Managing the contralateral breast in a gene mutation carrier with breast cancer.
A major risk factor for breast cancer is a personal history of the disease, which is more important than female sex, age or family history. The risk for development of contralateral breast cancer is approximately 0.5-0.75% per year and the risk of dying from a contralateral lesion is about 0.2% per year . Between 4% and 15% of patients who survive breast cancer will develop cancer in the opposite breast . Patients who undergo breast-conservation surgery have a risk of de novo cancer in both the contralateral and the remaining ipsilateral breast tissue. In this case, a true ipsilateral breast tumour recurrence must be distinguished from a new cancer. There is no evidence that scatter from external beam radiotherapy (5-10% of total dosage) significantly increases the chance of malignant change in the remaining breast tissue. Systemic adjuvant chemohormonal therapies reduce ipsilateral breast tumour recurrence by approximately one-third [3-5] and hormonal therapies such as tamoxifen and aromatase inhibitors can decrease the risk of contralateral disease by more than 50% [6,7]. More women are now being successfully treated for breast cancer at an earlier stage of disease. For younger women who do not die from non-breast cancer-related causes, survival is sufficiently prolonged to allow manifestation of a second, contralateral malignancy. For those patients diagnosed with breast cancer under the age of 50 years, the risk of contralateral breast cancer is 10-14-fold higher than for the general population. It has been estimated that fewer than 5% of women will have developed a contralateral breast cancer at 4 years and only 7% at 10 years .
Popularity of contralateral prophylactic mastectomy
Patients with a known BRCA1 mutation have at least a 60% risk of a contralateral breast cancer, and bilateral mastectomy is usually recommended for this group of patients if breast cancer develops prior to any ipsilateral prophylactic procedure . Over the past decade there has been a dramatic increase in rates of contralateral prophylactic mastectomy (CPM) among women treated for unilateral breast cancer. This has coincided with increased rates of bilateral prophylactic mastectomy (BPM) for genetic predisposition.
Prophylactic, or risk-reducing surgery is increasingly carried out in conjunction with immediate breast reconstruction and both these upward trends may be partly related to improved methods of, and cosmetic outcomes for, reconstructive surgery. Tuttle and colleagues recently reported an increase of 150% in rates of CPM in the USA between 1998 and 2003 . They used the Surveillance, Epidemiology and End Results database to identify more than 150,000 women with unilateral stage I, II or III breast cancer. Among those women undergoing mastectomy for treatment of unilateral breast cancer, the rate of simultaneous CPM increased from 4.2% in 1998 to 11.0% in 2003 irrespective of stage of disease. It is estimated that current rates of CPM (including delayed procedures) exceed 10,000 cases per annum within the USA. Reasons for this significant increase in choice of CPM are not clear, but are more pronounced among younger, non-Hispanic white women with a previous history of breast cancer .
Efficacy of CPM
Some women will opt for a CPM on the basis of a confirmed diagnosis of breast cancer in the absence of any strong family history or genetic predisposition. This is a personal choice. None the less, it is important to emphasise to patients that a contralateral procedure will not necessarily prolong life, but will reduce the chance of a further breast cancer developing. There is no conclusive evidence at the present time for any mortality reduction as a result of CPM in patients who have had cancer in one breast . The fate of this group of patients is determined by the index tumour and second contralateral cancers are usually of a more favourable prognosis and probably contribute to only about 5% of breast cancer mortality . This is partly related to detection at an earlier stage from routine follow-up surveillance. However, with heightened public awareness and breast screening programmes, patients are presenting with smaller cancers and at an earlier stage. Consequently, any prognostic advantage of contralateral cancers may be eroded in the future and these second cancers in the opposite breast could become more important in terms of overall patient mortality. This would strengthen any argument for a CPM in patients with an early stage breast cancer as it might confer an overall survival benefit for an individual patient and not just avoid further cancer treatment. Herrington and colleagues found evidence that CPM not only protected against development of contralateral breast cancer [hazard ratio (HR) 0.03; 95% confidence interval (CI) 0.006-0.13], but was associated with a cause-specific mortality reduction (HR 0.57; 95% CI 0.45-0.72) . However, all-cause mortality was relatively low and this was a retrospective cohort study (albeit involving 50,000 patients).
