乳腺癌内分泌治疗新思路和临床实践课件

乳腺癌内分泌治疗

新思路和临床实践乳腺癌内分泌治疗

新思路和临床实践1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新的治疗乳癌的治疗手段Surgery2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.?

MAIIIIIIIIIIIIIII乳癌内分泌治疗的发展1970198019902000Tamo3HormoneTherapyResponseRate(%)inDifferentReceptorStatusHormoneTherapyResponseRate4SurvivalbyResponse

Arimidex1mg02040608010001234CRorPRStable

24wksProgressionYearsfromRandomisation%Survival

SurvivalbyResponse

Arimidex5MAAG

PreventionDCIS/ Neoadj

5yearsMetastaticDisease1st2nd3rdAdjuvant

TAMTAMTAMTAMOV

ABL三苯氧胺（TAM)

最重要的乳癌内分泌治疗药物MAPreventionDCIS/5yearsM6Tamoxifenfor5Years

vsNoTreatmentPercentYearsER+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)vsYearsPercentTamoxifenfor5Years

vsNoT78TamoxifenAdjuvantTherapyforEBC

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

8TamoxifenAdjuvantTherapyfo9TamoxifenAdjuvantTherapyforEBC

合适的TAM服药时间为5年9TamoxifenAdjuvantTherapyfo10TamoxifenAdjuvantTherapyforEBC

ER阳性无论年龄大小都可用TAM10TamoxifenAdjuvantTherapyf11TamoxifenAdjuvantTherapyforEBC

降低对侧乳癌发生

增加子宫内膜癌的风险11TamoxifenAdjuvantTherapyfTamoxifenAdjuvantTherapyforEBC

ER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

TamoxifenAdjuvantTherapyfor12MAAG

PreventionDCIS/ Neoadj

5yearsMetastaticDisease1st2nd3rdAdjuvant1

TAMTAMTAMTAMOV

ABLTamoxifen

IndicationsinBreastCancer三苯氧胺乳癌内分泌治疗不可动摇的地位！？MAPreventionDCIS/5yearsM13SurvivalData

Anastrozole/MAMediantimetodeath(months)2yearsurvivalrate(%)P<0.05SurvivalData

Anastrozole/MA14MeanChangeinWeight(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MeanChangeinWeight(kg)+SE15

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

瑞宁得(Arimidex)

比MA更有效、更安全16

PreventionDCIS/ Neoadj5yearsMetastaticDisease1st2nd3rdAIAIAdjuvantTAMTAMTAMTAM1ArimidexinBreastCancerMAPreventionDCIS/5yearsMet17AnastrozoleisSuperiortoTamoxifeninFirstLineTherapy（0030）JCO2000;18:3748AnastrozoleisSuperiortoTam18* Hazardratio(tam:‘Arimidex’)1.44,lowerCL1.16.Study‘powered’forequivalence.Medianfollow-upof18months.71%progressedTrial0030:Kaplan-MeierCurveof

ProbabilityofTimetoProgression‘Arimidex’(n=171)Tamoxifen(n=182)MedianTTP*: ‘Arimidex’11.1months tamoxifen5.6months

p=0.005(2-sided)010203040506070809010006121824303642Timetoprogression(months)Percentagenotprogressed* Hazardratio(tam:‘Arimid19AIsisSuperiortoTamoxifen

asFirst-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AIsisSuperiortoTamoxifen

a20

PreventionDCIS/ Neoadj5yearsMetastaticDisease

AI1st2nd3rdAIAIAdjuvantTAMTAMTAMTAM1ArimidexinBreastCancerMAPreventionDCIS/5yearsMet21RationaleforAdjuvantTherapy

WithAromataseInhibitors(AIs)AIsEffectiveaftertamoxifenBetterthantamoxifenfirstlineWelltoleratedMayovercometamoxifen“resistance”RationaleforAdjuvantTherapy22TheGoldStandardTamoxifenFirst-LineLetrozoleis>Anastrozoleis>=Exemestaneis?>Neoadjuvant

Letrozoleis>Adjuvant？AnastrozoleTheGoldStandardTamoxifenFir23MilestonesActivated 1996Plannedaccrual 9366Accrualtodate Closed1999OngoingAIAdjuvantTrials:

