Abstract 611: Exploratory analyses suggest ovarian tumors with somatic or germline loss of function mutations in BRCA1 or BRCA2 are biologically similar and sensitive to PARP inhibition
Authors: Dougherty Brian , Lai Zhongwu , Ledermann Jonathan A. , Robertson Jane D. , Ho Tony W. , Wu Wenting , Hodgson Darren R. , Orr Maria C M , O'Connor Mark J. , Hawryluk Matthew J. , Brennan Timothy A. , Yelensky Roman , Sun James X. , Barrett J Carl 
Published: August 2015

The PARP inhibitor olaparib (LynparzaTM) elicits responses in ovarian cancer patients with inherited (germline) loss of function mutations in the BRCA1 or BRCA2 genes (gBRCAm). In the tumors of such patients the unmutated (wt) copy of the relevant BRCA gene is usually lost. Many patients are aware of their BRCA mutation status due to the wide availability of blood testing. However, in around a third of ovarian tumors with BRCA mutations the mutation has not been inherited but is tumor-specific (sBRCAm). Given the difference in origin of mutation, it is important to determine whether there are genotypic and phenotypic differences between sBRCAm and gBRCAm ovarian tumors. In a randomized, Phase II trial of 265 patients with platinum-sensitive relapsed serous ovarian cancer (NCT00753545; Study 19), maintenance treatment with olaparib (400 mg bid; capsules) led to a significant increase in progression-free survival (PFS) vs placebo in patients with a BRCA mutation (HR 0.18; 95% CI 0.10-0.31; P&lt;0.00001). Diagnostic tumor samples from the study were sequenced by Foundation Medicine. After filtering for common polymorphisms, BRCA gene variants were classified using American College of Medical Genetics standards as mutant, wild type or variant of unknown significance (VUS). VUS were further classified on the basis of information from the Breast Information Core database. Mutation origin (g vs s) and zygosity were determined by tumor allele frequency analysis and/or by comparison to germline sequencing, and heterogeneity was determined using the Foundation Medicine SGZ algorithm, which compares allele frequency to model expectations, taking into account tumor purity, ploidy and local copy number. BRCA mutations were found in 53% of the 209 samples with data available. Known germline BRCA mutations were correctly classified as germline by the SGZ algorithm. Tumor BRCA mutations were identified in 40 patients without confirmation of a mutation in a blood sample. Twenty of these patients were classified as sBRCAm (12 BRCA1 and 8 BRCA2) by the algorithm. Only one case was called without loss of the wt BRCA allele. It has been hypothesized that TP53 mutation is an early event and was found to be consistent between tumors and precursor lesions. Allele frequencies/clonality for BRCA and TP53 mutations were comparable and there was no evidence of systematic subclonality in the sBRCAm cases. An exploratory analysis of PFS and overall survival (OS) was performed on the 20 patients (10 received treatment and 10 placebo). Consistent with results from the gBRCAm population, a trend in event rate in favor of treatment over placebo was observed (3/10 vs 8/10 events for PFS and 3/10 vs 7/10 for OS). Although from a small number of patients, data are consistent with sBRCA mutation as an early event in tumorigenesis and support phenotypic similarity of gBRCA and sBRCA mutated tumors.

Citation Format: Brian Dougherty, Zhongwu Lai, Jonathan A. Ledermann, Jane D. Robertson, Tony W. Ho, Wenting Wu, Darren R. Hodgson, Maria C M Orr, Mark J. O'Connor, Matthew J. Hawryluk, Timothy A. Brennan, Roman Yelensky, James X. Sun, J Carl Barrett. Exploratory analyses suggest ovarian tumors with somatic or germline loss of function mutations in BRCA1 or BRCA2 are biologically similar and sensitive to PARP inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 611. doi:10.1158/1538-7445.AM2015-611