肺癌基因突变于化疗疗效分析

MingSoundTsao,MD,FRCPCDepartmentofPathology,PrincessMargaretHospitalDivisionofCellularandMolecularBiology,OntarioCancerInstituteUniversityofTorontoMolecularPathologyofLungCancerONTARIOCANCERINSTITUTE(OCI)PRINCESSMARGARETHOSPITAL

Objective:Toreporttheresultsof2importantclinicaltrialsreportedat2023AmericanSocietyofClinicalOncologistMainmessage:MolecularPathologywillsoonbeanimportantcomponentofpathologicaldiagnosisinlungcancerWorld’scancerincidenceandcancerdeathsIncidenceinthousands(%total)Deathsinthousands(%total)Lung1,305(12.7%)1,211(17.2%)Colon&rectum1,045(10.2%)608(6.7%)Breast1,032(10%)430(6.1%)Stomach973(9.5%)835(11.9%)Liver626(6.1%)611(8.7%)1999WHOPathologicalClassificationofLungCancerNon-smallCellLungCancerAdenocarcinomaSquamouscellcarcinomaNSCLC-SurvivalRateandProportionatPresentationvs.ClinicalstageClinicalStagePercentageofPatients5-yearsurvivalrateI36%60%II8%39%IIIA10%23%IIIB20%5%IV27%<1%~40%NationalCancerInstituteofCanada(NCIC-CTGBR.10Trial)AphaseIIIprospectiverandomizedstudyofadjuvantchemotherapywithvinorelbine(长春瑞滨)andcisplatin(顺铂)incompletelyresectednon-smallcelllungcancerwith

companiontumormarkerevaluationPrincipalInvestigator:Dr.TimWintonStartedin1994Completedin2023ResultspresentedatASCO2023

NCIC-CTGBR.10TrialEarlystageIandIINSCLCpatientshaveanoverall5-yearsurvivalrateof50%.PhaseIIresultssuggestedthatinadvancedNSCLC,vinorelbinepluscis-platinumyieldeda25-40%responserate.Clinicalquestion:CouldvinorelbineandcisplatinumhaveadjuvantbenefitsforsurvivalinstageIBandIINSCLCpatients?Molecularpathologyquestion:Couldweidentifymolecularmarkersinthetumortissueofthesepatientsthatcanpredictimprovementinsurvivalwithorwithoutadjuvantchemotherapy?NCIC-CTGBR.10TrialPatients’tumorandnormallungtissuecollectedinaparaffinblockandfrozentumorbankandanalysedforpresenceorabsenceofrasgenemutationNCIC-CTGBR.10TrialT1N0,T1-2N1Patients:CompleteSurgicalResectionStratification:Stage:N0vsN1Ras:absentvs.presentvs.unknownRANDOMIZATIONRasAnalysisObservationaloneChemotherapyPrimaryTx:NCIC-CTGBR.10TrialTumorBankingPatients’tumorandnormallungtissuecollectedinaparaffinblockandfrozentumorbankandanalysedforpresenceorabsenceofrasgenemutationGrowthfactorReceptorsNewEnglJMed323:561-5,1990CancerResearch52,2903-06,1992NCIC-CTGBR.10-ResultsRegistered:532,Randomized:48241patientsdeemedineligibleIncompletestaging/screening:7N2/M1/T4disease:15Incompleteresection:1Inadequate/abnormallabs18Analyses:Final,ITT,March2023NCIC-CTGBR.10-PatientCharacteristicsObservation(239)Vin/Cis(243)MedianAge(yrs)6161GenderMale64%66%Female35%34%HistologyAdenocarcinoma54%53%Squamous38%37%Undifferentiated7%8%Mixed2%2%NCIC-CTGBR.10-PatientCharacteristicsObservation(239)Vin/Cis(243)T113%16%287%84%N045%46%155%54%StageIB45%46%IIA13%16%IIB41%39%RasPresent23%24%Absent63%60%Unknown/pending14%15%JBR.10Recurrence-FreeSurvivalJBR.10–SurvivalsObservation(95%CI)Vin/Cis(95%CI)HRpMedianSurvival46.7monthsNotreached0.610.0004RF5yrSurvival48%(42-55%)61%(54-68%)0.012Observation(95%CI)Vin/Cis(95%CI)HRpMedianSurvival73months(48-~)94months(CI75-~)0.70.0125YearSurvival54%(48-61%)69%(CI62-75%)0.0022JBR.10-OverallSurvival____

Vin/Cis,____Observation*HR0.7,p=0.012YearsBenefitprimarilyforstageIIpatientsAdjuvantchemotherapyappearsnoteffectiveinpatientswhosetumorshaverasmutationP=0.88P=0.08Summaryonadjuvantchemotherapy

TheresultsofBR.10studytogetherwithresultsofotherrecentadjuvantchemotherapystudies(IALT,UFT,CALGB9633)willlikelychangethestandardoftreatmentforearlystage(IandII)non-smallcelllungcancerpatients.rasmutationmayfurtherdefinesubgroupofpatientswhowouldbenefitfromadjuvantchemotherapy.

