Preventive Surgery Works for BRCA Mutation Carriers

(MedPage Today) -- Prophylactic surgery can reduce the high risk of breast and ovarian cancer among BRCA mutation carriers and actually improve survival, researchers affirmed.

All-cause mortality dropped from 10% without salpingo-oophorectomy to 3% with it (hazard ratio 0.40, 95% confidence interval 0.26 to 0.61), found Timothy R. Rebbeck, PhD, of the University of Pennsylvania in Philadelphia, and colleagues.

The risk-reducing surgery also cut breast cancer-specific and ovarian cancer-specific mortality significantly, they reported in the Sept. 1 issue of the Journal of the American Medical Association.

Prophylactic mastectomy also reduced the risk of breast cancer but without an impact on survival in the prospective cohort study of BRCA1 and BRCA2 mutation carriers.

Risk-reducing salpingo-oophorectomy is already strongly recommended for these women given the lack of effective ovarian cancer screening, the researchers noted.

Prophylactic mastectomy hasn't gotten the same level of endorsement but clearly is an effective option for BRCA1/2 mutation carriers, although controversial and potentially overused in other settings, explained Judy Garber, MD, MPH, of the Dana-Farber Cancer Institute in Boston, in an interview.

Overall, the new data likely won't change practice but are good to have, commented Freya Schnabel, MD, of NYU Langone Medical Center in New York City.

"The reduction in mortality may have been something we assumed to be true –- now we have data that is confirmatory," she said in an e-mail to MedPage Today and ABC News.

Despite the relatively short three years of prospective follow-up in the study, the results provide more confidence in the risk reduction estimates physicians give to at-risk women considering surgery, commented Kathy J. Helzlsouer, MD, MHS, of Mercy Medical Center in Baltimore, Md.

Moreover, evidence that prevention works may help women take the initial step of getting genetic testing, Garber noted.

"It's difficult to decide to look and know whether you have a mutation," she explained in an interview. "But these data at least should help women feel there's something they can do if they're found to have this level of risk."

In an editorial accompanying the JAMA paper, Laura Esserman, MD, MBA, of the University of California San Francisco, and Virginia Kaklamani, MD, DSc, of Northwestern University in Chicago, noted that BRCA testing can be useful even for women who present with cancer.

Rebbeck's group showed reduced risk of ovarian cancer after prophylactic surgery among women with a prior breast cancer diagnosis (6% versus 1%, HR 0.14, 95% CI 0.04 to 0.59) as well as in those without prior breast cancer (6% versus 2%, HR 0.28, 95% CI 0.12 to 0.69).

This illustrates "why a woman may want to know about BRCA gene mutation status even if she chooses to undergo bilateral mastectomy," the editorialists wrote.

These procedures have improved a great deal, with salpingo-oophorectomy now available as a relatively low-risk outpatient laparoscopic surgery and with better cosmetic options for mastectomy, such as total skin sparing, Esserman and Kaklamani explained.

The study included 2,482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008 at 22 clinical and research genetics centers in Europe and North America.

Among them, only 10% chose risk-reducing mastectomy and 38% opted for risk-reducing salpingo-oophorectomy.

None of the 247 women who underwent prophylactic mastectomy developed breast cancer, compared with 7% of those who did not have risk-reducing mastectomy.

Salpingo-oophorectomy cut ovarian cancer risk by a significant 86% -- from an incidence of 6% without it to 1% with it.

The procedure also significantly reduced first breast cancers by 37% in BRCA1 carriers (20% versus 14% incidence) and by 64% in BRCA2 carriers (23% versus 7% incidence), but the effect on breast cancer risk appeared restricted to those who had the surgery before age 50.

With regard to mortality, salpingo-oophorectomy significantly cut breast cancer-specific mortality by 56% (6% versus 2% incidence without it) and ovarian cancer-specific mortality by 79% (3% versus 0.4% incidence without it).

The study included too few pure risk-reducing mastectomies to draw any new broad conclusions about its mortality impact, cautioned Schnabel.

The researchers also acknowledged that the study could not prove causality in the protective effect of these procedures due to the observational design, but noted that a randomized trial would be considered unethical.

This study was supported by grants from the Public Health Service; funding from the University of Pennsylvania Cancer Center; a grant from the Cancer Genetics Network; funding from the Marjorie Cohen Research Fund; a grant from the Dana-Farber/Harvard Cancer Center; grants from the U.S. Department of Defense; funding from the Utah Cancer registry and the Utah State Department of Health; grants from the Nebraska State Cancer and Smoking-Related Diseases Research Program; a Cancer Research UK grant; and a National Cancer Institute grant.

The researchers and editorialists reported having no conflicts of interest to disclose.

This article was developed in collaboration with ABC News.

Primary source: Journal of the American Medical Association Source reference: Domchek SM, et al "Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality" JAMA 2010; 304: 967-975.Additional source: Journal of the American Medical AssociationSource reference: Esserman L, Kaklamani V "Lessons learned from genetic testing" JAMA 2010; 304: 1011-1012.