MINT study - USF Health - University of South Florida

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Principal Investigator: Charles E. Cox, M.D.
Co Investigators: Stefan Glück, M.D.
MINT
•
Title: MINT I Multi-Institutional Neoadjuvant Therapy MammaPrint Project I
Principal Investigator: Charles E. Cox, M.D.
University of South Florida, Tampa FL
Co Investigators: Stefan Glück, M.D. and Alberto Montero M.D.
University of Miami/Sylvester Comprehensive Cancer Center University of
Miami, Miller School of Medicine FL
•
Total of 226 patients; up to 10 institutes in the
USA
•
44K gene expression profiling Agendia Inc
•
Central pathology review at Moffitt Cancer Center FL
•
Timelines; Oct 2011- Oct 2013
Breast Cancer Symphony Suite
MammaPrint: 70-gene profile
prognostic and predictive tumor analysis
Will patient benefit from chemotherapy?
TargetPrint: Gene expression of ER/PR/HER2
Centralized lab confirmation of receptor status
Will patient benefit from hormonal treatment?
BluePrint: 80-gene molecular subtyping profile
Basal, Luminal, and HER2 subtypes
Which therapy works best?
TheraPrint: Gene expression of 56 genes
Potential markers for prognosis and therapeutic response
Potential therapy options saved for the future
BluePrint - Identifies molecular subtypes of
breast cancer
Breast Cancer
Analysis of Entire
Human Genome
~25,000 Genes
Basal, Luminal, and HER2-type
BluePrint
Basal-Type
Luminal-Type
classification
Prognostic & Predictive
Breast Cancer Genes
Identified
HER2-Type
TargetPrint: quantification of ER/PR/HER2
mRNA levels
Breast Cancer
Analysis of Entire
Human Genome
~25,000 Genes
Centralized lab confirmation
of receptors
Prognostic & Predictive
Breast Cancer Genes
Identified
Microarray based readout of ER, PR and HER2
IHC
microarray
TheraPrint - Suggests alternative treatment
options in advanced disease
Breast Cancer
Analysis of Entire
Human Genome
~25,000 Genes
Gene expression analysis
for drug sensitivity
Prognostic & Predictive
Breast Cancer Genes
Identified
TheraPrint: quantitates 56 genes linked to
specific drug responses



Offers read-out of gene expression for 56 genes
Genes might have relevance in breast cancer therapy and
prognosis
No claims about mRNA level and response can be made
Genes Included:
The response to chemotherapy varies in the
different molecular subtypes
Straver1
Somlo2
n
pCR
n
pCR
n
pCR
n
pCR
%
21
0
14
1
29
1
64
2
3%
Luminal-type/MP High Risk
67
3
16
0
53
6
136
9
7%
HER2-type
41
13
18
10
24
12
83
35
42%
Basal-type
38
13
20
4
27
15
85
44
52%
Luminal-type/MP Low Risk
1. Straver et al. Breast Cancer Res Treat, 2009
2. Somlo et al. ASCO, 2009
3. Hess study as part of Krijgsman et al. In press, 2011
Hess3
Total
MINT; Study Objectives

To determine the predictive power of chemosensitivity of the
combination of MammaPrint and BluePrint as measured by pCR.

To compare TargetPrint single gene read out of ER, PR and HER2
with local and centralized IHC and/or CISH/FISH assessment of
ER, PR and HER2.

To identify possible correlations between the TheraPrint
Research Gene Panel outcomes and chemo-responsiveness.

To identify and/or validate predictive gene expression profiles
of clinical response/resistance to chemotherapy.

To compare the three BluePrint molecular subtype categories with
IHC-based subtype classification.
MINT; Eligibility Criteria
Inclusion criteria:


Women with histologically proven invasive breast cancer; T2(≥3.5cm)-T4, N0,M0 or
T2-4N1M0
DCIS or LCIS are allowed in addition to invasive cancer at T2 or T3 level.

Age ≥ 18 years.

Measurable disease in two dimensions

Adequate bone marrow reserves, adequate renal function, and hepatic function

Signed informed consent
Exclusion criteria

Patients with inflammatory breast cancer.

Tumor sample shipped to Agendia with ≤ 30% tumor cells or that fails QA or QC
criteria.

Patients who have had any prior chemotherapy, radiotherapy, or endocrine therapy for
the treatment of breast cancer.

Any serious uncontrolled inter current infections, or other serious uncontrolled
concomitant disease.
MINT; Nodal staging
Study Design Flowchart
Core
Needle
Biopsies
FFPE Slides
and
microscopic
worksheets to
USF
Pathology
Sample
placed in
RNA
Retain,
send to
Agendia*
Breast
Cancer
Symphony
Suite
successful
Breast
Cancer
Symphony
Suite not
successful
Patient
information
& informed
consent
Neoadjuvant
treatment
CRF
1
CRF
2
baseline
surgery
Surgery
Patient
ineligible
* (Diagnostic commercial testing for Symphony Breast cancer Suite)Suite
FFPE Slides
and
microscopic
worksheets to
USF
Pathology
Neo-adjuvant therapy
For HER2 negative patients:

TAC chemotherapy

TC chemotherapy

Dose Dense AC or FEC100 followed by paclitaxel or docetaxel
chemotherapy
For HER2 positive patients:

TCH chemotherapy
Dose adjustments

Hematological and non-hematological toxicities should be managed by
treating oncologist as per routine clinical practice.
Tissue Collection

Tissue should be collected by incisional biopsy (when placing port) or via
core needle biopsy.

