Prophylactic Mastectomy and the Prevention of Breast Cancer in BRCA1/2 Carriers

Abstract & Commentary

Synopsis: In a multi-institutional cooperative effort, Rebbeck and colleagues followed the course of 105 women with either BRCA1 or BRCA2 germline mutations who had elected bilateral mastectomy as a breast cancer preventive measure. Only 2 cases of breast cancer developed in this group of operated patients compared with 184 cases in the control group, demonstrating a remarkable risk reduction of > 90%. Although there are some methodological concerns with regard to the higher than expected incidence of breast cancer in the control group (even for those with BRCA mutation), the data clearly indicate a significant risk reduction and strengthen the rationale for prophylactic mastectomy in selected patients with germline BRCA mutations.

Source: Rebbeck TR, et al. J Clin Oncol. 2004;22: 1055-1062.

Women with the germline brca1 or brca2 (BRCA1/2) mutations have a markedly increased risk of breast and ovarian cancer (73% risk to age 70). Some may elect bilateral prophylactic mastectomy in order to reduce their risk of developing breast cancer. However, there are limited data on the efficacy of this approach. Rebbeck and colleagues from the PROSE Study Group followed 483 women with disease-associated germline BRCA 1/2 mutations. Of these, 105 had elected bilateral prophylactic mastectomy and 378 were matched controls (women with similar BRCA1/2 mutations who did not elect to undergo bilateral prophylactic mastectomy and were without known breast cancer). All women were followed for a mean of 6.4 years.

Of the 105 BRCA 1/2-mutation carriers with bilateral prophylactic mastectomy in the study, 2 (1.9%) were diagnosed with subcutaneous breast cancer post surgery, occurring 2.3 and 9.2 years later. Of the 378 controls (nonoperated), 184 (48.7%) developed breast cancer. Thus, compared with controls, the occurrence of breast cancer after bilateral prophylactic mastectomy corresponded to a hazard ratio of 0.05 to 0.09. These data demonstrate that bilateral prophylactic mastectomy significantly decreases the risk of breast cancer in women who carry these mutations. Bilateral prophylactic mastectomy reduces the risk of breast cancer by approximately 90%, translating into an overall breast cancer risk in BRCA1/2 mutation carriers of 7% to age 70. Additionally, in women with prior or concurrent bilateral prophylactic oophorectomy, bilateral prophylactic mastectomy reduced the risk of breast cancer by approximately 95%.

Comment by William B. Ershler, MD

Thus, bilateral prophylactic mastectomy reduces the risk of breast cancer in BRCA1/2 mutation carriers, as observed by the 90% risk reduction demonstrated in this series. After a mean follow-up of 5.5 years, only 2 cases developed among the 105 who underwent prophylactic mastectomy. Without question, this was significantly fewer than expected. Yet, the estimation of the actual risk reduction might have been overly inflated in this report by some difficult-to-control for methodological factors that were detailed in the accompanying editorial by Hartmann and colleagues.1 Of the 378 matched controls, 184 (49%) developed breast cancer over a mean follow-up of 6.4 years. This is an unusually high incidence, even for mutation carriers, suggesting that one or more inherent biases in matched-control selection were of operational importance. Rebbeck and colleagues recognized these potential confounding factors and performed additional analyses by which the risk-reduction value of prophylactic mastectomy remained apparent.

Although we remain without a prospective, randomized trial, the data on the efficacy of prophylactic mastectomy has been strengthened by this report, and must be considered sound.2-4 Nonetheless, the issues remain complex at all levels; biological, psychological, social and financial. For those who remain fundamentally opposed to this surgical approach, other methods of disease prevention need to be developed. In this regard, hormonal manipulations such as the use of anti-estrogens are under exploration, but success may be hampered by the known hormone receptor independence of the majority of breast cancers that develop in BRCA1 carriers.5

References

1. Hartmann LC, et al. J Clin Oncol. 2004;22:981-983.
2. Hartman LC, et al. N Engl J Med. 1999;340:77-84.
3. Hartmann LC, et al. J Natl Cancer Inst. 2001;93: 1633-1637.
4. Meijers-Heijboer H, et al. N Engl J Med. 2001;345: 159-164.
5. Lakhani SR, et al. J Clin Oncol. 2002;20:2320-2318.

William B. Ershler, MD INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC, is Editor of Clinical Oncology Alert.