肺癌基因突变于化疗疗效分析PPT课件.ppt

.,1,MingSoundTsao,MD,FRCPCDepartmentofPathology,PrincessMargaretHospitalDivisionofCellularandMolecularBiology,OntarioCancerInstituteUniversityofToronto,MolecularPathologyofLungCancer,.,2,ONTARIOCANCERINSTITUTE(OCI)PRINCESSMARGARETHOSPITAL,.,3,Objective:Toreporttheresultsof2importantclinicaltrialsreportedat2004AmericanSocietyofClinicalOncologistMainmessage:MolecularPathologywillsoonbeanimportantcomponentofpathologicaldiagnosisinlungcancer,.,4,Worldscancerincidenceandcancerdeaths,.,5,.,6,Non-smallCellLungCancer,Adenocarcinoma,Squamouscellcarcinoma,.,7,NSCLC-SurvivalRateandProportionatPresentationvs.Clinicalstage,40%,.,8,NationalCancerInstituteofCanada(NCIC-CTGBR.10Trial),AphaseIIIprospectiverandomizedstudyofadjuvantchemotherapywithvinorelbine(长春瑞滨)andcisplatin(顺铂)incompletelyresectednon-smallcelllungcancerwithcompaniontumormarkerevaluationPrincipalInvestigator:Dr.TimWintonStartedin1994Completedin2001ResultspresentedatASCO2004,.,9,NCIC-CTGBR.10Trial,EarlystageIandIINSCLCpatientshaveanoverall5-yearsurvivalrateof50%.PhaseIIresultssuggestedthatinadvancedNSCLC,vinorelbinepluscis-platinumyieldeda25-40%responserate.Clinicalquestion:CouldvinorelbineandcisplatinumhaveadjuvantbenefitsforsurvivalinstageIBandIINSCLCpatients?Molecularpathologyquestion:Couldweidentifymolecularmarkersinthetumortissueofthesepatientsthatcanpredictimprovementinsurvivalwithorwithoutadjuvantchemotherapy?,.,10,NCIC-CTGBR.10Trial,Patientstumorandnormallungtissuecollectedinaparaffinblockandfrozentumorbankandanalysedforpresenceorabsenceofrasgenemutation,.,11,NCIC-CTGBR.10Trial,T1N0,T1-2N1,Patients:,CompleteSurgicalResection,Stratification:,Stage:N0vsN1Ras:absentvs.presentvs.unknown,RANDOMIZATION,RasAnalysis,Observationalone,Chemotherapy,PrimaryTx:,.,12,NCIC-CTGBR.10TrialTumorBanking,Patientstumorandnormallungtissuecollectedinaparaffinblockandfrozentumorbankandanalysedforpresenceorabsenceofrasgenemutation,.,13,GrowthfactorReceptors,.,14,NewEnglJMed323:561-5,1990,.,15,CancerResearch52,2903-06,1992,.,16,NCIC-CTGBR.10-Results,Registered:532,Randomized:48241patientsdeemedineligibleIncompletestaging/screening:7N2/M1/T4disease:15Incompleteresection:1Inadequate/abnormallabs18Analyses:Final,ITT,March2004,.,17,NCIC-CTGBR.10-PatientCharacteristics,.,18,NCIC-CTGBR.10-PatientCharacteristics,.,19,JBR.10Recurrence-FreeSurvival,.,20,JBR.10Survivals,.,21,JBR.10-OverallSurvival,_Vin/Cis,_Observation*HR0.7,p=0.012,Years,.,22,BenefitprimarilyforstageIIpatients,.,23,Adjuvantchemotherapyappearsnoteffectiveinpatientswhosetumorshaverasmutation,P=0.88,P=0.08,.,24,Summaryonadjuvantchemotherapy,TheresultsofBR.10studytogetherwithresultsofotherrecentadjuvantchemotherapystudies(IALT,UFT,CALGB9633)willlikelychangethestandardoftreatmentforearlystage(IandII)non-smallcelllungcancerpatients.rasmutationmayfurtherdefinesubgroupofpatientswhowouldbenefitfromadjuvantchemotherapy.Inthefuture,itwillnotbeadequateforapathologisttomakeonlyhistopathologicaldiagnosiswithoutadditionalmolecularanalysisforlungcancerpatients.,.,25,FuturemolecularstudiestobeperformedonBR.10tumorsamples,Additionalmutationalanalyses:p53,p16Microarraystudies:mRNAexpressionprofilinggenomicDNAcopynumberchangesAdditionalgenespreviouslyidentifiedaspotentialprognosticmarkersbyotherinvestigators,.,26,(1)Selfsufficiencyingrowthsignals,Increasedgrowthfactorstimulation,.,27,EpidermalGrowthFactorandReceptorFamilies,ReceptorfamilyEGFR/HER-1/erbB1Neu/HER-2/erbB2HER-3/erbB3HER-4/erbB4,LigandfamilyEpidermalgrowthfactorTGF-a,.,28,HighEGFRExpressioninNSCLC,.,29,EGFR&TGF-aExpressioninNSCLC,.,30,SmallmoleculeEGFRinhibitors,Gefininib(Iressa),.,31,ARandomizedPlaceboControlledStudyofErlotinib(OSI-774,Tarceva)versusPlaceboinPatientswithIncurableNon-SmallCellLungCancerWhoHaveFailedStandardTherapyforAdvancedorMetastaticDisease,NCIC-CTGBR.21Trial,PrincipalInvestigator:Dr.FrancesShepherd,.,32,PreviousphaseIITrialresults,.,33,BR.21ParticipatingCentres,USA,Sweden,Israel,Australia,NewZealand,SouthAfrica,Argentina,Chile,Brazil,Mexico,HongKong,Germany,Singapore,Thailand,Greece,.,34,BR.21StudyDesign-2,RANDOMISE,Erlotinib*150mgdaily,Placebo“150mg”daily,*2:1Randomization,Stratified（分层）by:CentrePS,0/1vs2/3ResponsetopriorRx(CR/PR:SD:PD)Priorregimens,(1vs2)Priorplatinum,(Yesvsno),.,35,BR.21StudyEndpoints,PrimaryOverallsurvivalSecondaryQualityoflifeProgression-freesurvivalResponserate&durationofresponseToxicity&tolerability,.,36,BR.21Results,731patientsrandomizedAug/01Jan/0322ineligible2regimens(9)Onlysingleagentinyoungpatient(2)CTorRTgivenwithin2-4weeks,concurrentCT(5)Biochemicalabnormalities(4)SymptomaticCNSmetastases(2),.,37,BR.21PatientCharacteristics,.,38,BR.21ProgressionFreeSurvival,*Adjustedforstratificationfactors,Months,_Erlotinib,_Placebo*HR0.61,p=0.001,.,39,BR.21Overall,Progression-Freeand1-yearSurvival,*Adjustedforstratificationfactors,.,40,BR.21OverallSurvival,*Adjustedforstratificationfactors,_Erlotinib,_Placebo*HR0.72,p=0.001,Months,31%,22%,.,41,BR.21SurvivalbySmokingHistory,Months,_ErlotinibNon-Smoker_PlaceboNon-Smoker_ErlotinibSmoker_PlaceboSmoker,p=0.03*,*significantdifferenceacrossthelevelsofthefactor.,.,42,BR.21Summary,Thisisthefirstplacebocontrolledrandomizedtrialtoconfirmthatanoraltyrosine（酪氨酸）kinaseinhibitorofEGFRcanprolongsurvivalTreatmentwitherlotinibwasassociatedwithsignificantlylongeroverallsurvivallongerprogressionfreesurvivalimprovedlungcancer-relatedsymptomsimprovedqualityoflifeSurvivalsignificantlybetteramongnon-smokers,.,43,Mutations（突变）(pointmutationanddeletions)weredetectedinexons（外显子）18,19and21inthekinasedomainofEGFRgene.Mutationswerefoundin:26%(15/68)oflungcancersfromJapan2%(1/61)oflungcancersfromUSAMutationsamongJapanesepatients:14/15wereinadenocarcinoma8/14(57%)womenwithadenocarcinomahadmutationsMutationswerefoundin:all5patientswhorespondedtogefitinib(Iressa)treatmentatDFCInoneof4patientswhodidnotrespondtogefitinibtreatment,.,44,ActivatingMutationsintheEpidermalGrowthFactorReceptorUnderlyingResponsivenessofNonSmall-CellLungCancertoGefitinibThomasJ.Lynch,M.D.,DaphneW.Bell,Ph.D.,RaffaellaSordella,Ph.D.,SaradaGurubhagavatula,M.D.,RossA.Okimoto,B.S.,BrianW.Brannigan,B.A.,PatriciaL.Harris,M.S.,SaraM.Haserlat,B.A.,JeffreyG.Supko,Ph.D.,FrankG.Haluska,M.D.,Ph.D.,DavidN.Louis,M.D.,DavidC.Christiani,M.D.,JeffSettleman,Ph.D.,andDanielA.Haber,M.D.,Ph.D.MassachusettsGeneralHospitalandHarvardMedicalSchoolNEWENGLANDJOURNALOFMEDICINE,MAY20ISSUE,EGFRmutationswerefoundin:8of9lungcancerpatientswhowereresponsivetotreatmentwithIressa0of7lungcancerpatientswhowerenon-responsiveAll8tumorswereadenocarcioma5of8werefromwomennon-smokersMutationswerenotfoundin95non-lungcancertumors,.,45,.,46,InternationalAssociationfortheStudyofLungCancerEGFRSummitMeetingHighlightsJuly9-10,2004,Baltimore,USA,Thereare18mutationsthathavebeendescribedinexons18-23.Ratesofmutationsvariedaccordingtocountries:Adenocarcinomainneversmokers:60%intumorsfromTaiwan62%fromJapan3045%fromUSA(comparedto2%overall)80%fromHongKongAdenocarcinomaofeversmokerfromHK:40%EGFRmutationandRasmutationsaremutually（相互）exclusive排斥InK