalud-Auna, Lima, Peru
Background: TLR4 receptor is typically activated by bacterial lipopolysac-
Figure 1
S36
5-years DFS rates for de discovery set were LS=89%; IS=64.3%; HS=48.4%
(P=0.001) and for the validation set were LS=89.8%, IS=77.2%; HS=67.9%
(P=0.007). In the validation set, patients with residual disease had 5-years
DFS rates of LS=85.4%, IS=73.7%; HS=58.7% (P=0.004). Differences were
also observed in the groups with clinical stages I/II (P=0.031) and clinical
stages III (P=0.005), but not for PAM50 subtypes.
Conclusions: Levels of expression of genes involved in TLR4 signal
transduction plays an important role in response for Taxanes-Anthracyclines
therapy. We were able to identify a subgroup of patients with low score of
signalling genes who could benefit from taxane-based therapies.
MC13-0086
Acquired resistance to Hedgehog inhibitor through smoothened
mutation in basal cell carcinoma
P. Bossi 1 , F. Perrone 2 , B. Cortelazzi 2 , L. Licitra 1 . 1 Head and Neck Medical
Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;
2 Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale
dei Tumori, Milan, Italy
Background: Inappropriate activation of hedgehog (Hh) pathway is involved
in the pathogenesis of skin basal cell carcinoma (BCC). Loss of function of transmembrane receptor Patched (PTCH1), or gain of function of
Smoothened (SMO ), Sonic Hh (SHH ) and GLI family transcription factors
can be ligand-independent oncogenic drivers of this disease. Vismodegib is
a small molecule inhibitor of the Hh pathway that binds and inhibits SMO,
demonstrating activity in clinical trials against advanced BCC.
Purpose/Objective: To evaluate mechanisms of acquired resistance to
Vismodegib in a BCC case.
Materials and Methods: We report a case of BCC having a dramatic
response to Vismodegib treatment, further developing treatment resistance.
Formalin-fixed specimens of pre-treatment primary tumor and recurrence
arisen during vismodegib regimen were investigated for the mutational
status of the serpentine receptor SMO by sequencing (3500DX Genetic
Analyzer).
Results: From April 2012, a 78 years old man with a large, ulcerated and
bleeding BCC of the left scapula, not amenable to surgery or radiotherapy
was treated with Vismodegib 150 mg/day. The patient experienced a rapid
regression of disease, with a clinical complete remission after 6 months of
treatment. However, 11 months after treatment start, 2 subcutaneous nodules
within the previous tumor field appeared and were surgically removed, with
histological diagnosis of BCC. In the recurrence specimen SMO sequencing
revealed the presence of a G to C missense mutation at position 1697 leading
to the change D473Y within the exon 8. This nucleotide substitution was not
detected in the primary tumor specimen analysis.
Conclusions: The D473Y mutation in SMO could represent a mechanism
of acquired resistance to vismodegib in BCC. This finding is sustained by
a similar report in medulloblastoma in which the D473H mutation has been
demonstrated to confer SMO inhibitor resistance impairing the receptor’s
ability to bind the drug without affecting the ability of SMO to transmit the Hh
signal (Yauch et al. Science 2009, 326:572–574). Further elucidation of such
mechanisms can help in developing therapeutic strategies able to overcome
Hh inhibitors resistance.
MC13-0087
Epigenetic assay detects early stage non-small cell lung cancer in
sputum
L. Van Neste 1 , F. Moreau 1 , M.J. Kelley 2 , S.A. Belinsky 3 , J. Bigley 4 , W. Van
Criekinge 5 . 1 R&D, MDxHealth, Liège, Belgium; 2 School of Medicine, Duke
University, Durham, USA; 3 Lovelace Respiratory Research Institute, Duke
University, Albuquerque, USA; 4 Clinical Affairs, MDxHealth, Irvine, USA;
5 R&D, MDxHealth, Irvine, USA
Background: Similar to all other major cancers, lung cancer incidence
and mortality recently started to decline in the US. However, it is still
the main cause of cancer-related death. Improved surgical techniques and
combined therapies have increased the 1-year survival to ∼45%. When
detected early, the 5-year survival rate in localized (stage I or II) disease is
∼50%. Unfortunately, only a minority of cancers are detected early, resulting
in a 5-year survival of 17% overall. These survival rates emphasize the
importance of early detection. Recently, a study showed that the use of spiral
CT screening for lung cancer resulted in a 20% reduction in mortality, but a
high false positive rate (96%) was observed.
Poster Presentations
Purpose/Objective: Complementing traditional screening methods with
molecular triage markers has proven beneficial for diagnostic purposes.
Epigenetic markers, i.e. aberrant DNA-methylation, are observed early during
oncogenesis.
Materials and Methods: Sputum of a test set of 92 patients, 40 cancer
cases and 52 cancer-free controls, was evaluated as a non-invasive source
to detect the presence of non-small cell lung cancer. The methylation
status of 11 candidate markers (HOXA9, TAC1, DPSYL4, SOX17, HOXD1,
CDO1, RASSF1, JAM3, SFRP2, GPNMB andGREM1) was tested using a
quantitative methylation-specific PCR approach.
Results: Cutoffs for single markers were optimized and performance was
calculated. To demonstrate clinical utility, the minimal specificity was fixed
at 90%. Four genes showed adequate sensitivity (HOXA9 : 53%, CDO1:
58%, RASSF1: 75% and SFRP2 : 55%) as single markers. Combinations
of two markers were explored using all 11 genes in search of marker
complementarity. RASSF1 was present in all marker panels, with HOXA9,
TAC1, SOX17, HOXD1, CDO1, SFRP2 or GREM1 as second gene, reaching
sensitivities of 85%.
Twelve stage I or II lung cancers in this study were used for an early detection
subset analysis. Single marker assays of four genes were able to sensitively
identify such cases (HOXA9 : 67%, CDO1: 58%, RASSF1: 83% and SFRP2 :
67%). When RASSF1 was paired with HOXA9, SFRP2 or GREM1, all early
stage cases were successfully identified.
Conclusions: This feasibility study demonstrates that aberrant DNAmethylation can be specifically detected in sputum samples of cancer
patients. Panels of RASSF1 with either one of HOXA9, SFRP2 and GREM1
are particularly promising for the early detection of lung cancer, offering
therapeutic advantages and potentially better clinical outcomes.
MC13-0088
Controls for quantification of total cell free DNA qPCR analyses in
plasma
N. Pallisgaard 1 , R. Fredslund Andersen 1 , K.L. Garm Spindler 2 ,
I. Brandslund 1 , A. Jakobsen 2 . 1 Clinical Biochemistry, Vejle Hospital, Vejle,
Denmark; 2 Oncology, Vejle Hospital, Vejle, Denmark
Background: Analyses and quantification of total cell free DNA (cfDNA) in
plasma samples has potential as source for detection of cancer mutations
and to monitor treatment response. Since the concentration of cfDNA may
be very low a substantial fraction may easily be lost during the purification
process, or contaminated with DNA from lysated lymphocytes could result
in fasely increased levels. Hemolysis may occur during drawing as a result
of the pressure drop from vein to collection tube, lysis due to prolonged
storage times prior to plasma isolation or to profound pipetting when isolating
the plasma supernatant. Consequently, including of controls for preanalytical
pitfalls are of utmost importance.
Purpose/Objective: Develop qPCR control reactions to qualify the analysis
of cell free DNA in plasma.
Materials and Methods: Plasma DNA from 70 healthy individuals was
purified on a Maxwell purification robot and cfDNA from another 100 healthy
individuals was purified on a Qiasymphony robot. A 182 bp fragment from the
soya bean gene CPP1 was constructed from oligonucleotides and amplified
by PCR. The CPP1 fragment was used as a spike in control and added the
plasma samples prior to purification and subsequently measured in purified
cfDNA by qPCR. To identify lymphocyte DNA a multiplex qPCR assay (PBC)
detecting a substantial fraction of the unique immunoglobulin rearrangements
in B-cell DNA was developed. A qPCR targeting the single copy gene
beta-2-microglobulin (B2M) was used to measure the number of genomic
alleles in the samples and in parallel the CPP1 spike in and lymphocyte
control.
Results: In normal blood samples the number of measure B-cell alleles by the
PBC assay was 0.5% (standard deviation 0.44) of total number of alleles. The
variation was ascribed to individual genetic background and infection history
since 3 other IgH multiplex assays tested gave similar results. In plasma
samples the average number of alleles was 4700 per mL (standard deviation
2400) in samples where Lymphocyte DNA was not detected. Based on the
B-cell control we found that plasma samples contaminated with lymphocyte
DNA ranged between 10 and 50%.