ATAC(Anastrozole)Trialists’GroupTA.BrJCancer.2001;85:317.RANDOMI

ZESurgeryTamoxifen20mgodAnastrozole1mgodTamoxifen20mgodAnastrozole1mgod5yearsDFS/OSMilestonesOngoingAIAdjuvant24Kaplan–MeierCurvesof

Disease-freeSurvivalinITTPopulationCurvestruncatedat42monthsHR 95.2%CI p-valueANvsTAM 0.83 0.71–0.96 0.0129CombvsTAM 1.02 0.88–1.18 0.7718TamoxifenAnastrozoleCombinationTimetoevent(months)Proportioneventfree(%)Timetoevent(months)Proportioneventfree(%)08085909510006121824303642Kaplan–MeierCurvesof

Diseas25Kaplan–MeierCurvesofDisease-freeSurvival

inReceptor-positivePopulationCurvestruncatedat42monthsHR 95.2%CI p-valueANvsTAM 0.78 0.65–0.93 0.0054CombvsTAM 1.02 0.87–1.21 0.7786Timetoevent(months)Proportioneventfree(%)TamoxifenAnastrozoleCombination08085909510006121824303642Kaplan–MeierCurvesofDisease26Predefinedadverseevents*

HotflushesAArimidexTTamoxifenCCombination

1060TC12291243A%patientsAvsTCvsTAvsC0.791.020.78

OR<0.00010.75<0.0001pvaluePredefinedadverseevents*

Hot27AvsTCvsTAvsC0.520.940.56<0.00010.5<0.0001ORpvalueATCA,‘Arimidex’;C,combination;T,tamoxifen138253238%patientsPredefinedadverseevents

VaginalbleedingAvsT0.52<0.0001ORpvalueATCA28TheATAC

Earlybreastcancertrialinpostmenopausalpatients

Endometrialsub-protocolresultsTheATAC

Earlybreastcance29Demographics285womenfrom31centresin10countriesMeanage60yrs(44-80yrs)Meanageatmenopause50years80%4yearsormorepostmenopauseDemographics285womenfrom3130BaselineUltrasound12345678910>100102030405060nEndometrialthickness(mm)BaselineUltrasound1234567891031Medianendometrialthickness024681001224Endometrialthickness(mm)‘Arimidex’TamoxifenCombinationTime(months)Medianendometrialthickness0232AvsTCvsTAvsC0.230.460.500.020.110.51

ORpvalueATCA,‘Arimidex’;C,combination;T,tamoxifen3136%patientsPredefinedadverseevents

EndometrialcancerAvsT0.230.02ORpva33ATACSummaryAnastrozoleissuperiortotamoxifen

intermsof:Disease-freesurvivalin:

Overallpopulation(HR=0.83)

Receptor-positivepatients(HR=0.78)

Incidenceofcontralateralbreast

cancerin:

Overallpopulation(OR=0.42)ATACSummaryAnastrozoleissu34ConclusionsAnastrozoleisthefirstandonlyAItoshowsuperiorefficacyandimprovedtolerabilitycomparedwithtamoxifeninthetreatmentofEBCOverallrisk-benefitassessmentsupportsanastrozolebecomingthefutureadjuvanttreatmentofchoiceinpostmenopausalwomenAnastrozolealsoshowspromiseforthechemopreventionofbreastcancerConclusionsAnastrozoleisthe35AnalysisoftheIncidenceofNew(Contralateral)BreastPrimaries

Timetofirstcontralateralnewprimary(months)0612182430364209899100ProportionwithoutCLBCa(%)AnastrozoleTamoxifenCombinationOR 95%CI p-valueANvsTAM 0.42 0.22–0.79 0.0068CombvsTAM 0.84 0.51–1.40 0.5132AnalysisoftheIncidenceofN36Arimidex(Anastrozole)

inBreastcancerprevention:

DesignofIBISII

anddatafromATACArimidex(Anastrozole)

inBre37Whyusean

AromataseInhibitor?AtleastaseffectiveastamoxifeninABCATACtrialprovidesearlywarningon

sideeffectsATACtrialprovidesefficacydatainearlybreastcanceratallendpoints;strikingreductionincontralateralbreastcancereventsVerylowside-effectprofileWhyusean

