Risk-Reducing Surgery in BRCA Mutation Carriers

Women who have inherited mutations in the BRCA1 or BRCA2 (BRCA1/2) genes have substantially elevated risks of breast cancer and ovarian cancer, with a lifetime risk of breast cancer of 56% to 84%. Estimated ovarian cancer risks range from 36% to 63% for BRCA1 mutation carriers and 10% to 27% for BRCA2 mutation carriers.

Mastectomy and salpingo-oophorectomy are 2 options that have been utilized for risk management in these patients. There has been no effective screening mechanism devised for ovarian cancer; therefore, salpingo-oophorectomy, which has been demonstrated to decrease the risk of breast and ovarian cancer in BRCA1/2 mutation carriers, has been recommended for women for whom childbearing is complete. In this study, the investigators examined a large cohort of BRCA1/2 mutation carriers in an attempt to estimate risk and mortality reduction stratified by mutation and prior cancer status.

This study [JAMA. 2010;304(9):967-975] was a prospective, multicenter study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008 to assess the relationship of riskreducing mastectomy and salpingo-oophorectomy and cancer outcomes. The women were identified from 22 clinical and research genetics centers in Europe and North America. Patients were eligible for the study if they had no prior ovarian cancer diagnoses and no salpingo-oophorectomy at the time of ascertainment.

Patients were followed up until the end of 2009; median follow-up was 3.65 years among those who underwent surgery and 4.29 years among those who did not undergo surgery. Main outcome measures were breast and ovarian cancer risk, cancer-specific mortality, and overall mortality.

In the 247 women who underwent risk-reducing mastectomy, no breast cancer was found during 3 years of prospective follow-up. Of the 1372 women who did not undergo risk-reducing mastectomy, 98 (7%) were diagnosed with breast cancer during 3 years of prospective follow-up. Among those with no prior breast cancer, the risk-reduction estimate, expressed as a hazard ratio (HR) in all BRCA1 mutation carriers, was 0.31 (95% confidence interval [CI], 0.12-0.82).

No ovarian cancer events were seen in BRCA2 mutation carriers without prior breast cancer who underwent risk-reducing salpingo-oophorectomy during the 6 years of prospective follow-up. In contrast, 3% of women without salpingo-oophorectomy over a similar follow-up period were diagnosed with ovarian cancer. Among women with a prior diagnosis of breast cancer, the risk reduction in BRCA1 mutation carriers was an HR of 0.15 (95% CI, 0.04-0.63). No cases of ovarian cancer were diagnosed in BRCA2 mutation carriers after salpingo-oophorectomy.

Salpingo-oophorectomy was associated with a decreased risk of breast cancer in both BRCA1 mutation carriers (HR, 0.63; 95% CI, 0.41-0.96) and BRCA2 mutation carriers (HR, 0.36; 95% CI, 0.16-0.82) without prior diagnosis of breast cancer and was associated with significantly lower all-cause mortality in those with no prior breast cancer (HR, 0.45; 95% CI, 0.21-0.95) and those with prior breast cancer (HR, 0.30; 95% CI, 0.17-0.52).

When analyzed by mutation status, salpingooophorectomy was associated with significantly lower all-cause mortality in BRCA1 mutation carriers (HR, 0.38; 95% CI, 0.24-0.62). Salpingooophorectomy was also associated with lower breast cancer–specific mortality (HR, 0.44; 95% CI, 0.26-0.76) and ovarian cancer–specific mortality (HR, 0.21; 95% CI, 0.06-0.80).

In BRCA1 mutation carriers, salpingo-oophorectomy was associated with improved breast cancer–specific mortality (HR, 0.38; 95% CI, 0.20-0.72) and ovarian cancer–specific mortality (HR, 0.22; 95% CI, 0.06-0.83). There were no ovarian cancer deaths following salpingo-oophorectomy in BRCA2 mutation carriers, nor were there any breast cancer deaths in BRCA2 mutation carriers who underwent salpingo-oophorectomy prior to cancer diagnosis.

Ideally, the investigators said, the evaluation of risk-reducing surgery on cancer risk and mortality reduction would involve a randomized controlled trial design, but this would neither be acceptable nor ethical.