Contralateral Prophylactic Mastectomy in Women with Unilateral Breast Cancer Who Are Genetic Carriers, Have a Strong Family History or Are just Young at Presentation

The uptake of contralateral prophylactic mastectomy is rising with increasing trends that are possibly highest in the USA. Whilst its role is generally accepted in carriers of recognized high-risk predisposition genes such as BRCA1 and BRCA2 when the affected individual is premenopausal, controversy surrounds the benefit in less understood risk-profile clinical scenarios. This comprehensive review explores the current evidence underpinning the role of contralateral prophylactic mastectomy and its impact on contralateral breast cancer risk and survival in three distinct at-risk groups affected by unilateral breast cancer: known genetic carriers, those with strong familial risk but no demonstrable genetic mutation and women who are of young age at presentation. The review supports the role of contralateral prophylactic mastectomy in “high risk” groups where the evidence suggests a reduction in contralateral breast cancer risk. However, this benefit is less evident in women who are just young at presentation or those who have strong family history but no demonstrable genetic mutation. A multidisciplinary and personalized approach to support individuals in a shared-decision making process is recommended.


Introduction
The incidence of women with breast cancer who elect to undergo contralateral prophylactic mastectomy is steadily increasing, with preponderance amongst Caucasians, young women, and those with a higher socioeconomic status [1,2]. A study of 496,488 women with unilateral Stage I-III breast cancer, from the Surveillance, Epidemiology, End Results (SEER) Program database demonstrated an increase in contralateral prophylactic mastectomy rates performed for unilateral invasive breast cancer from 3.9% in 2002 to 12.7% in 2012 [3]. This effect was reproduced in a National Cancer Database review of 553,593 patients, showing an increase in contralateral prophylactic mastectomies from 4.1% in 2003 to 9.7% in 2010. This finding was most marked in young women, where those <45 years (n = 73,888) showed an increase from 9.3% in 2003 to 26.4% in 2010 [4].
Factors that contribute to this decision include patient age, disease stage, previous breast biopsies, genetic predisposition or family history of breast cancer, fear of recurrence, concern with cosmetic symmetry and physician recommendation [1,[5][6][7][8].
Patients tend to overestimate their risk of developing a contralateral breast cancer [9,10] as well as the extent of risk reduction conferred by contralateral prophylactic mastectomy [9,11]. Interestingly, whilst 43.9% of women with breast cancer considered contralateral prophylactic mastectomy, only 38.1% were aware that it did not improve survival, highlighting the importance of patient education [12]. Improvements in modern multidisciplinary management have led to a reduction in the incidence of contralateral breast cancer from approximately 0.6% to 0.2-0.5%/year [13]. Consequently, the role of contralateral prophylactic mastectomy and the context in which it is supported is debatable.
This comprehensive review explores the current evidence underpinning the role of contralateral prophylactic mastectomy and its impact on contralateral breast cancer risk and survival in three high-risk groups affected by breast cancer: (i) genetic carriers, (ii) strong family history with no demonstrable mutation, and (iii) young women.

Contralateral Prophylactic Mastectomy and Risk of Contralateral Breast Cancer
Contralateral prophylactic mastectomy reduces the risk of contralateral breast cancer in BRCA mutation carriers [14,26,27]. This risk reduction has been reported to be in the range of 91% [27]. This is further supported by a meta-analysis showing that contralateral prophylactic mastectomy resulted in a 93% reduction in contralateral breast cancer risk (RR 0.072; 95%CI 0.035-0.588) [26].
A meta-analysis by Valachis demonstrated no difference in breast-cancer-specific survival between BRCA carriers who underwent contralateral prophylactic mastectomy against those who did not (HR 0.78, 95% CI 0.44-1.39; p = 0.40) [14]. However, a meta-analysis including two additional studies demonstrated a decrease in "all-cause" mortality [26]. To further add to the ambiguity, a recent prospective study showed that contralateral prophylactic mastectomy conferred no benefit in 5-year overall survival between BRCA carriers and non-carriers with triple negative breast cancer [32]. The available findings should be interpreted with caution as they are mostly based on retrospective studies that may contain recognized and unrecognized biases. Mutations in CHEK2, TP53, ATM, PALB2, PTEN, and CDH1 account for a small fraction of familial breast cancers. The available studies are sparse and primarily family-based, with potential ascertainment bias. It should be noted that the existing literature focusses mainly on relative rather than absolute risk estimates.

