“Risk-reducing bilateral mastectomy allows a woman with a high-penetrance breast cancer-causing mutation to avoid an encounter with the experience of breast cancer diagnosis and treatment,” Seema A. Khan, MD, MPH, stated at the 2022 Lynn Sage Breast Cancer Symposium.1 For these women, by avoiding the cancer, risk-reducing bilateral mastectomy “very likely also avoids death from breast cancer,” she added. For carriers of moderate-penetrance mutations, the risk of breast cancer is relatively modest, and the benefit of risk-reducing mastectomy is uncertain.
Seema A. Khan, MD, MPH
Dr. Khan is Professor of Surgery and Bluhm Family Professor of Cancer Research, Comprehensive Cancer Center of Northwestern University, Chicago. The symposium was hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
High-Penetrance Mutations
Carriers of high-penetrance mutations (eg, BRCA1, BRCA2, PTEN, p53, PALB2) have a life-time breast cancer risk “approaching 60%,” Dr. Khan noted, but the estimated risk varies with age. “It is useful to think in terms of annual risk, and the annual risk for these high-penetration gene mutations is in the range of 2% to 2.5% a year,” she explained.
“In general, cancers in BRCA2 carriers have a later trajectory than cancers with BRCA1 carriers. It is shifted by about a decade,” she continued. Risk rises around age 30 for BRCA1, whereas for BRCA2, it rises closer to age 40.2
For other genes implicated in breast cancer, including PALB2, the “age at which the carrier risk departs from the standard population happens later,” Dr. Khan added.
Global Recommendations
“There are recommendations from various groups of experts around the world,” Dr. Khan noted, with varying degrees of concordance about what to do for women with genetic risks of breast cancer. “Where there is really good agreement about whether or not one should start talking about bilateral risk-reducing mastectomy—or therapeutic mastectomy and contralateral mastectomy—is for the high-penetrance genes.”
Referring to the 2022 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, for BRCA1/2 carriers, Dr. Khan noted that the first recommendation is to discuss the option of risk-reducing mastectomy. Counseling should include a discussion of the degree of protection, the reconstruction options, and their risks, as well as family history and the residual breast cancer risk with age. There is also a need to address psychosocial issues and quality-of-life aspects. “There were few data on this until recently, and the data are not perfect yet, but they are emerging,” she said.
“Risk reduction agents are clearly on the table in terms of discussion,” Dr. Khan added. “But so far, since we only have successful agents that reduce the risk of hormone receptor–positive cancer, that does limit the discussion in terms of a woman whose risk is clearly stronger for estrogen receptor–negative cancer.”
Moderate-Penetrance Genes
For individuals who have moderate-penetrance genes, “the recommendations are mostly for surveillance,” Dr. Khan noted. The surveillance benefits of MRI, mammogram, and added value mammogram are being investigated. Decisions on surveillance measures should take family history into account.
“The benefit of risk-reducing mastectomy in carriers of moderate-penetrance mutations is uncertain. The level of their risk is relatively modest,” and at up to 1% annually, it is “similar to the risk of atypical ductal hyperplasia,” Dr. Khan stated. “Our job is to try to inform and reassure patients that this type of risk doesn’t merit the kind of problems that could occur with bilateral surgery and reconstruction.” Risk-reducing mastectomy may be justified, however, if there is a strong family history of breast cancer.
Surgical Outcomes
The first formal evaluation of risk-reducing mastectomy was performed at the Mayo Clinic and involved 639 women with a family history of breast cancer and 401 with varied breast complaints. “Depending on the method of calculation, risk reduction ranged from 90% to 94%,” Dr. Khan reported, and “it was similar for BRCA carriers.”
A meta-analysis of 15 studies found that prophylactic mastectomies resulted in an 89% reduction in breast cancer risk and a 77% reduction in overall mortality.3 “The data are not as long term as we wish, but they still are consistent with very good protection against the occurrence of breast cancer with the use of this procedure,” Dr. Khan said.
“For mortality, there has not been good evidence so far. The reason probably is that particularly with intense surveillance and early detection as well as improving treatment, even when cancer occurs in someone who has not had this procedure, the cancer is treatable. Survival is going to be a hard endpoint for this intervention, just as it has been for medications. But, if it avoids the encounter with cancer and the treatment of cancer, that is valuable to most women.”
A 2018 Cochrane review included 61 studies with data on 15,077 women who had risk-reducing mastectomy. The effect on breast cancer occurrence was very strong, but the effect on breast cancer mortality remains uncertain.4 For contralateral prophylactic mastectomy, “there is insufficient evidence that it improves survival,” the authors wrote. This is due to “the continuing risk of recurrence or metastases from the original cancer,” Dr. Khan said. This is similar, she noted, to the situation of a patient with stage III breast cancer for whom a contralateral mastectomy “is not going to alter overall survival because of the threat of the already known cancer.”
There has been a “remarkable” increase in nipple-sparing surgery during the past 2 decades, Dr. Khan added. “Nipple preservation appears safe, but long-term data are not available. Newer techniques of nerve preservation and robotic surgery are evolving.”
DISCLOSURE: Dr. Khan reported no conflicts of interest.
REFERENCES
1. Khan S: Surgery in genetically induced breast cancer. 2022 Lynn Sage Breast Cancer Symposium. Presented September 23, 2022.
2. Hu C, Hart SN, Gnanaolivu R, et al: A population-based study of genes previously implicated in breast cancer N Engl J Med 384:440-451, 2021.
3. Li X, You R, Wang X, et al: Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: A meta-analysis and systematic review. Clin Cancer Res 22:3971-3981, 2016.
4. Carbine NE, Lostumbo L, Wallace J, et al: Risk-reducing mastectomy for the prevention of primary breast cancer. Cochrane Database Syst Rev 4:CD002748, 2018.
