The Breast (2000) 9, 301–305

# 2000 Harcourt Publishers Ltd

doi: 10.1054/brst.2000.0143, available online at http://www.idealibrary.com on

REVIEW ARTICLE

Management of the contralateral breast in patients with hereditary breast cancer

D. M. Eccles1 and D. Gareth Evans2

1Wessex Clinical Genetics Service, Princess Ann Hospital Level G, Coxford Road, Southampton SO16 5YA,UK; 2University Department of Medical Genetics and Regional Genetics Service, St Mary’s Hospital,Hathersage Road, Manchester M13 0JH, UK

SUMMARY . Approximately 5% of all breast cancers arise on a background of one of the high-risk breast cancergenes (hereditary breast cancer and hereditary breast and ovarian cancer). An estimated 20% of cases arise in thepresence of a less striking family history with later average age at onset and lower penetrance, familial breast cancer.For hereditary breast cancer, bilaterality is a recognized feature. Cancers often present at an early age with thecontralateral risk high. This article explores the current state of knowledge regarding management options for womenwith hereditary breast cancer. # 2000 Harcourt Publishers Ltd

BREAST CANCER GENETICS

A number of genes have been identified in the last 10years which, when inherited in a mutant form, confer ahigh risk of early onset breast cancer and often aspectrum of other cancers. These genes are relativelyuncommon (together estimated to occur in about 1 in300 individuals)1–3 in the general population and ac-count for about 5% of all breast cancers. The propor-tion of young breast cancers accounted for by these highrisk genes is, however, considerably higher.4–6 Inaddition to these high risk susceptibility genes thereare also likely to be a number of lower penetrance morecommonly occurring genetic polymorphisms whichincrease breast cancer risk and which are likely tointeract significantly with epidemiological risk factors.7

Not many such genes have been identified as yet. Inbroad terms we will refer to this ‘weaker’ geneticsusceptibility as familial breast cancer.

THE BRCA GENES

BRCA1 was mapped to chromosome 17q in 19908 andthe genetic sequence was finally published in 19949 along

Address correspondence to: D. M. Eccles, Wessex Clinical GeneticsService, Princess Ann Hospital Level G, Coxford Road, SouthamptonSO16 5YA, UK. Tel.: +44 1703 798537; Fax: +44 1703 794346;E-mail: del@soton.ac.uk

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with reports of the location of a second majorsusceptibility gene BRCA2.10 The sequence of BRCA2was published in 1995.11 These genes are both large andmutation analysis is expensive and time consuming.However, in families with a high chance of a geneticpredisposition genetic testing is offered in most UKRegional Genetics Centres. Thus an increasing numberof young women with a strong family history of breastand ovarian cancer may have the opportunity ofundergoing pre-symptomatic genetic testing.

TP53 is a tumour suppressor gene which plays an inte-gral role in maintaining the integrity of DNA – it hasbeen described as the ‘guardian of the genome’.12

Mutations in the TP53 gene are extremely common inall types of cancer however inherited mutations are rare.The Li Fraumeni syndrome is the striking pattern ofchildhood malignancy(typically soft tissue and osteo-sarcomas, gliomas or adrenocortical carcinoma) andvery early onset breast cancer (50% of female genecarriers have developed breast cancer by 30 years of age)which results from inherited TP53 muta-tions.13 There isgood in vitro evidence to suggest an abnormal responseto low dose radiation with defective apoptosis.14

Recognition of this syndrome is therefore importantnot least because it has implications for breast screeningmethods. Current practice is to avoid ionizing radiationfor screening purposes where possible.

Other recently discovered genes which confer anincrease in risk of breast cancer and are associated with

1

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bilateral benign and malignant breast disease are:Cowden’s disease(due to mutations in the PTEN gene)15

and Peutz Jehger syndrome (PJS) due to mutations inCDNK4.16 Both are rare but the diagnostic features forPJS are hamartomatous gastrointestinalpolyps andtypical skin and buccal mucosal pigmentation: fibroa-denosis and carcinoma of the breast are both increasedin frequency. Cowden’s disease is associated withmacrocephaly, benign and malignant disease of thebreasts and thyroid with hamartomas of the gut alsopresent in some patients.

For families in which BRCA1, BRCA2 or TP53mutations segregate, bilaterality is relatively commonand some use this as a criterion alone in an individualfor inferring high genetic risk. The contralateral riskcould be as high as 60% for BRCA1/2 mutationcarriers,8,17 but these estimates are based on familiesascertained for a strong likelihood of segregating ahighly penetrant dominant gene, ascertainment bias willenhance the risks estimated. Population based studies ofhigh-risk gene mutations give lower estimates for breastcancer risk (penetrance) than other methods.18 Bilateraldisease in an isolated case of later onset is much lesslikely to be an indicator of BRCA1 or 2 mutationcarriers.4,19 However, for a young onset breast cancer, inthe context of either a known or suspected geneticpredisposition,options for primary breast cancer man-agement and management of the contralateral breastmust be carefully considered and discussed with thepatient in the light of currently available information.