Conclusions: We have developed two qPCR control reactions to qualify the
analysis of cell free DNA in plasma samples which may identify contaminating
lymphocyte DNA and/or the loss of sample DNA during the purification.
Poster Presentations
MC13-0089
Epigenome-wide discovery of ovarian and breast cancer specific DNA
methylation markers
H. Lempiainen 1 , D. Mertens 1 , A. Brandenburg 1 , M. Remmert 1 ,
J. Hayward 2 , A. Jones 2 , S. Anjum 2 , M. Widschwendter 2 , M. Flesch 1 ,
J. Hoefkens 1 , T. Rujan 1 , T. Wittenberger 1 . 1 Expressionist, Genedata, Basel,
Switzerland; 2 Department of Women’s Cancer, University College London
Elizabeth Garrett Anderson Institute for Women’s Health, London, United
Kingdom
Background: Breast and ovarian cancers pose huge and unsolved challenges to the medical profession. Breast cancer is the most common cancer
in women in the EU: more than 332,000 women are diagnosed with breast
cancer each year and a woman dies every 6 minutes from this disease.
Ovarian cancer, whilst far less common than breast cancer, is often diagnosed
when the disease is at an advanced stage and has spread to other areas
of the body. More than 60% of ovarian cancer patients die within the first
5 years after diagnosis. Implementation of successful screening programs
has dramatically reduced the number of women dying from cervical cancer.
Similarly, the EU FP7 consortium EpiFemCare aims to reduce the number of
women diagnosed with late stage breast or ovarian cancer by 50%, reduce
the number of women who receive unnecessary long-term chemotherapy by
50%, and reduce the number of women dying from these cancers by 20%.
Purpose/Objective: EpiFemCare will establish and clinically validate a series
of blood tests based upon DNA methylation technology that will facilitate both
early detection and prediction of therapeutic outcome. The project consists
of three phases: (1) Epigenome-wide discovery of ovarian/breast cancer
specific DNA methylation markers. (2) Development of serum based assays
for cancer specific markers. (3) Validation of the serum test performance in
thousands of serial samples from prospective clinical trials.
Materials and Methods: In phase 1 Illumina Infinium Human Methylation450
BeadChip Array technology is used to assess the methylation status of
∼485,000 sites in cancer and control tissues. In parallel Reduced Representation Bisulfite Sequencing (RRBS) is used to identify & confirm cancer
specific methylated circulating DNA in matching serum samples.
Results: Using Genedata Expressionist® for Genomic Profiling, we have
established an automated bioinformatics pipeline for the detection of cancer
specific differentially methylated regions (DMRs) that are most likely to fulfill
the strict specificity criteria of a serum based test.
Conclusions: The most promising DMRs are taken forward for the serum
based clinical assay development and validation.
MC13-0090
Epigenetic silencing promotor gene of ESR1 in DNA circulating and not
expression of estrogen receptor in tumors of patients with breast
cancer
J. Martinez-Galan 1 , J.R. Delgado 1 , R. Del Moral 2 , B. Torres-Torres 3 ,
S. Ríos 4 . 1 Medical Oncology, Hospital Universitario Virgen de las Nieves,
Granada, Spain; 2 Radiotherapy Oncology, Hospital Universitario Virgen de
las Nieves, Granada, Spain; 3 Molecular Biology, Centro de Investigaciones
Biomédicas, Granada, Spain; 4 Molecular Biology, Departamento de
Radiología y Medicina Física, Granada, Spain
Background: Cell-free circulating DNA carries not only tumor-specific
changes in its sequence but also distinctive epigenetic marks, namely DNA
methylation in island CpG region promotor. Recent data suggest that benign
diseases have very specific methylation patterns within cell-free circulating
DNA, which are different from the pattern of a malignant tumor of the same
organ.
Purpose/Objective: To determine whether Estrogen Receptor 1 (ESR1)(+)
and ESR1(−) status relates to epigenetic changes in breast cancer-related
genes and to correlate with expression in tumor of estrogen receptor RE(+)
and RE(−).
Materials and Methods: We quantified methylation levels ERS1 gene in
serum of 92 pts breast cancer. A PCR quantitative technique was used to
analyze levels of methylation gene. We also examined and correlationed the
expression of ER in tumors by immunohistochemistry.
Results: Median age was 58 years (32–88); 69% were postmenopausal
women. Nodal involvement (N0, 63%; N1, 30%; N2, 7%), tumor size
(T1, 58%; T2, 35%; T3, 4%; T4, 4%) and grade (G1, 20%; G2, 37%;
G3, 30%). The methylated ESR1 in serum was significantly associated
with ESR1(−) in breast tumors >80% (p=0.0179). Methylation ESR1 was
preferably associated with triple negative (80%) and HER2+ (60%) subtype.
S37
Nevertheless unmethylation ESR1 was found more frequently in LA (71%)
and LB (59%) phenotype. With a median follow up of 6 years, we found worse
overall survival (OS) with more frequent ESR1 methylation gene (p>0.05),
Luminal A; ESR1 methylation OS at 6 years 81% vs 93% when was ESR1
unmethylation. Luminal B; ESR1 methylation 86% SG at 6 years vs 92% in
unmethylation ESR1. Triple negative; ESR1 methylation SG at 6 years 75%
vs 80% in unmethylation ESR1. HER2; ESR1 methylation SG at 6 years was
66.7% vs 75% in unmethylation ESR1.
Conclusions: Gene promoter region hypermethylation is a significant event
in primary breast cancer. However, its impact on tumor progression and potential predictive implications remain relatively unknown. Our study identifies
the presence of variations in global levels of methylation promoters ESR1
genes in breast cancer with different phenotype classes and shows that these
differences have clinical significance.
MC13-0091
MicroRNA in biofluids – Robust biomarkers for disease
P. Mouritzen 1 , T. Blondal 1 , D. Andreasen 1 , M. Wrang Teilum 2 ,
A. Thomsen 1 , N. Tolstrup 3 . 1 Research & Development, Exiqon, Vedbaek,
Denmark; 2 Services, Exiqon, Vedbaek, Denmark; 3 Bioinformatics, Exiqon,
Vedbaek, Denmark
Background: microRNAs constitute a class of small cellular RNAs (typically
19–23 nt) that function as post-transcriptional regulators of gene expression.
Current estimates indicate that more than one third of the human cellular
transcriptome is regulated by this small class of RNA (less than 2000 miRNA).
The study of extracellular microRNAs and their potential as pathophysiological
markers has greatly expanded in the last couple of years. microRNAs have
been shown to be actively exported from tissues into the circulation through
a variety of mechanisms including exosome and microvesicle transport, and
complexing with RNA binding proteins or HDL.
Purpose/Objective: The high relative stability of microRNAs in common
clinical source materials (FFPE blocks, plasma, serum, urine, saliva, etc.)
and the ability of microRNA expression profiles to accurately classify discrete
tissue types and specific disease states have positioned microRNAs as
promising new biomarkers for diagnostic application.
Materials and Methods: We have applied our highly sensitive LNA™-based
qPCR platform for detection of microRNAs, which has enabled microRNA
profiling in biofluids where levels are extremely low. The platform uses a single
RT reaction to conduct full miRNome profiling and allows high-throughput
profiling of microRNAs without the need for pre-amplification.
Results: Thousands of biofluid samples including serum/plasma and urine
have been profiled to determine normal reference ranges for circulating
microRNAs as well as to identify biomarkers of disease and toxicology.
Extensive data qualification and analysis methods have been developed and
are central parameters to secure high quality data from biofluids. Recently,
we have compared microRNA profiles of different exosome isolation methods
and evaluated the differences between these and standard profiles of whole
plasma and serum.
Conclusions: Robust microRNA biomarker discovery and validation in
serum/plasma and other biofluids depends on a highly sensitive and reliable
microRNA detection system as well as careful attention to sample preparation
and quality. The use of advanced sample and data qualification methods
improve data quality and will be central to the development of circulating
microRNAs as diagnostic markers.
MC13-0092
The National Cancer Institute (NCI) specimen resource locator
J. Demchok, S. Taube, B. Fombonne, I. Lubensky. National Institute of
Health, National Cancer Institute, Cancer Diagnosis Program
Background: The development of molecular technologies will advance the
identification of clinically useful biomarkers and development of diagnostic
assays to guide diagnosis and treatment of cancer patients with defined
molecular abnormalities. Discovery and validation of markers of cancer
prevention, diagnosis and response to therapy requires access to quality
clinical biospecimens ranging from relatively small case sets and tissue
microarrays to clinically annotated samples from patients uniformly treated in
multi-site, randomized clinical trials. The availability of diverse biospecimen
resources that procure and distribute such specimens is critical. However,
unless researchers can learn about a biospecimen resource, the value of
the resource cannot be fully realized. In response to this need the NCI’s
S38
Cancer Diagnosis Program has developed, and is expanding, a searchable
database: the Specimen Resource Locator (SRL). The SRL’s goal is to make
researchers aware of existing specimen resources, and to facilitate the use of
available biospecimens.
