肺癌基因突变于化疗疗效分析

MingSoundTsao,MD,FRCPCDepartmentofPathology,PrincessMargaretHospitalDivisionofCellularandMolecularBiology,OntarioCancerInstituteUniversityofToronto,MolecularPathologyofLungCancer,ONTARIOCANCERINSTITUTE(OCI)PRINCESSMARGARETHOSPITAL,Objective:Toreporttheresultsof2importantclinicaltrialsreportedat2004AmericanSocietyofClinicalOncologistMainmessage:MolecularPathologywillsoonbeanimportantcomponentofpathologicaldiagnosisinlungcancer,Worldscancerincidenceandcancerdeaths,Non-smallCellLungCancer,Adenocarcinoma,Squamouscellcarcinoma,NSCLC-SurvivalRateandProportionatPresentationvs.Clinicalstage,40%,NationalCancerInstituteofCanada(NCIC-CTGBR.10Trial),AphaseIIIprospectiverandomizedstudyofadjuvantchemotherapywithvinorelbine(长春瑞滨)andcisplatin(顺铂)incompletelyresectednon-smallcelllungcancerwithcompaniontumormarkerevaluationPrincipalInvestigator:Dr.TimWintonStartedin1994Completedin2001ResultspresentedatASCO2004,NCIC-CTGBR.10Trial,EarlystageIandIINSCLCpatientshaveanoverall5-yearsurvivalrateof50%.PhaseIIresultssuggestedthatinadvancedNSCLC,vinorelbinepluscis-platinumyieldeda25-40%responserate.Clinicalquestion:CouldvinorelbineandcisplatinumhaveadjuvantbenefitsforsurvivalinstageIBandIINSCLCpatients?Molecularpathologyquestion:Couldweidentifymolecularmarkersinthetumortissueofthesepatientsthatcanpredictimprovementinsurvivalwithorwithoutadjuvantchemotherapy?,NCIC-CTGBR.10Trial,Patientstumorandnormallungtissuecollectedinaparaffinblockandfrozentumorbankandanalysedforpresenceorabsenceofrasgenemutation,NCIC-CTGBR.10Trial,T1N0,T1-2N1,Patients:,CompleteSurgicalResection,Stratification:,Stage:N0vsN1Ras:absentvs.presentvs.unknown,RANDOMIZATION,RasAnalysis,Observationalone,Chemotherapy,PrimaryTx:,NCIC-CTGBR.10TrialTumorBanking,Patientstumorandnormallungtissuecollectedinaparaffinblockandfrozentumorbankandanalysedforpresenceorabsenceofrasgenemutation,GrowthfactorReceptors,NewEnglJMed323:561-5,1990,CancerResearch52,2903-06,1992,NCIC-CTGBR.10-Results,Registered:532,Randomized:48241patientsdeemedineligibleIncompletestaging/screening:7N2/M1/T4disease:15Incompleteresection:1Inadequate/abnormallabs18Analyses:Final,ITT,March2004,NCIC-CTGBR.10-PatientCharacteristics,NCIC-CTGBR.10-PatientCharacteristics,JBR.10Recurrence-FreeSurvival,JBR.10Survivals,JBR.10-OverallSurvival,_Vin/Cis,_Observation*HR0.7,p=0.012,Years,BenefitprimarilyforstageIIpatients,Adjuvantchemotherapyappearsnoteffectiveinpatientswhosetumorshaverasmutation,P=0.88,P=0.08,Summaryonadjuvantchemotherapy,TheresultsofBR.10studytogetherwithresultsofotherrecentadjuvantchemotherapystudies(IALT,UFT,CALGB9633)willlikelychangethestandardoftreatmentforearlystage(IandII)non-smallcelllungcancerpatients.rasmutationmayfurtherdefinesubgroupofpatientswhowouldbenefitfromadjuvantchemotherapy.Inthefuture,itwillnotbeadequateforapathologisttomakeonlyhistopathologicaldiagnosiswithoutadditionalmolecularanalysisforlungcancerpatients.,FuturemolecularstudiestobeperformedonBR.10tumorsamples,Additionalmutationalanalyses:p53,p16Microarraystudies:mRNAexpressionprofilinggenomicDNAcopynumberchangesAdditionalgenespreviouslyidentifiedaspotentialprognosticmarkersbyotherinvestigators,(1)Selfsufficiencyingrowthsignals,Increasedgrowthfactorstimulation,EpidermalGrowthFactorandReceptorFamilies,ReceptorfamilyEGFR/HER-1/erbB1Neu/HER-2/erbB2HER-3/erbB3HER-4/erbB4,LigandfamilyEpidermalgrowthfactorTGF-a,HighEGFRExpressioninNSCLC,EGFR&TGF-aExpressioninNSCLC,SmallmoleculeEGFRinhibitors,Gefininib(Iressa),ARandomizedPlaceboControlledStudyofErlotinib(OSI-774,Tarceva)versusPlaceboinPatientswithIncurableNon-SmallCellLungCancerWhoHaveFailedStandardTherapyforAdvancedorMetastaticDisease,NCIC-CTGBR.21Trial,PrincipalInvestigator:Dr.FrancesShepherd,PreviousphaseIITrialresults,BR.21ParticipatingCentres,USA,Sweden,Israel,Australia,NewZealand,SouthAfrica,Argentina,Chile,Brazil,Mexico,HongKong,Germany,Singapore,Thailand,Greece,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),BR.21StudyEndpoints,PrimaryOverallsurvivalSecondaryQualityoflifeProgression-freesurvivalResponserate&durationofresponseToxicity&tolerability,BR.21Results,731patientsrandomizedAug/01Jan/0322ineligible2regimens(9)Onlysingleagentinyoungpatient(2)CTorRTgivenwithin2-4weeks,concurrentCT(5)Biochemicalabnormalities(4)SymptomaticCNSmetastases(2),BR.21PatientCharacteristics,BR.21ProgressionFreeSurvival,*Adjustedforstratificationfactors,Months,_Erlotinib,_Placebo*HR0.61,p=0.001,BR.21Overall,Progression-Freeand1-yearSurvival,*Adjustedforstratificationfactors,BR.21OverallSurvival,*Adjustedforstratificationfactors,_Erlotinib,_Placebo*HR0.72,p=0.001,Months,31%,22%,BR.21SurvivalbySmokingHistory,Months,_ErlotinibNon-Smoker_PlaceboNon-Smoker_ErlotinibSmoker_PlaceboSmoker,p=0.03*,*significantdifferenceacrossthelevelsofthefactor.,BR.21Summary,Thisisthefirstplacebocontrolledrandomizedtrialtoconfirmthatanoraltyrosine（酪氨酸）kinaseinhibitorofEGFRcanprolongsurvivalTreatmentwitherlotinibwasassociatedwithsignificantlylongeroverallsurvivallongerprogressionfreesurvivalimprovedlungcancer-relatedsymptomsimprovedqualityoflifeSurvivalsignificantlybetteramongnon-smokers,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,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,InternationalAssociationfortheStudyofLungCancerEGFRSummitMeetingHighlightsJuly9-10,2004,Baltimore,USA,Thereare18mutationsthathavebeendescribedinexons18-23.Ratesofmutationsvariedaccordingtocountries:Adenocarcinomainneversmokers:60%intumorsfromTaiwan62%fromJapan3045%fromUSA(comparedto2%overall)80%fromHongKongAdenocarcinomaofeversmokerfromHK:40%EGFRmutationandRasmutationsaremutually（相互）exclusive排斥InKoreawher