老年女性要不要检测乳腺癌易感基因
乳腺癌易感基因检测对于乳腺癌的预防和治疗决策至关重要。对于有乳腺癌或卵巢癌家族史、德裔犹太人血统、雌激素受体阴性等风险因素的年轻女性，乳腺癌易感基因可遗传致病变异率高达10%。不过，对于年龄65岁的老年女性，乳腺癌易感基因可遗传致病变异率尚不明确。美国国家综合癌症网络指南建议，对于年龄65岁被诊断为乳腺癌的女性，外显率较高的基因出现致病变异概率可能小于2.5%，如果没有特定风险因素，那么乳腺癌易感基因检测的临床意义不大。
年7月22日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表梅奥医学中心、希望之城国家医学中心贝克曼研究所、哈佛大学陈曾熙公共卫生学院、宾夕法尼亚大学佩雷尔曼医学院、犹他大学、安布里遗传学、罗斯威尔帕克综合癌症中心、威斯康星大学、美国癌症学会、国家环境卫生科学研究所、波士顿大学斯隆流行病学中心、西雅图华盛顿大学、夏威夷大学癌症中心、弗雷德哈钦森癌症研究中心、南加利福尼亚大学凯克医学院、威斯康星大学密尔沃基分校约瑟夫齐伯公共卫生学院、英国牛津大学的研究报告，调查了年龄65岁女性各个易感基因的致病变异率和剩余寿命乳腺癌风险。
该多中心大样本人群研究对6项前瞻队列嵌套乳腺癌病例对照研究（BWHS、CPSII、CTS、MEC、NHS、WHI）、3项病例队列研究（CPS3、MMHS、SISTER）、3项乳腺癌病例对照研究（MCBCS、WCHS、WWHS）的2万例年龄65岁女性（其中乳腺癌患者占51.5%）进行乳腺癌易感基因（ATM、BARD1、BRCA1、BRCA2、CDH1、CHEK2、NF1、PALB2、PTEN、RAD51C、RAD51D、TP53）可遗传致病变异检测。对致病变异率以及各个基因致病变异与乳腺癌的相关性进行评定，并对携带致病变异非西班牙裔白人女性的剩余寿命乳腺癌风险进行估算。
结果，年龄65岁女性易感基因致病变异率：
有乳腺癌女性：3.18%
无乳腺癌女性：1.48%
BRCA1、BRCA2、PALB2致病变异率：
雌激素受体阴性乳腺癌女性：3.42%
雌激素受体阳性乳腺癌女性：1.0%
三阴性乳腺癌女性：3.01%
无一级亲属乳腺癌家族史女性的致病变异率显著较低。
CHEK2、PALB2、BRCA2、BRCA1致病变异与否相比，乳腺癌风险高2.9～4.0倍。
BRCA1、BRCA2、PALB2、CHEK2、ATM致病变异携带者的剩余寿命乳腺癌风险分别为18.4%、18.7%、15.9%、14.9%、9.9%。
因此，该研究结果表明，对于年龄65岁伴三阴性乳腺癌或雌激素受体阴性乳腺癌的女性都应该进行基因检测，对于年龄65岁伴BRCA1、BRCA2致病变异和可能伴PALB2、CHEK2致病变异的女性应该考虑进行磁共振成像筛查。
JClinOncol.Jul22.Onlineaheadofprint.
RiskofLate-OnsetBreastCancerinGeneticallyPredisposedWomen.
BoddickerNJ,HuC,WeitzelJN,KraftP,NathansonKL,GoldgarDE,NaJ,HuangH,GnanaolivuRD,LarsonN,YussufA,YaoS,VachonCM,Trentham-DietzA,TerasL,TaylorJA,ScottCE,SandlerDP,PesaranT,PatelAV,PalmerJR,OngIM,OlsonJE,OBrienK,NeuhausenS,MartinezE,MaH,LindstromS,LeMarchandL,KooperbergC,KaramR,HunterDJ,HodgeJM,HaimanC,GaudetMM,GaoC,LaDucaH,LaceyJV,DolinskyJS,ChaoE,CarterBD,BurnsideES,BertrandKA,BernsteinL,AuerPW,AmbrosoneC,YadavS,HartSN,PolleyEC,DomchekSM,CouchFJ.
