According to the results of this observational study, BRCA2 mutation, but not BRCA1 deficiency, was associated with improved survival and response to chemotherapy in women with high-grade serous ovarian cancer.
The authors note that women with BRCA1/2 germ line mutations have an increased risk of developing ovarian cancer. As deficiencies in the homologous recombination pathway (in which the BRCA1 and 2 tumour suppressor genes are involved) can impair tumour cells’ ability to repair DNA cross-links introduced by chemotherapy such as cisplatin, it has been hypothesised that BRCA-deficient patient may have a higher survival rate, due to a higher response to such agents.
Using data from The Cancer Genome Atlas research network, researchers assessed the association of BRCA1 and BRCA2 mutations with overall survival (OS), progression-free survival (PFS) and chemotherapy response in 316 women with high-grade serous ovarian cancer. Of these women, 219 had wild-type BRCA, 35 had BRCA1 mutations, 33 had BRCA1 methylation, and 27 had BRCA2 mutations. Two women with both BRCA1 and BRCA2 mutations were excluded.
The main findings were as follows:
• BRCA2 mutations (29 cases) were associated with significantly better OS than wild-type cases (adjusted hazard ratio [HR], 0.33; 95% CI, 0.16-0.69; P=0.003). Five-year OS was 61% and 25%, respectively.
• BRCA2 mutations were also associated with improved PFS (adjusted HR 0.40; 95% CI 0.22-0.74; P=0.004); 3-year PFS was 44% and 16%, respectively.
• Neither BRCA1 mutations (37 cases) nor BRCA1 methylation (33 cases) was associated with prognosis.
• In chemotherapy-sensitivity analyses, 100% of BRCA2-mutated tumours were sensitive to primary chemotherapy, compared with 82% (P=0.02) of wild-type tumours and 80% (P=0.05) of BRCA1-mutated tumours. Moreover, the length of time free of platinum-based chemotherapy was also longer in BRCA2-mutation cases (median of 18.0 months vs. 11.7 months [P=0.02] for wild-type and 12.5 months [P=.04] for BRCA1-mutated cases).
The authors say that their results provide evidence that only BRCA2 mutations are an independent predictor of ovarian cancer survival, and are associated with higher sensitivity to chemotherapy and longer platinum-free durations. They do however caution that their findings need to be validated due to the relatively small sample size.
An accompanying editorial discusses the study.