Paper 50
COMPREHENSIVE THERANOSTIC PROFILING OF
DIVERSE SARCOMAS IDENTIFIES FREQUENT CDK
AND PI3KCA/PTEN PATHWAY ABERRATIONS:
IMPLICATIONS FOR PRECISION MEDICINE
Rishi Agarwal1; Filip Janku1; Patel Shreyaskumar2;
Apostolia Tsimberidou1; Robert Benjamin2; Vinod Ravi,
MD2; Joseph A. Ludwig2; Pete Anderson2; Ralph Zinner1;
David Hong1; Funda Meric-Bernstam1;
Vivek Subbiah, MD1
1Investigational Cancer Therapeutics, The University of
Texas MD Anderson Cancer Center, Houston, TX, USA;
2Sarcoma Medical Oncology, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Objective: Sarcomas are extremely rare and diverse neoplasms
of mesenchymal origin. Therapeutic options are
limited and search for genomic alterations could lead to
identification of novel therapeutic options for patients with
relapsed and refractory sarcomas. Treatment with matched
targeted therapy could be beneficial in these patients.
Methods: We reviewed the charts of patients with advanced
sarcoma patients who were referred to investigational
cancer therapeutics department and had molecular
profiling by next-generation exome sequencing, multiplex
PCR/mass spectroscopy, morphoproteomics, and immunohistochemistry
done by CLIA certified labs. We analyzed
Table 1. Aberrant Pathways in Relapsed Sarcomas.
Aberrant Signaling Pathways Number of
patients Potential therapeutic options
P53 aberration/MDM2 amplification 15/7 MDM2 Inhibitors
CDK pathway (CDKN2A/B loss or mutation,
CDK4 amplification, and CCND1 amplification) 19 CDK inhibitors,
cell cycle inhibitors
PI3KCA/PTEN pathway (PIK3CA mutation,
PTEN loss, PIK3R1 mutation) 8 PI3K/Akt/mTOR
pathway inhibitors
ing human disease,
including the aberrant
karyotype and metastatic
behavior. Pten
was found haploinsufficient,
whereas the
wild-type allele of Tp53
invariably gained point
mutations. Gene ex131
the preliminary responses to matched therapy in these
patients.
Results: Among the fifty-seven patients analyzed, median
age was 48 years (M: F=25:32), median ECOG PS=1, median
no. of prior therapies=3. Most common subtypes were
leiomyosarcoma (n=13; 22%), rhabdomyosarcoma (n=8;
14 %), liposarcoma (n=7; 12 %), osteosarcoma (n=7; 12
%), clear cell sarcoma (n=3), and synovial sarcoma (n=3).
Forty-five/57 (78%) patients had > 1 genomic aberration
(Table 1). Aberrations involved CDKN2A/B loss or mutation
(n=10; 22 %), TP53 alterations (n=15; 33%), CDK4 amplification
(n=8; 17%), MDM2 amplification (n=7; 15%), and
RB1 loss/mutation (n=6; 13%). 4/8(50%) patients with aberration
in PI3K/mTOR pathway (PTEN loss (n=4), PI3KCA
mutation(n= 3), PIK3R1 mutation (n=1) were started on
matched therapy to elicit early response signals. Updated
clinical data will be presented.
Conclusion: Aberrations in CDK pathway (CDKN2A/B loss
or mutation, CDK4 amplification, and CCND1 amplification)
(n=19; 42%) were more common than aberrations in
MDM2 pathway and PI3KCA/PTEN pathway (n=15; 33%)
combined. Early signals of clinical benefit were noted even
in the heavily pre-treated patients(Table 2). Further large
scale analyses of sarcoma patients with clinical correlation
is needed to overcome the resistant and metastatic
phenotype.