AromataseInhibito38ATAC:incidenceofnew(contralateral)breastprimariesinITTpopulation9

invasive05101520253035Tamoxifen(n=3116)‘Arimidex’(n=3125)Combination(n=3125)5DCIS3DCIS23

invasive5DCIS30

invasiveNo.cases‘Arimidex’vstamoxifenOR0.42;95%CI0.22,0.79;p=0.007CombinationvstamoxifenOR0.84;95%CI0.51,1.40;p=0.51ATAC:incidenceofnew(contra39Women-yearsoffollow-upperarm3100x2.8=8600Rateofcontralateraltumoursinwomen

nottreatedwithtamoxifen(women-years) ExpectedcontralateraltumoursObservedontamoxifen

46%reductionObservedon‘Arimidex’

77%REDUCTIONATAC:projectedcontralateraltumourreductionratefor‘Arimidex’7/1000

613314Women-yearsoffollow-uppera40IBISI

Tamoxifeninprevention

Breastcancerincidenceisreducedby32%101(placebo)vs69(TAM)

OR0.68p=0.01IBISI

Tamoxifeninpreventio41IBISII:PreventionHigh-riskpostmenopausalwomen,

aged40-70years2-armtrialforhigh-riskpatients5-yeartreatment,placebocontrolledN=6000high-riskpatientsRandomizationArimidex1mgPlaceboIBISII:PreventionHigh-riskp42IBISII:DCISWomen,aged40-70years,whohavehadDCISdiagnosedwithintheprevious6months2-armtrial(noplaceboarm)5-yeartreatment,2tablets/day

N=4000Randomization‘Arimidex’1mgTamoxifen

20mgIBISII:DCISWomen,aged40-7043NSABPNSABPcentres:USAandCanadaDouble-blindrandomizedstudyPostmenopausal(n=3000)Startdate:Q42002Randomize1:15years’anastrozole1mgod5years’tamoxifen20mgodNSABPStartdate:Q42002Random44

PreventionDCIS/ Neoadj5yearsMetastaticDisease

AI1st2nd3rdAIAIAdjuvantTAMTAMTAMTAM1ArimidexinBreastCancerMAAI绝经后绝经前？AIAIPreventionDCIS/5yearsMet45绝经前乳癌内分泌治疗卵巢去势

绝经前抗芳香化酶

瑞宁得（阿那曲唑）氟隆依西美坦绝经后绝经前乳癌内分泌治疗绝经前绝经后46卵巢切除加口服依西美坦

治疗绝经前乳腺癌骨转移长期缓解

霍秀兰，女，41岁，住院号50982

2001.2多发骨转移，左锁上淋巴结转移，穿刺活检ER(+++)PR(+++)Her-2(+)

2001.4.6因患者未停经，予以双侧卵巢切除术，1月后骨痛症状改善，骨质修复；

2001.5.11口服依西美坦，2001.6.6骨痛进一步减轻，疗效评价：PR

卵巢切除加口服依西美坦

治疗绝经前乳腺癌骨转移长期缓解霍秀47Zoladex诺雷得

用于绝经前乳腺癌患者的治疗Zoladex诺雷得

用于绝经前乳腺癌患者的治疗48Zoladex与卵巢切除术

治疗复发转移乳癌效果比较Zoladex与卵巢切除术

治疗复发转移乳癌效果比较49Zoladex3.6mg用于绝经前进展期乳腺癌

II期临床试验资料来源于29个II期临床试验(n=228)CR+PR=36.4%中位缓解间期=22周耐受性好，未出现因不良反应退出抑制雌激素的药理作用是常见的面部潮红(75.9%)性欲减退(47.4%

)Zoladex3.6mg用于绝经前进展期乳腺癌

II期临50KlijnJGM,etal.JClinOncol2001;19:343–53.变量LHRH类似物LHRH类似物+Tamoxifen相对危险度p值OR(CR+PR)30%39%0.670.03PFS(中位)5.4月8.7月0.70<0.001OS(中位)2.5年2.9年0.780.02绝经前晚期乳腺癌的治疗中

