Location of mutation in BRCA2 gene and survival in patients with ovarian cancer

Purpose: BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of BRCA2 gene impacts the clinical outcome of OC patients. Experimental Design: A study cohort of 353 women with OC who underwent genetic germline testing for BRCA1 and BRCA2 genes were identified. Progression-free survival (PFS), platinum-free interval (PFI) and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of OC (n=316) was used as a validation cohort. Results: In the study cohort, 78 patients were carriers of germline mutations of BRCA2. After adjustment for FIGO stage and macroscopic residual disease, BRCA2 carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS (58%; adjusted Hazard ratio [HR], 0.36; 95% CI, 0.20-0.64; p=0.001) and prolonged PFI (29.7 vs 15.5 months, p=0.011), compared to non-carriers. BRCA2 carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42-1.07; p=0.094) or PFI (19 vs 15.5 months, p=0.146). In the TCGA cohort, only BRCA2 carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13-0.68; p=0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02-0.38; p=0.001). Conclusions: Among ovarian cancer patients, BRCA2 carriers with mutations located in the RAD51-BD (exon 11) have prolonged progression-free survival, platinum-free interval and overall survival.

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