06 Paul E. Goss. Management of Metastatic HER2 Positive Breast Cancer

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1、PaulE.Goss,MD,PhD,FRCPC,FRCP(UK)ProfessorofMedicine,HarvardMedicalSchoolDirectorofBreastCancerResearch,MassachusettsGeneralHospitalCancerCenterHERFamilysignalingresultsinamultitudeofcellulareffectsHER2HER3RASSosGrb2ShcPI3KAKTPDK1AKTRaf1.Celldivision2.S

2、urvival,apoptosisGSK3ßmTORNFκB3.AdhesionMEKCyclinD1BAD4.Migrationp275.Differentiation↓Apoptosis6.AngiogenesisMAPK↑SurvivalCellcyclecontrolAngiogenesisProliferationTargetedanti-HER2strategiesforMBCTrastuzumabPertuzumabT-DM1LapatinibApprovedApprovedAppro

3、vedApproved2007200220052008201020121998200520122013FirstPreoperativeInitialTrialsPhaseIIITrastuzumabTrialsReportedofT-DM1,TrialsofT-DM1PavingwayforuseasPertuzumab,AdjuvantTherapyNeratinib.ThreeLargePreoperativeAdyuvantTrialsTrialsofReportedDualBlockade

4、TrastuzumabTrastuzumab+ChemotherapyFirst+ChemotherapyFirst--LineLineMBCSubgroupAnalysisMBCSubgroupAnalysis––TTP*TTP*ACPaclitaxel1.01.0Herceptin+AC(n=143)Herceptin+Taxol(n=92)0.8AC(n=138)0.8Taxol(n=96)p<0.001p<0.0010.60.60.40.4Proportionof7.2mo5.8mo0.20

5、.2progression-freesurvival5.6mo2.9mo0.00.00510152025300510152025No.atrisk:MonthsMonthsH+AC143984012H+T925423AC13877206T96265*Medianfollow-up:35mo(range:30–51).Chemo+Trastuzumab>ChemoaloneSlamonetal.NEnglJMed.2001;344:783.Pertuzumabandtrastuzumabhavecom

6、plimentarymechanismsofPertuzumabactionHER2HER1/3/4TrastuzumabDimerizationdomainSubdomainIVTrastuzumab:Pertuzumab:•Inhibitsligand-independentHER2•Inhibitsligand-dependentHER2/HER3signalingdimerizationandsignaling•ActivatesADCC•ActivatesADCC•PreventsHER2

7、ECDsheddingADCC,antibody-dependentcell-mediatedcytotoxicity;ECD,extracellulardomainCLEOPATRA–Combinationanti-HER2TherapyinMBCCleopatra(Baselga,J.,NEnglJMed2012;366:109-119January2012)PUntreatedn=406Trastuzumab+PlaceboDHER2-positiveDocetaxel*≥6cyclesMBC

8、1:1recommendedcentrallyconfirmedPPertuzumab+trastuzumabD(N=808)Docetaxel*n=402≥6cyclesrecommendedStratificationgeographicregion/Priorneo/adjuvantchemotherapyY/N•Administrationq3weekly:−Pertuzumab/Placebo:840mgloadingdose,420mgmaintenanc