A systematic review of five retrospective cohort studies involving patients with a previous diagnosis of breast cancer who elected to undergo CPM evaluated intrinsic methodological biases of selection, performance, detection or attrition . None of these five studies specifically investigated subgroups of patients with a strong family history of breast cancer or BRCA1/2 mutation. There was general consensus that all studies found a significant reduction of breast cancer incidence following CPM, but results for mortality reduction were inconsistent [15-18]. One study suggested a trend towards improved disease-free survival at 15 years for stage 0, I and II breast cancer when the comparison group was adjusted for potentially confounding factors (P=0.06) . Another study reported a statistically significant survival advantage after a similar time period for patients receiving CPM . However, the majority of studies revealed no statistically convincing effects on survival outcomes and the reviewers concluded that there was insufficient evidence to support any reduction in mortality as a result of CPM . No randomised prospective data are available to address this issue and ethical considerations would preclude any such trial design.
Selection of patients for contralateral surgery
It has been suggested that current practices and recommendations relating to CPM should be 'rationally guided by genetic testing' . A diagnosis of unilateral breast cancer in the context of a documented mutation in a major breast cancer susceptibility gene provides a strong and objective argument in favour of CPM. None the less, other compelling reasons for seeking this procedure exist, and these must be judged carefully by clinicians as part of a shared decision-making process. Conversely, a recommendation for CPM is not mandatory for all patients with a genetic predisposition, some of whom can be managed with close monitoring and surveillance .
Many patients request CPM because they do not wish to endure further treatments for any new breast cancer. Such concerns often relate to chemotherapy rather than surgery per se, and of course a prophylactic mastectomy is relatively aggressive surgery. An adverse reaction to a particular chemotherapy regimen can have a profound influence on the prospect of a new tumour in the future and the desire to avoid treatment-related morbidity. Some patients with large breasts feel very lopsided after a unilateral mastectomy for cancer and seek to be flat chested. Occasionally, a single remaining heavy breast can create postural imbalance and lead to back problems. In addition a large remaining contralateral breast may preclude symmetric breast reconstruction and CPM with formal reconstruction may yield superior results to a contralateral reductional procedure .
CPM may be requested because of a fear of further cancer and patients may seek to minimise the chance of any recurrence or a second malignancy. It may be impossible to reassure patients that long-term survival is unlikely to be compromised in the event of a contralateral cancer. Younger women may have florid fibrocystic changes that make clinical examination/ breast self-awareness challenging and radiology difficult to interpret. Similarly, increased density of breast tissue renders mammographic surveillance within this group of women less accurate . Although magnetic resonance imaging (MRI) has much greater sensitivity than mammography for detecting cancer in younger women with denser breast tissue, there is no evidence for any reduction in mortality from any form of enhanced radiological surveillance of high-risk women . MRI screening has a lower specificity and 10-fold higher costs compared with mammography . Use of MRI as a screening tool increases sensitivity rates for detection of cancer among younger women , but yet may fail to provide reassurance that the opposite breast is tumour free. There is no longer any role for random contralateral biopsies , but improved percutaneous biopsy techniques for MRI-detected lesions will aid confirmation that a lesion is benign and avoid open diagnostic biopsy. However, increases in rates of CPM in recent years may reflect more widespread use of breast MRI and false-positive results associated with this.
Although CPM may be demanded by a patient through personal choice and in accordance with the principle of autonomy, there are also situations where CPM may be recommended on clinical grounds  (see Panel 1).
Genetics of breast cancer
Although many individuals may have a relative with breast cancer, only a minority (5-10%) have an autosomally dominant pattern of inheritance consistent with vertical transmission of a high-risk genetic predisposition from one generation to another. The level of genetic risk and probability of carriage of a mutation in a recognised gene is determined by an individual's family cancer history. The normal cumulative lifetime risk for breast cancer is approximately 10% (1 in 10 women affected). A method termed linkage analysis was previously used to calculate lifetime risk for development of breast cancer based on information from family cancer history such as number of affected first--and second-degree relatives with breast/ovarian cancer, age of onset and bilaterality of breast cancer. Many individuals have at least one relative with breast cancer, but their lifetime risk for development of breast cancer rarely exceeds 30%.
