Prognostic role of BRCA1/2 mutation type and location in advanced high-grade ovarian cancer

Background: The association of different BRCA1/2 gene mutation types and locations with survival outcomes and their impact on poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) efficacy in ovarian cancer remains unclear. This study aimed to evaluate the prognostic role of BRCA1/2 gene mutation type and location in patients with advanced-stage ovarian cancer. Methods: This retrospective cohort study included patients with a BRCA1 or BRCA2 gene mutation (either somatic or germline) who underwent cytoreductive surgery for advanced-stage (FIGO [International Federation of Gynecology and Obstetrics] stage III-IV) high-grade serous ovarian cancer at the European Institute of Oncology (IEO), Milan, between January 2016 and December 2023. BRCA1/2 mutations were classified by mutation type (missense, nonsense, frameshift, splicing), domain (Really Interesting New Gene [RING], DNA-binding domain [DBD], BRCA1 C-terminal [BRCT], RAD51-binding domain [RAD51-BD], “outside domain”), and exon location (exon 11 vs other). Disease-free survival (DFS) at 24 months was the primary endpoint; overall survival (OS) was investigated as a secondary endpoint. DFS was analyzed using the Kaplan-Meier curves and Cox regression models. Multivariate analysis was adjusted for FIGO stage, residual disease, type of surgery, and maintenance therapy (PARPi and/or bevacizumab). Results: In total, 201 patients were included: 141 (70.1%) with BRCA1 and 60 (29.9%) with BRCA2 mutation. Frameshift mutations were the most frequent type (n=87; 43.3%), followed by nonsense (n=74; 36.8%), missense (n=28; 13.9%), and splicing (n=12; 6.0%). Mutation distribution by domain was as follows: 26.4% DBD, 17.0% BRCT, 6.4% RING, 6.4% RAD51-BD, and 43.8% outside domain. Follow-up and recurrence data were available for 198 out of 201 patients. In total, 104 patients (52.52%) had a disease recurrence (86 BRCA1 and 18 BRCA2), with a median time to recurrence of 41 months (IQR, 26.5–58.5). In the BRCA1 group, 24-month DFS was 38.0% (95% CI, 21.4–54.5) for BRCT, 44.9% (95% CI, 17.7–69.0) for RING, and 79.4% (95% CI, 61.6–89.6) for DBD (p=0.06). Among BRCA2-mutated cases, 24-month DFS was 86.5% (95% CI, 55.8–96.5) for the DBD domain and 27.4% (95% CI, 1.6–66.6) for RAD51-BD (p<0.01). Multivariate analysis showed BRCA1 BRCT (HR, 2.33 [95%, 1.21–4.49]), BRCA1 RING (HR, 2.86 [95%, 1.10–7.42]), and BRCA2 RAD51-BD (HR, 6.7 [95%, 1.2–38.35]) domains were associated with a higher likelihood of recurrence at 24 months compared to DBD. In both BRCA1 and BRCA2 cohorts, mutation type and exon 11 involvement were not statistically significantly associated with DFS. Conclusion: Specific BRCA1/2 mutation functional domains, rather than mutation type or exon 11 status, appear to influence prognosis in advanced high-grade serous ovarian cancer. Mutations within the DBD of BRCA1 and BRCA2 were associated with improved DFS, whereas variants in the RING, BRCT, and RAD51-BD correlated with less favorable outcomes. Integrating domain-level BRCA mutation characterization—beyond traditional binary BRCA1/2 status (mutated vs wild-type)—into clinical decision-making represents a step toward personalized precision oncology in ovarian cancer care.