Abstract 58: Differences in genomic alterations revealed by sequencing of 182 genes in recurrent ovarian cancer specimens compared to TCGA analysis: rearrangements in PTCH1 and FLT3; high frequency of RAS pathway alteration.

Abstract

Abstract Recent comprehensive genomic analyses of advanced stage, high grade serous ovarian carcinomas carried out by TCGA (Nature 274: 609-615, 2011) have revealed their heterogeneous nature and provide an explanation for the failure of molecularly targeted drugs evaluated without consideration of the tumor molecular characteristics of the patients treated. Copy number (CN) alterations or mutations in RB, RAS-MAPK, and PI3K-AKT pathway genes occur in ∼35%, 20%, and 35% of the tumors, respectively. Activation of these pathways may confer sensitivity to drugs that target them (e.g., PI3K or AKT inhibitors, MEK inhibitors, CDK inhibitors) as well as resistance to drugs (e.g., HER2 or EGFR inhibitors) that have failed in ovarian cancer clinical trials. A comprehensive evaluation of the genetic aberrations in targetable pathways can therefore inform the selection of appropriate drugs and combinations for each patient in the context of clinical trials. As part of molecular profiling analyses performed for recurrent ovarian cancer patients to inform selection of their next treatment, the presence of mutations or alterations (e.g., CN changes) in 182 genes that encode proteins that are key mediators in oncogenic and tumor suppressive pathways were determined using a validated exon-capture sequencing platform provided in a CLIA-certified laboratory setting. 20 serous (4 primary/16 recurrent) and 4 recurrent mixed or pure clear cell ovarian tumor samples were analyzed. A median of 2.5 (range 0-7) alterations were detected in the serous histology specimens; frequencies of p53 mutations (16; 80%) and amplifications in CCND1 (1; 5%), CCND2 (1; 5%), CCNE1 (2; 10%) are consistent with those observed in the TCGA tumors. In contrast, more frequent RAS pathway aberrations (45% vs. 20%) corresponding to KRAS amplification (3;15%) and mutations/truncations in NF1 (5; 20%) or NF2 (1; 5%) were observed, possibly reflecting the recurrent nature of these samples (TCGA used primary tumors). Only one PIK3CA amplification was detected (i.e., 5%) in contrast to the 18% observed in the TCGA dataset. Amplifications of IGF1R (3; 15%) and ERBB2 (1;5%) were also detected in the serous histology tumors, while PIK3CA and KRAS mutations were only detected in the tumors with mixed cc and endometrioid histologies. Interestingly, a predicted protein-truncating rearrangement in PTCH1 and a kinase-activating exon duplication in FLT3 were detected in tumors from single patients suggesting drugs targeting the HH pathway and FLT3 as options for ovarian cancer patients. While it is important to increase the number of samples analyzed, these data suggest that selection of patients for clinical trials should be informed by comprehensive molecular characterization of recurrent tumor specimens. Citation Format: Deborah A. Zajchowski, Doron Lipson, Gary Palmer, Laura K. Shawver. Differences in genomic alterations revealed by sequencing of 182 genes in recurrent ovarian cancer specimens compared to TCGA analysis: rearrangements in PTCH1 and FLT3; high frequency of RAS pathway alteration. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 58. doi:10.1158/1538-7445.AM2013-58