By contrast, the estimated lifetime risk for others is of the order 80-90% and they are almost certain to suffer the disease assuming they live for a reasonable period of time and do not succumb to any other cause of death. This hereditary predisposition occurs in a minority of breast cancer cases (5-10%) and is conferred by cancer susceptibility genes that conform to Knudson's model or 'two-hit hypothesis' [26,27]. The breast cancer susceptibility genes BRCA1 and BRCA2 are tumour suppressor genes that are located on chromosomes 17q21 and 13q12, respectively, and display an autosomal dominant pattern of inheritance with variable penetrance [28,29]. Mutations within these two genes account for approximately three-quarters of hereditary breast cancer cases and are associated with a lifetime risk of between 80% and 85% by the age of 70 years (i.e. a 10-fold increase compared with baseline lifetime risk of 7-8%). BRCA1 and BRCA2 are recessive and both copies of an allele must be lost or mutated for cancer progression. Individuals with a germline mutation in these genes have a dominantly inherited susceptibility and the second 'hit' occurs in the somatic copy. Tumours from genetically predisposed patients show loss of heterozygosity in the wild-type BRCA1 allele but mutations of BRCA1 and BRCA2 are uncommon in sporadic breast cancers [30,31].
Mutations in these two particular breast cancer genes are implicated in about half of all hereditary breast cancer. The majority of family clusters are not attributable to any of these high-risk susceptibility genes and attention has recently turned to 'low-risk' genes such as FGFR2 and TNCR9, which may collectively be responsible for up to 25% of familial breast cancer .
An essential prerequisite for prophylactic surgery is the existence of a reliable genetic test to identify those individuals with a mutated allele. Genetic testing represents a great advance in provision of accurate risk quantification. Once a mutation has been identified for a particular family, those members who test negative have no more increased risk of developing breast cancer than an age-matched individual from the general population (no specific surveillance or treatment is indicated). By contrast, a family member with a documented mutation has a very high chance of developing the disease without some form of intervention. Herein lies a potential dilemma; when women consent to genetic testing, they must be counselled appropriately and be able to cope with the information gained from the test--whatever the result . Most women overestimate their risk and genetic testing allows accurate risk assessment that more confidently informs any proposed management decisions .
Bilateral prophylactic mastectomy
Bilateral prophylactic surgery reduces the expected risk of breast cancer by about 90%. In a retrospective study of more than 600 women at moderate to high risk who had undergone BPM, the incidence of breast cancer was reduced by 89.5% (P<0.001) . An established Gail model for risk estimation was used to predict the number of breast cancer cases expected in these two groups without surgical intervention. This study, together with several smaller studies, has validated BPM as a management option for women at significantly increased risk for development of breast cancer. It is interesting that although rates of BPM have increased in recent years, most women do not opt for prophylactic mastectomy even when high-quality immediate breast reconstruction is available. There can be profound psychological sequelae from this radical form of intervention, and studies have shown that 3-6% of women do regret their decision to choose a surgical option for risk reduction . Regret is more likely when women have been 'talked into' the operation. Health professionals should inform rather than 'sell' this option; there is a difference between offering and recommending BPM and the final decision must be left to the patient . Women should be allowed plenty of time to reach a final decision and must fully understand the risks, benefits and limitations of BPM, which should probably not be undertaken under the age of about 25 years. Conversely, the older a women is when she has prophylactic surgery, the smaller are the absolute benefits because of a corresponding reduction in the remaining estimated lifetime risk . The mean age of patients in most studies of BPM is 42 years, and there is minimal benefit from carrying out this procedure over the age of 60 years. The gains in life expectancy with BPM are typically between 3 and 5 years and may be a matter of months for older patients. Patients with a BRCA2 gene mutation who have a 70-80% lifetime risk of developing breast cancer would reduce their absolute risk of death from breast cancer by only 2.5% . Moreover, it should be remembered that survival rates from breast cancer have greatly improved and these patients are likely to have a screen-detected lesion or at least a small palpable tumour.