Methods and Materials: The SRL serves as a public comprehensive
database of resources where investigators have access to thousands of
specimens of different tumor types. Biobanks with specimens from a variety
of anatomic sources and diagnoses are available on the SRL. Currently the
SRL includes NCI supported cancer specimen repositories, and their url link
and contact information. Future plans will include other NIH sponsored and
U.S. repositories.
Results: Investigators can search the database and retrieve a list of resources
that can furnish the specimens for a fee as well as for collaboration. Searches
can be performed by tumor type, specimen type, or tissue preservation
Poster Presentations
method. An advanced search can be performed by requesting annotation
criteria and specimen number requirement. If no match of specimen to
investigator is available, the SRL refers researchers to the Tissue Expediter
(tissexp@mail.nih.gov). The Tissue Expediter is distinct from the SRL in that
it is an individual who helps the investigator locate appropriate resources.
Conclusion: The availability of specimens and data resources is crucial
to increase our understanding of cancer biology and to translate important
research discoveries to clinical application. The SRL helps resources to
operate more efficiently by allowing researchers to search their database and
retrieve a list of resources likely to meet their research needs. The SRL will
reduce inappropriate requests to resources and will lead investigators directly
to appropriate resource. By funding the SRL and making biospecimens
readily available to investigators, the National Cancer Institute facilitates
translational research.
S39
Author Index
Page numbers are followed by abstract number(s) in parentheses.
A
Abecassis, I., S33 (MC13-0078)
Abolins, A., S34 (MC13-0081)
Adang, E.M.M., S15 (MC13-0014)
Adriaensens, P., S20 (MC13-0032)
Agrawal, L., S25 (MC13-0047)
Aguilar, A., S35 (MC13-0085)
Aguilar-Mahecha, A., S33 (MC13-0077)
Ahuja, N., S33 (MC13-0076)
Alain, T., S7 (SP024)
Alarcon, I., S26 (MC13-0051)
Alpana, S., S18 (MC13-0025)
Alpy, F., S18 (MC13-0023)
Amadori, D., S31 (MC13-0067)
Ancukiewicz, M., S29 (MC13-0062)
Andersen, R.F., S11 (MC13-0026)
Andreasen, D., S37 (MC13-0091)
Anghileri, E., S21 (MC13-0033),
S32 (MC13-0072)
Anjum, S., S37 (MC13-0089)
Appelt, A.L., S11 (MC13-0026)
Aquino, D., S32 (MC13-0072)
Arnaud, M.P., S25 (MC13-0048)
Atac, F., S15 (MC13-0010)
Azad, N., S33 (MC13-0076)
B
Banerji, U., S7 (SP025)
Barillot, E., S1 (SP002)
Basik, M., S33 (MC13-0077)
Batchelor, T.T., S29 (MC13-0062)
Bathen, T.F., S23 (MC13-0044)
Batist, G., S33 (MC13-0077)
Becker, K.F., S9 (SP033), S10 (SP036)
Becker, R., S4 (SP013)
Belcari, F., S31 (MC13-0067)
Belenguer-Querol, L., S30 (MC13-0066)
Belinsky, S.A., S36 (MC13-0087)
Benos, P.V., S33 (MC13-0078)
Berry, D., S2 (SP005)
Bertolini, F., S21 (MC13-0033)
Bharti, S., S31 (MC13-0068)
Bie, L., S13 (MC13-0004, MC13-0005,
MC13-0006)
Bigley, J., S36 (MC13-0087)
Blondal, T., S37 (MC13-0091)
Boerman, O.C., S21 (MC13-0036)
Bogaerts, J., S5 (SP016)
Bogers, J.P., S13 (MC13-0001)
Bollen, M., S35 (MC13-0084)
Bossi, P., S34 (MC13-0082), S36 (MC13-0086)
Boutros, P.C., S14 (MC13-0009)
Brandenburg, A., S37 (MC13-0089)
Brandslund, I., S36 (MC13-0088)
Braun, S., S17 (MC13-0021, MC13-0022),
S18 (MC13-0024)
Bristow, R.G., S14 (MC13-0009)
Brünner, N., S19 (MC13-0028)
Bruzzone, M.G., S21 (MC13-0033),
S32 (MC13-0072)
Buch, S., S33 (MC13-0078)
Buxton, M., S2 (SP005)
C
Calleri, A., S21 (MC13-0033)
Camlioglu, E., S33 (MC13-0077)
Campo, E., S30 (MC13-0065)
Campone, M., S2 (SP006)
Carcangiu, M.L., S34 (MC13-0082)
Cardoso, F., S6 (SP022)
Casey, M., S26 (MC13-0052), S27 (MC13-0053,
MC13-0054)
Cavenagh, M.M., S31 (MC13-0068)
Chan, K., S23 (MC13-0039)
Chao, S., S30 (MC13-0066)
Chao, S.L., S19 (MC13-0029), S22 (MC13-0037)
Chelsky, D., S8 (SP030)
Chen, A., S3 (SP007)
Chen, G., S23 (MC13-0040)
Chenard, M.P., S18 (MC13-0023)
Cheng, Y.Y., S20 (MC13-0031)
Chernyaev, V., S21 (MC13-0034)
Cheung, A., S23 (MC13-0039)
Cheung, I., S6 (SP021)
Cheung, N., S6 (SP021)
Chippada Venkata, U., S32 (MC13-0070)
Choe, G., S19 (MC13-0027)
Choi, Y., S23 (MC13-0041)
Christensen, I.J., S19 (MC13-0028)
Ciniselli, C.M., S8 (SP031)
Colombo, M., S34 (MC13-0082)
Colomer, A., S26 (MC13-0051),
S30 (MC13-0065)
Colomo, L., S30 (MC13-0065)
Condeelis, J., S16 (MC13-0019)
Conley, B., S3 (SP007), S11 (MC13-0060),
S31 (MC13-0068)
Conley, B.A., S31 (MC13-0068)
Corcoran, R.B., S12 (MC13-0075)
Cornelis, A., S13 (MC13-0001)
Cortelazzi, B., S36 (MC13-0086)
Cuppini, L., S21 (MC13-0033), S32 (MC13-0072)
D
D’Cruz, A., S26 (MC13-0050)
Dal Pra, A., S14 (MC13-0009)
Danesi, R., S31 (MC13-0067)
Danilova, L., S33 (MC13-0076)
Darquennes, K., S20 (MC13-0032)
Davidovic, R., S15 (MC13-0015)
Davis, S., S2 (SP005)
Davison, C., S17 (MC13-0022),
S18 (MC13-0024)
de Geus-Oei, L.F., S15 (MC13-0014)
De Greve, J., S23 (MC13-0040)
de Vries, E., S5 (SP018)
de Wilt, J.H.W., S15 (MC13-0014)
Debetancourt, D., S28 (MC13-0059)
Del Moral, R., S37 (MC13-0090)
Del Re, M., S31 (MC13-0067)
Deleu, M., S13 (MC13-0001)
Delgado, J.R., S37 (MC13-0090)
Delmas, A., S33 (MC13-0076)
Delord, J.P., S2 (SP006)
Delpous, S., S18 (MC13-0023)
Demchok, J., S37 (MC13-0092)
DeMichele, A., S2 (SP005)
Dempsey, P.W., S17 (MC13-0020)