LHRHa+tamoxifen优于单用LHRHa

EORTCMeta分析资料OR =客观反应PFS =无疾病进展生存OS =总生存KlijnJGM,etal.JClinOnco51Overalllogranktest:p=0.0114Time(years)02468100102030405060708090100%patientsOverallsurvival

AllpatientsLHRHagonist+tamoxifenLHRHagonistTamoxifenOveralllogranktest:p=0.011452

Zoladex=卵巢切除术

Zoladex+TAM>Zoladex

Arimidex>TAM

Zoladex+Arimidex

诺雷得+瑞宁得绝经前乳癌内分泌治疗

Zoladex53

诺雷德+瑞宁得治疗绝经前患者田XX，女，39岁，住院号53056

2001.10多发骨转移、肝转移ER(++)PR(+)Her-2(++)2001.11.~2002.1Herceptin治疗PD

2002.01.~2002.3.TA化疗2周期SD2mo

2002.3.28

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

诺雷德+瑞宁得治疗绝经前患者田XX，女，39岁，住院号54ARandomizedTrialof

Zoladex+TAM

vs

Zoladex+Arimidex

inper/perimenopausalpatientswithhormonedependentABCARandomizedTrialof

Zolade55Zoladex+TAMvsZoladex+Arimidex

inper/perimenopausalABCpatients1999.1-2001.12119casesABCFirstlineER(+)Zoladex3.6mg/28d+TAM20mg/dZoladex3.6mg/28d+Arimidex1mg/dZoladex+TAMvsZoladex+56Zoladex+ArimidexvsZoladex+TAM

inpre/perimenopausalABCpatients

Zoladex+ArimidexZoladex+TAM

CR+PR80%53%MediandurationofCB12.1months8.3monthsMediantimetoDeath18.9months14.3monthsZoladex+ArimidexvsZoladex57

Zoladex+Arimidex

iseffcientandwelltolerated

shouldbeconsideredfor

firstlinetherapy

inper/perimenopausalwomenwithhormonedependentABC

Milla-Santos,SAB2002,Dec

Zoladex+Arimidex

iseffci58OverviewofLHRHainBreastCancerAdjuvantTherapy

–BenefitsofReversibleOvarianAblationOverviewofLHRHainBreastC591.EBCTCG.Lancet1996;348:1189–96.2.BrinckerH,etal.JClinOncol1987;5:1771–8.Zoladex用于辅助治疗‘Zoladex’3.6mg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1.EBCTCG.Lancet1996;348:160Estimationofthehazardratioforrelapse

betweenwomenwith

drug-inducedamenorrhea(groupA)

andthosewithout(groupB)10publishedstudies(1995)Results:1. In9/10studiesRFSlongeringroupAthaningroupB NBBonadonna’sCMFstudy:20-yearRFS=39%vs30%(=22%reduction;p=NS)2. Meanhazardratio:0.56(0.39-0.86)*delMastroetal.NEnglJMed1995;333:596-597Conclusion:Drug-inducedamenorrheaisassociatedwitha

44%reductionintherateofrelapseEstimationofthehazardratio61*Aebietal.Lancet2000;355:1869-1874Impactofchemotherapy-inducedamenorrhea(AM+)intheadjuvantsettingbyage*IBCSGstudiesI,II,V,VII:treatmentwithchemotherapyonly

ER+AM-ER+AM+ER-AM-ER-AM+<35years(n=169)37%47%59%50%35years(n=1714)57%64%65%58%10-yearoverallsurvival*Aebietal.Lancet2000;355:162‘Zoladex’TrialsinPremenopausalWomenwithEarlyBC7TrialsusingZoladexZEBRAAustrian(AC05)INT101(ECOG/SWOG)ZEBRA-NOZIPP(combinedanalysis)GROCTA02IBCSGVIII>8000patientsDesignConferringadditionalbenefitwhenaddedtostandardtreatmentPotentialreplacementforchemotherapy‘Zoladex’TrialsinPremenopau63ZEBRA试验

(‘Zoladex’EarlyBreastCancerResearchAssociation)“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