BREAST CANCER TREATMENT

Since the days of Halsted’s radical mastectomy, andeven forequarter amputations, breast cancer treatmenthas come along way. There are now good data to showthat treatment of early breast cancer with wide excisionfollowed up with adjuvant radiotherapy to the breast isas effective at achieving good local control and long-term survival as is simple mastectomy.20–22 The use ofother adjuvant therapies can also independently and incombination improve survival.23–25 In a modern multi-disciplinary approach to breast cancer treatment breastconservation is now an option presented to and chosenby many women with early breast cancer in preferenceto mastectomy. For women in whom mastectomy isdeemed necessary, reconstructive surgery has becomepopular, in many cases this has been traditionallyoffered a few years from diagnosis and treatment onceprognosis is easier to judge, but in recent years,combined mastectomy and reconstruction has beenincreasingly offered in many centres.26

TREATMENT OF HEREDITARY BREAST

CANCER

Once breast cancer develops in an individual, appro-priate management of that cancer is the primaryconsideration. Since many of these patients are youngand present with early cancers, breast conservation is inmany cases technically possible. Wide local excision andaxillary node dissection or sampling with adjuvantradiotherapy might be expected to produce equivalentresults to simple mastectomy if this disease is similar inall respects to sporadic breast cancer.

For hereditary breast cancer there are some interest-ing biological differences compared with apparentlysporadic cancers. Firstly, for BRCA1 there is a greaterproportion which are high grade and histologicallymedullary or atypical medullary in type.27–28 Thesetumours are also more likely to be oestrogen receptornegative29 and less likely to be in situ (and usuallycomedo or high grade when present).30 Overall survivalhas been variously reported for hereditary cancers asworse31 better32 and the same29,33 when compared withsporadic cancers. All of these features may influencebreast cancer management.

For TP53 mutation carriers, response to low doseradiation is abnormal in vitro and although there is noevidence of excessive acute toxicity from high doseradiation (radiotherapy) data are sparse as this is a rarecondition. Nonetheless, data are emerging indicating avery high risk of sarcoma in the radiation field.34

Breast conserving treatment

The question of whether breast conserving surgery isappropriate should take into account the prognosticfactors for the disease itself, the feasibility of breastconservation and the wishes of the woman being treated.Secondly, for a woman with either a proven or suspectedgenetic susceptibility the chance of ipsilateral orcontralateral new primary must be taken into account.In order to discuss this rationally some idea of the riskinvolved is required. As familial cancers are more likelyto be multifocal and bilateral the risk of a new primaryon the treated side is likely to be high without adjuvanttherapy. We have experience of one BRCA1 carrierdeveloping five primary tumours in the same breast overa 5-year period from 29 years of age. Radiotherapy maysignificantly reduce the number of viable breast epithe-lial cells primed for transformation; however, anysurviving cells could be more likely to become malignantdue to unrepaired DNA damage from radiation. Againwe have evidence for two BRCA1 mutation carriers whohave developed a new ipsilateral primary 3 and 10 years

Management of the contralateral breast 303

after irradiation. Long-term (10–20 years) follow-upshould provide answers not only to recurrence ratesafter radiotherapy but also to the risk of ipsilateral newprimary.

Following a report on the outcome of breastconservation in a small number of hereditary versussporadic early age breast cancers in an Americancohort,35 we have completed retrospective review of304 breast cancer patients. The patients were classifiedaccording to genetic status into 142 hereditary breastcancer cases (75 known gene carriers, the remainder witha significant family history in addition to the index case)and 162 sporadic controls. The hereditary and sporadicgroups were well matched for age at diagnosis,tumoursize and stage and length of follow-up. There was nodifference in overall survival and no difference in chanceof ipsilateral recurrence in the hereditary compared withthe sporadic group over a median follow-up period of 7years.36,37 Thus at present there is no clear contra-indication to breast conservation for the affected breastin the first 5 years or so from diagnosis.

Management of the contralateral breast

There are substantial data pointing to an increase in riskof bilateral breast cancer in women with a hereditarypredisposition. The overall risk to the contralateralbreast for a woman with her first primary breast cancerand a hereditary predisposition has been estimated to beas high as 60%.17The greatest chance of recurrence ofbreast cancer, either locoregional or metastatic, is in thefirst 2 years after diagnosis. In our own series thecumulative risk of contralateral breast cancer at 2 yearsfrom diagnosis was 6% for hereditary cases compared to1% in the sporadic group rising to 35% compared with7% at 10 years.35 Thus contralateral breast cancer risk ishigh and at the very least close surveillance isimperative.

Surveillance

Of course for young women with an increased geneticrisk, screening for early breast cancer is of uncertainbenefit in terms of a clear reduction in mortality38,39

although early cancers can undoubtedly be detected.40–42

Conventional mammographic screening may be lesssensitive in the younger breast38 although the positionremains unclear. There is an increase in the rate of falsepositive results in younger women undergoing regularbreast screening.43 The efficacy of other methodsincluding magnetic resonance imaging and ultrasoundscanning also at present remain unproven. Clinical

follow-up in this context is also of unproven benefit as ithas not been formally evaluated.