Derome, A., S26 (MC13-0052),
S27 (MC13-0053, MC13-0054)
Di Stefano, A., S21 (MC13-0033),
S32 (MC13-0072)
Diaz, Z., S33 (MC13-0077)
Dondi, E., S25 (MC13-0048)
Donovan, M., S26 (MC13-0051),
S30 (MC13-0065)
Doroshow, J., S11 (MC13-0060)
Doroshow, J.H., S3 (SP007)
Douillard, J.Y., S17 (MC13-0021, MC13-0022),
S18 (MC13-0024)
Dowsett, M., S1 (SP003)
Drisis, S., S19 (MC13-0029), S30 (MC13-0066)
Duda, D.G., S29 (MC13-0062)
E
Eberhard, D., S3 (SP008)
Emblem, K., S29 (MC13-0062)
Endo, M., S12 (MC13-0079)
Engel, K.B., S9 (SP035)
Engelman, J.A., S12 (MC13-0075)
Eoli, M., S21 (MC13-0033), S32 (MC13-0072)
Erill, N., S26 (MC13-0051), S30 (MC13-0065)
Esserman, L., S2 (SP005)
Evangelista, A.F., S29 (MC13-0063),
S32 (MC13-0073)
F
Fan, L.Q., S12 (MC13-0071)
Fang, P., S31 (MC13-0069)
Felisiak-Golabek, A., S24 (MC13-0045)
Ferrer, I., S26 (MC13-0051)
Finocchiaro, G., S21 (MC13-0033),
S32 (MC13-0072)
Flaherty, K.T., S12 (MC13-0075)
Flamen, P., S30 (MC13-0066)
Flesch, M., S37 (MC13-0089)
Flores, C., S35 (MC13-0085)
Fombonne, B., S37 (MC13-0092)
Forbes, T., S11 (MC13-0060)
Fredslund Andersen, R., S36 (MC13-0088)
Freidlin, B., S11 (MC13-0049)
G
Galderisi, C., S31 (MC13-0069)
Galibert, M.D., S25 (MC13-0048)
Galon, J., S28 (MC13-0059)
Galsky, M., S32 (MC13-0070)
Gandemer, V., S25 (MC13-0048)
Ganee, L., S26 (MC13-0052), S27 (MC13-0053,
MC13-0054)
Garcia, C., S30 (MC13-0066)
Gardovskis, J., S34 (MC13-0081)
Garm Spindler, K.L., S36 (MC13-0088)
Gauri, G., S18 (MC13-0025)
Gavoille, C., S2 (SP006)
Geers, C., S23 (MC13-0040)
Gelb, A.B., S27 (MC13-0055)
Gelmini, S., S8 (SP031)
Gerstner, E.R., S29 (MC13-0062)
Gertler, F., S16 (MC13-0019)
Geveart, O., S35 (MC13-0084)
Gigot, J.F., S28 (MC13-0059)
Glass, A., S16 (MC13-0019)
S40
Goldkorn, A., S17 (MC13-0020)
Golfinopoulos, V., S6 (SP022)
Gologan, A., S33 (MC13-0077)
Gómez, H., S35 (MC13-0085)
Goncalves, A., S2 (SP006)
Gong, Y., S32 (MC13-0070)
Gravanis, I., S4 (SP012)
Groelz, D., S9 (SP033)
Grose, R., S6 (SP023)
Grunnet, M., S19 (MC13-0028)
Guan, P., S28 (MC13-0057)
Guendisch, S., S9 (SP033)
Guhathakurta, D., S12 (MC13-0071)
Guiot, T., S30 (MC13-0066)
Guozhen, Z., S14 (MC13-0008)
H
Haber, D.A., S12 (MC13-0075)
Haicheur, N., S28 (MC13-0059)
Hall, J., S6 (SP022)
Halytskiy, V., S28 (MC13-0058)
Hamoir, M., S29 (MC13-0064)
Hariharan, P., S28 (MC13-0057)
Harrington, R., S11 (MC13-0060)
Hartmann, C.C., S8 (SP031)
Hartmut, J., S9 (SP032)
Haukaas, T.H., S23 (MC13-0044)
Haustermans, K., S35 (MC13-0084)
Have, C.L., S14 (MC13-0009)
Hayward, J., S37 (MC13-0089)
Hegi, M., S8 (SP028)
Heinrich, M., S10 (SP036)
Herman, J., S33 (MC13-0076)
Heskamp, S., S21 (MC13-0036)
Hidalgo, M., S7 (SP026)
Hoefkens, J., S37 (MC13-0089)
Hong, X., S13 (MC13-0006)
Horrigan, K., S32 (MC13-0074)
Hoyer-Hansen, G., S19 (MC13-0028)
Huang, E., S11 (MC13-0049)
Huang, L., S27 (MC13-0055)
Hupé, P., S1 (SP002)
Hylton, N., S2 (SP005)
I
Ignatiadis, M., S19 (MC13-0029)
Imtiyaz, A., S18 (MC13-0025)
Isaka, M., S12 (MC13-0079)
Isambert, N., S2 (SP006)
Isebaert, S., S35 (MC13-0084)
Ishkanian, A.S., S14 (MC13-0009)
J
Jacinthe, B., S25 (MC13-0048)
Jadin, L., S27 (MC13-0055)
Jain, R.K., S29 (MC13-0062)
Jakobsen, A., S11 (MC13-0026),
S36 (MC13-0088)
Jamsheed, J., S18 (MC13-0025)
Janssens, J., S13 (MC13-0001)
Jeffrey, S., S5 (SP017)
Jensen, L.H., S19 (MC13-0028)
Jiang, P., S27 (MC13-0055)
Jiang, T.A.O., S14 (MC13-0008)
Jones, A., S37 (MC13-0089)
Jones, J., S16 (MC13-0019)
Joniau, S., S35 (MC13-0084)
Jurisica, I., S14 (MC13-0009)
K
Kakkar, N., S16 (MC13-0017)
Kamal, M., S1 (SP002), S2 (SP006)
Kane, S., S26 (MC13-0050)
Kao, S.C., S20 (MC13-0031)
Author Index
Kap, M., S9 (SP033)
Kelley, M.J., S36 (MC13-0087)
Kenmotsu, H., S12 (MC13-0079)
Kertesz, N., S26 (MC13-0052),
S27 (MC13-0053, MC13-0054)
Khajuria, R., S16 (MC13-0017)
Khambata-Ford, S., S3 (SP010)
Khurani, N., S18 (MC13-0025)
Kim, M.A., S19 (MC13-0027)
Kim, S., S23 (MC13-0041)
Kim, W.H., S19 (MC13-0027)
Kim, Y., S23 (MC13-0041)
Kirkwood, J.M., S33 (MC13-0078)
Kirschner, M.B., S20 (MC13-0031)
Kneitz, B., S35 (MC13-0084)
Kochukoshy, T., S32 (MC13-0070)
Koh, Y., S12 (MC13-0079)
Kovacevic, R., S15 (MC13-0015)
Kramer, K., S6 (SP021)
Krieger, L., S10 (SP036)
Kristof, J., S31 (MC13-0069)
Kruhoffer, M., S9 (SP033)
Kubista, M., S8 (SP031), S10 (SP036)
Kuk, D., S6 (SP021)
Kummar, S., S3 (SP007), S11 (MC13-0060)
Kupryjanczyk, J., S24 (MC13-0045)
Kushner, B., S6 (SP021)
L
Lacombe, D., S6 (SP022)
Lahuerta, J.J., S14 (MC13-0007)
Lalonde, E., S14 (MC13-0009)
Lam, W.L., S14 (MC13-0009)
Lamba Saini, M., S29 (MC13-0064)
Lamichhane, S., S23 (MC13-0044)
Lamote, K., S25 (MC13-0046)
Lan, C., S33 (MC13-0077)
Lassen, U., S19 (MC13-0028)
Le Tourneau, C., S2 (SP006)
Lecumberri, R., S14 (MC13-0007)
Lee, B.H., S32 (MC13-0074)
Lee, H., S20 (MC13-0030)
Lee, H.S., S19 (MC13-0027)
Lee, K.H., S20 (MC13-0030)
Leenders, W., S21 (MC13-0035)
Lemort, M., S19 (MC13-0029), S30 (MC13-0066)
Lempiainen, H., S37 (MC13-0089)
Leroy, C., S25 (MC13-0048)
Lerut, E., S35 (MC13-0084)
Lessinger, J.M., S18 (MC13-0023)
LeTourneau, C., S1 (SP002)
Li, B., S23 (MC13-0039)
Li, J., S31 (MC13-0069)
Li, M., S13 (MC13-0004)
Li, Y., S13 (MC13-0005, MC13-0006)
Licitra, L., S34 (MC13-0082), S36 (MC13-0086)
Lih, C., S11 (MC13-0060), S31 (MC13-0068)
Lih, J., S3 (SP007)
Lin, H., S16 (MC13-0019)
Lin, S., S22 (MC13-0038)
Lin, Y., S14 (MC13-0008)
