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BRCA carriage improved epithelial ovarian cancer survival

Bolton KL.  JAMA. 2012;307:382-389.

Issue: March 10, 2012

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Women with invasive epithelial ovarian cancer who carried a BRCA mutation had better 5-year survival rates than noncarriers, according to study results.

The aim of the trial was to determine whether BRCA carriers with epithelial ovarian cancer have different survival rates from noncarriers, as well as whether survival patterns are similar among BRCA1 and BRCA2 carriers. The pooled analysis involved 26 observational studies. The primary outcome measure was 5-year overall mortality.

The analysis involved 909 women with BRCA1 mutations, 304 women with BRCA2 mutations and 2,666 noncarriers.

Participants had been followed up at variable times from 1987 to 2010. The median year of diagnosis was 1998.

Noncarriers demonstrated a 36% (95% CI, 34-38) 5-year OS rate vs. 44% (95% CI, 40-48) for BRCA1 carriers and 52% (95% CI, 46-58) for BRCA2 carriers.

Results of a further analysis in which adjustments were made for study and year of diagnosis indicated that carriers of both mutations had more favorable survival than noncarriers. HRs were 0.78 (95% CI, 0.68-0.89) for BRCA1 carriers and 0.61 (95% CI, 0.50-0.76) for BRCA2 carriers.

After further adjustment for stage, grade, histology and age at diagnosis, this trend persisted, with BRCA1 carriers demonstrating an HR of 0.73 (95% CI, 0.64-0.84) and BRCA2 carriers demonstrating an HR of 0.49 (95% CI, 0.39-0.61).

The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity=.003), the researchers said.

A germline BRCA mutation in epithelial ovarian cancer was linked to improved OS, and the prognosis was most encouraging for BRCA2 carriers, the researchers added.

Familial breast cancer susceptibility is commonly the result of inherited mutations in the autosomal dominant genes BRCA1 and BRCA2. These mutations are responsible for approximately 5% to 10% of all breast cancers and approximately 7% to 10% of all ovarian cancers. Women who carry BRCA1 or BRCA2 mutation have an estimated lifetime breast cancer risk of up to 85%. Women have a lifetime ovarian cancer risk of up to 60% if they carry BRCA1 mutation and 25% if they carry BRCA2 mutation. The impact of these germline mutations in survival of ovarian cancer has been previously reviewed in small retrospective studies; however, results were conflicting and the previous studied had been affected by biases. This current study is a well-designed, large-scale study that demonstrates a favorable impact of BRCA mutation on ovarian cancer survival.

Previous studies have shown that ovarian cancerpatients with BRCA mutation have better response to platinum-based chemotherapy. Platinum sensitivity is known to be a very important prognostic factor in ovarian cancer patients. This can theoretically explain the mechanism of association between BRCA mutation and ovarian cancer prognosis. This study, along with other molecular studies, can provide us with some insight in designing agents that target BRCA dysfunction. PARP inhibitors are new biologic agents that restore BRCA function and early studies have shown promising results.

Mehdi Kebria, MD
Women’s Health Institute
Cleveland Clinic

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