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Mutations in BRCA1 and BRCA2 are found in approximately 1 in 300 individuals in the general population and 1 in 40 individuals of Ashkenazi Jewish descent. Such mutations are associated with very elevated risks of breast cancer (lifetime risk approximately 70% by age 80 years) and ovarian cancer (45% for BRCA1 and 20% for BRCA2 mutation carriers).1 Increased risks of pancreatic cancer and high-grade prostate cancer are also seen, particularly for BRCA2 mutation carriers. Recommendations from the National Comprehensive Cancer Network2 for genetic testing for BRCA1 and BRCA2 mutations continue to expand and now include (but are not limited to) all women with ovarian cancer; breast cancer diagnosed younger than 45 years, triple-negative breast cancer younger than 60 years, or breast cancer with Ashkenazi Jewish ancestry; all individuals with pancreatic cancer; and all men with breast cancer or metastatic prostate cancer. With proliferating genetic testing options (including the controversial availability of a direct-to-consumer option for the Ashkenazi Jewish founder mutations3), rapidly falling costs, and ongoing discussions regarding the potential in the future for population screening, rates of testing are expected to continue to increase. Thus, it is likely that more women will be identified as having BRCA1 and BRCA2 mutations and will face decisions regarding risk-reducing mastectomy.
The decision to have and timing of risk-reducing mastectomy is very clear for some women. For others, there is uncertainty as they weigh the possibility of developing an often curable disease against the potential harms and limitations of surgery. Although the risk of breast cancer is high among women with BRCA1 and BRCA2 mutations, it is not absolute; some women will not develop cancer; thus, mastectomy would have been unnecessary. Conversely, despite screening and early detection, not all breast cancers will be curable but may have been prevented with risk-reducing mastectomy. Timing of risk-reducing mastectomy can be influenced by life events such as dating, breastfeeding, time off from career, and the need for help during the postoperative recovery period (particularly if caring for young children). These decisions are complicated, unique to each individual, and in the absence of a diagnosed cancer, time can be taken to make a decision, there is no immediate urgency.
Risk-reducing mastectomy is the most effective way to avoid the development of breast cancer and to obviate the need for chemotherapy. Prospective cohort studies of BRCA1 and BRCA2 mutation carriers demonstrate that risk-reducing mastectomy is associated with 90% or more decreased risk of breast cancer with a residual risk of 1% to 2%.4,5 Without risk-reducing mastectomy, the risk of breast cancer among BRCA1 and BRCA2 mutation carriers is approximately 70%,1 a risk that is possibly reduced by risk-reducing salpingo-oophorectomy and selective estrogen receptor modulators. Risk-reducing salpingo-oophorectomy is strongly recommended for women with mutations in BRCA1 (between ages 35 and 40 years) and BRCA2 (between ages 40 and 45 years)2 because risk-reducing salpingo-oophorectomy is associated with a significant reduction in ovarian cancer and lower all-cause mortality.4
More difficult to quantify is the effect of risk-reducing mastectomy on breast cancer–specific and overall mortality. No randomized studies have compared risk-reducing mastectomy with enhanced screening (annual magnetic resonance imaging [MRI] beginning at 25 years, mammogram alternating with MRI at 30 years) along with risk-reducing salpingo-oophorectomy at the appropriate age, and it is unlikely that any will be conducted. In the available retrospective and prospective cohort studies, assessment of mortality may be affected by detection bias, potential confounders (such as differential use of risk-reducing salpingo-oophorectomy), and limitations on data regarding adherence to recommended surveillance in the group that does not undergo risk-reducing mastectomy. Nevertheless, these studies along with modeling approaches have suggested a mortality benefit. One study reported 10-year overall survival for women undergoing risk-reducing mastectomy of 99% compared with 96% for women who did not have surgery,6 and modeling studies have estimated mortality benefits of between 6% and 8% for BRCA1 and 3% for BRCA2 mutation carriers by age 80 years.7,8 When considering absolute risk reduction estimated in cohort studies, incomplete data regarding adherence to surveillance and use of risk-reducing salpingo-oophorectomy may inflate the estimates of mortality benefit for risk-reducing mastectomy.
Even assuming that these mortality benefits are accurate, many other considerations bring nuance to the discussion regarding mastectomy and include the following:
BRCA1 and BRCA2 Mutations Give Rise to Related But Distinct Cancer Susceptibility Syndromes: Early prospective studies combined BRCA1 and BRCA2 mutation carriers for analysis. However, timing of breast and ovarian cancer development, breast cancer subtypes, and other cancer risks differ between the 2 types. Specifically, the risk of ovarian cancer is higher and the age of onset younger among BRCA1 mutations carriers; the peak incidence of BRCA1 mutation–associated breast cancer is between the ages of 41 and 50 years compared with between the ages of 51 and 60 years for BRCA21 carriers; BRCA1-associated breast cancer is usually triple-negative (estrogen-receptor, progesterone-receptor, and HER2/neu negative) vs usually estrogen-receptor positive for BRCA2; BRCA2 mutations are also associated with an increased risk of pancreatic and other cancers. These details factor into the discussion regarding mastectomy: a BRCA1 mutation carrier diagnosed with a stage I breast cancer while undergoing screening MRI will very likely still require chemotherapy for a triple-negative breast cancer.
Decade-Specific and Residual Lifetime Risks: Lifetime risk estimates for BRCA1 and BRCA2 mutation carriers are high; however, an individual’s current age and estimated risk over 5 to 10 years should be considered in the discussion. For example, the risk of breast cancer by age 30 years is less than 5% for BRCA1 and BRCA2 mutation carriers.1 Although a 25-year-old woman’s lifetime risk is high, her absolute risk over the near term is not so she has time to consider her options. Conversely, a BRCA2 mutation carrier who is older than 60 years and without cancer may have a residual lifetime risk of breast cancer (to age 80 years) of less than 15%. She is unlikely to obtain a survival benefit from risk-reducing mastectomy.
Complications and Reconstruction: Complications of risk-reducing mastectomy include the risk of bleeding, infection, chronic pain, and need for revisions. The rates and types of complications are influenced by the choice of reconstruction.5 Women undergoing implant reconstruction also need to consider the rare risk of implant-associated lymphoma and the need to have implants replaced over time. For women who have not yet had children and are contemplating mastectomy, there are limited published data regarding abdominal-free flaps and subsequent pregnancy.
Screening Considerations: Breast MRI screening using gadolinium-based contrast agents, although very sensitive for the detection of invasive breast cancer, is associated with a high rate of false-positive results that can lead to unnecessary procedures and increased anxiety. In addition, gadolinium is retained in minute amounts in the body, more so with linear than macrocyclic agents. Apart from the rare risk of nephrogenic systemic fibrosis in individuals with significant renal impairment, no harmful effects have been identified. On the basis of the current evidence, the benefits of using these agents outweigh the risks.9
Quality of Life: Risk-reducing mastectomy often affects body image and sexual function.2 This may be of concern for some women including some who desire and yet do not yet have a life partner. In addition, women who wish to breastfeed their children often consider this in the timing of risk-reducing mastectomy.
Individualized Risk: Women are interested in more precise risk estimates based on personal risk factors and details of their family history. There is an awareness that some BRCA1 and BRCA2 mutation carriers will never develop breast cancer and for these women mastectomy can only cause harm. Increasing data demonstrate that genetic modifiers exist and that a polygenic risk score may be able to determine which women are at relatively higher vs relatively lower risk of breast cancer. However, whether such information would be useful to women and their physicians in making these decisions is unknown.
Women with BRCA1 and BRCA2 mutations need to be provided with detailed information about risk-reducing mastectomy including the potential risks and benefits of the procedure and place it into the context of their specific life goals. As women contemplate their options, it is important to emphasize that these decisions need not be rushed. Indeed, close monitoring (including breast MRI) and support with open and recurrent dialogue may help women make choices that incorporate both their risks and preferences. Equally important is the need to continue research to understand how to individualize risk and develop nonsurgical preventive options for BRCA1 and BRCA2 mutation carriers. Ongoing work is examining the possibilities of receptor activator of nuclear factor κB ligand (RANKL) inhibitors, selective estrogen receptor modulators, poly [ADP-ribose] polymerase (PARP) inhibitors, and immune approaches for prevention. Women deserve better choices.
Corresponding Author: Susan M. Domchek, MD, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, 3400 Civic Center Blvd, 10 South PCAM, Philadelphia, PA 19104 (email@example.com).
Published Online: December 6, 2018. doi:10.1001/jama.2018.18942
Domchek SM. Risk-Reducing Mastectomy in BRCA1 and BRCA2 Mutation CarriersA Complex Discussion. JAMA. Published online December 06, 2018. doi:10.1001/jama.2018.18942
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