(‘Zoladex’EarlyBre64ZEBRA试验设计

手术±放疗‘Zoladex’3.6mg

1/28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试验设计

手术±放疗‘Zoladex’3.65ZEBRA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ZEBRA临床试验结论Zoladex在受体阳性病例与C66CMFx6‘Zoladex’3.6mg/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CMFx6‘Zoladex’3.6mg/28天

x67ABCSGAC05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.ABCSGAC05临床试验结果Zoladex3.6m682,648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

³2年Tamoxifen20mg/天³2年Zoladex3.6mg/28天+TAM³2年无进一步治疗

HoughtonJ,etal.ASCO2000;19:93a,Abstr359.Zoladex用于绝经前患者(ZIPP)

2,648例标准治疗手术.Zoladex3.6mg/69ZIPP结果

乳癌术后在标准治疗中加用ZoladexDFS显著改善(HR=0.77p<0.001)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ER–ve或不详的患者更有益HoughtonJ,etal.ASCO2000;19:93a,Abstr359.BaumM.BreastCancerResTreat1999;57:30,Abstr24.ZIPP结果

乳癌术后在标准治疗中加用ZoladexD70INT-0101

ECOG/SWOG临床试验

手术CAFx6随机化

1:1:1CAFx6

Zoladex

x5年CAFx6

Zoladex+TAMx5年DavidsonNE,etal.Breast1999;8:232–3,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

ECOG/SWOG临床试验71INT-0101:5-Year结果* CAF+ZoladexvsCAFalone # CAF+Zoladex+TAMvsCAF+‘Zoladex’3.6mg+ 目前尚无统计分析发表NS=无意义

CAF CAF+ZoladexCAF+Zoladex+TAM

(n=494) (n=502) (n=507)DFS(%) 67 70(p=0.06)*77(p<0.01)#

<40岁患者DFS(%) 54 65+ 72+总体生存率 85 86(NS) 86(NS)KuterI.Oncologist1999;4:299–308.DavidsonNE,etal.Breast1999;8:232–3,Abstr069.INT-0101:5-Year结果* CAF+Z72

Zoladex辅助治疗试验结果总结

研究 治疗 疾病基本情况 DFS结果

ZEBRA ZOLvs.CMF LNM+ZOL对ER+患者与

CMF等效

(n=1,640) 74%ER+ AC05 ZOL+TAM ER/PR+

ZOL+TAM较CMF更有效

(n=1,045) vs.CMF GROCTA TAM+Ov.Supp. ER+ NS(n=244) vs.CMF INT-0101 CAFvs. LNM+CAFZTvs.CAFZ更有效

(n=1,504) CAF+ZOLvs. ER/PR+ CAF+ZOL+TAM

CAFZ

vs.CAF更有效趋势

但无统计学差异(p=0.06)ZIPP ZOL+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

Zoladex辅助治疗试验结果总结研究 治疗 疾病基本73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Zoladex±TAM的效果更好

Zoladex可作为绝经前、受体阳性早期乳癌辅助治疗

结论Zoladex对绝经前受体阳性早期乳癌辅助治74N-

lowrisk

N-

average/

highrisk

N+TAMornone

1.Ovabl+TAMCT

2.CT+TAMOvabl

3.TAM

4.Ovabl

1.CT+TAMOvabl

2.Ovabl+TAMCTTAMornone

1.TAM

2.CT+TAM

1.CT+TAM

2.TAM

ER+veOvabl,oophorectomyorGnRHanalogue;CT,chemotherapyGuidelinesforadjuvanttherapy

ofbreastcancer

StGallen2001RiskgroupER-vePremenopausalPostmenopausalNA

CT

CTN-

lowriskTAMornone

TAM75QuestionsDoesendocrinetherapyaddtochemotherapy?

Answer:yesDoeschemotherapyaddtooptimalendocrinetherapy?

Answer:

InpremenopausalER-positivebreastcancer:unknownprobablynooronlyminorextrabenefitreplacementoftamoxifenbyanaromatase

inhibitormightimproveoptimalendocrine

therapyQuestionsDoesendocrinetherap76Studydesign