Somatic mutations in homologous recombination pathway genes in ovarian cancer.

Abstract

5545 Background: 15% of patients with OC have a germline BRCA 1 / 2 mut & 6% of OC have a somatic BRCA 1/ 2 mut. Inhibitors of poly ADP ribose polymerase (PARPi) are approved in this setting. Data is evolving as to activity of PARPi in BRCA wild type OC with somatic homologous recombination (HR) gene deficiency. We sought to determine the prevalence of somatic alterations in HR genes in an unselected cohort of epithelial OC of any histologic type. Methods: From 03/2014-10/2016 patients consented to an IRB approved protocol for tumor-normal sequencing, via a custom next-generation sequencing panel (MSK-IMPACT) with return of results for tumor mut only. Muts in 14 HR genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, MRE11, NBN, PALB2, PTEN, RAD51D, RAD51C) and p53were assessed. Statistics were analyzed using GraphPad Prism v. 6. Results: 260 tumors were sequenced; 156 (60%) high grade serous (HGS), 34 (13%) low grade serous (LGS), 34 (13%) clear cell, 10 (4%) mucinous, 8 (3%) endometrioid, 18 (7%) mixed/other histology. 151 (97%) of HGS and 24 (23%) of the remaining tumors harbored p53 mut. 48 (18%) somatic HR mut were identified. (Table 1) 26 HGS (17%) tumors and 22 (21%) of the remaining tumors harbored a HR gene mut (HGS vs other histology, p=0.4). Notably, 8 (24%) of clear cell cancers demonstrated HR gene muts (vs HGS, p=0.3). 18 (38%) of the identified muts in the overall cohort were in BRCA 1/2. There were no somatic HR gene muts identified in the mucinous OC, which were characterized by frequent p53 (90%) and KRAS(60%) muts. Conclusions: In this cohort of OC, 17% of tumors harbor somatic HR gene muts. The prevalence of HR somatic muts was similar in HGS vs other histologies, with the exception of mucinous OC. BRCA1/2 muts predominated, however 60% of identified muts were in other genes. Accrual is ongoing to increase histologic cohort sizes. Broad HR gene somatic mutational profiling may identify a wider cohort of OC patients with potential to benefit from PARPi therapy. [Table: see text]