Balmaña, J.

Castiglione, M.

Diez, O.

Rubio, I.

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Annals of Oncology 21 (Supplement 5): v20–v22, 2010doi:10.1093/annonc/mdq161clinical practice guidelinesBRCA in breast cancer: ESMO Clinical PracticeGuidelinesJ. Balman˜a1, O. Diez2,3, I. Rubio4 & M. Castiglione5On behalf of the ESMO Guidelines Working Group*1Department of Medical Oncology; 2Oncogenetics Laboratory, University Hospital Vall d’Hebron; 3Vall d’Hebron Institute of Oncology (VHIO); 4Breast Cancer SurgicalUnit, Breast Cancer Center, University Hospital Vall d’Hebron, Barcelona, Spain; 5RGT, University of Geneva, Geneva, Switzerlandprevalence and penetrance of BRCAmutationsFamilial susceptibility to breast cancer accounts for 25% of allbreast cancer cases. In familial breast cancer, mutations inBRCA1, BRCA2, CHEK2, TP53 and PTEN genes accountfor 5%–10% of breast and ovarian cancer cases overall.BRCA1 and BRCA2 are high-penetrance breast cancerpredisposition genes while mutations in CHEK2, ATM, BRIP1and PALB2 are rare and confer an intermediate risk of breastcancer. Association studies have further identified othercommon variants associated with low-penetrance breast cancerpredisposition. Nevertheless, >70% of the geneticpredisposition to breast cancer remains unexplained.The estimated population frequency of mutations in BRCA1/2 genes is 1/800 to 1/1000 per gene. Overall this equates to15%–20% of the excess familial risk of breast cancer. Theprevalence of BRCA1 or BRCA2 germline mutations variesconsiderably among ethnic groups and geographical areas.Population-specific mutations and recurrent mutations havebeen described among Ashkenazi Jews, in Iceland, theNetherlands, Sweden, Norway, Germany, France, Spain,Canada, and countries of eastern and southern Europe.BRCA1 and BRCA2 mutation frequencies in breast andovarian cancer patients unselected for family history or age atonset are generally low (<1%–7% for BRCA1 and 1%–3% forBRCA2). Higher prevalence is associated with a family historyof breast or ovarian cancer, young age at onset, male breastcancer or multiple tumours (bilateral breast cancer or breastand ovarian cancer in the same patient).Based on pooled data from cases unselected for familyhistory it is estimated that average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% [confidence interval(CI) 44%–78%] for breast cancer and 39% (18%–54%) forovarian cancer. The corresponding estimates for BRCA2 were45% (31%–56%) and 11% (2.4%–19%). The relative risk ofmale breast cancer is elevated for both genes, particularlyBRCA2 (6%). An elevated risk of prostate cancer has also beenshown in BRCA2 carriers, particularly in men aged <65 years.Other cancers at increased risk are pancreatic (up to 2%),stomach, and head and neck.referral for BRCA testingGenetic testing criteria may differ between countries based onmutation prevalence. Widely accepted clinical criteria forreferral include: three or more breast and/or ovarian cancercases, at least one <50 years; two breast cancer cases <40 years;male breast cancer and ovarian cancer or early onset femalebreast cancer; Ashkenazi Jew with breast cancer of <60 years,young onset bilateral breast cancer, and breast and ovariancancer in the same patient [IV, C]. In some countries, thecriterion for testing is based on an a priori 10%–20%probability of finding a mutation based on predictive modelssuch as BRCAPRO, BOADICEA or Manchester Score, whileless specific criteria include a potential benefit in the medical orsurgical management of the individual or his/her relatives.Pathological features of breast cancer such as medullarycarcinoma and triple negative phenotype (estrogen receptor,progesterone receptor and no overexpression of HER2neu). Inall cases, genetic testing should be performed in adults,usually >25 years old, after having received genetic counsellingand informed consent. Carriers should be encouraged to adviseclose family members to obtain genetic counselling.mutation detectionThe majority of clinically significant deleterious mutations areprotein-truncating mutations and a small number are missensemutations. Several mutation detection techniques are in use,but direct DNA sequencing is the gold standard. GenomicDNA, extracted from blood is used as a template and codingexons with flanking intronic sequences are analysed. Inaddition, since 2%–12% of high-risk families may harboura large genomic alteration, specific techniques to detectduplications or deletions of one or more exons such as*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.Taddei 4, CH-6962 Viganello-Lugano, Switzerland;E-mail: clinicalrecommendations@esmo.orgApproved by the ESMO Guidelines Working Group: June 2007, last update November2009. This publication supercedes the previously published version—Ann Oncol 2009;20 (Suppl 4): iv19–iv20.Conflict of interest: The authors have reported no conflicts of interest.ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.orgmultiplex ligation-dependent probe amplification (MLPA) arerecommended [III, B].risk reduction: non-surgical preventiveoptionssurveillanceSurveillance of breast cancer in BRCA carriers includes monthlyself-examinations, clinical breast examinations twice a year,yearly mammograms and magnetic resonance imaging (MRI)of breasts starting at age 25–30 [IIa, B]. There are yet no dataavailable to determine whether alternating mammogram andMRI every 6 months or having both once yearly is moreeffective at young ages, considering the high rate of intervalcancers.chemopreventionAdjuvant tamoxifen reduces the risk of contralateral breastcancer in affected BRCA mutation carriers [III, B], while thebenefit of tamoxifen for primary prevention of breast cancer inBRCA carriers has not been demonstrated [Ib, A].risk reduction: prophylactic surgicaloptionsprophylactic bilateral mastectomyIt is the most effective strategy available for risk reduction ofbreast cancer in mutation carriers [III, B], although no benefitin survival has been demonstrated and many women do notfind this strategy acceptable for cosmetic reasons. Contralateralprophylactic mastectomy is an option to consider in thoseBRCA mutation carriers with early breast cancer undergoingunilateral mastectomy [III, B].Types of prophylactic mastectomy may range from totalmastectomy to skin-sparing mastectomy, and nipple-sparingmastectomy. The different options should be discussed with thepatient and include the benefits and risks for each. Aconcurrent discussion of the benefits and risks of immediatebreast reconstruction should be approached.At this time, there is insufficient evidence to recommendroutine sentinel node biopsy for patients undergoingprophylactic mastectomy.prophylactic bilateral salpingo-oophorectomyThere is evidence that it is associated with a primary riskreduction of breast cancer in premenopausal BRCAmutation carriers (statistically significant for BRCA2), riskreduction of ipsilateral breast cancer recurrence afterbreast conserving surgery and radiotherapy, risk reduction ofovarian and gynaecological cancer, and reduction in overallmortality [III, B]. Bilateral salpingo-oophorectomy isrecommended after age 35 and when childbearing decisions arecomplete [IV, C].Short-term hormonal replacement therapy afterbilateral salpingo-oophorectomy seems not to decrease theoverall benefit of this strategy for breast cancer risk reduction[III, B].risk modifiersBRCA-associated breast cancer risk can be modified by externalfactors. Hormonal and reproductive factors such as pregnancy(number and age at first pregnancy), history of breast feedingand oral contraceptives have been associated with riskmodification in BRCA mutation carriers with contradictoryresults. Parity seems to confer protection from breast cancer inwomen with BRCA mutations as in the general population[III, B].breast cancer treatmentsurgeryBreast conserving surgery and radiotherapy in BRCA mutationcarriers who undergo prophylactic oophorectomy have beenassociated with a similar rate of ipsilateral breast recurrenceversus sporadic controls at 10 years. The risk of contralateralbreast cancer in BRCA carriers is higher versus sporadiccontrols, regardless of hormonal intervention.Decisions about the surgical treatment of breast cancer inBRCA mutation carriers should be based on the sameparameters as sporadic cancer, while considering the overallhigher risk of contralateral breast cancer, and ipsilateralrecurrence if undergoing breast conserving surgery followed byradiotherapy in those not performing oophorectomy [III, B].systemic treatmentCurrent evidence suggests that overall prognosis of breastcancer in BRCA carriers is similar to sporadic breast cancersand BRCA1/2 deficiency seems to be predictive ofchemosensitivity [III, B].An ongoing Phase II randomized clinical trial in themetastatic setting is testing the sensitivity to platinum-basedchemotherapy of BRCA tumours versus taxane-basedtreatment.PARP inhibitors are being developed as single therapeuticagents for BRCA breast and ovarian cancer patients. Thesedrugs inhibit a pathway of DNA