HER2阳性EBC的应对策略.ppt

HER2阳性EBC的应对策略 AdjuvantCMF Riskofrecurrence Bonadonnaetal BMJ2005 330 217 1976 TheCMFprogramme CMFvsobservation C cyclophosphamide M methotrexate F 5 fluorouracil Firstpublication Bonadonnaetal NEnglJMed1976 294 405 410 Latestdata Riskofdeath 1976 Adjuvanttamoxifen 36 Riskofrecurrence Riskofdeath Firstpublication Lancet1983 1 257 261 BrJCancer1988 57 608 611 Latestdata 1983 NATOtrial Tamoxifenvsobservation Adjuvantanthracyclines Riskofrecurrence Firstpublication Levineetal JClinOncol1998 16 2651 2658 Latestdata Levineetal JClinOncol2005 23 5166 5170 1998 NCICMA 5 CEFvsCMF C cyclophosphamide E epirubicin F fluorouracil M methotrexate Adjuvanttaxanes Riskofrecurrence Riskofdeath 1998 Firstpublication Hendersonetal ProcAmSocClinOncol1998 17 101a abs390A CALGB9344 AC PvsAC 17 A doxorubicin C cyclophosphamide P paclitaxel Latestdata Hendersonetal JClinOncol2003 21 976 983 Adjuvantaromataseinhibitors Riskofrecurrence Firstpublication Baumetal BreastCancerResTreat2001 69 210 abs8 2001 ATAC Anastrozolevstamoxifen Howelletal Lancet2005 365 60 62 Latestdata AdjuvantHerceptin 36 34 Riskofrecurrence Riskofdeath Firstpresentation Piccart Gebhartetal ASCO2005 Smithetal Lancet2007 369 29 36 Latestdata 3furtherlargestudieshavealsodemonstratedsimilarsignificantreductionsinriskofrelapseandriskofdeath Romondetal NEnglJMed2005 353 1673 1684 Slamonetal SABCS2006 abs52 2005 HERA 1 yearHerceptinvsobservationafterchemotherapy HER2 roleinbreastcancer Humanepidermalgrowthfactorreceptor2 HER2 isatransmembraneproteinandpartoftheHERfamilyof4growthfactorreceptors HER1toHER4 1OverexpressionofHER2and oramplificationoftheHER2geneoccursinupto30 ofbreastcancers1 3HER2positivityisassociatedwith2 4aggressivediseaseahighriskofrelapsepoorsurvivalHER2istheonlymemberoftheHERfamilyacknowledgedinguidelinesforitsprognosticandpredictivevalueinbreastcancer5HER2isanimportanttherapeutictarget SlamonDJ etal Science1989 244 707 712SlamonDJ etal Science1987 235 177 182Penault LlorcaF etal JClinOncol MeetingAbstracts 2005 23 69s abs764PressMF etal JClinOncol1997 15 2894 2904GoldhirschA etal AnnOncol2006 17 1722 1776 InhibitionofHER2 mediatedsignalling Activationofantibody dependentcellularcytotoxicity ADCC HerceptiniseffectiveacrossallstagesofdiseasebyactivatingtheimmunesystemandsuppressingHER2 AdditionalmechanismsPreventsformationoftruncatedHER2 p95 InhibitionofHER2 regulatedangiogenesis SlamonDJ etal NEnglJMed2001 344 783 792MartyM etal JClinOncol2005 23 4265 4274BaselgaJ Oncology2001 61 Suppl2 14 21Piccart GebhartMJ etal NEnglJMed2005 353 1659 1672RomondEH etal NEnglJMed2005 353 1673 1684SlamonD etal BreastCancerResTreat2005 94 Suppl1 S5 abs1SlamonD etal Abstract52presentedatthe29thSABCS SanAntonio Texas USA 14 17December2006SmithI etal Lancet2007 369 29 36 ThefascinatinghistoryofHerceptin PhaseIINDforrhuMAbHER2 MurineHER2 neugenecloned HumanHER2genecloned muMAb4D5 AssociationofHER2withpoorclinicaloutcome Paclitaxel HandHmonoUSapproval Paclitaxel HandHmonoEUapproval 1stIAofHERA 1992 1985 1990 1981 1987 2000 