PROPHYLACTIC SURGERY FOR BRCA MUTATION CARRIERS

August 31, 2010 — A large new study has confirmed the benefits of prophylactic mastectomy and salpingo-oophorectomy in women with BRCA1 and BRCA2 mutations. Women who underwent the prophylactic surgery had a greatly reduced risk for breast or ovarian cancer and a reduction in cancer-related mortality.

The findings appear in the September 1 issue of the Journal of the American Medical Association.

This study adds evidence supporting the benefits of preventive surgery — that it can reduce the risk for cancer-related mortality and for breast/ovarian cancer developing in the first place, explained senior author Timothy Rebbeck, PhD, professor of epidemiology at the University of Pennsylvania School of Medicine in Philadelphia.

Dr. Rebbeck and colleagues investigated a cohort of nearly 2500 women with BRCA1 or BRCA2 mutations, 10% of whom chose to undergo a risk-reducing mastectomy and 38% of whom chose a risk-reducing salpingo-oophorectomy.

No breast cancers were diagnosed in the women who underwent mastectomy during the 3 years of prospective follow-up. However, 7% of those who did not undergo a prophylactic mastectomy during a similar follow-up period were diagnosed with breast cancer.

There were no cases of ovarian cancer events during the 6 years of prospective follow-up in BRCA2 carriers without previous breast cancer who underwent salpingo-oophorectomy. Conversely, 3% of women who did not undergo the procedure over a similar follow-up period were diagnosed with the disease.

Among BRCA1 carriers with a previous diagnosis of breast cancer, undergoing a salpingo-oophorectomy was associated with a reduced risk for ovarian cancer (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04 - 0.63); there were no cases diagnosed in BRCA2 carriers.

Overall, results showed that, compared with women who did not undergo prophylactic salpingo-oophorectomy, those who underwent the procedure had an overall lower risk for ovarian cancer, including those with previous breast cancer (6% vs 1%; HR, 0.14; 95% CI, 0.04 - 0.59) and those without previous breast cancer (6% vs 2%; HR, 0.28; 95% CI, 0.12 - 0.6); a lower risk for first diagnosis of breast cancer in BRCA1 carriers (20% vs 14%; HR, 0.63; 95% CI, 0.41 - 0.96) and BRCA2 carriers (23% vs 7%; HR, 0.36; 95% CI, 0.16 - 0.82); lower all-cause mortality (10% vs 3%; HR, 0.40; 95% CI, 0.26 - 0.61); lower breast-cancer-specific mortality (6% vs 2%; HR, 0.44; 95% CI, 0.26 - 0.76); and lower ovarian-cancer-specific mortality (3% vs 0.4%; HR, 0.21; 95% CI, 0.06 - 0.80).

Data for Surveillance Group Limited

The women who opted not to have prophylactic surgery were counseled to undergo intensive screening. Although surveillance isn't prevention, it can result in earlier detection and improved survival, but the nonsurgery group of the study was not specifically evaluated for surveillance practices, said Dr. Rebbeck.

"We don't have data on the survival or mortality in women who underwent optimal screening," he told Medscape Medical News. "Having said that, the breast cancer risk reduction among women in the oophorectomy group is substantial but comparable to that in the general population of women who took tamoxifen."

There are no data to date for women with BRCA1/2 mutations and primary prevention of breast cancer with tamoxifen use, he added. "While there are no comparison data available, it may be possible that the risk reduction by oophorectomy is comparable to that of other measures."

But Dr. Rebbeck emphasized that an important point to remember is that oophorectomy is primarily recommended to reduce ovarian cancer risk or death, not breast cancer. "Women should be using oophorectomy as an ovarian cancer prevention tool — the benefit to breast cancer is just a side benefit," he said.

Importance of Counseling, Fear of Genetic Testing

It is important to identify and counsel women who have a family history of breast cancer, so that they will better understand their risks and options, and ways to reduce those risks, note the authors of an accompanying editorial.

"At a minimum, primary care clinicians should be familiar with the American Society of Clinical Oncology or National Comprehensive Cancer Network guidelines and should be able to refer at-risk patients to a genetic counselor," write Laura Esserman, MD, MBA, from University of California, San Francisco, and Virginia Kaklamani, MD, DSc, from Northwestern University, Chicago, Illinois.

The editorialists point out that now that there are better data available on the potential outcomes of these interventions, women can make more informed choices about whether to opt for prophylactic surgery or intensive surveillance.

But even though the techniques for prophylactic surgery and cosmetic options have improved, many women still might not opt for this. In such cases, there are other approaches that are less invasive than surgery but more aggressive than surveillance, explained Dr. Kaklamani.

"We have chemopreventive agents such as tamoxifen that can help, and there are other agents that are being tested, such as PARP inhibitors," she told Medscape Medical News.

In addition, some people fear the implications that positive genetic tests, including those for BRCA mutations, can have on their insurance premiums. The Genetic Information Nondiscrimination Act of 2008 was designed to protect people from insurance and employer discrimination on the basis of genetic tests, and Dr. Kaklamani emphasized the importance of educating women about this.

"There are laws that protect us from insurance discrimination from genetic testing and, with this study, we now know that procedures that we recommend have a positive impact on survival," she said.

Evidence Added

The study adds to the growing body of literature concerning the benefits of prophylactic surgery for women with BRCA1/2 mutations. As previously reported by Medscape Medical News, 4 separate analyses showed that having a bilateral mastectomy reduced the risk for breast cancer by 90%.

Another study found that women carrying the BRCA gene mutation who underwent a prophylactic mastectomy reduced their risk for breast cancer to less than 1%. Although estimates vary, mutation carriers have an approximate lifetime risk for breast cancer that ranges from 56% to 84%.

Improved Research Mechanisms Needed

"The discovery of biomarkers that identify high-risk individuals for a specific disease and integration of these biomarkers into clinical practice enables the systematic study of these populations — and development and testing of interventions to reduce their risk," write the editorialists.

They note that the study required more than 20 collaborating clinical centers to collect data from thousands of women who participated in the research, and point out that better methods are needed.

Improved mechanisms are needed to study and evaluate "the introduction of new tests, like BRCA gene mutation testing, and to capture key pieces of de-identified information — such as the uptake of testing, results, clinical decisions, and outcomes — so that clinicians and researchers can continually learn from their experience," they write.

The study was supported by grants and funding from the Public Health Service, the University of Pennsylvania Cancer Center, the Cancer Genetics Network, the Marjorie Cohen Research Fund, SPORE grant from the Dana-Farber/Harvard Cancer Center, the US Department of Defense, the Utah Cancer Registry and the Utah State Department of Health, Nebraska State Cancer and Smoking-Related Diseases Research Program, Cancer Research UK, National Cancer Institute, and the National Institute for Health Research. Olufunmilayo I. Olopade, MD, a coauthor of the study, from the University of Chicago Medical Center in Illinois, has received funding as the Doris Duke Distinguished Clinical Scientist. The other study authors and the editorialists have disclosed no relevant financial relationships.

JAMA. 2010;304:967-975, 1011-1012.