Association of BRCA1 and BRCA2 Mutations With Survival, Chemotherapy Sensitivity, and Gene Mutator Phenotype in Patients With Ovarian Cancer

    loading  Checking for direct PDF access through Ovid

Abstract

BRCA1 and BRCA2 are tumor suppressor genes that repair DNA, preventing uncontrolled cell growth and malignant transformation. Mutations of these genes in certain ethnic populations predispose individuals to breast and ovarian cancer.

Previous studies have assessed the potential associations of BRCA mutations with ovarian cancer survival and response to chemotherapy; most analyzed combined BRCA1/2 mutations. There is evidence for differences between BRCA1 and BRCA2 deficiencies with respect to patient survival and response to chemotherapy in ovarian cancer. The significance of BRCA1/2 mutations on patient outcomes after ovarian cancer develops is unclear. Some studies found a more favorable clinical course among ovarian cancer patients with BRCA1/2 germ line mutations, whereas others reported the opposite.

This observational study evaluated the association between BRCA1/2 deficiencies in ovarian cancer and patient overall survival (OS) and progression-free survival (PFS) rates, response to chemotherapy, and whole-exome mutation rates. BRCA1/2 mutation and promoter hypermethylation deficiencies were examined. Multidimensional genomic and clinical data were obtained for 316 patients with high-grade serous ovarian cancer from The Cancer Genome Atlas project. The association of BRCA1/2 mutations with chemotherapy response was determined for both primary chemotherapy response and platinum-free duration.

Among the 316 cases, mutations were identified in 37 BRCA1 and 29 BRCA2 cases.

The 5-year OS rate of BRCA2 mutation carriers was significantly higher than that of wild-type BRCA cases (61% vs. 25%); the adjusted hazard ratio (HR) was 0.33, with a 95% confidence interval (CI) of 0.16–0.69 (P = 0.003). There was significantly longer 3-year PFS for BRCA2 mutation carriers compared with wild-type BRCA carriers (44% vs. 16%; HR, 0.40; 95% CI, 0.22–0.74, P = 0.004). The survival rates for the BRCA1-mutated cases (n = 37) and BRCA1-hypermethylated cases (n = 33) were similar to that of wild-type BRCA cases (significantly shorter survival compared with BRCA2-mutated cases). Improved outcomes were also found among BRCA2-mutated cases with respect to chemotherapy response and sensitivity to platinum-based therapy. BRCA2 mutations had a significantly higher primary chemotherapy sensitivity rate (100%) compared with BRCA wild-type (85%; P = 0.02) and BRCA1-mutated cases (80%; P = 0.05). The median platinum-free duration was significantly longer for patients with BRCA2 mutations (18 months) compared with those with BRCA1 mutations (12.5 months) or wild-type BRCA cases (11.7 months); P values were 0.04 and 0.02, respectively.

These findings provide evidence that BRCA2 mutations in women with serous ovarian cancer are associated with improved survival, PFS, and chemotherapy response compared with BRCA1 mutations and BRCA wild-type.

Related Topics

    loading  Loading Related Articles