1998 2005 2006 HERArecruitmentopens HERA2 yearfollow up AdjuvantHapproval 2008 HERA4 yearfollow upand1 yearHvs2 yearHIA 2011 HERAfinalanalysis1 yearHvs2 yearH HER2 humanepidermalgrowthfactorreceptor2 H Herceptin IA interimanalysis AdjuvantChemotherapy HERAstudydesign Herceptinq3wx1year Observation HER2 positiveearlybreastcancer IHC3 and orFISH n 5102 Herceptinq3wx2years OptiontocrossovertoHerceptin afterIA2005 Surgery neo adjuvantchemotherapy radiotherapy IHC immunohistochemistry FISH fluorescenceinsituhybridisation EndpointsoftheHERAtrial PrimaryendpointDFS1 yearHerceptinvsobservation2 yearHerceptinvsobservationSecondaryendpointsOS RFS distantDFS safety1 yearHerceptinvsobservation2 yearHerceptinvsobservationcompareDFS OS RFS distantDFSandsafety1 yearHerceptinvs2 yearHerceptin DFS disease freesurvival OS overallsurvival RFS relapse freesurvival HERA2008interimanalysis 2 yearvs1 yearHerceptin StatisticalassumptionsHR 0 80DFSabsolutereduction4 9 5 yearDFS1 yeararm 70 5 yearDFS2 yeararm 74 9 pvalue 0 014forearlyreleaseofresults Finalanalysistriggeredby725events 2011 Trialcontinuesasplanned Nodatarelease HR hazardratio IDMC IndependentDataMonitoringCommittee HERA IDMCrecommendationsOctober2008 Donotreleaseinformationonthe2 yearHerceptinarmContinuethe1 yearHerceptinvs2 yearHerceptincomparisonReleaseupdatedinformationon1 yearHerceptinvsobservation NoconclusionscanbedrawnregardingtheefficacyofHerceptintherapyfor2yearsvs1year HERAstudydesign HER2 positiveearlybreastcancer IHC3 and orFISH n 5102 Surgery neo adjuvantchemotherapy radiotherapy Herceptinq3wx1year Observation HERA DFSandOSovertime1and2years follow up No ofdeathsH1yearvsobservation 0 1 2 FavoursHerceptin FavoursnoHerceptin HR OSbenefit 29vs37p 0 26 200511year 0 59vs90p 0 0115 Medianfollow up follow uptimeafterselectivecrossover 200622years 4 1 200511year 0 Medianfollow up follow uptimeafterselectivecrossover 200622years 4 3 No ofDFSeventsH1yearvsobservation 127vs220p 0 0001 218vs321p 0 0001 0 1 2 FavoursHerceptin FavoursnoHerceptin HR DFSbenefit 1Piccart Gebhartetal2005 2Smithetal2007 DFS 4 yearmedianfollow up 100 80 60 40 20 0 0 6 12 18 24 30 48 36 42 Monthsfromrandomisation 16981703 15641619 14401552 13631485 12971414 12401352 712854 11801280 9921020 No atrisk Events458369 4 yearDFS72 278 6 HR0 76 95 CI0 66 0 87 pvalue 0 0001 1 yearHerceptin Observation 6 4 Patients OS 4 yearmedianfollow up 0 6 12 18 24 30 48 36 42 Monthsfromrandomisation 16981703 16421660 16011640 15561615 15191577 14711524 828953 13981447 11751149 Events213182 4 yearDFS87 789 3 HR0 85 95 CI0 70 1 04 pvalue0 1087 1 6 1 yearHerceptin Observation 100 80 60 40 20 0 Patients No atrisk HERA DFSandOSovertime No ofdeathsH1yearvsobservation 0 1 2 FavoursHerceptin FavoursnoHerceptin HR OSbenefit 29vs37p 0 26 200511year 0 59vs90p 0 0115 182vs213p 0 1087 Medianfollow up follow uptimeafterselectivecrossover 200622years 4 1 20084years 30 9 200511year 0 Medianfollow up follow uptimeafterselectivecrossover 200622years 4 3 20084years 33 8 No ofDFSeventsH1yearvsobservation 