早期乳腺癌内分泌治疗的一些进展.ppt

早期乳腺癌内分泌治疗的一些进展,南京医科大学第一附属医院乳腺内分泌外科王水,乳腺癌：一种全身性疾病治疗：综合性规范化：循证医学个体化：target24(18S):933s.AbstractLBA527TheIntergroupExemestaneStudy(IES)group.Lancet.2007Feb17;369(9561):559-70.,AIsExtended目前结论,MA17、B-33、ABCSG6a等研究：Extended方案能显著降低患者复发风险Extended方案显示良好的安全性,2007年StGallen共识,绝经后患者芳香化酶抑制剂的应用策略委员会倾向于Switch方案，即他莫昔芬治疗2-3年后换用AIs，少数人同时支持起始就使用AIs，几乎没有人倾向于他莫昔芬治疗5年后换用AIs的策略对于已经完成5年他莫昔芬治疗的病人，大部分委员支持在淋巴结阳性的病人中再用一段时间的AIs对于高危病人或HER2阳性的病人，更多接受起始使用AIs有过半的委员也支持对于接受SSRI类抗抑郁药的病人起始使用AIs,AI的安全性特征与TAM不同,他莫昔芬：血栓栓塞子宫内膜问题、阴道出血/排液等妇科事件芳香化酶抑制剂：肌肉关节症状BMD降低，骨质疏松AI对心血管系统和血脂代谢的影响,目前仍然存在的问题,临床上如何判断真绝经？Upfront、Switch或Extended方案的合理选择？内分泌药物的合理选择？内分泌药物的安全性问题？如何介入？如何确定内分泌治疗的有效性？延长治疗时间、增加治疗剂量、辅助其它药物能否提高疗效和安全性？,ATLAS:IsThereBenefittoLongerTamoxifen(5+Years)Therapy?,5yearsoftamoxifentherapyinpatientswithER-positivebreastcancerReducesannualrecurrenceratethroughfirstdecadeRiskofrecurrencepersists,leadingtoquestionsofpossiblebenefittolongertherapyPreviousNSABPB-14randomizedextensiontrialshowednoadditionalbenefitbeyond5years1StudymayhavebeenunderpoweredCurrentATLAStrial2Largerstudyofpatientsrandomizedto5or10yearsoftamoxifen,1.FisherB,etal.JNatlCancerInst.2001;93:684-690.2.PetoR,etal.SABCS2007.Abstract48.,ATLAS:LongervsShorterTamoxifeninER-PositiveBreastCancer,Tamoxifentreatmentfor5additionalyears,Patientswithbreastcancertreatedwithadjuvanttamoxifenfor5years(N=11,500),NoadditionalTamoxifen,Year10,Year5,PetoR,etal.SABCS2007.Abstract48.,Annualassessmentsincludedcompliance,hospitaladmissions,breastcancerrecurrence(ornewcontralateraldisease),othernewprimarycancer,anddeath.,ATLAS:DiseaseRecurrenceandOSRates,RRsignificantlylowerwithcontinuedtamoxifen;trendtowardOSbenefit(NS)CaveatsNumberofpatientswithER-positivecancerprobably90%(not100%)SomepatientswithuntestedtumorslikelyERnegativeTamoxifenbenefitprobablyunderestimatedsincecompliancerate80%,PetoR,etal.SABCS2007.Abstract48.,P=.005,ATAC:AvsTinPostmenopausalWomenWithLocalizedBreastCancer,1.HowellA,etal.Lancet.2005;365:60-62.2.ForbesJFM,etal.SABCS2007.Abstract41.,Postmenopausalwomenwithearly-stageinvasivebreastcancer(N=6241),Anastrozole(n=3125),Tamoxifen(n=3116),Long-termfollow-up,Year5,PreviousATACresultsshowedlessdiseaserecurrenceinpostmenopausalwomenwithlocalizeddiseaseonanastrozolevstamoxifen1AnastrozolewelltoleratedbuthigherriskoffracturesCurrentstudyassessedlong-termefficacyandtoxicityofanastrozole2,ATAC:EfficacyResults,ForbesJF,etal.SABCS2007.Abstract41.,Long-termresultsshowedthatanastrozolesuperiortotamoxifenforDFS,TTR,TTDR,andCLBC,butnotforOSanddeathsafterrecurrenceSimilarfindingsobservedwhenanalysesrestrictedtohormonereceptorpositivepopulation,ATAC:AdverseEventsforAnastrozolevsTamoxifen,ForbesJF,etal.SABCS2007.Abstract41.,ExcessinfracturesdiminishedaftercessationoftherapyRRoffractureforanastrozolevstamoxifenforYears0-5:1.55(P1fractureepisodeallowed,AIsandBoneLoss,AI-inducedestrogenablationacceleratesbonelossandaugmentsfractureriskinpostmenopausalwomenAI-inducedbonelossmorerapidthanbonelossassociatedwithpostmenopausalstatusaloneIVbisphosphonatesmaydecreaseAI-associatedboneloss1-yearfollow-upofZ-FASTtrialusingthebisphosphonateZApreviouslyreported1CurrentZ-FASTstudyevaluated36-monthsafetyandefficacyofupfrontvsdelayedIVZAindecreasingAI-associatedbonelossinpostmenopausalwomenwithearlybreastcancer2,1.BrufskyA,etal.JClinOncol.2007;25:829-836.2.BrufskyA,etal.SABCS2007.Abstract27.,Z-FAST:UpfrontvsDelayedZA,BrufskyA,etal.SABCS2007.Abstract27.,PostmenopausalwomenwithER-positiveorPgR-positivebreastcancer(N=602),*AllpatientstreatedwithcalciumandvitaminD.ZAinitiatedwhenT-scoredecreasedto-2orclinicalfractureoccurs.,DelayedZA*+Letrozole2.5mg/day(n=301),UpfrontZA*4mgIVevery6months+Letrozole2.5mg/day(n=301),Z-FAST:ChangeinBMDforDelayedvsUpfrontZA,LumbarspineandtotalhipBMDincreasedforpatientsonupfrontZAbutdecreasedforpatientsondelayedZABy36months,62(21%)patientsinthedelayedarminitiatedZA36-monthfracturerates:5.7%forupfrontarmvs6.3%ondelayedZAarmTrendtowardlessdiseaserecurrenceinupfrontarmvsdelayedarm9(3.5%)vs16(6.9%),respectively(P=.13),BrufskyA,etal.SABCS2007.Abstract27.,-4,-3,-2,-1,0,1,2,3,4,LumbarSpineBMD,TotalHipBMD,ChangeinBMDat36Mos(%),P.0001,P.0001,UpfrontZA,DelayedZA,IBIS-IISubstudy:RisedronatevsPlaceboforBoneLoss,SinghS,etal.SABCS2007.Abstract28.,*Preliminaryresultsforpatientswhocompletedfirstyearoftreatment;finalNwillbe1000.T-scoresatlumbarspineorfemoralneck.,Observation(n=227112anastrozole),Postmenopausalwomenathighriskforbreastcancer(N=350*),StratumI(Normal)T-score-1(n=227),StratumII(Osteopenic)-2.5T-score-1(n=80),StratumIII(Osteoporotic)-4T-score6months,PhaseIII,randomized,double-blind,placebocontrolledtrialPrimaryendpoint:%changeinlumbarspineBMDfrombaselinetoMonth12MeasuredusingDEXA,Denosumab:EffectonLumbarSpineBoneMineralDensity,Moreseriousadverseevents(reportedlynotrelatedtotreatment)indenosumabarm(15%)vsplacebo(9%),EllisG,etal.SABCS2007.Abstract47.,OvarianSuppression+TAMorANAZA:ABCSG-12TrialDesign,GnantM,etal.ASCO2008.AbstractLBA4.,Accrual1999-20061803premenopausalbreastcancerpatientsEndocrine-responsive(ERand/orPgRpositive)StageIandII,250mg,NEWEST:ImpactofHigh-andLow-DoseFulvestrantonKi67Labeling,GreaterreductioninKi67labelingindexwithhigh-dosefulvestrantcorrespondswithsignificantlygreaterreductioninERexpressionat4weeks(P.0003)AtWeek16,reductionsinKi67labelingindex(P.0001),ERexpression,andPgRexpressiongreaterwithhigh-dosefulvestrantcomparedwithstandard-dosefulvestrant,KuterI,etal.SABCS2007.Abstract23.,NEWEST:TumorResponseRatesinEvaluablePatients,KuterI,etal.SABCS2007.Abstract23.,Fulvestrant250mg(n=69),Fulvestrant500mg(n=69),0,20,40,60,80,100,ResponsetoTreatment(%),30.4,88,36.2,58.0,11.6,ORR(CR+PR*),SD,OR:1.30(0.64-2.64),53.6,10.1,PD,*PRdefinedas65%reductionintumorvolume.,NeoadjuvantEverolimus+LetrozoleinER-PositivePostmenopausalWomen,Everolimus10mg/day+Letrozole2.5mg/day(n=138),Placebo+Letrozole2.5mg/day(n=132),PostmenopausalwomenwithER-positiveinvasivebreastcancer2(N=270),Surgery,Week16,1.AwaadaA,etal.EurJCancer.Nov24;Epubaheadofprint.2.BaselgaJ,etal.SABCS2007.Abstract2066.,Everolimus:kinaseinhibitorofmTORTargetsthemTOR-phosphoinositide3kinase-Aktaxis,whichisactivatedinbreastcanceroncogenesisSuppressescellgrowth