gBRCA1 and gBRCA2 mutations in specific different domains affect ovarian cancer prognosis: A multicenter retrospective study

BACKGROUND: The prognostic value of germline BRCA1/2 mutations (g BRCA1/2 m) in ovarian cancer is controversial, and the clinical implications of specific mutation domains within BRCA1/2 remain underexplored. This study aimed to investigate the impact of distinct g BRCA1/2 m domains on survival outcomes in patients with ovarian cancer. METHODS: This multicenter retrospective study, conducted between 2010 and 2022 at three major academic centers in China, analyzed 313 patients with epithelial ovarian cancer with pathogenic g BRCA1/2 m. We evaluated associations between g BRCA1/2 m domains and clinical outcomes including progression-free survival (PFS) and platinum-free interval. RESULTS: Patients who received platinum-based chemotherapy without maintenance therapy with BRCA1 C-terminal domain 1 (BRCT1) mutations showed significantly prolonged PFS (37.8 vs . 22.6 months; hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.19-0.99; P = 0.042), whereas those with Really Interesting New Gene (RING) mutations had shorter PFS (13.1 vs . 23.2 months; HR, 1.82; 95% CI, 0.89-3.72; P = 0.097). In the subgroup of gross residual disease, RING mutations were significantly associated with reduced PFS (12.9 vs . 21.8 months; HR, 3.25; 95% CI, 1.29-8.18; P = 0.008). A higher likelihood of primary platinum-refractory disease (odds ratio, 7.78; 95% CI, 1.25-48.31; P = 0.028) was observed. Across all mutation locations, poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy demonstrated benefits, notably for patients with BRCA1 RING mutations (HR, 0.10; 95% CI, 0.01-0.84; P = 0.010) and BRCA2 RAD51-binding domain (RAD51-BD) mutations (HR, 0.29; 95% CI, 0.11-0.79; P = 0.010). CONCLUSIONS: BRCA1 BRCT1 mutations are associated with improved prognosis following platinum-based chemotherapy, whereas BRCA1 RING domain mutations are linked to a heightened risk of primary platinum-refractory disease. Our findings underscore the need for complete resection with no gross residual disease in patients harboring RING mutations. Furthermore, PARPi maintenance therapy exhibits variable efficacy based on mutation location, with BRCA1 RING and BRCA2 RAD51-BD mutations conferring significant benefits.