Litovkin, K., S35 (MC13-0084)
Liu, H., S22 (MC13-0038)
Liu, S.V., S17 (MC13-0020)
Lively, T.G., S31 (MC13-0068)
Locati, L.D., S34 (MC13-0082)
Lockhart, N., S28 (MC13-0057)
Longatto, A.F., S32 (MC13-0073)
Loueslati, B.Y., S15 (MC13-0010)
Louis, E., S20 (MC13-0032)
Lu, X., S26 (MC13-0052), S27 (MC13-0053,
MC13-0054)
Lubensky, I., S37 (MC13-0092)
Lujic, N., S15 (MC13-0015)
Lund, I.K., S19 (MC13-0028)
Lyandres, J., S2 (SP005)
Lydolph, M., S19 (MC13-0028)
M
Macedo, T., S29 (MC13-0063), S32 (MC13-0073)
Machiels, J.P., S28 (MC13-0059)
Maheswaran, S., S12 (MC13-0075)
Mak, D.F.Y., S14 (MC13-0009)
Malentacchi, F., S8 (SP031)
Malgundkar, S., S26 (MC13-0050)
Malloff, C., S14 (MC13-0009)
Mancuso, P., S21 (MC13-0033)
Manoukian, S., S34 (MC13-0082)
Marbaix, E., S29 (MC13-0064)
Marino, A.F.L., S32 (MC13-0073)
Mariyam, Z., S18 (MC13-0025)
Marliot, F., S28 (MC13-0059)
Marques, M.M.C., S29 (MC13-0063),
S32 (MC13-0073)
Martens, J., S4 (SP011)
Martin, A., S26 (MC13-0052), S27 (MC13-0053,
MC13-0054)
Martinez-Galan, J., S37 (MC13-0090)
Martínez-López, J., S14 (MC13-0007)
Mateos, M.V., S14 (MC13-0007)
Mathelin, C., S18 (MC13-0023)
Matveev, V.B., S21 (MC13-0034)
McCaughan, B.C., S20 (MC13-0031)
McDermott, U., S3 (SP009)
McGregor, P., S11 (MC13-0060)
McLean, J., S28 (MC13-0057)
McNamara, S., S33 (MC13-0077)
Mehaffey, M., S11 (MC13-0060)
Meng, A., S14 (MC13-0009)
Mertens, D., S37 (MC13-0089)
Mesotten, L., S20 (MC13-0032)
Meynier, F., S26 (MC13-0052), S27 (MC13-0053,
MC13-0054)
Mezlini, A.M.E.L., S15 (MC13-0010)
Milosevic, M., S14 (MC13-0009)
Mir, R., S18 (MC13-0025)
Mitry, E., S2 (SP006)
Mlecnik, B., S28 (MC13-0059)
Modak, S., S6 (SP021)
Moestue, S.A., S23 (MC13-0044)
Molkenboer-Kuenen, J.D.M., S21 (MC13-0036)
Moon, N., S14 (MC13-0009)
Moore, H., S9 (SP035), S25 (MC13-0047)
Moreau, F., S36 (MC13-0087)
Mori, K., S12 (MC13-0079)
Mourad, M., S29 (MC13-0064)
Mourin, A., S28 (MC13-0059)
Mouritzen, P., S37 (MC13-0091)
N
Nackaerts, K., S25 (MC13-0046)
Nair, S., S26 (MC13-0050)
Nakajima, T., S12 (MC13-0079)
Nam, K., S19 (MC13-0027)
Navis, A., S21 (MC13-0035)
Nazarian, R.M., S12 (MC13-0075)
Netea-Maier, R.T., S15 (MC13-0014)
Nikiforova, Z.N., S21 (MC13-0034)
Noeparast, A., S23 (MC13-0040)
O
O’Donnell, L., S26 (MC13-0052),
S27 (MC13-0053, MC13-0054)
Oelmueller, U., S10 (SP036)
Oh, W., S32 (MC13-0070)
Ohde, Y., S12 (MC13-0079)
Öhrling, K., S17 (MC13-0022)
Oktay, M., S16 (MC13-0019)
Author Index
Oliner, K., S7 (SP027)
Oliveira, R.J.S., S29 (MC13-0063)
Ostrovnaya, I., S6 (SP021)
Oyen, W.J.G., S15 (MC13-0014),
S21 (MC13-0036)
P
Pachmann, K., S34 (MC13-0080)
Pagès, F., S28 (MC13-0059)
Pal, D., S16 (MC13-0017)
Pallisgaard, N., S11 (MC13-0026),
S36 (MC13-0088)
Palmer, M., S32 (MC13-0074)
Palmer, M.R., S31 (MC13-0069)
Paoletti, X., S1 (SP001), S2 (SP006)
Passardi, A., S31 (MC13-0067)
Patil, A., S26 (MC13-0050)
Pavars, M., S34 (MC13-0081)
Pazzagli, M., S8 (SP031), S10 (SP036)
Peeters, M., S17 (MC13-0021, MC13-0022),
S18 (MC13-0024)
Peissel, B., S34 (MC13-0082)
Pelak, K., S31 (MC13-0069)
Pellegatta, S., S21 (MC13-0033)
Pelosof, L., S33 (MC13-0076)
Perlmutter, J., S2 (SP005)
Perrone, F., S36 (MC13-0086)
Petersen-Baltussen, H., S21 (MC13-0035)
Pineda-Lucena, A., S14 (MC13-0007)
Pinho, M.C., S29 (MC13-0062)
Pintilie, M., S14 (MC13-0009)
Pinto, J., S35 (MC13-0085)
Piris, A., S12 (MC13-0075)
Pizon, M., S34 (MC13-0080)
Pizzamiglio, S., S8 (SP031)
Podgorska, A., S24 (MC13-0045)
Polley, E., S11 (MC13-0049, MC13-0060)
Polley, M., S11 (MC13-0049)
Postow, M., S5 (SP019)
Poyet-Gelas, F., S26 (MC13-0052),
S27 (MC13-0053, MC13-0054)
Prakash, R., S18 (MC13-0025)
Prasad, R., S16 (MC13-0017)
Prasant, Y., S18 (MC13-0025)
Price, T., S17 (MC13-0021), S18 (MC13-0024)
Prodi, E., S32 (MC13-0072)
Prósper, F., S14 (MC13-0007)
Przybytkowski, E., S33 (MC13-0077)
Puchades-Carrasco, L., S14 (MC13-0007)
Puig, P., S26 (MC13-0051), S30 (MC13-0065)
Q
Qi, L., S28 (MC13-0057)
Qin, W.Q., S15 (MC13-0012)
Quinn, D.I., S17 (MC13-0020)
R
Radice, P., S34 (MC13-0082)
Rahier, J., S29 (MC13-0064)
Ramnarine, V.R., S14 (MC13-0009)
Reekmans, G., S20 (MC13-0032)
Reese, E., S32 (MC13-0070)
Reid, G., S20 (MC13-0031)
Reix, N., S18 (MC13-0023)
Remmert, M., S37 (MC13-0089)
Renard, M., S23 (MC13-0040)
Riegman, P., S10 (SP036)
Riegman, P.H.J., S9 (SP033)
Rio, M.C., S18 (MC13-0023)
Ríos, S., S37 (MC13-0090)
Ripamonti, C.B., S34 (MC13-0082)
Ristic, D., S15 (MC13-0015)
Robert, G., S25 (MC13-0048)
Robinson, B., S16 (MC13-0019)
S41
Rodon, J., S2 (SP004)
Rohan, J., S31 (MC13-0068)
Rohan, T., S16 (MC13-0019)
Romkes, M., S33 (MC13-0078)
Rong, A., S17 (MC13-0021)
Rosen, B.R., S29 (MC13-0062)
Rothenberg, S.M., S12 (MC13-0075)
Rubinstein, L., S3 (SP007)
Rujan, T., S37 (MC13-0089)
S
Sadhana, K., S26 (MC13-0050)
Sagar, D., S18 (MC13-0025)
Salgado, R., S6 (SP022)
San Miguel, J.F., S14 (MC13-0007)
Saul, M., S33 (MC13-0078)
Sauter, E., S15 (MC13-0012)
Scotti, A., S32 (MC13-0072)
Sedgewick, A., S33 (MC13-0078)
Serizawa, M., S12 (MC13-0079)
Servant, N., S1 (SP002)
Settleman, J., S12 (MC13-0075)
Shak, S., S4 (SP014)
Sharma, U., S16 (MC13-0017)
Shazia, F., S18 (MC13-0025)
Sheikh, N.A., S12 (MC13-0071)
Shepard, H.M., S27 (MC13-0055)
Shevchenko, V.E., S21 (MC13-0034)
Shive, C., S28 (MC13-0057)
Sidhu, R., S17 (MC13-0021, MC13-0022),
S18 (MC13-0024)
Siena, S., S17 (MC13-0021, MC13-0022),
S18 (MC13-0024)
