Abstract
The risk factors and clinical features for contralateral breast cancer are reviewed. Prevention is afforded by adjuvant systemic treatments but the largest risk reduction (95%) occurs with prophylactic mastectomy. Satisfaction with this procedure is high in selected individuals and studies but the potential complications should not be taken lightly. For those with a high risk of contralateral disease and a primary tumor with relatively good prognosis, it is quite reasonable to discuss and perform contralateral mastectomy with or without breast reconstruction.
When diagnosed with a screen-detected breast cancer, the patient and the treating physician usually focus their treatment plans upon the primary lesion and mammography plus a careful physical exam to rule out synchronous contralateral disease. The option of a contralateral prophylactic mastectomy (CPM) for those patients undergoing breast-conserving surgery is not usually raised. However, for those women who are faced with the need for a mastectomy as primary treatment, especially if there are significant risk factors for the development of contralateral breast cancer, a discussion regarding the advantages and disadvantages of CPM is appropriate.
The aim of this perspective is to review the risk factors for contralateral breast cancer, estimate the prognosis for patients who develop a contralateral cancer, review the prevention strategies available, discuss the efficacy, satisfaction and regret rates for those who have chosen a CPM, and lastly, propose a treatment algorithm that takes into account these findings so that an efficient discussion of the advantages and disadvantages for this surgical procedure can be accomplished.
Risk of contralateral breast cancer
The average annual risk for the development of contralateral breast cancer is between 0.5 and 1% and the cumulative 10–20-year rate is approximately 10–15%. Broet found that the incidence of contralateral breast cancer maintained a linear rate of approximately 1% from the time of diagnosis for at least 8 years [1]. Mamounas and colleagues, in a study of more than 15,000 patients from National Surgical Adjuvant Breast Project (NSABP) trials, found that the rate of contralateral breast cancer was 7.4/1000 women (0.74%)/year for those not receiving tamoxifen and 4.4 in those receiving it [2]. One would expect an even smaller rate of contralateral cancer if an aromatase inhibitor was used. Thus, most women with early stage breast cancer are treated with curative intent with unilateral breast-conserving surgery plus breast radiation or with unilateral mastectomy because the risk of developing a second contralateral breast cancer is not judged to be sufficiently high enough that they would choose to undergo a CPM.
However, there are subgroups with a significantly increased risk of contralateral breast cancer. Those women with known mutations in the breast cancer genes BRCA1 or BRCA2 have an actuarial 10-year risk between 30 and 40% for contralateral breast cancer with BRCA1 carriers having a higher rate of developing contralateral disease than those with BRCA2 mutations [3]. Furthermore, a recent study by Shahedi found that those women with hereditary or familial non-BRCA1/2-associated breast cancer also have a very high cumulative probability of developing contralateral breast cancer [4]. This approached 40% over 15 years and suggests that one should not limit discussions regarding contralateral mastectomy to only those women with a definite mutation in the BRCA1/2 genes in the face of a very strong family history.
In addition to risk from genetic changes, other factors, such as younger age, increase the risk for the development of contralateral disease. Broet found a relative risk increase of 1.4 for those under the age of 55 years compared with older patients [1], while others have suggested that risk increases in a more continuous fashion with younger age [5]. Lobular histology, whether it be invasive lobular or lobular carcinoma in-situ, has also consistently been associated with an increase in the incidence of bilateral disease [1,5,6]. The relative risk appears to be to be approximately 1.5 [1]. Other well-known risk factors for contralateral breast cancer include the diagnosis and treatment of Hodgkin's disease and other genetic alterations including Cowden's disease and Li Fraumeni syndrome.
The clinical characteristics of contralateral breast cancers were studied within a population of 1624 women treated at the Joint Centre for Radiation Therapy [5]. A total of 77 patients developed contralateral breast cancer (10-year actuarial rate: 7%) and the average size of the contralateral second tumor was 2.4 cm and was node positive in 31% of the cases. Furthermore, the development of contralateral disease was associated with a poor prognosis and increased rate of distant disease.
Prevention of contralateral breast cancer
Clearly, alternative options for the prevention of contralateral breast cancer should be discussed with patients contemplating contralateral mastectomy and Table 1 lists approximate percentage reductions associated with various treatments. The use of adjuvant therapy will reduce contralateral new primaries and lessen the overall absolute benefit from prophylactic mastectomy. However, the aim of this perspective is to focus on contralateral prophylactic surgery and how some might derive benefit from this surgery. Solid evidence has emerged that mastectomy produces approximately a 95% reduction of contralateral breast cancer in women diagnosed with unilateral breast cancer and a positive family history [7]. Hartmann also found a similar risk reduction from prophylactic mastectomy in high-risk women [8]. Some studies have even suggested that prophylactic mastectomy may be associated with an improved prognosis for those women with unilateral breast cancer. Herrinton and colleagues reviewed 1072 women who were diagnosed with unilateral breast cancer and who also underwent CPM. They used a computerized database and adjusted for the initial breast cancer characteristics, treatment and other breast cancer risk factors and compared the outcome of these patients to 317 women who did not have CPM from an overall group of approximately 50,000. The hazard ratio for breast cancer-specific death was 0.57 for those who underwent prophylactic mastectomy compared with those who did not (95% confidence interval (CI): 0.45–0.72). This 43% relative reduction in breast cancer deaths produced a 4% absolute decrease in death. The all-cause mortality hazard ratio was 0.60 (95% CI: 0.5–0.72) [9]. However, it is very surprising that a procedure that could only reduce contralateral cancers by 3–6% in the 5.7 years of follow-up would produce such a dramatic risk reduction. However, Peralta also found that CPM appeared to improve disease-free survival (DFS) for those who selected this procedure compared with those that did not (DFS at 15 years: 55 vs 28%, respectively) [10]. Overall survival was also improved (64 vs 48% respectively) but this was not significant (p = 0.26).
