Breast Cancer Risk Reduction for BRCA 1/2 Carriers by Bilateral Mastectomy
Abstract & Commentary
By Jerome W. Yates, MD
Hematology/Immunology Unit, National Institute on Aging, National Institutes of Health
Dr. Yates reports no financial relationships relevant to this field of study.
Financial Disclosure: Clinical Oncology Alert’s Editor, William Ershler, MD; nurse planner, Irene Q. Flores, RN, BSN, OCN; peer reviewer, V.R. Veerapalli, MD; executive editor, Leslie Coplin; and managing editor, Neill Kimball report no financial relationships relevant to this field of study.
Synopsis: In a prospective analysis, healthy women known to be carriers of BRCA1 or BRCA2 mutations chose either bilateral mastectomy or active surveillance. Ascribing to careful methodological detail, the investigators found that those who chose surgery had lower risk for breast cancer occurrence and better survival. Nonetheless, the authors note that longer follow-up and a larger sample size are needed to confirm statistical significance of their observations.
Source: Heemskerk-Gerritsen BA, et al. Substantial breast cancer risk reduction and potential survival benefit after bilateral mastectomy when compared with surveillance in healthy BRCA1 and BRCA2 mutation carriers: A prospective analysis. Ann Oncol 2013;24:2029-2035.
Germ-line BRCA1 or BRCA2 mutations carry an increased risk for the development of breast and/or ovarian cancer.1,2 Strategies to reduce breast cancer risk include rigorous adherence to mammography or MRI schedules, chemoprevention, and bilateral risk-reducing mastectomy (BRRM). In addition, risk-reducing salpingo-oophorectomy (RRSO) aimed at reduction of ovarian cancer risk also reduces the risk of breast cancer.3 Previous reports have described a reduction of breast cancer risk after BRRM in healthy BRCA1 or BRCA2 mutation carriers.4-6 However, trials were small, retrospective, and inconclusive based on various methodological concerns, including biases associated with defining the start of follow-up as well as testing bias.
In an attempt to gain further insight, Heemskerk-Gerritsen and colleagues throughout the Netherlands examined prospective data on the efficacy of BRRM when compared with surveillance on breast cancer risk and mortality in healthy BRCA1 and BRCA2 mutation carriers. They followed 570 healthy female mutation carriers (405 BRCA1, 165 BRCA2) who were selected from the institutional Family Cancer Clinic database. Eventually, 156 BRCA1 and 56 BRCA2 mutation carriers underwent BRRM. The effect of BRRM vs surveillance was estimated using Cox models.
During 2037 person-years of observation (PYO), 57 breast cancer cases occurred in the surveillance group vs 0 cases during 1379 PYO in the BRRM group (incidence rates, 28 and 0 per 1000 PYO, respectively). In the surveillance group, four women died of breast cancer, while one woman in the BRRM group presented with metastatic breast cancer 3.5 years after BRRM (no primary breast cancer), and died afterward, yielding a hazard ratio of 0.29 (95% confidence interval 0.02-2.61) for breast cancer-specific mortality.
The authors concluded that in healthy BRCA1/2 mutation carriers, BRRM when compared with surveillance reduces BC risk substantially. Nonetheless they point out that a longer follow-up is warranted to confirm the observed survival benefit.
COMMENTARY
This article examined the risk reduction and mortality from breast cancer for a group of healthy women known to be mutation carriers for BRCA1 and BRCA2. As noted, the investigators concluded from this prospective analysis, the group of women who elected BRRM had a "substantial breast cancer risk reduction" when compared with those who chose active surveillance. The data support the conclusions derived from retrospective studies and from projections based on mathematical models with simulated cohorts, yielding maximal survival probability for BRCA1/2 mutation carriers undergoing both BRRM and RRSO.7-9
In the general population, breast cancer incidence increases with aging and the same is more striking for the carriers of these mutations.10 (See Table.)
| Table: Cancer by Age (proportion, %) |
| |
≤ 45 years |
≥ 70 year |
| BRCA1 alone |
20-40% |
35-85% |
| BRCA2 alone |
10-25% |
45-85% |
| BRCA1 and BRCA2 |
15-30% |
35-65% |
Although the current paper provides a compelling argument for the efficacy of BRRM, there are two significant concerns: the relative short follow-up noted by the authors, but more importantly the surveillance group is substantially older with 42% aged 40 and older while only 25% of those selecting BRRM were 40 and older. The efficacy of BRRM over surveillance is supported by this prospective study, but comparability in age groups for both is necessary to set aside this potential bias.
References
1.King MC, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003;302:643-646.
2.Struewing JP, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401-1408.
3.Rebbeck TR, et al. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst 2009;101:80-87.
4.Domchek SM, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304:967-975.
5.Meijers-Heijboer H, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345:159-164.
6.Rebbeck TR, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: The PROSE Study Group. J Clin Oncol 2004;22:1055-1062.
7.Grann VR, et al. Effect of prevention strategies on survival and quality-adjusted survival of women with BRCA1/2 mutations: An updated decision analysis. J Clin Oncol 2002;20:2520-2529.
8.Kurian AW, et al. Online tool to guide decisions for BRCA1/2 mutation carriers. J Clin Oncol 2012;30:497-506.
9.Kurian AW, et al. Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers. J Clin Oncol 2010;28:222-231.
10.McClain MR, et al. Adjusting the estimated proportion of breast cancer cases associated with BRCA1 and BRCA2 mutations:Public health implications. Genet Med 2005;7:28-33.
