BARCELONA-Healthy women with BRCA1 gene mutations who opted for bilateral prophylactic mastectomy had their lives prolonged in comparison with similar women who did not. But in healthy women with the BRCA2 mutation, the procedure did not improve overall survival even though it reduced their risk of breast cancer in the next 10 years. These findings were reported at the 2018 European Breast Cancer Conference from an analysis of the Netherlands national Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) database (Abstract PB-035).

"From previous studies, we already knew that by [having] prophylactic mastectomy you reduced the risk of breast cancer very strongly, but it was not proven that as a consequence survival was better," said first author Annette Heemskerk-Gerritsen, PhD, a postdoctoral researcher at Erasmus Medical Center in Rotterdam.

Surgery or Not?

Among 1,696 healthy women with the BRCA1 mutation, those who had preventive surgery were compared with those who did not. The same comparison-bilateral risk-reducing mastectomy (BRRM) or no surgery-was also done for 1,139 women who carried the BRCA2 gene mutation. In all cases, the women in the study had no history of cancer and had both breasts and both ovaries.

In both genetic variant groups-BRCA1 and BRCA2 carriers-about one-third of women eventually chose to have prophylactic bilateral mastectomy.

Breast Cancer Specific Survival

Since such surgery is known to reduce the incidence of breast cancer in a woman with any BRCA mutation, Heemskerk-Gerritsen noted the aim was to distinguish between breast cancer specific survival (BCSS) and overall survival (OS).

"After a mean follow-up of about 10 years, we observed BRCA1 mutation carriers who opted for mastectomy indeed reduced the risk of breast cancer very strongly, that overall survival was better, and also that breast cancer specific survival was better," she said.

BRCA1 Carriers

In BRCA1 mutation carriers, there were 269 breast cancer cases and 50 deaths (19 from breast cancer) in the surveillance group after a mean follow-up of 9.5 years. Among women who had BRRM, there were seven breast cancer cases and 11 deaths (one due to breast cancer) after a mean follow-up of 10.8 years. For OS, the hazard ratio (HR) was 0.55 in favor of the BRRM group. At the age of 65 years, the OS was 83 percent for the surveillance group and 90 percent for women who had BRRM. For BCSS, the HR was 0.07. BCSS was 93 percent for the surveillance group and 99.6 percent for the BRRM group.

Heemskerk-Gerritsen said that for BRCA1 carriers the message from these data was that BRRM saved lives.

BRCA2 Carriers

For BRCA2 mutation carriers, the message was quite different. Surgery conferred no statistically significant difference in OS. "Yes. They reduced their risk of developing breast cancer. [But] there wasn't [any] improved overall survival. The breast cancer specific survival was about the same in the mastectomy group [as in] the surveillance group," she noted.

Among BRCA2 mutation carriers there were 144 breast cancer cases and 32 deaths (seven due to breast cancer) in the surveillance group after a mean follow-up of 8.5 years. In women who had BRRM, there were no breast cancer cases and two deaths (neither due to breast cancer) after a mean follow-up of 9.5 years. The HR for OS was 0.32 in favor of the BRRM group. At the age of 65 years, the OS was 88 percent for the surveillance group and 95 percent for the BRRM group. The BCSS at age 65 was 98 percent for women who chose surveillance and 100 percent for those who had prophylactic surgery.

Decision-Making for Healthy Carriers

When she was asked how these data could help clinicians advise patients with mutated BRCA, Heemskerk-Gerritsen said that, while decision should always be taken by any woman herself, the study provided new information. "Clinicians can tell BRCA1 mutation carriers that, by having your healthy breast removed, you not only reduce the risk of developing breast cancer but you also improve your survival," she said.

"But they can tell BRCA2 mutation carriers that, yes, the risk of breast cancer is reduced by having your healthy breast removed. But in the end, survival may be the same if you stay on surveillance.

"If a BRCA2 mutation carrier is very much in doubt about having her breast removed, we can tell her that if she wants to take the risk of developing breast cancer-and to undergo treatment if she has breast cancer-in the end survival may be the same."

BRCA2 Different

BRCA2-associated cancers were different from the BRCA1 associated cancers, she said. "They were found at an older age, they were more often in situ, were smaller, not triple-negative-but had receptors for estrogen, progesterone, or HER2. So they had more treatment options, [including] endocrine therapy and trastuzumab. So it makes sense that the probability of staying alive is better for BRCA2 mutation carriers," she stated. "Doctors should counsel according to the type of mutation and counsel the BRCA2 mutation carriers differently from the BRCA1 mutation carriers."

Co-chair of the conference, Isabel T. Rubio, MD, PhD, Director of the Breast Surgical Unit at Clinica Universidad de Navarra, Spain, who was not involved with the research, commented that women who carry the BRCA1 or BRCA2 gene mutations face real uncertainty about how to reduce their risk of developing breast cancer and of dying from the disease. "A double mastectomy is invasive and can have uncomfortable-sometimes serious-adverse effects such as losing sensitivity in the breast and nipple area," she said.

Whereas double mastectomy would seem to reduce the risk of developing breast cancer, women who opted for surveillance lived with the knowledge that the disease could develop and that then they would have to go through treatment. "These are hard choices and every woman is different," said Rubio.

"The research by Heemskerk-Gerritsen and colleagues gives these women valuable information on which to base their decisions about their overall risk of death and of dying from the disease," she added. "[But] more information is warranted to find out the ages at which women gain the greatest benefit from either mastectomy or surveillance."

Peter M. Goodwin is a contributing writer.