CHEK2 Mutation Carriers and Contralateral Breast Cancer Risk
In a recent meta-analysis, Akdeniz demonstrated an increased contralateral breast cancer risk for CHEK2* 1100delC carriers (RR 2.75, 95% CI 1.77-4.27) [33]. This mutation is associated with bilateral disease and an increased risk of bilateral breast cancer which varies between two to six-fold [15,[34][35][36][37][38][39][40] ( Table 2). It has been suggested that CHEK2 carriers may be more sensitive to ionizing radiation that may contribute to contralateral breast cancer rates in patients receiving adjuvant radiotherapy following breast conserving surgery [40,41]. The true impact of radiation in this context is questionable as consistently increased contralateral breast cancer risk has been demonstrated in patients treated with or without radiotherapy (HR 4.12, 95% CI 2.49-6.83 and HR 3.17, 95% CI 1.36-7.35, respectively) [39,41].

TP53 Mutation Carriers and Contralateral Breast Cancer Risk
There are no studies estimating contralateral breast cancer risk in TP53 carriers with breast cancer.

ATM Mutation Carriers and Contralateral Breast Cancer Risk
In a multicentre, population-based, case-control study, Concannon suggested that four common variants of ATM (c.1899-55T>G; c.3161C>G; c.6348-54T>C and c.5558A>T) were associated with a lower contralateral breast cancer risk (overall RR 0.8, 95% CI 0.6-0.9) compared to those with rare, missense ATM mutations. The protective mechanisms may occur through an alteration in ATM activity as an initiator of DNA damage response or through its role in TP53 regulation [42]. Bernstein suggested that common ATM variants may exert a protective effect and reduce contralateral breast cancer risk, while rare ATM missense, deleterious variants may act synergistically with radiation exposure to increase this risk [43]. In this study, the variants: c.1899-55T>G (RR 0.5, 95% CI 0.3-0.8), c.3161C>G (RR 0.5, 95% CI 0.3-0.9), c.5558A>T (RR 0.2, 95% CI 0.1-0.6), and c.6348-54T>C (RR 0.2, 95% CI 0.1-0.8) were associated with significantly reduced risk. On the other hand, female carriers of any rare missense ATM variant, who received radiation therapy for their first breast cancer, had a significantly elevated contralateral breast cancer risk compared to unexposed women (RR = 2.8 for <1.0 Gy dose and RR = 3.3 for ≥1.0 Gy dose to the contralateral breast).
The direct relationship between the presence of ATM variants and the overall risk of contralateral breast cancer remains controversial, although the combination of radiotherapy and certain ATM missense variants appears to accelerate tumour development [44].

PALB2 Mutation Carriers and Contralateral Breast Cancer Risk
There are no studies estimating contralateral breast cancer risk in PALB2 carriers with breast cancer.

CDH1 Mutation Carriers and Contralateral Breast Cancer Risk
There are no studies on the risk of contralateral breast cancer in CDH1 carriers.

PTEN Mutation Carriers and Contralateral Breast Cancer Risk
There are no studies estimating contralateral breast cancer risk in PTEN carriers with breast cancer.

Contralateral Prophylactic Mastectomy and Risk of Contralateral Breast Cancer
No studies have investigated the role of contralateral prophylactic mastectomy in the risk reduction of contralateral breast cancer in patients with a diagnosis of breast cancer that harbor a genetic mutation in non-BRCA1/2 genes (CHEK2, TP53, ATM, PALB2, CDH1 and PTEN).

Contralateral Prophylactic Mastectomy and Survival
There is no data to support any survival benefit from contralateral prophylactic mastectomy in this group of patients ("other" genetic carriers). This would be even more challenging in those with TP53, CDH1 and PTEN mutations because of the additional competing cancer risk. In view of the limited evidence, no further comment can be made, except to reinforce that contralateral prophylactic mastectomy should be considered on an individual basis for women with unilateral breast cancer in this group.

