Contralateral mastectomy for women with hereditary breast cancerBMJ 2014; 348 doi: http://dx.doi.org/10.1136/bmj.g1379 (Published 11 February 2014) Cite this as: BMJ 2014;348:g1379
- Karin B Michels, associate professor
- 1Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Angelina Jolie’s disclosure in May 2013 of her prophylactic bilateral mastectomy triggered a wide range of reactions among women, caregivers, and scientists. In an editorial in the New York Times the actress announced that she was a carrier of a BRCA1 genetic mutation, significantly increasing her risk of breast and ovarian cancer. Jolie’s decision was intended to lower her risk of developing and dying from breast cancer.
Carriers of a mutation in the BRCA1/2 gene who develop breast cancer face a decision similar to that of Jolie’s: should they part with their unaffected breast to prevent a second tumour? The question such women ask is: will this reduce my risk of dying from breast cancer? In a linked paper (doi:10.1136/bmj.g226), Metcalfe and colleagues present new data for consideration by affected women and their doctors. Results from this observational study suggest that preventive mastectomy of the contralateral breast may reduce the risk of dying from breast cancer by 48% within 20 years after the first diagnosis.
As the most common malignancy among women worldwide, breast cancer is a serious threat to women’s health. The prospect that 12% of women will develop breast cancer throughout their lifetime has raised awareness of the importance of the disease and has spurred research aiming at prevention and cure. The cumulative incidence of breast cancer is even higher among carriers of BRCA1/2 mutations: women with a mutation in this tumour suppressor gene have an approximately 60% risk of developing the disease during their lives. Moreover, among women with a genetic defect in BRCA1 or BRCA2, many breast cancers become apparent at an early age and often are the more aggressive types, such at triple negative breast cancer, and are therefore more lethal.
Interestingly, comparative data on the survival advantage of preventive contralateral mastectomy among BRCA1/2 carriers with breast cancer are limited. Metcalfe and colleagues derived their study population from families with a documented BRCA mutation, and included women from these families with a diagnosis of early stage breast cancer before the age of 65. All 390 women included underwent mastectomy: 209 unilateral and 181 bilateral, with prophylactic mastectomy of the contralateral breast at initial surgery or during the following years. In this study, the apparent survival advantage among women with bilateral mastectomy was greatest during the second decade after diagnosis, although most deaths from breast cancer were noted during the first decade: 59 breast cancer related deaths occurred during the first 10 years and 20 (including nine among women with contralateral breast cancer) during the subsequent 10 years.
As with previous studies, the study by Metcalfe and colleagues is limited by the relatively small number of endpoints, which provide unstable estimates and make statistical inferences more challenging. The reduction in breast cancer related deaths associated with bilateral mastectomy was statistically significant only during the second decade after initial diagnosis of breast cancer but not during the first decade. Moreover, sensitivity analyses confined to women for whom positive BRCA1/2 test results were available resulted in an effect estimate of similar magnitude but lacked statistical power to achieve significance. Subgroup analyses matched by propensity score had similar limitations, and generated a non-significant association between bilateral mastectomy and a lower risk of breast cancer related death.
Observational studies are further limited by the potential for confounding. Bilateral oophorectomy is an important factor potentially confounding the association between mastectomy and survival. In Metcalfe and colleagues’ study, women who opted for bilateral mastectomy were 50% more likely to also undergo oophorectomy than women who underwent unilateral mastectomy. Although this difference was adjusted for in the analyses, residual and unmeasured confounding by this and other factors may remain. In another recent study, contralateral mastectomy improved survival in women with BRCA1/2 associated breast cancer, but the 10 year survival of women who chose to also undergo oophorectomy was even higher. The least biased and hence most informative data for women making these decisions would come from randomised clinical trials. But randomisation of prophylactic contralateral mastectomy may not be feasible, given the personal and individual nature of the choice to remove a healthy breast surgically.
Carriers of BRCA1/2 mutations have an about five times increased lifetime risk of breast cancer in either breast. The risk of contralateral breast cancer is increased both for carriers of the mutation and for women with sporadic breast cancer, since first and second cancers are not independent events, but mutation carriers are about four to five times more likely than women without these mutations to develop cancer in the contralateral breast. Given the worse prognosis of BRCA1/2 associated breast cancers, the absence of mammary tissue after a contralateral mastectomy should translate into a reduction of breast cancer related deaths. Nevertheless, larger studies tackling this issue are needed and will undoubtedly be generated in the years to come.
But statistics remain statistics. Breasts are, however, not statistics. They are essential parts of women’s identity, sexuality, and self perception. Parting with a breast may result in anxiety, lack of self esteem, and possibly depression. Parting with a healthy breast (or two) to prevent a probability is even more difficult. The decision to undergo a bilateral mastectomy is an individual and personal choice that a woman has to make together with her doctor. A woman needs to weigh up alternative options, including regular close monitoring and the use of tamoxifen or raloxifene, while considering the opportunities but also possible complications of reconstructive surgery. No statistics and no statistician can make this decision for her.
Cite this as: BMJ 2014;348:g1379
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare the following interests: None.
Provenance and peer review: Commissioned; not externally peer reviewed.