CPM in mutation carriers
Several of the issues relating to BPM are pertinent to CPM in patients with a proven BRCA1 or BRCA2 mutation. It is clear that this group has an elevated risk of developing breast cancer due to an inherent genetic predisposition present within all cells of the contralateral breast tissue. If a BRCA1 or BRCA2 mutation carrier without any personal history of breast cancer is considered eligible for BPM, then a CPM in the same individual with a breast cancer must be easier to justify on statistical probability for breast cancer development. A BPM is protective for women at increased risk of breast cancer on the basis of family history or known BRCA1 or BRCA2 mutations and is associated with risk reductions of 85-100% [38,39]. Breast-conserving surgery with radiotherapy has been found to be relatively safe (in terms of radiation toxicity and radiation-induced second cancers) and associated with acceptable rates of ipsilateral breast tumour recurrence in this subgroup of mutation carriers. None the less, rates of new contralateral breast cancers are 4-5-fold higher compared with sporadic cases [40-42]. Most of these women do not undergo a CPM and therefore there is a paradoxical situation of surgical procedures for prevention becoming more radical than for treatment of established disease.
Few data are available that specifically address the efficacy of CPM in BRCA1 and BRCA2 mutation carriers, either in terms of risk reduction or improved survival. Van Sprundel and colleagues  examined the incidence of invasive contralateral breast cancer among a group of 148 women who were mutation carriers for BRCA1 and BRCA2 and had received treatment for unilateral invasive breast cancer (stages I-IIIa). Just over half of these women (n=79) underwent CPM whereas the others remained under intensive surveillance. At a median follow-up of 3.5 years, one patient had developed an invasive contralateral cancer in the CPM group, whereas six were observed in the surveillance group (P<0.001) . Therefore CPM reduced the risk of contralateral breast cancer by more than 90%, which is of similar magnitude to the risk reduction associated with BPM reported above. It is interesting that some of these patients underwent bilateral prophylactic oophorectomy (BPO) and multivariate Cox analysis suggested that this led to a significant benefit in overall survival at 5 years. There was no impact of CPM on breast cancer-specific survival with this limited period of follow-up, which is in accord with the conclusions of the Cochrane review by Lostumbo and colleagues .
There would appear to be a compelling argument for recommending (not just offering) CPM in patients with proven hereditary predisposition and/or a strong family history of breast cancer combined with a diagnosis of unilateral breast cancer [19,20]. Additional factors such as dense breast parenchyma and/or florid benign changes would further support prophylactic surgery.
Prophylactic surgery cannot remove all breast tissue and up to 15% may remain when the nipple-areolar complex is preserved (subcutaneous mastectomy) . With the advent of skin-sparing mastectomy, it is possible to remove all breast tissue while preserving most of the skin envelope of the breast and maximising cosmetic results . When patients elect to undergo either BPM or CPM to reduce breast cancer risk, skin-sparing mastectomy is the procedure of choice. This involves removal of the nipple-areolar complex through a circumareolar incision; access to the axilla is not required for prophylactic mastectomy and therefore no 'tennis racket' extension or counter-incision in the axilla is required. When the skin envelope must be reduced to achieve a smaller overall breast size (patient choice or need for symmetry), then either a Wise pattern or Lejour incision can be employed (Figure 1) .
[FIGURE 1 OMITTED]
Areolar preservation can be considered in the context of prophylactic surgery for those patients with a relatively large-diameter areola. Cosmetic outcome may be greatly improved by areola (but not nipple) preservation and pathological analysis of resected breast tissue confirms infrequent malignant infiltration of the areola (0.9%) compared with 6.7% for nipple involvement . When immediate reconstruction is not contemplated, a total mastectomy is an acceptable option.
Alternative management strategies
By analogy with patients harbouring BRCA1 and BRCA2 gene mutations who elect not to undergo BPM, not all patients with these mutations opt for contralateral mastectomy when ipsilateral mastectomy is indicated for breast cancer. There are issues of regret pertaining to CPM as for BPM; among a group of 296 respondents who were questioned following CPM, 18 (6%) expressed regrets about their decision to undergo CPM . This is a similar level of dissatisfaction as documented for BPM, although it is interesting that regrets were less frequent when discussion of CPM had been initiated by the surgeon rather than the patient. None the less, most patients must be well motivated and provided with sufficient factual material to make an informed decision. Montgomery and colleagues  also reported a degree of dissatisfaction with the cosmetic results of reconstruction among 18 out 111 (16%) patients who had undergone CPM. Levels of regret were lower among the group of women who opted not to have breast reconstruction, suggesting that issues of body image as well as fear of cancer are important factors for patients considering CPM. Although genetic testing permits objective assessment of risk, estimates of risk reduction in published studies are liable to innate biases (cancer-inducing testing bias; familial event bias) and confounding by indication . These methodological problems associated with evaluation of efficacy of prophylactic breast surgery should be factored into the decision-making process. Patients may be dissuaded from seeking prophylactic surgery when there are alternative options such as MRI surveillance and novel chemopreventive agents (though perhaps such considerations are less likely to influence decisions on CPM).