Familial Breast Cancers with No Demonstrable Genetic Mutation and Contralateral Breast Cancer Risk
A positive family history remains a strong risk factor for contralateral breast cancer, even after excluding mutation carriers [46][47][48]. Table 3 summarizes the current literature on the impact of positive family history on contralateral breast cancer risk and survival. In a multicentre, population-based, case-control study of 1521 contralateral breast cancer cases against 2212 matched controls of unilateral breast cancer, Reiner demonstrated that non-mutation carriers with any 1st or 2nd degree relative of breast cancer had a nearly two-fold increased contralateral breast cancer risk (RR 1.8, 95% CI 1.3-2.4), compared to individuals without a family history. This risk is similar to that shown in previous studies [49,50]. In this non-mutation carrier group, a 1st degree family history of bilateral breast cancer increased the contralateral breast cancer risk by more than three-fold (RR 3.4, 95% CI 1.5-7.4). Where there is only an affected 2nd degree relative, the individual is at a 40% increased risk compared to an individual without a family history. The 10-year absolute contralateral breast cancer risk in non-mutation carriers with a 1st or 2nd degree family history is 8.3% (95% CI 5.5-12.6) and 6.6% (95% CI 4.4-10) respectively [46].  In a retrospective study of 6230 women from high risk families, with or without a known BRCA1/2 mutation, Rhiem observed a cumulative contralateral breast cancer risk, 25 years after a first breast cancer diagnosis of 44.1% (95% CI 37.6-50.6) in BRCA1 positive families, 33.5% (95% CI 22.4-44.7) in BRCA2 positive families and 17.2% (95% CI 14.5-19.9) in BRCA1/2 negative families [56]. This effect was previously demonstrated in smaller cohort studies linking a higher contralateral breast cancer risk with a family history with and without a young age of first breast cancer diagnosis [51,53].
The age at which the affected relative is diagnosed with their first breast cancer and the presence of bilateral disease impacts on contralateral breast cancer risk. Rhiem further observes that patients diagnosed with breast cancer at age <40 years had a cumulative risk 25 years from primary diagnosis of 55.1% and 38.4% for BRCA1 and BRCA2-positive family history, respectively. The corresponding risk was 28.4% in patients from non-BRCA families [56].
The highest risk lies with women who have relatives with early-onset, bilateral breast cancer [52][53][54]57]. The 10-year absolute risk in individuals whose 1st degree relative received a unilateral breast cancer diagnosis at a young age (<40 years) is similar to that of an individual with a 1st degree relative diagnosed with bilateral breast cancer (13.5% and 14.1% respectively). When there was a combination of a family history of a 1st degree relative, an affected relative with bilateral breast cancer or at a young age (<40 years), the 10-year contralateral breast cancer risk increased significantly to 36% [46]. A similar cumulative risk of contralateral breast cancer by the age of 80 (32%, 95% CI 13-66) was observed in a study of 78,775 breast cancer patients, with a maternal history of bilateral breast cancer [53].

Contralateral Prophylactic Mastectomy and Risk of Contralateral Breast Cancer
Contralateral prophylactic mastectomy may reduce the risk of contralateral breast cancer in women with an elevated genetic or familial risk [21]. This meta-analysis demonstrated a risk reduction in women with BRCA-positive families (HR 0.03; p = 0.0005). However, only 4% (19/430) of the cohort were non-carriers, with the remaining 96% representing mutation carriers. Fayanju reported a significant reduction in pooled relative (RR 0.04, 95% CI 0.02-0.09) and absolute risk (−24%, 95% CI (−35)-(−12.4)) of metachronous contralateral breast cancer amongst recipients of contralateral prophylactic mastectomy [58]. This analysis included studies with a significant proportion of BRCA carriers which may lead to an overestimation of risk. A case-control study of women with stage I/II breast cancer and a positive family history reported a 95% decreased risk (HR 0.05, 95% CI 0.01-0.19; p < 0.0001) of contralateral breast cancer following contralateral prophylactic mastectomy, at a median follow-up of 17.3 years, compared to a matched cohort of women who did not receive mastectomy. However, this cohort, with either an affected 1st or 2nd degree relative was not screened for mutation status [55].
McDonnell also demonstrated a contralateral breast cancer risk reduction following contralateral prophylactic mastectomy in pre-and postmenopausal women with a strong family history of breast/ovarian cancer i.e., 94.4% (95% CI 87.7-97.9) and 96% (95% CI 85.6-99.5) respectively, at a median follow up of 10 years using the Anderson model [59] to predict the risk [60]. Although the cohort had a strong family history, the patients had not been screened for mutations. Similar to studies with undefined gene carriers within the study population, this data should be interpreted with caution as the effect from contralateral prophylactic mastectomy may be overestimated from competing risks conferred by mutation carriers.

