Decoding BRCA1 and BRCA2 Mutations in High-Grade Serous Ovarian Cancer: Impact of Location and Type of Mutation on Prognosis and PARP Inhibitor Treatment

OBJECTIVE: Pathogenic mutations in BRCA1/2 are associated with improved survival in high-grade serous ovarian carcinoma, but the prognostic impact of specific mutations remains unclear. The primary aim of this study was to evaluate the role of different locations, types, and functions of BRCA1/2 mutations on survival in patients with high-grade serous ovarian carcinoma. METHODS: This study included a total of 174 patients with advanced-stage high-grade serous ovarian cancer, 74 women with BRCA1/2 mutations, and 100 wild-type controls. Mutations were categorized based on gene (BRCA1 vs BRCA2), location (inside exon 11 vs outside; functional domains), type (frameshift, nonsense, missense), and function (truncated protein vs amino acid change). Poly (adenosine diphosphate-ribose) polymerase inhibitor exposure was defined as receipt of maintenance therapy in first or subsequent lines. Survival outcomes were analyzed using univariate and multi-variate models. RESULTS: In multi-variate analysis, adjusted for residual tumor and International Federation of Gynecology and Obstetrics stage, mutations in BRCA2 RAD51-BD (hazard ratio 0.03, P=.001) and in BRCA1 DNA-binding domain (hazard ratio 0.23, p =.008) were associated with the most favorable prognosis compared to wild type. In contrast, BRCA1 BRCT or RING domain mutations showed survival outcomes similar to wild type. Frameshift (hazard ratio 0.17, p