127vs220p 0 0001 218vs321p 0 0001 369vs458p 0 0001 0 1 2 FavoursHerceptin FavoursnoHerceptin HR DFSbenefit 1Piccart Gebhartetal2005 2Smithetal2007 4yearDFS 78 6 vs 72 2 4年OS 89 3 vs 87 7 CrossovertoHerceptinof65 ofthepatientsoriginallyallocatedtoobservationdisruptedtherandomisedcomparisonbetween1 yearHerceptinandobservationQuestion TowhatextentmightcrossoverhavebiasedtheITTanalysis Specificquestion1 Flowchartofobservationpatients bystatuson16May2005 1698patientsoriginallyrandomisedtoobservation 1354patientsaliveanddisease free 16May 2005 344patientsDFSeventorlosttofollow up198alivepostDFSevent Timetoselectivecrossoverbycalendardate n 885 0 6 0 5 0 4 0 3 0 2 0 0 16May2005 22Aug2005 28Nov2005 6Mar2006 12Jun2006 18Sep2006 25Dec2006 1354 1193 596 209 116 71 30 0 1 SwitchedtoHerceptin No atriskObservation Proportion Randomisationto1stdoseDiagnosisto1stdoseFollow upfrom1stdose Mediantime range months22 8 1 52 7 30 9 9 1 58 3 29 1 0 8 34 5 Baselinecharacteristicsofobservationpatientsaliveanddiseasefreeon16May2005 ComparedtopatientswhodidnotselectivelycrossovertoHerceptin thosewhodidweremorelikelyto beyoungerhavereceivedanthracyclinesandanthracyclinesplustaxanesbediagnosedwithnode positivediseasehavehormonereceptor positivetumours 885of1354patients 65 intheobservationgroupwhowerealiveanddiseasefreeonMay162005crossedoverandreceivedHerceptinQuestions Whatwasthecourseofdiseaseinthesubgroupsofobservationpatientswhodidordidnotcrossovertoactivetherapy IsthereanyeffectofthelateintroductionofHerceptin Specificquestion2 Landmarkof16May2005 Thelandmarkanalysisconsidersonlypatientswhowerealiveanddiseasefreeon16May2005 0 Herceptin Aliveanddiseasefreeon16May2005 6 12 18 24 30 36 42 48 1481 1480 1473 1447 1399 1351 1280 1020 854 100 80 60 40 20 0 No atrisk Patientsaliveanddiseasefree DFS landmarkanalysis Herceptinvsobservation Observation Aliveanddiseasefreeon16May2005 Monthsfromrandomisation 1354 1353 1339 1316 1278 1239 1180 992 712 DFS landmarkanalysis observation alive noDFSevent selectivecrossoverandnocrossover 100 80 60 40 20 0 0 Patientsaliveanddiseasefree 6 12 18 24 30 36 42 48 No atrisk 0 Monthsfromrandomisation 6 12 18 24 30 36 42 48 13541481 13541481 13501481 13441474 13321461 13161438 12701378 10651094 759910 100 80 60 40 20 0 OS landmarkanalysis Herceptinvsobservation No atrisk Patientsaliveanddiseasefree Herceptin Aliveanddiseasefreeon16May2005 Observation Aliveanddiseasefreeon16May2005 Observation Aliveanddiseasefreeon16May2005 0 Monthsfromrandomisation 6 12 18 24 30 36 42 48 100 80 60 40 20 0 No atrisk Patientsalive OS landmarkanalysis crossovervsno crossover 1354 1354 1350 1344 1332 1316 1270 1065 759 Cardiacsafety CardiacdeathSevereCHF NYHAIIIandIV SymptomaticCHF II IIIandIV ConfirmedsignificantLVEFdrop 1 0 1 0 0 0 3 0 2 13 0 8 0 0 0 13 0 8 33 2 0 62 3 7 87 5 2 No patients Observationan 1719 1 yearHerceptinn 1682 Herceptindiscontinuedduetocardiacproblems aPatientswhocrossedoverarecensoredfromthedateofstartingHerceptintreatment CHF congestiveheartfailure NYHA NewYorkHeartAssociation LVEF