Inthefuture,itwillnotbeadequateforapathologisttomakeonlyhistopathologicaldiagnosiswithoutadditionalmolecularanalysisforlungcancerpatients.FuturemolecularstudiestobeperformedonBR.10tumorsamples

Additionalmutationalanalyses:p53,p16Microarraystudies:mRNAexpressionprofilinggenomicDNAcopynumberchangesAdditionalgenespreviouslyidentifiedaspotentialprognosticmarkersbyotherinvestigators(1)SelfsufficiencyingrowthsignalsIncreasedgrowthfactorstimulationEpidermalGrowthFactorandReceptorFamiliesReceptorfamilyEGFR/HER-1/erbB1Neu/HER-2/erbB2HER-3/erbB3HER-4/erbB4LigandfamilyEpidermalgrowthfactorTGF-aHighEGFRExpressioninNSCLCEGFR&TGF-aExpressioninNSCLCSmallmoleculeEGFRinhibitorsGefininib(Iressa)ARandomizedPlaceboControlledStudyofErlotinib(OSI-774,Tarceva)versusPlaceboinPatientswithIncurableNon-SmallCellLungCancerWhoHaveFailedStandardTherapyforAdvancedorMetastaticDisease

NCIC-CTGBR.21TrialPrincipalInvestigator:Dr.FrancesShepherdPreviousphaseIITrialresultsResultErlotinibGefitinibIDEAL1250mg500mgGefitinibIDEAL2250mg500mgNumber57104106102114ResponseRate12.3%18%19%12%9%MedianSurvival8.4m7.6m8.0m7.0m6.0m1-YrSurvival40%35%29%27%24%BR.21ParticipatingCentresUSASwedenIsraelAustraliaNewZealandSouthAfricaArgentinaChileBrazilMexicoHongKongGermanySingaporeThailandGreeceBR.21StudyDesign-2RANDOMISEErlotinib*150mgdailyPlacebo“150mg”daily*2:1RandomizationStratified（分层）by:CentrePS,0/1vs2/3 ResponsetopriorRx(CR/PR:SD:PD)

Priorregimens,(1vs2)Priorplatinum,(Yesvsno)BR.21StudyEndpointsPrimaryOverallsurvivalSecondaryQualityoflifeProgression-freesurvival Responserate&durationofresponseToxicity&tolerabilityBR.21Results731patientsrandomizedAug/01–Jan/0322ineligible>2regimens(9)Onlysingleagentinyoungpatient(2)CTorRTgivenwithin2-4weeks,concurrentCT(5) Biochemicalabnormalities(4)SymptomaticCNSmetastases(2)BR.21PatientCharacteristicsErlotinib(N=488)Placebo(N=243)MedianAge(yrs)62.259.5GenderMale65%66%Female35%34%ECOGPS(%)013%14%152%54%226%23%39%9%HistologyAdenocarcinoma50%49%Other50%51%BR.21ProgressionFreeSurvival*AdjustedforstratificationfactorsMonths

___Erlotinib,_____Placebo *HR0.61,p=<0.001BR.21Overall,Progression-Freeand1-yearSurvivalErlotinib(N=488)Placebo(N=243)HR*LogRankPProgressionFreeSurvival2.2m1.8m0.61<0.001OverallSurvival6.7m4.7m0.720.001I-yearsurvival31%22%*AdjustedforstratificationfactorsBR.21OverallSurvival*Adjustedforstratificationfactors

___Erlotinib,_____Placebo *HR0.72,p=0.001Months31%22%BR.21SurvivalbySmokingHistoryMonths_____

ErlotinibNon-Smoker_____PlaceboNon-Smoker_____ErlotinibSmoker

_____PlaceboSmokerp=0.03**significantdifferenceacrossthelevelsofthefactor.BR.21SummaryThisisthefirstplacebocontrolledrandomizedtrialtoconfirmthatanoraltyrosine（酪氨酸）kinaseinhibitorofEGFRcanprolongsurvivalTreatmentwitherlotinibwasassociatedwithsignificantlylongeroverallsurvivallongerprogressionfreesurvivalimprovedlungcancer-relatedsymptomsimprovedqualityoflifeSurvivalsignificantlybetteramongnon-smokersEGFRMutationsinLungCancer:CorrelationwithClinicalResponsetoGefitinibTherapy.

PaezJG,JannePA,LeeJC,TracyS,GreulichH,GabrielS,HermanP,KayeFJ,LindemanN,BoggonTJ,NaokiK,SasakiH,FujiiY,EckMJ,SellersWR,JohnsonBE,MeyersonM.DanaFarberCancerInstituteandHarvardUniversity

ScienceApril29,2023

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)treatmentatDFCInoneof4patientswhodidnotrespondtogefitinibtreatmentActivatingMutationsintheEpidermalGrowthFactorReceptorUnderlyingResponsivenessofNon–Small-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-lungcancertumorsInternationalAssociationfortheStudyofLungCancer

EGFRSummitMeeting–Highlights

July9-10,2023,Baltimore,USA

Thereare18mutationsthathavebeendescribedinexons18-23.Ratesofmutationsvariedaccordingtocountries:Adenocarcinomainneversmokers: