An accurate assessment of the risk of breast cancer is the first step in planning future preventive strategies. Women at high risk of breast cancer are those with known BRCA mutations or a strong family history characterized by multiple relatives with breast cancer, early age at diagnosis, and in some cases, ovarian cancer. These women currently have three management options: cancer surveillance, prophylactic surgery (mastectomy and/or oophorectomy), and/or chemoprevention. Prophylactic mastectomy includes bilateral prophylactic mastectomy in a high-risk woman who has not had cancer and contralateral prophylactic mastectomy, defined as mastectomy of the opposite breast in a woman with a primary breast cancer. In this review, we discuss the currently available literature on prophylactic mastectomy, its indications, and role in breast cancer prevention.
Surgical Techniques
Surgical options for prophylactic mastectomy include subcutaneous mastectomy or total mastectomy, usually followed by breast reconstruction. Subcutaneous mastectomy is performed via an inframammary incision through which the breast tissue is resected, sparing the nipple-areolar complex.[1] Historically, subcutaneous mastectomy was performed more commonly than total mastectomy, which removes the majority of the breast tissue along with the nipple-areolar complex through an elliptical skin incision. Given current nipple reconstruction techniques, total mastectomy is the preferred prophylactic procedure today.[2] With both procedures, however, small amounts of remaining breast tissue—which can develop into cancer—may be left behind in the axilla, inframammary fold, and skin flaps.[3] This issue must be clearly explained to the patient, because the risk of breast cancer, therefore, cannot be completely eradicated with prophylactic mastectomy.
Historical Perspective
Prophylactic mastectomy has been performed for decades. Historically, contralateral prophylactic mastectomy was advocated to reduce the increased risk of a second primary breast cancer in women who had had a first breast cancer. Bloodgood was the first to report on this strategy, in his 1921 discussion of the management of the remaining breast after radical removal of the opposite breast for carcinoma.[4] With the availability of breast implants for reconstruction, and the increasing awareness of familial breast cancer risk, bilateral prophylactic mastectomy began to be more commonly performed in the 1960s and 1970s.
In 1989, Pennisi and Capozzi published data on 1,500 women who had undergone subcutaneous mastectomy.[5] Patients were identified through solicitations to the membership of the American Board of Plastic Surgery. A total of 165 plastic surgeons contributed cases. A family history of breast cancer (first-degree, second-degree, maternal, or paternal relatives) was noted in 41% of involved patients. Of the 1,500 patients, 139 underwent a contralateral subcutaneous prophylactic mastectomy after a modified radical mastectomy of the opposite breast for primary breast cancer.
Subsequently, six women (0.4%) developed breast cancer, leading the authors to conclude that the procedure provided effective prophylaxis. However, some of the limitations regarding this study included a possible bias toward inclusion of patients with a favorable outcome, lack of definition of the patients’ risk of breast cancer, a high "lost-to-follow-up" rate of 30%, and inclusion of women with a history of cancer in the opposite breast.[5]
In 1997, the Cancer Genetics Studies Consortium, organized by the National Human Genome Research Institute, published a consensus statement on the optimal care of individuals carrying mutations in the BRCA1 and BRCA2 genes.[6] Regarding prophylactic mastectomy, their recommendation stated,
There is insufficient evidence to recommend for or against prophylactic mastectomy as a measure for reducing breast cancer risk. Individuals should be counseled that this is an option available to them. Those considering prophylactic mastectomy should be counseled that cancer has been documented to occur after the procedure; its efficacy in reducing risk is uncertain.[6]
Indeed, case reports had detailed the recurrence of breast cancer in residual breast tissue following both total and subcutaneous prophylactic mastectomy.[7-9] Several studies of the efficacy of the procedure (see below) have been published since this consensus statement.
Efficacy of Prophylactic Mastectomy
Bilateral Prophylactic Mastectomy
Mayo Clinic Study—In an effort to quantify the risk reduction associated with prophylactic mastectomy, Hartmann and colleagues at the Mayo Clinic performed a retrospective cohort analysis of 639 women with a family history of breast cancer who had undergone prophylactic mastectomy between 1960 and 1993.[10] Women were assigned retrospectively to either a moderate-risk group (425 women) or high-risk group (214 women) based on the extent of their family history of breast cancer. Follow-up was available for 99% of the cohort for a minimum of 2 years; median follow-up was 14 years (9,095 person-years).
The investigators compared the total number of breast cancers observed among study participants with the total number predicted by the Gail model (for the moderate-risk group) and by a nested sister control study (for the high-risk group). The Gail model predicted that 37.4 women in the moderate-risk group would develop breast cancer by the median follow-up of 14 years. However, only four of these women developed the disease, representing an 89.5% reduction (P < .00001) in incidence following prophylactic mastectomy. The Gail model also predicted that 10.4 women in the moderate-risk group would die of breast cancer, but, in fact, no deaths from breast cancer occurred in these women.
With regard to the high-risk group, 3 of the 214 women developed breast cancer after prophylactic mastectomy. From their sisters’ experiences, 30 breast cancers were predicted in these high-risk women (see Table 1).[10] Thus, prophylactic mastectomy was associated with a 90% reduction in the risk of breast cancer in high-risk women. Similarly, compared with the expected number of breast cancer deaths in the probands, prophylactic mastectomy in the high-risk group resulted in an 81% to 94% reduction in breast cancer mortality.
Dutch Study—A recent prospective Dutch study evaluated 139 BRCA1 or BRCA2 carriers followed at the Rotterdam Family Cancer Clinic; none had a history of breast cancer.[11] A total of 76 of these women elected to undergo prophylactic mastectomy, and 63 remained under careful surveillance. At a mean follow-up of 2.9 ± 1.4 years, no cases of breast cancer were observed in the prophylactic mastectomy group, compared to eight cases in the surveillance group (hazard ratio: 0; 95% confidence interval [CI]: 0-0.36).
Of the eight cases, four were interval cancers diagnosed between scheduled screening tests. Four of the cancers involved axillary lymph nodes, and seven were estrogen-receptor and progesterone(Drug information on progesterone)-receptor negative. The interval from initiation of surveillance to diagnosis of cancer ranged from 2 to 42 months. These investigators concluded that in women with a BRCA1 or BRCA2 mutation, at 3 years of follow-up, prophylactic bilateral total mastectomy reduced the incidence of breast cancer (relative risk reduction: 100%, absolute risk reduction: 12.7%).
Contralateral Prophylactic Mastectomy
Contralateral breast cancers occur at a rate of approximately 0.5% to 1.0% per year of follow-up after a primary breast cancer in women at average risk.[12] In women with a family history of breast cancer, Harris et al described a 35% risk of contralateral breast cancer by 16 years after the first breast cancer diagnosis.[13] However, in carriers of a BRCA1 or BRCA2 mutation, the contralateral breast cancer rate is higher, ranging from 12% at 5 years in BRCA2 carriers, to 20% to 31% at 5 years in BRCA1 carriers[14] and Ashkenazi BRCA1 or BRCA2 carriers.[15]
Data on the efficacy of contralateral prophylactic mastectomy have been relatively sparse. However, two recent studies have addressed this issue.
Peralta et al Study—Peralta et al studied the efficacy of contralateral prophylactic mastectomy in a retrospective analysis of 64 patients with a personal history of breast cancer who underwent this procedure, compared with 182 controls who did not.[16] The end points were contralateral breast cancer rate, disease-free survival, and overall survival. The groups were matched by age, stage, surgery, chemotherapy, and hormonal therapy.
In the contralateral prophylactic mastectomy group, three incidental contralateral breast cancers (4.5%) were found at the time of prophylactic mastectomy, but none occurred subsequently; 36 contralateral breast cancers occurred in the control group (P = .005). The mean follow-up was 6.8 years (range: 0.3-23.6 years). Overall survival at 15 years was 64% (95% CI: 45%-78%) in the contralateral prophylactic mastectomy group vs 49% (95% CI: 39%-58%) in the control group (P = .26). The researchers concluded that contralateral prophylactic mastectomy prevented contralateral breast cancer and that the potential benefit was greatest when the risk of contralateral breast cancer was highest.[16]
McDonnell et al Study—McDonnell et al followed 745 women (388 premenopausal, 357 postmenopausal) with a first breast cancer and a family history of breast and/or ovarian cancer who underwent contralateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993.[17] Using life tables for contralateral breast cancers (referred to as the Anderson model),[18,19] the investigators considered current age, age at first breast cancer, and type of family history (which is based only on breast cancer events in the family and requires one of three types of pedigree—parent-affected, sibling-affected, second-degree relative-affected). With these data, they predicted the number of contralateral breast cancers in this cohort had patients not undergone contralateral prophylactic mastectomy. The median length of follow-up was 10 years, with a minimum follow-up of 2 years for 98% of the cohort.
Eight women developed contralateral breast cancer. Six events were observed in the premenopausal group of 388 women compared with 106.2 predicted, representing a risk reduction of 94.4% (95% CI: 87.7%-97.9%). In the postmenopausal group of 357 subjects, two events were observed compared with 50.3 predicted, representing a 96% risk reduction (95% CI: 85.6%-99.5%). The incidence of contralateral breast cancer, therefore, appears significantly reduced after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.[17]
Schrag et al Study—Schrag et al performed a decision analysis using a Markov model to predict years of life gained through various prevention strategies in BRCA1 or BRCA2 carriers.[20] They estimated the probabilities of developing contralateral breast cancer and ovarian cancer, dying from these cancers, and dying from primary breast cancer, based on published studies. They also calculated reductions in the incidence and mortality of cancer resulting from prophylactic surgeries and/or tamoxifen(Drug information on tamoxifen).
Using hypothetical breast cancer patients with BRCA1 or BRCA2 mutations who faced secondary cancer prevention strategies, they assessed the effect of contralateral prophylactic mastectomy, bilateral prophylactic oophorectomy, and 5 years of tamoxifen therapy on their life expectancy. Based on the assumed penetrance of BRCA mutations, compared to surveillance alone, 30-year-old, early-stage breast cancer patients with BRCA mutations gain 0.4 to 1.3 years of life expectancy with tamoxifen therapy, 0.2 to 1.8 years with prophylactic oophorectomy, and 0.6 to 2.1 years with contralateral prophylactic mastectomy. The magnitude of the gain was highest for women with high-penetrance mutations.[20]
Thus, contralateral prophylactic mastectomy provides a potential benefit for patients at high risk of contralateral breast cancer, with chemoprevention and close surveillance being important alternatives. It is essential to provide each patient with appropriate counseling regarding the risk of recurrence of her primary breast cancer, the risk of contralateral breast cancer, and the efficacy of contralateral prophylactic mastectomy (and its cosmetic outcomes), in order to optimize the ultimate outcome, including patient satisfaction.
