Attempts to determine the clinical significance of BRCA1/2 mutations in ovarian cancer (OvCa) have produced conflicting results.
To determine the relationships between BRCA1/2 deficiency (i.e., mutation and promoter hypermethylation) and overall survival (OS), progression-free survival (PFS), chemotherapy response, and whole exome mutation rate in OvCa.
Design, Setting, and Patients
Observational study of multidimensional genomics and clinical data on 316 high-grade serous OvCa cases that were made public between 2009 and 2010 via The Cancer Genome Atlas project.
Main Outcome Measures
OS and PFS rates (primary outcomes) and chemotherapy response (secondary outcome).
BRCA2 mutations (29 cases) were associated with significantly better OS (adjusted hazard ratio [HR], 0.33; 95% CI, 0.16–0.69, P=0.003; 5-year OS: 61% for BRCA2 mutated vs. 25% for BRCA wild-type [wt] cases) and PFS (adjusted HR, 0.40; 95% CI, 0.22–0.74, P=0.004; 3-year PFS: 44% for BRCA2 mutated vs. 16% for BRCA wt cases), whereas neither BRCA1 mutations (37 cases) nor BRCA1 methylation (33 cases) were associated with prognosis. Moreover, BRCA2 mutations were associated with a significantly higher primary chemotherapy sensitivity rate (100% for BRCA2 mutated vs. 82% [P=0.02] and 80% [P=0.05] for BRCA wt and BRCA1 mutated cases, respectively) and longer platinum-free duration (median platinum-free duration: 18.0 months for BRCA2 mutated vs. 11.7 [P=0.02] and 12.5 [P=0.04] months for BRCA wt and BRCA1 mutated cases, respectively). Further investigation revealed that BRCA2 mutated, but not BRCA1 mutated cases, exhibited a “mutator phenotype” by containing significantly more mutations than BRCA wt cases across the whole exome (median mutation number per sample: 84 for BRCA2 mutated vs. 52 for BRCA wt cases, false-discovery rate <0.1).
BRCA2 mutation, but not BRCA1 deficiency, is associated with improved survival, chemotherapy response, and genome instability compared with BRCA wild-type.