乳腺癌内分泌治疗的新思路和临床实践

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1970198019902000TamoxifenTamoxifenMAAG新的芳香化酶抑制剂Exemestane/MA新的芳香化酶抑制剂TamoxifenpureA.E.?MAIIIIIIIIIIIIIIIHormoneTherapyResponseRate(%)inDifferentReceptorStatus0102030405060ER+PR+ER+PR-ER-PR+ER-PR-SurvivalbyResponseArimidex1mg02040608010001234CRorPRStable24wksProgressionYearsfromRandomisation%SurvivalMAAGPreventionDCIS/Neoadj5yearsMetastaticDisease1st2nd3rdAdjuvantTAMTAMTAMTAMOVABL三苯氧胺（TAM)最重要的乳癌内分泌治疗药物Tamoxifenfor5YearsvsNoTreatmentPercentYearsER+85.276.168.273.762.754.911.5(SE0.9)13.4(SE1.1)13.4(SE1.4)68.2%54.9%020406080100051015vsRecurrencesBreastDeaths020406080100051015ER+73.0%64.0%91.480.973.087.873.264.03.6(SE0.7)7.8(SE1.0)9.0(SE1.4)vsYearsPercent8TamoxifenAdjuvantTherapyforEBC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6-337215028-1001020304050%reductionERpoorERunknownER+veRiskreductionbyERstatus(5yrstherapy)RecurrenceMortality9TamoxifenAdjuvantTherapyforEBC合适的TAM服药时间为5年2211341751280102030405060%reduction1year2yrs5yrsoftherapyReductionsinriskinER+patientsRecurrenceMortality10TamoxifenAdjuvantTherapyforEBCER阳性无论年龄大小都可用TAM4532371154340102030405060%reduction5050-5960patientage(years)Riskreductionbyage,(ER+)RecurrenceMortality11TamoxifenAdjuvantTherapyforEBC降低对侧乳癌发生增加子宫内膜癌的风险15791942020406080100120140160no.ofcasescontralat.b.c.EndometrialcancerIncidencein20,000patientfollow-upyearsPlaceboTamoxifenTamoxifenAdjuvantTherapyforEBCER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5055606570758年DFS8年OSCAF-TCAFT-TTAMMAAGPreventionDCIS/Neoadj5yearsMetastaticDisease1st2nd3rdAdjuvant1TAMTAMTAMTAMOVABLTamoxifenIndicationsinBreastCancer三苯氧胺乳癌内分泌治疗不可动摇的地位！？SurvivalDataAnastrozole/MA0102030405060ArimidexMAMediantimetodeath(months)2yearsurvivalrate(%)P0.05MeanChangeinWeight(kg)+SEMMonthsfromStartofTherapy01234569-2-1012345megestrolacetate4x40mg(n=85)Arimidex10mg(n=92)瑞宁得1mg(n=98)瑞宁得用药9个月没有明显的体重变化瑞宁得(Arimidex)比MA更有效、更安全瑞宁得(Arimidex)1mg在复发转移乳癌治疗中缓解率/临床获益率相当生存期更长耐受性更好PreventionDCIS/Neoadj5yearsMetastaticDisease1st2nd3rdAIAIAdjuvantTAMTAMTAMTAM1ArimidexinBreastCancerMAAnastrozoleisSuperiortoTamoxifeninFirstLineTherapy（0030）JCO2000;18:37480102030405060CR+PR(%)Clinicalbenefit(%)TTP(weeks)ArimidexTAM*Hazardratio(tam:‘Arimidex’)1.44,lowerCL1.16.Study‘powered’forequivalence.Medianfollow-upof18months.71%progressedTrial0030:Kaplan-MeierCurveofProbabilityofTimetoProgression‘Arimidex’(n=171)Tamoxifen(n=182)MedianTTP*:‘Arimidex’11.1monthstamoxifen5.6monthsp=0.005(2-sided)010203040506070809010006121824303642Timetoprogression(months)PercentagenotprogressedAIsisSuperiortoTamoxifenasFirst-lineTherapyforAdvancedBreastCancer芳香化酶抑制剂取代三苯氧胺成为标准的一线内分泌治疗PreventionDCIS/Neoadj5yearsMetastaticDiseaseAI1st2nd3rdAIAIAdjuvantTAMTAMTAMTAM1ArimidexinBreastCancerMARationaleforAdjuvantTherapyWithAromataseInhibitors(AIs)•AIs–Effectiveaftertamoxifen–Betterthantamoxifenfirstline–Welltolerated–Mayovercometamoxifen“resistance”TheGoldStandardTamoxifen•First-Line–Letrozoleis–Anastrozoleis=–Exemestaneis?•Neoadjuvant–Letrozoleis•Adjuvant？–AnastrozoleMilestonesActivated1996Plannedaccrual9366AccrualtodateClosed1999OngoingAIAdjuvantTrials:ATAC(Anastrozole)Trialists’GroupTA.BrJCancer.2001;85:317.RANDOMIZESurgeryTamoxifen20mgodAnastrozole1mgodTamoxifen20mgodAnastrozole1mgod5yearsDFS/OSKaplan–MeierCurvesofDisease-freeSurvivalinITTPopulationCurvestruncatedat42monthsHR95.2%CIp-valueANvsTAM0.830.71–0.960.0129CombvsTAM1.020.88–1.180.7718TamoxifenAnastrozoleCombinationTimetoevent(months)Proportioneventfree(%)Timetoevent(months)Proportioneventfree(%)08085909510006121824303642Kaplan–MeierCurvesofDisease-freeSurvivalinReceptor-positivePopulationCurvestruncatedat42monthsHR95.2%CIp-valueANvsTAM0.780.65–0.930.0054CombvsTAM1.020.87–1.210.7786Timetoevent(months)Proportioneventfree(%)TamoxifenAnastrozoleCombination0808590951000612182430364201020304050Predefinedadverseevents*HotflushesAArimidexTTamoxifenCCombination1060TC12291243A%patientsAvsTCvsTAvsC0.791.020.78OR0.00010.750.0001pvalue012345678910AvsTCvsTAvsC0.520.940.560.00010.50.0001ORpvalueA,‘Arimidex’;C,combination;T,tamoxifen138253238%patientsPredefinedadverseeventsVaginalbleedingTheATACEarlybreastcancertrialinpostmenopausalpatientsEndometrialsub-protocolresultsDemographics•285womenfrom31centresin10countries–Meanage60yrs(44-80yrs)–Meanageatmenopause50years–80%4yearsormorepostmenopauseBaselineUltrasound12345678910100102030405060nMedianendometrialthickness024681001224Endometrialthickness(mm)‘Arimidex’TamoxifenCombinationTime(months)0.00.10.20.30.40.5AvsTCvsTAvsC0.230.460.500.020.110.51ORpvalueA,‘Arimidex’;C,combination;T,tamoxifen3136%patientsPredefinedadverseeventsEndometrialcancerATACSummary•Anastrozoleissuperiortotamoxifenintermsof:–Disease-freesurvivalin:Overallpopulation(HR=0.83)Receptor-positivepatients(HR=0.78)–Incidenceofcontralateralbreastcancerin:Overallpopulation(OR=0.42)Conclusions•AnastrozoleisthefirstandonlyAItoshowsuperiorefficacyandimprovedtolerabilitycomparedwithtamoxifeninthetreatmentofEBC•Overallrisk-