Abstract A12: Mutations in homologous recombination genes and response to treatment in GOG 218: An NRG Oncology Study.
Authors: Barbara M. Norquist, Mark F. Brady, Maria I. Harrell, Tom D. Walsh, Ming K. Lee, Suleyman Gulsuner, Sarah S. Bernards, Silvia Casadei, Robert A. Burger, Susan A. Davidson, Robert S. Mannel, Paul A. DiSilvestro, Heather A. Lankes, Nilsa C. Ramirez, Mary Claire King, Michael J. Birrer, Elizabeth M. Swisher
Journal: Clinical Cancer Research (2016)

Abstract Objective: Bevacizumab is an anti-vascular endothelial growth factor monoclonal antibody with activity in ovarian cancer. GOG 218 was a phase III, randomized trial in advanced primary ovarian, fallopian tube, and peritoneal carcinoma (collectively, OC), examining the role of adding bevacizumab to a regimen of q21 day carboplatin and paclitaxel. Our objective was to examine whether mutations in homologous recombination (HR) genes affect response to treatment. Methods: We sequenced germline (from blood) and/or somatic (from neoplastic tissue) DNA from 1195 women enrolled in GOG 218 using the targeted capture and multiplex sequencing assay BROCA-HR, focusing on 16 DNA repair genes. Defects in HR were defined as germline or somatic mutations in genes predicted to affect HR, including BRCA1, BRCA2, and others. Proportional hazards models were used to provide estimates of relative hazards for progression free survival (PFS) and overall survival (OS) adjusted for clinical characteristics. Results: Of 1195 women with OC, germline or somatic mutations were identified in 147 (12.3%) in BRCA1, 78 (6.5%) in BRCA2, and 81 (6.8%) in other, non-BRCA HR genes. Total mutation frequency (all genes combined) in those with high-grade serous histology was 26.9% (261/971), but this was not significantly higher than the mutation frequency in endometrioid histology (10/42, 23.8%), clear cell histology (6/28, 21.4%), or unspecified carcinoma (20/90, 22.2%). Mutation frequency also did not differ by disease site. Median PFS and OS by group were as follows: BRCA1: 15.6 and 53.7 months, BRCA2: 21.6 and 75.2 months, non-BRCA HR: 16 and 56 months, and no mutation: 12.6 and 42 months. Adjusting for study treatment, stage, residual disease, and initial performance status, hazards for progression and death compared to those without mutations were significantly lower for those with mutations, specifically with BRCA1 mutations (hazard ratio (HR) 0.80, 95% CI 0.66 – 0.97, p=0.02 for PFS; HR 0.75, 95% CI 0.60 – 0.95, p=0.02 for OS), with BRCA2 mutations (HR 0.52, 95% CI 0.40 – 0.67, p&amp;lt;0.0001 for PFS; HR 0.37, 95% CI 0.25 – 0.53, p&amp;lt;0.0001 for OS), and with non-BRCA HR mutations (HR 0.73, 95% CI 0.57 – 0.94, p=0.01 for PFS; HR 0.67, 95% CI 0.50 – 0.90, p=0.007 for OS). The analysis of PFS and OS by mutation status and treatment arm is underway. Conclusions: Women with OC with either germline or somatic mutations affecting HR have significantly longer PFS and OS than those without mutations. Disease site and histology were not predictive of mutation status. The effect of mutation status on response by treatment arm will be reported at presentation. Citation Format: Barbara M. Norquist, Mark F. Brady, Maria I. Harrell, Tom D. Walsh, Ming K. Lee, Suleyman Gulsuner, Sarah S. Bernards, Silvia Casadei, Robert A. Burger, Susan A. Davidson, Robert S. Mannel, Paul A. DiSilvestro, Heather A. Lankes, Nilsa C. Ramirez, Mary Claire King, Michael J. Birrer, Elizabeth M. Swisher. Mutations in homologous recombination genes and response to treatment in GOG 218: An NRG Oncology Study. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A12.