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

Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma (OC) 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 OC 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 OC, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared to those without mutations were lower for women with non-BRCA HRR 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) and BRCA1 mutations (hazard ratio (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 OC and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status.

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