Diagnosis PI3KCA/PTEN
pathway Aberration Matched Clinical Trial RECIST Response
(Duration of response)
Rhabdomyosarcoma PIK3CA mutation Novel PI3K inhibitor SD (18 weeks)
Unclassified sarcoma PTEN loss Temsirolimus +
Bevacizumab + Sorafenib
SD (16 weeks with
26% tumor shrinkage)
Leiomyosarcoma # 1 PTEN deletion Pazopanib + Everolimus SD (16 weeks)
Leiomyosarcoma# 2 PIK3R1 mutation Sirolimus + Vorinostat SD (15 weeks)
Table 2. Response to Matched Therapies on Phase I Clinical Trials
Paper 051
IDENTIFICATION OF POTENTIAL MOLECULAR
BIOMARKERS FOR RESPONSE OF SOFT TISSUE
SARCOMA TO ERIBULIN - TRANSLATIONAL
RESULTS OF EORTC TRIAL 62052
Agnieszka Wozniak1; Erik A. Wiemer2; Herman Burger2;
Joke Allemeersch3; Rudy van Eijsden3;
Ron H J. Mathijssen2; Stefan Sleijfer2; Marcel Smid2;
Giuseppe Floris4; Sandrine Marreaud5;
Axelle Nzokirantevye5; Raf Sciot4; Patrick Schöffski1
1Lab of Experimental Oncology and Department of
General Medical Oncology, KU Leuven and University
Hospitals in Leuven, Leuven, Belgium; 2Department of
Medical Oncology, Erasmus MC Cancer Institute,
Rotterdam, Netherlands; 3Nucleomics Core, VIB,
Leuven, Belgium; 4Department of Pathology,
KU Leuven and University Hospitals in Leuven,
Leuven, Belgium; 5European Organisation for Research
and Treatment of Cancer (EORTC), Brussels, Belgium
Objective: The phase II study EORTC 62052 demonstrated
potential antitumor activity of eribulin, a tubulininteracting
cytotoxic agent, which is a synthetic analogue
of the natural compound halichondrin B, in patients with
various subtypes of metastatic soft tissue sarcoma (STS)
including leiomyo- (LMS) and adipocytic (ADI)1. In addition
to histotypes, we aimed to identify potential biomarkers
responsible for eribulin sensitivity or resistance to eribulin
using gene expression and miRNA profiling.
Methods: From 68 consenting patients archived tumor
tissue was collected, including 22 LMS, 15 ADI, 10 synovial
(SYN) and 21 other (OTH) sarcoma histotypes. Total
Number of differentially
expressed transcripts
Number of differentially
expressed miRNAs
Downregulated*
Upregulated*
Potential
biomarker
Downregulated*
Upregulated*
Potential
biomarker
All STS 20 42 ALS2CR11 18 8 miR-17-92 cluster
subtypes**
ADI 58 500 MYLK3 8 0 miR-106b
LMS 11 19 SLC8A1 6 2 miR-146a; 1271;
590-3p; 29b-2#
OTH 66 93 IGF2, COL1A2
1 0 miR-186
Differentially expressed transcripts and miRNA, discriminating patients responding
and non-responding to eribulin
*in responders; ** SYN subgroup not taken into account as only one patient reached PFS at 12
weeks
132
RNA was isolated from 65 samples and analyzed using
GeneChip Human Exon ST Array (for mRNA expression)
and Taqman Low Density Array (for miRNA). Progression
free survival (PFS) at week 12 (RECIST 1.0) was the primary
endpoint of the clinical trial and used for correlative
studies. Eighteen out of 56 (32.1%) evaluable patients in
this analyzed subset had non progressive disease at week
12 ("responders").
Results: Overall expression of 62 transcripts including
ALS2CR11 (uncorrected p<0.001) and 26 miRNAs (p<0.05)
differed significantly between non-responders and responders.
Additional transcripts and miRNAs were identified when
considering the different histological groups (Table).
Conclusion: The level of (mi)RNA expression in soft tissue
sarcoma samples may predict response of soft tissue sarcoma
to eribulin. Further validation studies are required.
References: 1Schöffski P et al. Lancet Oncol. 2011 ;12:1045.
The EORTC 62052 clinical trial and translational research
were supported by Eisai