leftventricularejectionfraction Cardiacsafety observationgroup CardiacdeathSevereCHF NYHAIIIandIV SymptomaticCHF II IIIandIV ConfirmedsignificantLVEFdrop 0 0 0 0 0 0 1 0 2 5a 1 1 0 0 0 0 0 0 9 1 0 26 2 9 43 4 9 Crossovern 885 Herceptindiscontinuedduetocardiacproblems aFor3ofthepatients theLVEFdropoccurredbetween16May05andthedateofthepatientdecisionandmayhaveinfluencedthepatientdecision Nocrossoverafter16May05n 469 HERA4 yearfollow updata summary 1 Theupdatedanalysisat4yearswaslimitedto1 yearHerceptinvsobservationasrecommendedbyIDMCExtensiveselectivecrossoverofobservationpatientstoactivetherapybiasedtheITTcomparisonLandmarkanalysisofobservationpatientswhowerediseasefreeon16May2005exploredtheeffectsoflaterintroductionofHerceptinLackofrandomisationlimitstheinterpretationofthelandmarkanalysisdifferentoutcomeduetodrugeffectorpatientcharacteristics HERA4 yearfollow updata summary 2 InHERA theDFSbenefitassociatedwithHerceptinismaintainedat4 yearmedianfollow up50 ofpatientsintheobservationarmcrossedovertoHerceptintreatment thereforetheOSbenefitisnolongerstatisticallysignificantPatientscrossingoveratalaterdateappeartobenefitfrom1yearofHerceptin HERA conclusionsandnextsteps 4 yearfollow updatasupportthehypothesisthattheriskofrelapseinHER2 positiveearlybreastcancerpersistsovertimeProlongedexposuretotheHerceptinantibodymayimproveefficacyThisisbeingtestedinthecomparisonofthe1 yearand2 yeargroupsintheHERAstudy aBasedonsmallsubgroupsofpatientswithHER2 positivebreastcancer bDDFS CTx chemotherapy AC doxorubicin cyclophosphamide P paclitaxel T docetaxel Carbo carboplatin V vinorelbine CEF cyclophosphamide epirubicin 5 fluorouracil AdditionalstudiesdemonstrateconsistentDFSbenefitforHerceptin 3 4 5 4 Giannietal2008 Giannietal2009 Joensuuetal2009 Slamonetal2006 Perezetal2007 Smithetal2007 Spielmannetal2007 3 3 Medianfollow up years DFSbenefit B 31 N9831AC PH HERACTx H1year FinHeraVH TH CEFb PACS 04aCTx H1year BCIRG006AC TH TCarboH n 231 n 528 NOAHCTx H H1year 3 0 1 2 FavoursHerceptin FavoursnoHerceptin HR 1 yearHerceptintreatmentconsistentlyreducestheriskofdeathbyone third 0 1 2 B 31 N9831AC PH 3 HERACTx H1year 4 OSbenefit BCIRG006AC TH 3 TCarboH 3 FavoursHerceptin FavoursnoHerceptin HR 5 FinHerVH TH CEF n 231 Medianfollow up years Giannietal2009 Joensuuetal2009 Slamonetal2006 Perezetal2007 Smithetal2007 HER2 positivebreastcancer outstandingquestions ConcurrentorsequentialHerceptintherapy Herceptinefficacyinlower riskpatients Optimaltreatmentduration Translationalresearch Newcombinations ALTTO Herceptin lapatinib BETH Herceptin Avastin Ldqd Hcq3wfor52weeks Lbqdfor52weeks ALTTO PhaseIIIrandomisedopen labeltrialcomparingadjuvantlapatinib Herceptin Surgeryandcompletionof neo adjuvantanthracycline basedchemotherapy Concurrenttaxanesefor12weeks aHerceptin8mg kgivloadingdosefollowedby6mg kgq3w bLapatinib1500mg cHerceptin4mg kgivloadingdosefollowedby2mg kgqw dLapatinib1000mg ePaclitaxel80mg m2qwordocetaxelq3w Notaxane Hcqwfor12weeks Haq3wfor52weeks 6 weekwashout Lbqdfor34weeks HER2 positiveearlybreastcancer