If the tissue is obtained by incisional biopsy then the tissue sample should
be no greater than 3 to 4 mm in thickness and between 8 to 10 mm in
diameter.

Core needle biopsies should be obtained with a 14 gauge or larger needle.
◦ If a 14 gauge needle is used: 5 cores
◦ If a 11 gauge needle is used: 4 cores
◦ If a 9 gauge needle is used: 3 cores
Sending Sample to Agendia
A.
Remove large specimen tube from kit and open it.
B.
Place large screw cap with small specimen vial on
table and open small specimen vial.
C.
Place a barcode label from the completed
requisition form on to the vial.
D.
Place the small specimen vial into the large
specimen tube and place the tube into the
specimen safety bag.
E.
Place the sealed specimen bag into the shipping
kit along with the requisition form. IMPORTANT:
ensure that the study sticker is affixed to the
requisition form.
F.
Package the kit into the FedEx shipping pack and
attach the pre printed label for shipment to
Agendia Inc.
G.
Please call Fed Ex for pickup.
Central Pathology Review
Initial core/incisional biopsy specimens

Cold ischemic time (time from collection of specimen to fixation solution)
should be restricted to < 1 hour

Tissue submitted for histopathological analysis will be fixed in 10% buffered
formalin for 6 to 48 hours

Send 1 H&E, original ER, PR, and HER2 IHC stains, and 10 unstained sections
of representative tumor on positive-charged glass slides for central review
(Appendix III).

If receptor studies are not available, an additional 10 unstained sections on
positive-charged glass slides of representative tumor will be required.
Central Pathology Review
Gross specimen processing
1. Lumpectomy/partial mastectomy

The specimen is oriented, inked in 6 colors, and sectioned at 0.3-0.4 cm intervals.

If gross residual tumor is identified:
◦ Dimensions (width, length, height) are recorded
◦ Distance from all margins if < 0.2 cm is noted, otherwise the closest margin is
recorded
◦ The gross residual tumor is entirely submitted in sequential sections (Appendix IV)
◦ Sampling of margins is performed

If no-grossly identifiable residual tumor is present:
◦ The dimensions of the biopsy site and surrounding fibrosis/ induration is recorded
◦ The specimen is entirely submitted sequentially (Appendix IV)
◦ Description of margin status is recorded as noted above
Central Pathology Review
2. Total mastectomy/modified radical mastectomy

The specimen is oriented and inked accordingly

If gross residual tumor is identified:
◦ Dimensions (width, length, height) are recorded
◦ Distance from all margins if < 0.2 cm is noted, otherwise the closest margin is
recorded
◦ The gross residual tumor is entirely submitted in sequential sections (Appendix IV)
◦ Sampling of margins is performed

If no-grossly identifiable residual tumor is present:
◦ The dimensions of the biopsy site and surrounding fibrosis/ induration is recorded
◦ The area of fibrosis (“tumor bed”), to include biopsy site, is entirely submitted
sequentially (Appendix IV)
◦ Description of margin status is recorded as noted above
Central Pathology Review
Sentinel lymph node processing

Sentinel lymph nodes will be serially sectioned along the long axis at 2-mm intervals. If
the lymph node measures 0.5 cm in greatest dimension, it may be bivalve. Specimens are
then entirely submitted (Appendix IV).
Clinical Report Form

Web based data collection/electronic CRF
◦ CRF1; Baseline information
◦ CRF2; After surgery
Relatively easy to complete compared to drug trial
15-20 minutes for CRF1 and 2
Accessing the Database
◦ There is one hyperlink to access all the electronic Case Report Forms (CRFs)
https://trials.agendia.com/MINT
◦ You will receive an institution specific site number and password from your
Agendia Clinical Research Manager.
Institution:
CRF Overview Administrative page
Detailed Data Entry Instructions will be sent to site.
Samples will appear in the database if they are found to be eligible.
CRF 1: Questions
Baseline Patient characteristics
Pathology

Age at diagnosis

Date of histologic diagnosis

Ethnicity/ origin

Histopathologic tumor type

Menopausal status

Histological grade

Date of biopsy

ER, PR and Her2-neu status

Specimen type

Vascular invasion

TNM

Nodal staging
Tumor measurements

Date nodal staging

Kind of imaging used

If sentinel lymph node

Primary tumor size

Number of sentinel nodes removed

Size largest metastatic lymph node

Number of counts

Blue dye

Histology of SLN:

Concordance of nodal histology to
primary tumor
CRF 2: Questions
Neo-adjuvant treatment

Regimen given

Was specified number of cycles
completed?

Any grade 4 or 5 CTC for Adverse Events
observed?
Surgery information

Date breast carcinoma surgery

Type of surgery

Lymph node assessments
Pathology

Nodal status

ypTN
Tumor measurements

What kind of imaging has been used ?

Primary tumor size

Size largest metastatic lymph node

Treatment response
Lymph node assessments
Sentinel Lymph Node Procedure (SLNP) If yes
•Number
of sentinel nodes examined
•Number
of positive sentinel nodes
•Number
of negative sentinel nodes
•Blue
dye
•Concordance
of nodal histology to primary
tumor
Axillary Lymph Node Dissection (ALND) If yes
•Number of axillary nodes examined
•Number of positive axillary nodes
•Number of negative axillary nodes
SLNP and ALND if yes:
Contacts:

Jessica Gibson, Clinical Research Manager
(619)316-1416
[email protected]
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