Silva, V.A.O., S32 (MC13-0073)
Simon, R., S11 (MC13-0049, MC13-0060)
Sims, D., S11 (MC13-0060)
Simtniece, Z., S34 (MC13-0081)
Singh, S.K., S16 (MC13-0017)
Sirko-Osadsa, D.A., S32 (MC13-0074)
Smit, J.W.A., S15 (MC13-0014)
Smith, C.S., S15 (MC13-0012)
Sopta, J., S15 (MC13-0015)
Sorensen, A.G., S29 (MC13-0062)
Sorensen, M., S19 (MC13-0028)
Spahn, M., S35 (MC13-0084)
Sparano, J., S16 (MC13-0019)
Spindler, K., S11 (MC13-0026)
Spittle, C., S31 (MC13-0069)
Squire, J., S14 (MC13-0009)
Staha, J., S31 (MC13-0069)
Stathopoulos, K., S19 (MC13-0029)
Stein, E.L., S34 (MC13-0080)
Strauss, W., S17 (MC13-0020)
Strumfa, I., S34 (MC13-0081)
Suazo, J., S35 (MC13-0085)
Sweet, W., S26 (MC13-0052), S27 (MC13-0053,
MC13-0054)
Sykes, J., S14 (MC13-0009)
Symmans, F., S9 (SP034)
Symmons, W.F., S2 (SP005)
Szafron, L., S24 (MC13-0045)
Thoms, J., S14 (MC13-0009)
Thomsen, A., S37 (MC13-0091)
Tolstrup, N., S37 (MC13-0091)
Tomasetto, C., S18 (MC13-0023)
Tops, B., S21 (MC13-0035)
Torres-Torres, B., S37 (MC13-0090)
Trager, J.B., S12 (MC13-0071)
Tredan, O., S2 (SP006)
Tribouley, C., S31 (MC13-0069)
Triche, T.J., S17 (MC13-0020)
Troadec, M.B., S25 (MC13-0048)
Tsai, H.L., S16 (MC13-0018)
Tsao, C., S32 (MC13-0070)
Tsao, G., S23 (MC13-0039)
Turano, P., S9 (SP033), S10 (SP036)
U
Ulivi, P., S31 (MC13-0067)
Ulloa Montoya, F., S5 (SP020)
Um, K.S., S28 (MC13-0057)
Umelo, I., S23 (MC13-0040)
V
Valdiviezo, P., S35 (MC13-0085)
Vallee, A., S25 (MC13-0048)
Vallejos, C., S35 (MC13-0085)
Van Cleemput, J., S25 (MC13-0046)
Van Criekinge, W., S36 (MC13-0087)
Van den Eynde, M., S28 (MC13-0059)
van der Graaf, W.T.A., S21 (MC13-0036)
van der Kwast, T., S14 (MC13-0009)
Van Eynde, A., S35 (MC13-0084)
van Kruchten, M., S5 (SP018)
van Laarhoven, H.W.M., S21 (MC13-0036)
van Meerbeeck, J.P., S25 (MC13-0046)
Van Neste, L., S36 (MC13-0087)
Van Raaij, A., S21 (MC13-0035)
van Zandwijk, N., S20 (MC13-0031)
Vanags, A., S34 (MC13-0081)
Vandeurzen, K., S20 (MC13-0032)
Vanhove, K., S20 (MC13-0032)
Vansteenkiste, J., S23 (MC13-0040)
Vant’Veer, L., S2 (SP005)
Varin-Blank, N., S25 (MC13-0048)
Vasko, E., S34 (MC13-0081)
Vaught, J., S25 (MC13-0047)
Velazco, R., S35 (MC13-0085)
Verderio, P., S8 (SP031)
Verdi, H., S15 (MC13-0010)
Verjans, M., S13 (MC13-0001)
Verrijp, K., S21 (MC13-0035)
Vettukattil, R., S23 (MC13-0044)
Vidal, D.O., S32 (MC13-0073)
Vidal, N., S26 (MC13-0051)
Vieira, R.A.C., S32 (MC13-0073)
Viertler, C., S9 (SP033), S10 (SP036)
Villaruz, L., S33 (MC13-0078)
Volkova, M.I., S21 (MC13-0034)
Vriens, D., S15 (MC13-0014)
Vu, T., S12 (MC13-0071)
W
T
Tabernero, J., S17 (MC13-0021, MC13-0022),
S18 (MC13-0024)
Tabor, D., S28 (MC13-0057)
Takahashi, T., S12 (MC13-0079)
Taube, S., S37 (MC13-0092)
Tawbi, H., S33 (MC13-0078)
Tejpar, S., S6 (SP022)
Ter Laan, M., S21 (MC13-0035)
Teugels, E., S23 (MC13-0040)
Thomas, G., S8 (SP029)
Thomeer, M., S20 (MC13-0032)
Walsh, W., S11 (MC13-0060)
Wang, J.Y., S16 (MC13-0018)
Wang, L., S32 (MC13-0070)
Wang, Y., S14 (MC13-0008), S32 (MC13-0074)
Wargo, J.A., S12 (MC13-0075)
Wei, G., S27 (MC13-0055)
Weisbuch, S., S8 (SP031)
Welsh, A., S18 (MC13-0023)
Wen, P.Y., S29 (MC13-0062)
Wendling, C., S18 (MC13-0023)
Wesseling, P., S21 (MC13-0035)
Weynand, B., S29 (MC13-0064)
S42
Widschwendter, M., S37 (MC13-0089)
Williams, M., S3 (SP007)
Williams, P.M., S11 (MC13-0060),
S31 (MC13-0068)
Wittenberger, T., S37 (MC13-0089)
Wrang Teilum, M., S37 (MC13-0091)
Wu, S., S28 (MC13-0057)
Wyrich, R., S8 (SP031), S9 (SP033)
Author Index
Y
Yamamoto, N., S12 (MC13-0079)
Yan, Z., S31 (MC13-0069)
Yazici, A., S15 (MC13-0010)
Yee, D., S2 (SP005)
Yee, T., S32 (MC13-0070)
Yerram, S., S33 (MC13-0076)
Yilmaz-Yalcin, Y., S15 (MC13-0010)
Yu, Y., S32 (MC13-0074)
X
Xu, T., S17 (MC13-0020)
Xu, Y., S17 (MC13-0020)
Xue, X., S16 (MC13-0019)
Z
Zafarana, G., S14 (MC13-0009)
Zaffaroni, D., S34 (MC13-0082)
Zatloukal, K., S9 (SP033), S10 (SP036)
Zhang, J.I.N.G., S14 (MC13-0008)
Zhang, X., S13 (MC13-0004)
Zhao, Q., S27 (MC13-0055)
Zhao, Y., S11 (MC13-0060)
Zhu, J., S32 (MC13-0070)
Zidi, S., S15 (MC13-0010)
Zimon, D., S34 (MC13-0080)
Zingde, S., S26 (MC13-0050)
Zoli, W., S31 (MC13-0067)
S43
Disclosures
Last Name
First Name
Abst ID
Category
COI Description
Abbruzzese
James
NA
Faculty
Yes
Agrawal
Alain
Lokesh
Tommy
MC13-0047
SP024
No
No
Arnaud
Banerji
Marie-Pierre
Udai
MC13-0048
SP025
Becker
Robert
SP013
Belenguer-Querol
Bie
Bie
Bie
Bogaerts
Laura
Li
Li
Li
Jan
MC13-0066
MC13-0006
MC13-0005
MC13-0004
SP016
Bossi
Bossi
Boutros
Carey
Chao
Chelsky
Paolo
Paolo
Paul
Lisa
Shih-Li
David
MC13-0082
MC13-0086
MC13-0009
NA
MC13-0037
SP030
Chernyaev
Cheung
Vitaly
Nai-Kong
MC13-0034
SP021
POSTER
Faculty & Speakers
Presentation
POSTER
Faculty & Speakers
Presentation
Faculty & Speakers
Presentation
POSTER
POSTER
POSTER
POSTER
Faculty & Speakers
Presentation
POSTER
POSTER
POSTER
Faculty
POSTER
Faculty & Speakers
Presentation
POSTER
Faculty & Speakers
Presentation
Conley
Corcoran
Dancey
de Vries
Barbara
Ryan
Janet
Elisabeth
MC13-0068
MC13-0075
NA
SP018
Del Re
Delpous
Demchok
DeMichele
Marzia
Stéphanie
Joanne
Angela
MC13-0067
MC13-0023
MC13-0092
SP005
deSouza
Diaz
Dittrich
Nandita
Zuanel
Christian
NA
MC13-0077
NA
Donovan
Donovan
Dowsett
Michael
Michael
Mitchell
MC13-0051
MC13-0065
SP003
Drisis
Eberhard
Stylianos
David
MC13-0029
SP008
Emblem
Eoli
Eoli
Esteva
Evangelista
Febbo
Goldkorn
Gorlia
Gravanis
Kyrre E.