n 8000 Ldqd Hcq3wfor52weeks Lbqdfor52weeks Hcqwfor12weeks Haq3wfor52weeks 6 weekwashout Lbqdfor34weeks BETH PhaseIIIrandomisedtrialcomparingHerceptin containingadjuvantregimens Avastin aActualrecruitmenttodate 300 bDocetaxel75mg m2q3w carboplatinAUC6q3wordocetaxel100mg m2 FEC CTx chemotherapy q3w threeweekly CTxb Herceptin Avastin Resectednode positiveorhigh risknode negativeHER2 positiveearlybreastcancern 3600 maximum a Herceptincontinuedq3wuntil1yeartotal Herceptin Avastincontinuedq3wuntil1yeartotal Primaryendpoint DFSSecondaryendpoints OS RFS distantrecurrence freeinterval safety biomarkeranalysis StGallenTreatmentGuidelines2007 summaryRecommendation HER2andHerceptintreatment PatientswithHER2 positivediseaseathighriskofearlyrecurrencegainsubstantialbenefitfromtreatmentwithHerceptinHerceptinshouldbegiveneitherwithorafterCTaforintermediate orhigh riskpatientswithconfirmedHER2overexpression amplification irrespectiveofendocrineresponsiveness aHerceptinislicensedintheEUandSwitzerlandfortheadjuvanttreatmentofHER2 positiveearlybreastcancerfollowingchemotherapy 根据左心室射血分数 LVEF 的赫赛汀 辅助治疗方案选择指定原则 LVEF检查时间表 赫赛汀治疗前 治疗4 8个月期间 治疗12个月时 有临床需要时 对化疗方案选择方面无明显限制 赫赛汀 不宜同蒽环类药物同时使用 LVEF检查时间表 赫赛汀治疗前 每三个月一次 有临床需要时 化疗后使用赫赛汀单药序贯治疗 赫赛汀可联合不含蒽环类的化疗药物 临床慎用 LVEF 50 LVEF40 50 LVEF 40 左室射血分数 LVEF 基线值评估 首选 心超 亦可选用 MUGA扫描 准确的HER2评估 HER2阳性 赫赛汀 辅助治疗心脏不良事件的建议 HER2 患者从赫赛汀 辅助治疗的获益远大于心脏不良事件的风险赫赛汀 辅助治疗相关心脏事件是可逆性 发生后2 4月内自行恢复的概率高不影响后续的治疗治疗前心功能评估及方案选择可以更好的保证治疗中的心脏安全性接受赫赛汀 辅助治疗的患者 LVEF 40 大多数患者可以继续接受赫赛汀 治疗 建议每3个月检测LVEFLVEF 40 建议停赫赛汀 治疗 心内科随访并每月进行一次LVEF检测 2007StGallen共识 赫赛汀 辅助方案 NeoadjuvantChemotherapy 赫赛汀新辅助治疗 NOAH研究设计 HER2 humanepidermalgrowthfactorreceptor2 LABC locallyadvancedbreastcancer IHC immunohistochemistry FISH fluorescenceinsituhybridisation H Herceptin 8mg kgloadingthen6mg kg A doxorubicin 60mg m2 T paclitaxel 150mg m2 CMF cyclophosphamide 600mg m2 methotrexate 40mg m2 5 fluorouracil 600mg m2 aHormonereceptor positivepatientsreceiveadjuvanttamoxifen GiannietalASCO2007 poster532 HER2 negativeLABC IHC0 1 ATq3wx3 Tq3wx4 CMFDays1 8q4wx3 Surgery n 99 Tq3wx4 CMFDays1 8q4wx3 Surgery HER2 positiveLABC IHC3 orFISH n 113 n 115 H ATq3wx3 H Tq3wx4 Hq3wx4 CMFDays1 8q4wx3 Surgery Hcontinuedq3wx7Radiotherapya ATq3wx3 Radiotherapya Radiotherapya NOAH 临床缓解率 ORR CR PR SD PD H n 115 80 960 020 90 94 3 H n 113 73 451 322 15 36 2 65 725 240 410 110 1 HER2positive HER2negative n 99 GiannietalASCO2007 poster532 ORR overallresponserate CR completeresponse PR partialresponse SD stabledisease PD progressivedisease NOAH 赫赛汀 化疗新辅助化疗可显著提高病理学缓解率 0 10 20 30 40 50 H H HER2negative H H HER2negative Patients HER2positive HER2positive pCR tpCR 43 23 17 38 20 16 p 0 29 p 0 002 p 0 003 p 0 43 pCR pathologicalcompleteresponse tpCR totalpathologicalcompleteresponseinbreastandnodes GiannietalASCO2007 poster532 SuperiorpCRinHerceptinpatients NOAH tumourresponse EFS HER2 positivepopulation 1 00 0 75 0 50 0 25 0 00 0 6 12 18 24 30 36 42 Probability EFS Months H CTCT Events3652 HRa0 56 pa0 006 Patients115112 Medianfollow upis3yearsaUnadjustedforstratifica