single-strand break repair andlead to apoptosis in BRCA-deficient cancer cells, which alreadyhave a deficiency in homologous recombination repair. SeveralPhase II trials are testing the specific DNA-repair deficiency ofBRCA-associated tumours with the use of PARP inhibitors inthe metastatic setting. Two Phase II trials with the oral PARPinhibitor olaparib in advanced breast and ovarian cancerpatients with BRCA germline mutations have recently reportedan encouraging clinical efficacy at 400 mg bid continuously(response rate: 41% and 33%, and progression-free survival: 5.7and 5.8 months, respectively).Up to now there is no definitive conclusion on the bestchemotherapy regimen for BRCA breast cancer patients [III, B].Nowadays standard prognostic features should be used todecide adjuvant treatment in BRCA mutation carriers withbreast cancer.noteLevels of evidence [I–V] and grades of recommendation [A–D]as used by the American Society of Clinical Oncology are givenin square brackets. Statements without grading were consideredAnnals of Oncology clinical practice guidelinesVolume 21 | Supplement 5 | May 2010 doi:10.1093/annonc/mdq161 | v21justified standard clinical practice by the experts and the ESMOfaculty.literature1. Fackental JD, Olopade OI. Breast cancer risk associated with BRCA1 and BRCA2in diverse populations. Nat Rev Cancer 2007; 7: 937–948.2. Ford D, Easton DF, Stratton M et al. Genetic heterogeneity and penetranceanalysis of the BRCA1 and BRCA2 genes in breast cancer families. The BreastCancer Linkage Consortium. Am J Hum Genet 1998; 62: 676–689.3. Pharoah PD, Antoniou A, Easton D, Ponder B. Polygenes, risk prediction, andtargeted prevention of breast cancer. N Engl J Med 2008; 358: 2796–2803.4. Antoniou A, Pharoah PD, Narod S et al. Average risks of breast and ovariancancer associated with BRCA1 or BRCA2 mutations detected in case seriesunselected for family history: a combined analysis of 22 studies. Am J HumGenet 2003; 72: 1117–1130.5. Walsh T, Casadei S, Coats KH et al. Spectrum of mutations in BRCA1, BRCA2,CHEK2, and TP53 in families at high risk of breast cancer. JAMA 2006; 295:1379–1388.6. Kriege M, Brekelmans CT, Boetes C et al. Efficacy of MRI and mammography forbreast cancer screening in women with familial or genetic predisposition. N EnglJ Med 2004; 351: 427–437.7. Gronwald J, Tung N, Foulkes WD et al. Tamoxifen and contralateral breastcancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer 2006; 118:2281–2284.8. Meijers-Heijboer H, van Geel B, van Putten WL et al. Breast cancer afterprophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.N Engl J Med 2001; 345: 159–164.9. Gerber B, Krause A, Dieterich M et al. The oncologic safety of skin sparingmastectomy with conservation of the nipple-areola complex and autologousreconstruction: an extended follow-up study. Ann Surg 2009; 249:461–468.10. Boughey JC, Khakpour N, Meric-Bernstam F et al. Selective use of sentinellymph node surgery during prophylactic mastectomy. Cancer 2006; 107:1440–1447.11. Pierce LJ, Levin AM, Rebbeck TR et al. Ten-year multi-institutional results ofbreast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/IIbreast cancer. J Clin Oncol 2006; 24: 2437–2443.12. Andrieu N, Goldgar D, Easton D et al. Pregnancies, breast-feeding, and breastcancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS). J NatlCancer Inst 2006; 98: 535–544.13. Domcheck SM, Friebel TM, Neuhausen SL et al. Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohortstudy. Lancet Oncol 2006; 7: 223–229.14. Kauff N, Domcheck SM, Friebel TM et al. Risk reducing salpingo-oophorectomyfor the prevention of BRCA1- and BRCA2-associated breast and gynaecologiccancer: a multicenter, prospective study. J Clin Oncol 2008; 26: 1331–1337.15. Domcheck SM, Weber BL. Clinical management of BRCA1 and BRCA2 mutationcarriers. Oncogene 2006; 25: 5825–5831.16. Robson M, Offit K. Management of an inherited predisposition to breast cancer.N Engl J Med 2007; 357: 154–162.17. Rottenberg S, Jaspers JE, Kersbergen A et al. High sensitivity of BRCA1-deficientmammary tumors to the PARP inhibitor AZD2281 alone and in combination withplatinum drugs. Proc Natl Acad Sci USA 2008; 105: 17079–17084.18. Drew Y, Calvert H. The potential of PARP inhibitors in genetic breast and ovariancancers. Ann N Y Acad Sci 2008; 1138: 136–145.clinical practice guidelines Annals of Oncologyv22 | Balman˜a et al. Volume 21 | Supplement 5 | May 2010

BRCA in breast cancer: ESMO Clinical Practice Guidelines

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