Surveillance and close monitoring of patients
It is reasonable to consider surveillance and close clinical monitoring in the following circumstances:
* Older patients (> 60 years) who have fewer years remaining at risk;
* More advanced disease which determines prognosis (and not to any contralateral tumour);
* Patients with soft, non-lumpy breasts and no extensive fibrocystic changes;
* Radiolucent breasts that are relatively easy to image and interpret;
* Patients who are not unduly concerned about issues of asymmetry and breast reconstruction.
Patients should undergo regular clinical examination and mammography at a frequency determined by local practice guidelines (usually annual mammogram).
Bilateral prophylactic oophorectomy
BPO not only reduces the risk of ovarian cancer by removal of ovarian tissue, but significantly affects the subsequent risk of breast cancer--irrespective of any genetic predisposition to the disease. Indeed, iatrogenic BPO in women under the age of 40 years reduces breast cancer risk by approximately two-thirds. Studies have shown that among women who carry mutations of BRCA1 and BRCA2, BPO reduces breast cancer risk by between 50% and 75% [49,50]. Therefore BPO can potentially reduce the incidence of both breast and ovarian cancer and this should be discussed with those women with a hereditary predisposition. Studies suggest that BPO is more 'acceptable' as a risk-reducing strategy than BPM and is chosen by more than 85% of heterozygotes for BRCA1 and BRCA2. BPO can be incorporated into a risk-reducing strategy as an alternative to CPM and will not only reduce the risk of contralateral breast cancer, but also can improve overall survival .
Chemoprevention with agents such as tamoxifen and raloxifene can reduce the incidence of breast cancer by up to 50%, but has no effect on survival from all causes of death [51-54]. All chemopreventive agents have potential side effects and it should be remembered that these agents are administered to otherwise healthy women. The risk elevation for entry into chemoprevention trials is a projected risk of 1.66% at 5 years . The absolute benefit for an individual woman must be quantified and balanced against risks of endometrial cancer or thromboembolism; and for aromatase inhibitors, prolonged oestrogen deprivation, which can impact on bone health and cognitive function, must also be considered [56,57].
Rates of CPM have more than doubled in recent years despite absence of robust data indicating any reduction in the chance of death from breast cancer. A contralateral procedure reduces the risk of developing disease in the opposite breast by more than 90% irrespective of any genetic predisposition. Management of women with BRCA1 and BRCA2 gene mutations remains controversial and the issues involved are complex; options include BPM, chemoprevention, surveillance and BPO, which is the only intervention shown to yield any survival benefit .
For women with a unilateral breast cancer of favourable prognosis combined with mutation carriage, there is a strong argument for CPM. Although a known gene mutation can 'rationally' guide management, other non-genetic factors influence the decision-making process and may act for or against CPM. With a continuing stage shift and smaller tumours at presentation, CPM may confer overall survival gains when the risk of systemic relapse from ipsilateral cancer is minimal. In the future, molecular profiling will help assess recurrence risk and such information must be integrated into models to aid decision-making for both patients and clinicians.
Panel 1: Reasons for recommending CPM
* Moderately strong family history of breast cancer
* The presence of extensive lobular carcinoma in situ in association with a lobular phenotype in the ipsilateral breast cancer (higher chance of bilaterality)
* Dense nodular breast parenchyma or a mammographically occult index lesion--this limits the sensitivity of clinical and radiological surveillance
* Patients who have received mantle irradiation for Hodgkin's disease are at high risk for bilateral breast cancers and a CPM should be considered when a unilateral tumour develops in this group of patients
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John R Benson
Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge, UK
Correspondence to: John Benson, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK (email: email@example.com)
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|Title Annotation:||Feature Article|
|Author:||Benson, John R.|
|Publication:||Advances in Breast Cancer|
|Date:||Mar 1, 2009|
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