Marica
Marica
Francisco
Adriane
Philip
Amir
Thierry
Iordanis
MC13-0062
MC13-0033
MC13-0072
NA
MC13-0063
NA
MC13-0020
NA
SP012
Grose
Grunnet
Guan
Guhathakurta
Richard
Mie
Ping
Debraj
SP023
MC13-0028
MC13-0057
MC13-0071
POSTER
ORAL
Faculty
Faculty & Speakers
Presentation
POSTER
POSTER
POSTER
Faculty & Speakers
Presentation
Faculty
POSTER
Faculty
POSTER
POSTER
Faculty & Speakers
Presentation
POSTER
Faculty & Speakers
Presentation
POSTER
POSTER
POSTER
Faculty
POSTER
Faculty
POSTER
Faculty
Faculty & Speakers
Presentation
Faculty
POSTER
POSTER
ORAL
No
Yes
Honoraria/Consultaion fees Merck Advro Biotech, Stock share holders
Pharmacydics, Jennerx
Research supports/grants from Novartis, AstraZeneca, Johnson & Johnson,
Chugai and consultation fees from Novartis, Debiopharm, Chugai, Merck.
No
No
No
No
No
No
No
No
No
No
No
No information received.
No
Yes
No
No
No
Yes
No
No
No
Yes
No
No
Yes
Yes
Yes
Yes
No
Yes
Memorial Sloan-Kettering Cancer Center (MSKCC) has a patent application on
hu3F8 and 8H9, and Dr. Cheung was named as one of the inventors. MSKCC
has licensed the patent on beta-glucan to Biotec Pharmacon and Dr. Cheung
was named as one of the inventors.
My institution received grants from Roche, Genentech and Novartis for imaging
research.
Research Funding: Genentech, Pfizer, Roche, Incyte, Wyeth, Millenium
Advisory Board: Pfizer.
I have a conflict of interest with several pharmaceutical companies, the drigs of
which woill be mentioned during my chairmanship, predomantily in form of
unrestricted grants dedicated to the research institite I am directing and also
honoraria for consulting.
I am a consultant to Althia Health, S.L.
I am a consultant to Althia Health, S.L.
Particpation in company: Astrazeneca. Grants/research supports: Astrazeneca,
Roche, Pfizer and consultation fees from Nanostring, Roche, genetix.
Receipt honoraria/consultation fees from Onyx, Biodesix, Flagship
Biosciences.
No
No
No
No
No
No information received.
No
No
No information received.
No
No
No
Yes
Sponsorship: All authors are employees of Dendreon Corporation.
S44
Disclosures
Last Name
First Name
Abst ID
Category
COI Description
Hall
Halytskiy
Hartmut
Jacqueline
Volodymyr
Juhl
NA
MC13-0058
SP032
No
No
No
Hegi
Monika
SP028
Heskamp
Hidalgo
Sandra
Manuel
MC13-0036
SP026
Hilsenbeck
Ignatiadis
Jadin
Janssens
Susen
Michail
Laurence
Jaak
NA
NA
MC13-0055
MC13-0001
Faculty
POSTER
Faculty & Speakers
Presentation
Faculty & Speakers
Presentation
POSTER
Faculty & Speakers
Presentation
Faculty
Faculty
POSTER
POSTER
Jeffrey
Stefanie
SP017
Jones
Joan
MC13-0019
Kaplan
Khambata-Ford
Richard
Shirin
NA
SP010
Kim
Edward
NA
Kim
Kirschner
Koh
Kummar
Seung
Michaela
Yasuhiro
Shivaani
MC13-0041
MC13-0031
MC13-0079
SP007
Lacombe
Denis
SP022
Lamba Saini
Lamote
Le Tourneau
Monika
Kevin
Christophe
MC13-0064
MC13-0046
SP006
Lee
Lempiainen
LI
Li
Lih
MC13-0030
MC13-0089
MC13-0039
MC13-0069
MC13-0060
Lin
Lin
Lin
Lively
LoRusso
Loueslati
Louis
Macedo
Martens
Ha-young
Harri
Bin
Jin
Chih Jian
(Jason)
Frank
Yi
Shiu-Ru
Tracy
Patricia
Yacoubi
Evelyne
Taciane
John
NA
MC13-0008
MC13-0038
NA
NA
MC13-0010
MC13-0032
MC13-0073
SP011
Martinez-Galan
McDermott
Joaquina
Ultan
MC13-0090
SP009
Mir
Monzon
Moore
Rashid
Federico
Helen
MC13-0025
NA
SP035
Mouritzen
Nair
Nam
O’Donnell
O’Donnell
O’Donnell
Oelmueller
Peter
Sudhir
Kyung Han
Lynellen
Lynellen
Lynellen
Uwe
MC13-0091
MC13-0050
MC13-0027
MC13-0052
MC13-0053
MC13-0054
SP036
Oh
Oliner
William
Kelly
MC13-0070
SP027
Pachmann
Pal
Pallisgaard
Katharina
Deeksha
Niels
MC13-0080
MC13-0017
MC13-0088
Yes
No
No
No
Yes
Yes
Yes
Faculty & Speakers
Presentation
POSTER
No
Faculty
Faculty & Speakers
Presentation
Faculty
Yes
Yes
Yes
Yes
POSTER
POSTER
ORAL
Faculty & Speakers
Presentation
Faculty & Speakers
Presentation
POSTER
POSTER
Faculty & Speakers
Presentation
POSTER
POSTER
POSTER
POSTER
ORAL
No
No
No
No
Faculty
POSTER
POSTER
Faculty
Faculty
POSTER
POSTER
POSTER
Faculty & Speakers
Presentation
POSTER
Faculty & Speakers
Presentation
POSTER
Faculty
Faculty & Speakers
Presentation
POSTER
POSTER
POSTER
POSTER
POSTER
POSTER
Faculty & Speakers
Presentation
POSTER
Faculty & Speakers
Presentation
POSTER
POSTER
POSTER
No
No
No
No
No
No
No
No
No
Consultation fees from Veridex.
I am an employee of Halozyme Therapeutics, Inc.
I am medical advisor to pharmaceutical and medical device companies. My
wife is CEO in a medical device company. Sponsorship: This study was
conducted without any sponsorship from the medical device industry or from
pharmaceutical industries.
I sit on the Advisory Board of MetaStat. I own equity in the company. I am an
inventor of intellectual property licensed by MetaStat. Sponsorship: MetaStat.
Grant support from Astrazeneca.
Employee of Novartis Pharmaceuticals corporation.
Receipt grant/research supports from Eli Lilly, Celgen, Novartis.
Honoraria/consultaion fees Boerhinger Ingelheim.
No
No
No
No
No
No
No
No
No
No
No
No
No information received.
No
No
No
No
Yes
Yes
Yes
Yes
No
Yes
No
No
No
I work for BioMerieux, Inc.
I work for BioMerieux, Inc.
I work for BioMerieux, Inc.
Employee of QIAGEN GMBH, management committee co-chair of the
QIAGEN.
I am an employee of Amgen, Inc.
Disclosures
S45
Last Name
First Name
Abst ID
Category
COI Description
Palmer
Paoletti
Michael
Xavier
MC13-0074
SP001
Yes
No
Pazzagli
Mario
SP031
Peeters
Marc
MC13-0021
POSTER
Faculty & Speakers
Presentation
Faculty & Speakers
Presentation
POSTER
Peeters
Marc
MC13-0022
POSTER
Yes
Peeters
Marc
MC13-0024
POSTER
Yes
Pelosof
Pinto
Podgorska
Polley
Polley
Polley
Postow
Lorraine
Joseph
Agnieszka
Eric
Mei
Mei
Michael
MC13-0076
MC13-0085
MC13-0045
NA
NA
MC13-0049
SP019
No
No
No
No
No
No
Yes
PuchadesCarrasco
Rodon
Leonor
MC13-0007
POSTER
POSTER
POSTER
Faculty
Faculty
ORAL
Faculty & Speakers
Presentation
POSTER
Jordi
SP004
No
Salgado
Sauter
Sedgewick
Servant
Roberto
Edward
Andrew
Nicolas
NA
MC13-0012
MC13-0078
SP002
Shak
Steven
SP014
Sidransky
Simtniece
Sopta
Spindler
NA
MC13-0081
MC13-0015
MC13-0026
Stadler
David
Zane
Jelena
Karen-Lise
Garm
Walter
Faculty & Speakers
Presentation
Faculty
POSTER
POSTER
Faculty & Speakers
Presentation
Faculty & Speakers
Presentation
Faculty
POSTER
POSTER
ORAL
NA
Sweep
Fred
NA
Employment and stock ownership. Sponsorship: Novartis.