MayoClinic,Rochester,MN;BeckmanResearchInstituteofCityofHope,Duarte,CA;HarvardUniversityT.H.ChanSchoolofPublicHealth,Boston,MA;PerelmanSchoolofMedicineattheUniversityofPennsylvania,Philadelphia,PA;UniversityofUtah,SaltLakeCity,UT;AmbryGenetics,AlisoViejo,CA;RoswellParkComprehensiveCancerCenter,Buffalo,NY;UniversityofWisconsin-Madison,Madison,WI;AmericanCancerSociety,Atlanta,GA;NIEHS,Durham,NC;SloneEpidemiologyCenteratBostonUniversity,Boston,MA;UniversityofWashington,Seattle,WA;UniversityofHawaiiCancerCenter,Honolulu,HI;FredHutchinsonCancerResearchCenter,Seattle,WA;UniversityofOxford,Oxford,UnitedKingdom;KeckSchoolofMedicine,UniversityofSouthernCalifornia,LosAngeles,CA;UWMJosephJ.ZilberSchoolofPublicHealth,Milwaukee,WI.
PURPOSE:Theprevalenceofgermlinepathogenicvariants(PVs)inestablishedbreastcancerpredispositiongenesinwomeninthegeneralpopulationoverage65yearsisnotwell-defined.However,testingguidelinessuggestthatwomendiagnosedwithbreastcanceroverage65yearsmighthave2.5%likelihoodofaPVinahigh-penetrancegene.ThisstudyaimedtoestablishthefrequencyofPVsandremainingrisksofbreastcancerforeachgeneinwomenoverage65years.
METHODS:Atotalof26,womenoverage65yearsfrompopulation-basedstudies(51.5%withbreastcancerand48.5%unaffected)weretestedforPVsingermlinepredispositiongene.FrequenciesofPVsandassociationsbetweenPVsineachgeneandbreastcancerwereassessed,andremaininglifetimebreastcancerriskswereestimatedfornon-HispanicWhitewomenwithPVs.
RESULTS:ThefrequencyofPVsinpredispositiongeneswas3.18%forwomenwithbreastcancerand1.48%forunaffectedwomenoverage65years.PVsinBRCA1,BRCA2,andPALB2werefoundin3.42%ofwomendiagnosedwithestrogenreceptor(ER)-negative,1.0%withER-positive,and3.01%withtriple-negativebreastcancer.FrequenciesofPVswereloweramongwomenwithnofirst-degreerelativeswithbreastcancer.PVsinCHEK2,PALB2,BRCA2,andBRCA1wereassociatedwithincreasedrisks(oddsratio=2.9-4.0)ofbreastcancer.Remaininglifetimerisksofbreastcancerwere≥15%forthosewithPVsinBRCA1,BRCA2,andPALB2.
CONCLUSION:Thisstudysuggeststhatallwomendiagnosedwithtriple-negativebreastcancerorER-negativebreastcancershouldreceivegenetictestingandthatwomenoverage65yearswithBRCA1andBRCA2PVsandperhapswithPALB2andCHEK2PVsshouldbeconsideredformagneticresonanceimagingscreening.
KEYOBJECTIVE:Womenoverage65yearswithpathogenicvariants(PVs)incancerpredispositiongenesrarelybenefitfromhereditarycancergenetictesting.Thispopulation-basedstudyexaminedwhetherwomeninthisagecategorymayqualifyforclinicalgenetictestingandmagneticresonanceimagingscreening(≥20%lifetimeriskofbreastcancer).
KNOWLEDGEGENERATED:Womenwithestrogenreceptor-negativebreastcancerdiagnosedoverage65yearsandtriple-negativebreastcancerdiagnosedoverage60yearshad2.5%probabilityofPVsinthehigh-riskBRCA1,BRCA2,andPALB2genes.CarriersofBRCA1andBRCA2PVshadestimatedremaininglifetimerisksapproaching20%,whereasPALB2andCHEK2carriershad15%remainingrisks.
RELEVANCE:AllBRCA1,BRCA2,andPALB2PVcarrierswithestrogenreceptor-negativebreastcancerortriple-negativebreastcancerdiagnosedoverage65and60years,respectively,shouldreceivegenetictesting.WomenwithBRCA1andBRCA2PVsandperhapsthosewithPALB2andCHEK2PVsshouldbeconsideredformagneticresonanceimagingscreening.
PMID:
DOI:10./JCO.21.
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