Contralateral Prophylactic Mastectomy and Survival
The evidence on the effect of contralateral prophylactic mastectomy on disease-free and overall survival is conflicting (Table 4).
A Cochrane review of 1708 women with variable familial risk, who underwent contralateral prophylactic mastectomy, concluded that although this decreased the incidence of contralateral breast cancer, there was no association with survival improvement [61]. The meta-analysis conducted by Fayanju demonstrated no association with breast-cancer-specific and overall survival, despite a reduction in the risk of distant metastases or recurrence [58]. The lack of survival benefit from contralateral prophylactic mastectomy in breast cancer patients with elevated familial risk is also reported in smaller, retrospective cohort studies [27,62,63] but with notable exceptions. Boughey reported improved overall (HR 0.77, 95% CI 0.60-0.98; p = 0.03) and disease-free survival (HR 0.67, 95% CI 0.54-0.84) on multivariate analysis [55]. In a review of 908 patients receiving against 46,368 not receiving contralateral prophylactic mastectomy, Herrinton demonstrated that mastectomy reduced breast cancer mortality (HR 0.57, 95% CI 0.45-0.72) and overall mortality (HR 0.6, 95% CI 0.5-0.72) across all levels of familial risk [64]. Furthermore, Davies demonstrated that young women (<40 years) with unilateral, stage I disease and a 1st degree relative with bilateral breast cancer, were the only group to have a quality-adjusted life year benefit from contralateral prophylactic mastectomy, which was similar to that of a BRCA1/2 carrier [63].

Young Women with Breast Cancer and Contralateral Breast Cancer Risk
The definition of 'young' age group in the literature, varies from the "under-35"-to 50 years. Young age at first primary breast cancer diagnosis is associated with an increased contralateral breast cancer risk, poor prognosis and serves as an independent predictor of recurrence and breast-cancer-related death [66][67][68][69][70][71] (Table 5). Older studies did not account for BRCA mutation carriers, which may confound contralateral breast cancer risk and survival. Furthermore, they do not consider risk-reducing adjuvant therapies. In a retrospective study of 652 patients ≤35 years compared to 2608 women >35 years, the relative risk of contralateral breast cancer was 2.48 in the younger, compared to the older group [70]. This finding is supported by Li, who demonstrated an increased HR of 2.8 (95% CI 1.1-6.9), 2.1 (95% CI 1.1-4.4) and 1.9 (95% CI 1.1-3.5) in the ≤29 years, 30-34 years and 35-39 years age groups, compared to women diagnosed at age ≥40 [67]. The contralateral breast cancer risk is further elevated in HER2-overexpressing and triple negative subtypes [70].

Contralateral Prophylactic Mastectomy and Risk of Contralateral Breast Cancer
The younger age group is generally underrepresented in studies evaluating the role of contralateral prophylactic mastectomy. Using a Surveillance, Epidemiology, End Results database analysis of 107,106 women, of whom 8902 (8.3%) underwent contralateral prophylactic mastectomy, Bedrosian conducted a subgroup analysis of young women (<50 years) and the risk of contralateral breast cancer after contralateral prophylactic mastectomy, in both ER-negative and ER-positive, early-stage breast cancer. In ER-positive disease, the cumulative incidence of contralateral breast cancer during the 6-year study period was 0.13% vs. 0.46% (p = 0.07) in the contralateral prophylactic mastectomy vs. non-mastectomy group, and in ER-negative disease, 0.16% vs. 0.90% (p = 0.05) respectively [74]. These results should be interpreted with caution though as the study population was not screened for genetic carriers and also patients with a strong family history were not excluded.

Contralateral Prophylactic Mastectomy and Survival
There is conflicting data on the impact of contralateral prophylactic mastectomy on survival in this patient group. In a population-based study of 614 women <35 years, 81 (13.2%) of whom were elected for contralateral prophylactic mastectomy, Bouchard-Fortier demonstrated that recurrences, defined as local, regional or distant, were significantly fewer for patients with contralateral prophylactic mastectomy than without (32.1% vs. 52.9%, p < 0.001; HR 0.61; p = 0.02). However, this did not translate to an improvement in breast cancer-specific survival [75].
In an analysis of the National Cancer Database between 2004 and 2014, Lazow demonstrated that after controlling for patient demographics, tumor grade and use of adjuvant therapies, bilateral mastectomy in women < 40 years was associated with increased 10-year overall survival (HR 0.75, 95% CI 0.59-0.96; p = 0.023), compared to the unilateral mastectomy group [76]. This trend was also observed in a preceding National Cancer Database review from 1998-2002, demonstrating a 5-year overall survival benefit of 2% in young patients (adjusted HR 0.88, 95% CI 0.83-0.93; p < 0.001) between these two groups [78]. In a retrospective study of 42/481 (8.73%) young women <40 years, who were elected for contralateral prophylactic mastectomy, Zeicher reported that this was associated with improved 10-year overall survival (HR 2.35, 95% CI 1.02-5.41; p = 0.046), although this effect was not demonstrable for 5-year overall survival [71].
There is a suggestion that contralateral prophylactic mastectomy may confer benefit in young women with early-stage, ER-negative breast cancer. In a population-based study of 107,106 breast cancer patients, 3731 (3.48%) of whom were young (18-49 years), contralateral prophylactic mastectomy was associated with improved disease-specific mortality (HR 0.68, 95% CI 0.53-0.88; p = 0.004). This effect was not reproduced in young women with early-stage, ER-positive breast cancer [74].
Other retrospective cohort or population-based studies refute the survival benefit of contralateral prophylactic mastectomy in young women [72,73,75,77]. In a review of 9044 young women (<40 years) with breast cancer, Chen demonstrated no improvement in overall or breast cancer-specific survival [2]. This was supported in a retrospective study of 10,226 patients with invasive lobular carcinoma, demonstrating no overall survival benefit from contralateral prophylactic mastectomy in the 18-50 years group, at a median follow up of 6.9 years [72]. Moreover, in a review of 14,627 women and at median follow-up of 6.1 years, having matched for tumour size/grade, ER status and nodal status, Pesce demonstrated that contralateral prophylactic mastectomy offered no overall survival benefit, in women aged <45 years, with stage I/II breast cancer (HR 0.93, p = 0.39) [73].
Overall, these findings should be interpreted with caution as the quality of the data does not allow for definitive conclusions to be drawn.

