By William B. Ershler, MD, Editor
SYNOPSIS: For patients with BRCA-associated breast cancer, it had been previously demonstrated that a second breast cancer occurs in approximately one-third of patients by 15 years after diagnosis and that this risk was reduced significantly by contralateral mastectomy. In the current observational study, breast cancer mortality at 20 years was shown to be significantly reduced in BRCA-associated breast cancer patients undergoing prophylactic contralateral mastectomy when compared to those treated with unilateral mastectomy alone. Notably, the breast cancer survival benefit associated with contralateral mastectomy was observed in the second decade after initial breast cancer diagnosis.
SOURCE: Metcalfe K, Gershman S, Ghadirian P, et al. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: Retrospective analysis. BMJ 2014;348:g226.
It is now understood that women who carry a germline mutation in either the BRCA1 or BRCA2 gene have a high risk (perhaps 60-70%) for developing breast cancer over their lifetime.1 Further, once diagnosed with breast cancer, such patients have a high risk of a second primary breast cancer.2,3 Thus, for patients with hereditary breast cancer, the goals of therapy include the eradication of the primary breast cancer and prevention of a second primary cancer. In discussing breast cancer outcomes, investigators typically focus their attention on the 10-year period after diagnosis, inasmuch as this is when the majority of cancer-related deaths occur. However, a mortality benefit from preventing a second primary breast cancer is unlikely to be apparent in such a short timespan, given that second primary cancers accumulate slowly and for an extended period.2,4 There remains limited information on the long-term survival experience of women with a BRCA1 or BRCA2 mutation who are treated for breast cancer, and no previous study has examined mortality as it relates to contralateral mastectomy.5,6This is highly relevant in North America, where approximately 50% of women with a BRCA mutation-associated breast cancer will undergo mastectomy of the contralateral breast to prevent a second breast cancer,3 but it has not yet been shown that contralateral mastectomy reduces breast cancer-related mortality. To address this issue, Metcalfe and colleagues reviewed the 20-year survival experience of 390 women with early stage breast cancer, diagnosed from 1975 to 2009, who are known carriers or likely carriers of the BRCA1 or BRCA2 gene and were treated with unilateral or bilateral mastectomy and followed for up to 20 years from diagnosis. Of the 390 patients, 181 had mastectomy of the contralateral breast.
During the follow-up period, 79 women died of breast cancer (18 in the bilateral mastectomy group and 61 in the unilateral mastectomy group). The median follow-up time was 14.3 years (range 0.1-20.0 years). At 20 years, the survival rate for women who had mastectomy of the contralateral breast was 88% (95% CI: 83% to 93%) and 66% for those who did not (59% to 73%). In a multivariable analysis, controlling for age at diagnosis, year of diagnosis, treatment, and other prognostic features, contralateral mastectomy was associated with a 48% reduction in death from breast cancer (hazard ratio 0.52, 95% confidence interval 0.29 to 0.93; P = 0.03). Based on these results, the authors predict that of 100 women treated with contralateral mastectomy, 87 will be alive at 20 years, compared with 66 of 100 women treated with unilateral mastectomy.
This study suggests that women who are positive for BRCA mutations and who are treated for stage I or II breast cancer with bilateral mastectomy are less likely to die from breast cancer than women who are treated with unilateral mastectomy. The observed mortality benefit associated with contralateral mastectomy was most apparent in the second decade of follow-up, during which the majority of breast cancer deaths (55%) were from a second primary. This is consistent with the prior observations that for breast cancer patients with a BRCA1 or BRCA2 mutation, the appearance of second malignancies was delayed, on average, 5.7 years.7 It is also known that BRCA1 or BRCA2 breast cancer patients younger than 50 years are more likely to develop a second breast cancer in the contralateral breast, as are those patients with two or more first-degree relatives with early-onset breast cancer.
Thus, in this observational study, women with BRCA-associated breast cancer who were treated with bilateral mastectomy were 48% less likely to die of breast cancer within 20 years of diagnosis than women treated with unilateral mastectomy. The benefit in breast cancer mortality reduction by contralateral mastectomy was most notable in the second decade (35% reduction in the first decade, 80% in the second decade). Yet, the overall number of patients in each of the two study cohorts was relatively small, and additional confirmatory research is necessary. Nonetheless, in light of the accumulated data from this and prior studies, bilateral mastectomy should be discussed as an option, particularly for young BRCA mutation-positive breast cancer patients.
- Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130.
- Metcalfe K, Lynch HT, Ghadirian P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2004;22(12):2328-2335.
- Metcalfe KA, Lubinski J, Ghadirian P, et al. Predictors of contralateral prophylactic mastectomy in women with a BRCA1 or BRCA2 mutation: The Hereditary Breast Cancer Clinical Study Group. J Clin Oncol. 2008;26(7):1093-1097.
- Narod SA. The impact of contralateral mastectomy on mortality in BRCA1 and BRCA2 mutation carriers with breast cancer. Breast Cancer Res Treat. 2011;128(2):581-583.
- Rennert G, Bisland-Naggan S, Barnett-Griness O, et al. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med. 2007;357(2):115-123.
- Robson ME, Chappuis PO, Satagopan J, et al. A combined analysis of outcome following breast cancer: Differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res. 2004;6(1):R8-R17.
- Metcalfe K, Gershman S, Lynch HT, et al. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2011;104(9):1384-1392.