现代乳癌内分泌治疗新方法

乳癌内分泌治疗新思路和临床实践,乳癌的治疗手段,Surgery手术Radiationtherapy放疗Chemotherapy化疗Hormonetherapy内分泌治疗Biotherapy生物治疗Newtherapies新的治疗,乳癌内分泌治疗的发展,1970,1980,1990,2000,Tamoxifen,Tamoxifen,MAAG,新的芳香化酶抑制剂,Exemestane/MA,新的芳香化酶抑制剂,TamoxifenpureA.E.?,MA,III,I,II,III,HormoneTherapyResponseRate(%)inDifferentReceptorStatus,SurvivalbyResponseArimidex1mg,0,20,40,60,80,100,0,1,2,3,4,CRorPR,Stable,24wks,Progression,YearsfromRandomisation,%Survival,MAAG,PreventionDCIS/Neoadj,5years,MetastaticDisease,1st,2nd,3rd,Adjuvant,TAM,TAM,TAM,TAM,OVABL,三苯氧胺（TAM)最重要的乳癌内分泌治疗药物,Tamoxifenfor5YearsvsNoTreatment,Percent,Years,ER+,85.2,76.1,68.2,73.7,62.7,54.9,11.5(SE0.9),13.4(SE1.1),13.4(SE1.4),68.2%,54.9%,0,20,40,60,80,100,0,5,10,15,vs,Recurrences,BreastDeaths,0,20,40,60,80,100,0,5,10,15,ER+,73.0%,64.0%,91.4,80.9,73.0,87.8,73.2,64.0,3.6(SE0.7),7.8(SE1.0),9.0(SE1.4),vs,Years,Percent,8,TamoxifenAdjuvantTherapyforEBC辅助内分泌治疗的决定因素是激素受体状况ER阳性效果最好,9,TamoxifenAdjuvantTherapyforEBC合适的TAM服药时间为5年,10,TamoxifenAdjuvantTherapyforEBCER阳性无论年龄大小都可用TAM,11,TamoxifenAdjuvantTherapyforEBC降低对侧乳癌发生增加子宫内膜癌的风险,TamoxifenAdjuvantTherapyforEBCER阳性TAM和化疗合用比单用TAM更有效CAF与TAM序贯合用比同时效果更好,MAAG,PreventionDCIS/Neoadj,5years,MetastaticDisease,1st,2nd,3rd,Adjuvant,1,TAM,TAM,TAM,TAM,OVABL,TamoxifenIndicationsinBreastCancer,三苯氧胺乳癌内分泌治疗不可动摇的地位！？,SurvivalDataAnastrozole/MA,Mediantimetodeath(months),2yearsurvivalrate(%),PAnastrozoleis=Exemestaneis?NeoadjuvantLetrozoleisAdjuvant？Anastrozole,MilestonesActivated1996Plannedaccrual9366AccrualtodateClosed1999,OngoingAIAdjuvantTrials:ATAC(Anastrozole),TrialistsGroupTA.BrJCancer.2001;85:317.,RANDOMIZE,Surgery,Tamoxifen20mgod,Anastrozole1mgod,Tamoxifen20mgod,Anastrozole1mgod,5years,DFS/OS,KaplanMeierCurvesofDisease-freeSurvivalinITTPopulation,Curvestruncatedat42months,KaplanMeierCurvesofDisease-freeSurvivalinReceptor-positivePopulation,Curvestruncatedat42months,Predefinedadverseevents*Hotflushes,AArimidexTTamoxifenCCombination,1060,T,C,1229,1243,A,%patients,AvsTCvsTAvsC,0.791.020.78,OR,0.00010.750.0001,pvalue,AvsTCvsTAvsC,0.520.940.56,TAMZoladex+Arimidex诺雷得+瑞宁得,绝经前乳癌内分泌治疗,诺雷德+瑞宁得治疗绝经前患者,田XX，女，39岁，住院号530562001.10多发骨转移、肝转移ER(+)PR(+)Her-2(+)2001.11.2002.1Herceptin治疗PD2002.01.2002.3.TA化疗2周期SD2mo2002.3.28诺雷德+瑞宁得PR症状明显改善，生活自理，KPS90分B超示肝脏病灶明显缩小X光片示骨病灶好转至2002年11月疾病依然处于缓解期,ARandomizedTrialofZoladex