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. 2018 Feb 15;24(4):777-783.
doi: 10.1158/1078-0432.CCR-17-1327. Epub 2017 Nov 30.

Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study

Barbara M Norquist  1 , Mark F Brady  2 , Maria I Harrell  3 , Tom Walsh  4   5 , Ming K Lee  4   5 , Suleyman Gulsuner  4   5 , Sarah S Bernards  3 , Silvia Casadei  4   5 , Robert A Burger  6 , Krishnansu S Tewari  7 , Floor Backes  8 , Robert S Mannel  9 , Gretchen Glaser  10 , Cheryl Bailey  11 , Stephen Rubin  12 , John Soper  13 , Heather A Lankes  14 , Nilsa C Ramirez  14 , Mary Claire King  4   5 , Michael J Birrer #  15 , Elizabeth M Swisher #  3   4
Affiliations

Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study

Barbara M Norquist et al. Clin Cancer Res. .

Abstract

Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab.Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS).Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57-0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50-0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66-0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59-0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40-0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25-0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations.Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777-83. ©2017 AACR.

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Figures

Figure 1
Figure 1. Progression-free and overall survival in OC patients by mutation category
A. – B. Kaplan-Meier curves for progression-free and overall survival by mutation category, with adjusted hazard ratios for progression or death. Hazard ratios were adjusted for study treatment, stage of disease, size of residual disease, and initial performance status. The no mutation group was the referent group. Events were progression or death in 60 months. Abbreviations: aHR (adjusted hazard ratio).
Figure 2
Figure 2. Effect of extended bevacizumab on survival in OC patients with and without mutations
A. – D. Kaplan-Meier curves for progression-free and overall survival in OC patients with and without mutations in genes affecting HRR. E. – F. Adjusted hazard ratios for progression or death by individual mutation categories. Using a test of interaction, mutation status did not significantly modify the effect of extended bevacizumab on progression (0.95/0.71) = 1.33, 95% CI 0.95 – 1.85, p = 0.10.
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