No
Yes
MP: consultant and participated in advisory boards for Amgen and has also
received honoraria and research funding from Amgen, Merck Serono, Ipsen,
Novartis, Roche, and Sanofi. JYD: Amgen: participation in Steering Committee,
Advisory Board, Symposia, consultant Merck Serono: participation in Advisory
Board, Symposia, consultant, research funding Roche: participation in
Advisory Board, Symposia, consultant Boerhinger Ingelheim: participation in
Advisory Board. SS: member of Advisory Boards for Amgen, AstraZeneca,
Sanofi-Aventis, Bayer, Celgene, Health Genomics, Roche. TP: participation in
Advisory boards for Amgen, Roche and Merck Serono. JT: advisory role:
Amgen, Boehringer, Bristol-Myers Squibb, Genentech, Imclone, Lilly, Merck
KGaA, Millennium, Novartis, Onyx, Pfizer, Roche, Sanofi, Celgene. Honoraria
for presentations: Amgen, Merck KGaA, Novartis, Roche, Sanofi. RS: Amgen
Inc. employee. SB: Amgen GmbH employee. AR: Amgen Inc. employee.
MP: consultant and participated in advisory boards for Amgen and has also
received honoraria and research funding from Amgen, Merck Serono, Ipsen,
Novartis, Roche, and Sanofi. JYD: Amgen: participation in Steering
Committee, Advisory Board, Symposia, consultant Merck Serono: participation
in Advisory Board, Symposia, consultant, research funding Roche:
participation in Advisory Board, Symposia, consultant Boerhinger Ingelheim:
participation in Advisory Board. SS: member of Advisory Boards for Amgen,
AstraZeneca, Sanofi-Aventis, Bayer, Celgene, Health Genomics, Roche. TP:
Advisory boards for Amgen, Roche and Merck Serono. JT: advisory role:
Amgen, Boehringer, Bristol-Myers Squibb, Genentech, Imclone, Lilly, Merck
KGaA, Millennium, Novartis, Onyx, Pfizer, Roche, Sanofi, Celgene. Honoraria
for presentations: Amgen, Merck KGaA, Novartis, Roche, Sanofi. RS: Amgen
Inc. employee. SB: Amgen GmbH employee. CD: Amgen Ltd employee.
MP: consultant and participated in advisory boards for Amgen and has also
received honoraria and research funding from Amgen, Merck Serono, Ipsen,
Novartis, Roche, and Sanofi. JYD: Amgen: participation in Steering Committee,
Advisory Board, Symposia, consultant Merck Serono: participation in Advisory
Board, Symposia, consultant, research funding Roche: participation in
Advisory Board, Symposia, consultant Boerhinger Ingelheim: participation in
Advisory Board. SS: member of Advisory Boards for Amgen, AstraZeneca,
Sanofi-Aventis, Bayer, Celgene, Health Genomics, Roche. TP: participation in
Advisory boards for Amgen, Roche and Merck Serono. JT: advisory role:
Amgen, Boehringer, Bristol-Myers Squibb, Genentech, Imclone, Lilly, Merck
KGaA, Millennium, Novartis, Onyx, Pfizer, Roche, Sanofi, Celgene. Honoraria
for presentations: Amgen, Merck KGaA, Novartis, Roche, Sanofi. RS: Amgen
Inc. employee. SB: Amgen GmbH employee. AR: Amgen Inc. employee.
Bristol-Myers Squibb research funding.
No
Yes
No
No
No
Honoraria/Consultaion fees from Roche, Histogenex.
Yes
Genomic Health, Inc. employee and stockholder.
Yes
No
No
No
Consultation fees and stock shareholders “Champions Oncology”.
Faculty
Yes
Consultation fees and grant research support: Active Biotech, Bayer,
Bristol-Myers-Squibb, Boerhinger-Ingelheim, Dendreon Exilixis, Novartis,
Genentech (Roche), Glaxo-Smith-Kline, Medivation, Pfizer, ImClone (Lilly),
Amgen, Takeda (Millenium).
Faculty
No
S46
Disclosures
Last Name
First Name
Abst ID
Category
Symmans
Frazer
SP034
Tejpar
Thomas
Sabine
Geraldine
NA
SP029
Thurin
Tops
Ulloa Montoya
Magdalena
Bastiaan
Fernando
NA
MC13-0035
SP020
Umelo
Van den Eynde
Van Eynde
Van Neste
Vettukattil
MC13-0040
MC13-0059
MC13-0084
MC13-0087
MC13-0044
Vriens
Ijeoma
Marc
Aleyde
Leander
Muhammad
Riyas
Dennis
Faculty & Speakers
Presentation
Faculty
Faculty & Speakers
Presentation
Faculty
POSTER
Faculty & Speakers
Presentation
POSTER
POSTER
POSTER
POSTER
POSTER
COI Description
MC13-0014
POSTER
Yes
Wang
Welch
Williams
Zatloukal
Jaw Yuan
Jack
Paul
Kurt
MC13-0018
NA
NA
SP033
POSTER
Faculty
Faculty
Faculty & Speakers
Presentation
No
No
No
No
No information received.
No
Yes
Consultation fees AstraZeneca
No
No
Yes
GSK Vaccines employee and stock ownership.
No
No
Yes
Yes
No
Patent application filed, but no financial interest.
Employee of MDxHealth.
No conflicts of interest. Sponsorship: This project was funded in part by the
Netherlands Organisation for Health Research and Development (ZonMW).
S47
Abstracts Index
Speakers’ Presentations
SP024
SP025
SP013
SP016
SP030
SP021
SP018
SP005
SP003
SP008
SP012
SP023
SP032
SP028
SP026
SP017
SP010
SP007
SP022
SP006
SP011
SP009
SP035
SP036
SP027
SP001
SP031
SP019
SP004
SP002
SP014
SP034
SP029
SP020
SP033
Alain, T., S7
Banerji, U., S7
Becker, R., S4
Bogaerts, J., S5
Chelsky, D., S8
Cheung, N., S6
de Vries, E., S5
DeMichele, A., S2
Dowsett, M., S1
Eberhard, D., S3
Gravanis, I., S4
Grose, R., S6
Hartmut, J., S9
Hegi, M., S8
Hidalgo, M., S7
Jeffrey, S., S5
Khambata-Ford, S., S3
Kummar, S., S3
Lacombe, D., S6
Le Tourneau, C., S2
Martens, J., S4
McDermott, U., S3
Moore, H., S9
Oelmueller, U., S10
Oliner, K., S7
Paoletti, X., S1
Pazzagli, M., S8
Postow, M., S5
Rodon, J., S2
Servant, N., S1
Shak, S., S4
Symmans, F., S9
Thomas, G., S8
Ulloa Montoya, F., S5
Zatloukal, K., S9
Six Best Poster Abstracts – Oral Presentations
MC13-0075
MC13-0071
MC13-0079
MC13-0060
MC13-0049
MC13-0026
Corcoran, R.B., S12
Guhathakurta, D., S12
Koh, Y., S12
Lih, C., S11
Polley, M., S11
Spindler, K., S11
Poster Presentations
MC13-0047
MC13-0048
MC13-0066
MC13-0004
MC13-0005
MC13-0006
MC13-0082
MC13-0086
MC13-0009
MC13-0037
MC13-0034
MC13-0068
MC13-0067
MC13-0023
MC13-0092
Agrawal, L., S25
Arnaud, M.P., S25
Belenguer-Querol, L., S30
Bie, L., S13
Bie, L., S13
Bie, L., S13
Bossi, P., S34
Bossi, P., S36
Boutros, P.C., S14
Chao, S.L., S22
Chernyaev, V., S21
Conley, B., S31
Del Re, M., S31
Delpous, S., S18
Demchok, J., S37
MC13-0077
MC13-0051
MC13-0065
MC13-0029
MC13-0062
MC13-0033
MC13-0033
MC13-0063
MC13-0020
MC13-0028
MC13-0057
MC13-0058
MC13-0036
MC13-0055
MC13-0001
MC13-0019
MC13-0041
MC13-0031
MC13-0064
MC13-0046
MC13-0030
MC13-0089
MC13-0039
MC13-0069
MC13-0038
MC13-0008
MC13-0010
MC13-0032
MC13-0073
MC13-0090
MC13-0025
MC13-0091
MC13-0050
MC13-0027
MC13-0052
MC13-0053
MC13-0054
MC13-0070
MC13-0080
MC13-0017
MC13-0088
MC13-0074
MC13-0021
MC13-0022
MC13-0024
MC13-0076
MC13-0085
MC13-0045
MC13-0007
MC13-0012
MC13-0078
MC13-0081
MC13-0015
MC13-0035
MC13-0040
MC13-0059
MC13-0084
MC13-0087
MC13-0044
MC13-0014
MC13-0018
Diaz, Z., S33
Donovan, M., S26
Donovan, M., S30
Drisis, S., S19
Emblem, K., S29
Eoli, M., S21
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