+TAMvsZoladex+Arimidexinper/perimenopausalpatientswithhormonedependentABC,Zoladex+TAMvsZoladex+Arimidexinper/perimenopausalABCpatients,1999.1-2001.12119casesABCFirstlineER(+)Zoladex3.6mg/28d+TAM20mg/dZoladex3.6mg/28d+Arimidex1mg/d,Zoladex+ArimidexvsZoladex+TAMinpre/perimenopausalABCpatients,Zoladex+ArimidexZoladex+TAMCR+PR80%53%MediandurationofCB12.1months8.3monthsMediantimetoDeath18.9months14.3months,Zoladex+Arimidexiseffcientandwelltoleratedshouldbeconsideredforfirstlinetherapyinper/perimenopausalwomenwithhormonedependentABCMilla-Santos,SAB2002,Dec,OverviewofLHRHainBreastCancerAdjuvantTherapyBenefitsofReversibleOvarianAblation,1.EBCTCG.Lancet1996;348:118996.2.BrinckerH,etal.JClinOncol1987;5:17718.,Zoladex用于辅助治疗,Zoladex3.6mg单用或与tamoxifen合用在晚期乳腺癌治疗中显示其良好的疗效和耐受性EBCTCG1996年资料明确了绝经前早期乳腺癌治疗中卵巢去势延长生存的作用,Estimationofthehazardratioforrelapsebetweenwomenwithdrug-inducedamenorrhea(groupA)andthosewithout(groupB),10publishedstudies(1995)Results:1.In9/10studiesRFSlongeringroupAthaningroupBNBBonadonnasCMFstudy:20-yearRFS=39%vs30%(=22%reduction;p=NS)2.Meanhazardratio:0.56(0.39-0.86),*delMastroetal.NEnglJMed1995;333:596-597,Conclusion:Drug-inducedamenorrheaisassociatedwitha44%reductionintherateofrelapse,*Aebietal.Lancet2000;355:1869-1874,Impactofchemotherapy-inducedamenorrhea(AM+)intheadjuvantsettingbyage*,IBCSGstudiesI,II,V,VII:treatmentwithchemotherapyonly,ER+AM-ER+AM+ER-AM-ER-AM+,8000patientsDesignConferringadditionalbenefitwhenaddedtostandardtreatmentPotentialreplacementforchemotherapy,ZEBRA试验(ZoladexEarlyBreastCancerResearchAssociation),“诺雷德”（戈舍瑞林）与CMF辅助治疗绝经期前和更年期妇女乳腺癌的疗效比较,ZEBRA试验设计,手术放疗,Zoladex3.6mg1/28天2年,绝经前/围绝经期LNM()早期乳腺癌年龄50岁,随访,CMF1/28天x6程,随机化1:1(开放多中心),肿瘤复发,死亡,死亡,ZEBRA临床试验结论,Zoladex在受体阳性病例与CMF疗效相等ER水平检测对治疗起关键作用Zoladex较之CMF有更小的不良反应Zoladex单药治疗是对ER+、淋巴结阳性、绝经前/围绝经期早期乳腺癌CMF化疗之外的又一治疗选择,CMFx6,Zoladex3.6mg/28天x3年+TAM20mg/天x5年,随机分组1:1,绝经前ER+和/或PgR+ve乳腺癌,JakeszR,etal.BreastCancerResTreat1999;57:25,Abstr2.JakeszR,etal.EurJSurgOncol2000;26:281,Abstr110.,1,045可评估病例淋巴结+/,ABCSGAC05临床试验奥地利乳腺癌辅助治疗试验,ABCSGAC05临床试验结果,Zoladex3.6mg加用TAM组DFS显著提高总生存率亦有提高趋势Zoladex3.6mg加用TAM较CMF对绝经前受体阳性乳腺癌辅助治疗更为有效,JakeszR,etal.BreastCancerResTreat1999;57:25,Abstr2.JakeszR,etal.EurJSurgOncol2000;26:281,Abstr110.,2,648例随机化试验淋巴结+/-无论ER状态标准治疗=放疗化疗tamoxifen,标准治疗,手术,.,Zoladex3.6mg/28天2年,Tamoxifen20mg/天2年,Zoladex3.6mg/28天+TAM2年,无进一步治疗,HoughtonJ,etal.ASCO2000;19:93a,Abstr359.,Zoladex用于绝经前患者(ZIPP),ZIPP结果乳癌术后在标准治疗中加用Zoladex,DFS显著改善(HR=0.77p0.001)提高生存的趋势(HR=0.78p=0.08)对侧乳腺癌发生率降低(HR=0.60p=0.05)ER+ve患者较ERve或不详的患者更有益,HoughtonJ,etal.ASCO2000;19:93a,Abstr359.BaumM.BreastCancerResTreat1999;57:30,Abstr24.,INT-0101ECOG/SWOG临床试验,手术,CAFx6,随机化1:1:1,CAFx6Zoladexx5年,CAFx6Zoladex+TAMx5年,DavidsonNE,etal.Breast1999;8:2323,Abstr069.,多中心试验1,504例合格病例绝经前淋巴结+、受体+比较局部复发率/DFS/生存率,INT-0101:5-Year结果,*CAF+ZoladexvsCAFalone#CAF+Zoladex+TAMvsCAF+Zoladex3.6mg+目前尚无统计分析发表NS=无意义,CAFCAF+ZoladexCAF+Zoladex+TAM(n=494)(n=502)(n=507)DFS(%)6770(p=0.06)*77(p0.01)#40岁患者DFS(%)5465+72+总体生存率8586(NS)86(NS),KuterI.Oncologist1999;4:299308.DavidsonNE,etal.Breast1999;8:2323,Abstr069.,Zoladex辅助治疗试验结果总结,研究治疗疾病基本情况DFS结果ZEBRAZOLvs.CMFLNM+ZOL对ER+患者与CMF等效(n=1,640)74%ER+AC05ZOL+TAMER/PR+ZOL+TAM较CMF更有效(n=1,045)vs.CMFGROCTATAM+Ov.Supp.ER+NS(n=244)vs.CMFINT-0101CAFvs.LNM+CAFZTvs.CAFZ更有效(n=1,504)CAF+ZOLvs.ER/PR+CAF+ZOL+TAMCAFZvs.CAF更有效趋势但无统计学差异(p=0.06)ZIPPZOL+标准治疗70%ER+标准治疗ZOL(n=2,648)vs.较单用标准治疗更有效标准治疗*标准治疗=+/-放疗+/-化疗+/-tamoxifen,结论,Zoladex对绝经前受体阳性早期乳癌辅助治疗有效Zoladex单药或联合TAM疗效不比化疗效果差在标准化疗的基础上加ZoladexTAM的效果更好Zoladex可作为绝经前、受体阳性早期乳癌辅助治疗,N-lowriskN-average/highriskN+,TAMornone1.Ovabl+TAMCT2.CT+TAMOvabl3.TAM4.Ovabl1.CT+TAMOvabl2.Ovabl+TAMCT,TAMornone1.TAM2.CT+TAM1.CT+TAM2.TAM,ER+ve,Ovabl,oophorectomyorGnRHanalogue;CT,chemotherapy,GuidelinesforadjuvanttherapyofbreastcancerStGallen2001,Riskgroup,ER-ve,Premenopausal,Postmenopausal,NACTCT,Questions,Doesendocrinetherapyaddtochemotherapy?Answer:yesDoeschemotherapyaddtooptimalendocrinetherapy?Answer:,InpremenopausalER-positivebreastcancer:,unknownprobablynooronlyminorextrabenefitreplacementoftamoxifenbyanaromataseinhibitormightimproveoptimalendocrinetherapy,StudydesignBOOG1,Multicentre,open,randomizedtrialinhigh-riskER-positiveprimarybreastcancerMainquestion:doeschemotherapy(CT)addtooptimalendocrinetherapyinsteroidreceptor-positivepatients?RandomizationoptimalendocrinetherapyRToptimalendocrinetherapy+standardCTRTStratification:nodalstatus(N0,N1-4,N4)agecategories(40vs40years)cDNAmicroarrayprofileBCTvsmastectomy,StudydesignBOOG1(2),Zoladex+Arimidex(5yrs),Zoladex+Arimidex(5yrs)+CT(5xFEC),R,OngoingInternationalClinicalTrial,ArimidexvsArimidex+HerceptinforER/PRpositiveandHer-