Hormonal therapy

Oophorectomy was one of the earliest adjuvant treat-ments for premenopausal breast cancer and is still anoption presented to patients with premenopausal ERpositive breast tumours today.25 It makes sense for abreast cancer patient with a family history of breast andovarian cancer and a proven mutation in BRCA1 orBRCA2 to consider an oophorectomy particularly foran ER positive tumour. This may not only improve herchance of disease free survival but also reduce her risk ofsubsequent ovarian cancer. A radiation induced meno-pause would be less appropriate because of the potentialrisk of future ovarian malignancy. The position for anearly onset breast cancer in the context of a familyhistory of breast only cancer and an ER negativetumour is less clear. Some of these will be due toBRCA1 gene mutations (for more than three youngbreast cancers in close relatives an estimated 21–28%)44

but the majority will be due to other genes. The later theaverage age at onset of the cancers, the less likely is thecluster to be due to a high risk dominant gene. Data arenot available to inform decisions in the less clear cutsituation and management should be based on bestpractise in terms of treating the primary cancer.

The use of tamoxifen as a primary preventive agentseems to be effective in reducing the incidence of ERpositive tumours in the short term.45 However, ERnegative tumours may be unaffected by oestrogen receptor blocking agents.46,47 Nonetheless, primary preventionof breast cancer by suppression of cell proliferation andthus accumulation of mutations remains a possibility.Although for BRCA related tumours where 50% ofgene carriers have developed breast cancer by 50 yearsof age, intervention at an earlier age than 35 years maybe necessary for any reduction in risk to ensue. Otheragents are likely to be tried as chemoprevention for thisvery high-risk group and may be best explored initiallyin trials of adjuvant therapy for primary breast cancersby observing the effect on the contralateral breast inclearly genetically defined groups. Recent evidence of aneffect of tamoxifen in improving disease free survival forpatients undergoing treatment for DCIS48 is encoura-ging but again may be less relevant for BRCA1genecarriers in particular.

Breast surgery

Scientific and media attention has recently focused onthe option of prophylactic mastectomy which is now

304 The Breast

becoming a more acceptable option in some countries(notably the UK and USA)49 but still culturallyunacceptable to most women in countries such as Italyand France.50 For the first time this year data have beenpublished which indicate a substantial reduction inbreast cancer risk from this option.51 However,operativetechniques differ widely and presumably the residualrisk will relate to a large extent to the amount of breasttissue left in situ. In addition, of course there has beencontroversy about breast implants and a possibleadverse effect on health. Mastectomy without recon-struction as a primary preventive procedure is chosenmuch less frequently in centres able to offer reconstruc-tion.52

The situation is complicated for a woman undergoingbreast cancer treatment because the prognosis of thepresenting disease has to be taken into consideration indecisions about radical treatment. This may be anargument for delaying preventive options for a year ortwo. Also the logic of conserving the affected breastwhilst removing the unaffected breast would be difficultto understand for most women. Women who are able tohave pre-symptomatic genetic testing because there is aknown BRCA1 or 2 mutation within their family, areincreasingly opting for bilateral mastectomy as preven-tion; to date 12/24 (50%) of asymptomatic gene carriersin Manchester have chosen this option. Given the needfor a fairly rapid decision as to the type of initial surgerythat is to be performed there may be case for a fast trackgenetic test for some women keen on the idea ofdetermining whether contralateral breast cancer is likelyafter diagnosis. However, in the context of a clearhereditary pattern a negative test could still be falselyreassuring. The health service may also be unlikely topay for commercial testing at $2400 per test.

CONCLUSION

Where a genetic predisposition to breast cancer isknown or suspected there is a high risk of contralateralinvasive breast cancer over time. Breast conservingtreatment appears to be as effective in gene carriers as inmatched controls but this evidence is retrospective.Bilateral mastectomy at the time of diagnosis might beviewed by some as a fairly radical measure but it is onewhich some women cogniscent of their risks andinformed about their genetic status and primaryprognosis may welcome as a treatment option. Thisoption could be presented at the time of diagnosis (andin certain circumstances should be). Many BRCA1 genecarriers will have high-grade ER negative tumours, forthese women chemotherapy is almost inevitable giving 4

to 6 months of treatment during which the surgicaloptions can be more rationally reviewed. For womenwho choose bilateral mastectomies,some may preferimmediate reconstruction if this is possible. Data aboutcontralateral breast cancer risk and ipsilateral recur-rence risks must be derived from good long-termprospective studies before risks can be further clarified.On the current imperfect data all treatment choices fornewly diagnosed primary breast cancer may still bevalid. The patient’s choice based on contemporary dataprovided by a multidisciplinary team should underpinmanagement decisions and should ensure that asatisfactory decision is reached in each individual case.

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