Prevention options for contralateral breast cancer.
Satisfaction with contralateral prophylactic mastectomy
Given that CPM effectively reduces contralateral breast cancer and may produce a better outcome, what are the satisfaction rates and psychosocial outcomes in this population? To help answer this question, Borgen's group at Memorial Sloan Kettering developed a volunteer registry of 296 women who responded to advertisements in national magazines and who had undergone CPM. Approximately one in three women had synchronous bilateral mastectomy, while the remainder had a delayed contralateral procedure. Of the 111 women who had reconstruction, 32% were self-reported to have excellent cosmetic results and 48% reported acceptable results. Only 16% gauged their ultimate cosmesis to be unacceptable and 11% expressed regret at having undertaken the contralateral mastectomy. Interestingly, of those who had mastectomy but no reconstruction, only 3% expressed regret. The most common reasons for regret were poor cosmesis, decreased sexuality and lack of information regarding alternative options. These findings emphasize the importance of appropriate counseling regarding contralateral breast cancer risk and alternatives to the procedure, as well as education regarding realistic cosmetic expectations following reconstructive surgery [11].
Frost and colleagues performed a descriptive study of 583 women who elected to have contralateral prophylactic subcutaneous or simple mastectomy with or without implant reconstruction at the Mayo Clinic between 1960 and 1993. The survey was completed an average of 10.3 years following the surgery and they found that approximately 80% of the patients who underwent CPM were very satisfied or somewhat satisfied. Only 9% of the surveyed women ‘probably would not’ or ‘definitely would not’ undergo CPM again. Interestingly, those treated with a subcutaneous mastectomy were twice as likely to report dissatisfaction as those who underwent a simple mastectomy (13 vs 6%; p = 0.0006). Dissatisfaction was once again associated with poor cosmetic results, complications related to the surgery and a diminished body image. The need for further surgery was an important factor. Of the 583 respondents, 157 (27%) needed at least one unanticipated reoperation. Almost three-quarters of these reoperations were implant-related. Those who undergo implant reconstruction should be informed of the reasonably high chance that surgical adjustments to the reconstructed breast may be necessary, especially after subcutaneous mastectomy, which, by definition, leaves the nipple intact, but whose position may not be optimal postoperatively [12].
Geiger and colleagues used a number of psychosocial instruments to evaluate the associations between the quality of life in those cancer survivors with or without CPM. Over 86% of 519 women studied were satisfied with their decision to have contralateral mastectomy and 76% reported high levels of contentment, which was similar to those breast cancer survivors without the contralateral mastectomy [13].
Thus, CPM is associated with the following potential advantages. There is a definite and profound risk reduction for contralateral breast cancer. Even though the summary benefit is related to the risk of contralateral disease, one should not forget that contralateral cancers can add to the risk of distant disease. This may explain the reported improvement in disease-free and overall survival in two studies. Body symmetry is important to many women and some choose contralateral mastectomy to achieve a symmetric result. The vast majority of women undergoing this procedure claim to be satisfied, whether they chose reconstruction or not.
On the opposite side of the ledger are the following disadvantages. The vast majority of women with breast cancer will not develop contralateral disease and thus most will be ‘overtreated’. Every surgical intervention, including contralateral mastectomy, carries the risk of operative complications. For example, postmastectomy pain syndrome can be a significant problem, more so, perhaps, if it occurs after prophylactic treatment. Postoperative complications may also be magnified if the patient feels that ‘extra surgery’ was proposed without a good indication. There will always be some patients with dissatisfaction or regret even after a cosmetically excellent breast reconstruction. Nipple sensation is, of course, lost. Finally, despite the previous reports, it is hard to accept that short-term survival (<10 years) would be significantly altered by contralateral mastectomy for most breast cancer patients because of the much larger risk from their index cancer and its response to treatment.
Decision aid for consideration of contralateral prophylactic mastectomy.
Future perspective
The clinical, histological and phenotypic parameters that are currently used to quantify the chance of developing a contralateral breast cancer will give way to genetic signatures that will better predict this risk. The important genetic markers may exist in the primary cancer or perhaps be found by examining the ‘normal’ breast tissue from one or both breasts. The investigation into these genetic alterations may provide helpful knowledge into the study of carcinogenesis as here we have a situation of increased risk and the possibility of monitoring these changes over time.
As treatments for breast cancer continue to improve and survival rates increase, the option of contralateral mastectomy with its record of effective prophylaxis may well be chosen by more women who are at increased risk of contralateral breast cancer. Thus, over the short term, the use of this procedure may increase. However, it is hoped that prevention strategies, screening and treatment will improve enough so that most women are cured of early stage cancer after breast-conserving procedures, and then this option will become needless.
Executive summary
Average annual risk for the development of contralateral breast cancer is between 0.5 and 1 %.
Lobular histology, whether it be invasive lobular or lobular carcinoma in-situ, is also associated with an increased relative risk of bilaterality of 50% (0.75–1 % annually).
Those with known mutations of the breast cancer genes BRCA1 or 2 have an actuarial 10-year risk between 30 and 40% for contralateral breast cancer.
Development of contralateral breast cancer is associated with a poor prognosis and increased rate of distant disease.
Contralateral prophylactic mastectomy reduces risk by approximately 95% and may be associated with an improved prognosis.
80% of patients who undergo contralateral prophylactic mastectomy are very satisfied or somewhat satisfied.
The best candidates are those with significant risk factors for bilaterality and a primary cancer associated with a good prognosis.