Discussion
Contralateral prophylactic mastectomy is increasingly being performed despite an ambiguity of evidence to support an oncological benefit. In 2007 and 2009, two studies reported that contralateral prophylactic mastectomy rate had increased 148% and 150% among all patients diagnosed with non-invasive and invasive breast cancer respectively [79,80]. Current trends in the U.S.A show an absolute percentage increase in the range of 25% [81]. This trend is modest in European studies suggesting a difference in practice and healthcare environments [82][83][84]. Nonetheless, this increased utilization of contralateral prophylactic mastectomy is a cause of concern for clinicians because of the associated surgical risks, complications, and psychological and financial burden in the absence of robust evidence to support significant oncological benefits.
Although intuitively it is expected that contralateral prophylactic mastectomy would decrease the risk of contralateral breast cancer, the available data only support this in patients with BRCA1/2 gene mutations [14,26,27]. In women with strong family history or young age at diagnosis, the effect of contralateral prophylactic mastectomy is less well studied and the existing literature should be interpreted with caution because of the potential biases. At present, there are no models that allow for calculation of contralateral breast cancer risk in a polyfactorial model. Such a model might be useful in stratifying risk and aiding physicians to provide precise and unbiased estimation of risk, in order to offer individualized counselling to patients, inform decision-making and mitigate patient overestimation of cancer risk which may drive unnecessary surgery.
Despite the potential decrease in contralateral breast cancer, the effect of contralateral prophylactic mastectomy on oncological outcomes is debatable as studies suggest that this reduction is not translated into survival benefit. Moreover, the role of contralateral prophylactic mastectomy per se as a contributing factor for improved outcomes in women with unilateral breast cancer is difficult to accurately define, as the majority of the available data is of limited quality. Meta-analyses are only as strong as the independent studies they comprise. The majority of studies are retrospective cohorts and based on population/family studies. Therefore, the results should be interpreted with caution because of potential uncontrolled biases. The way to address these issues is with higher quality data but it is unlikely that the future will harbour randomized clinical trials investigating the impact of contralateral prophylactic mastectomy on contralateral breast cancer risk and survival due to patient preference and ethical considerations. One proposal is to set up robust prospective registries to help enhance our knowledge in the field. The majority of existing studies do not account for the significant role conferred by improved systemic therapies and its effect on contralateral breast cancer risk and improved oncological outcomes, factors that merit future research.
Recently, and in order to aid clinicians approach this controversial topic, both the American Society of Breast Surgeons and Association of Breast Surgery published consensus statements on the utilization of contralateral prophylactic mastectomy. Both were aligned on supporting its use in women with significant contralateral breast cancer risk i.e., BRCA1/2 mutations, patients with a history of mantle field radiation to the chest before age 30 years [85,86]. However, a multidisciplinary, individualised approach is required to help women in their informed decision-making process.

Conclusions
In conclusion, contralateral prophylactic mastectomy may be supported in 'high-risk' groups as evidence indicates a possible reduction in contralateral breast cancer risk and also potentially improved oncological outcomes. The evidence to demonstrate that this may confer benefit in the other risk groups or in older patients is less established. It is therefore imperative to follow a multidisciplinary, personalised approach, to educate women on the best available evidence and to support individuals in a shared-decision making process.
Funding: This research received no external funding.