病理学家在肺癌个体化靶向治疗中的职责(英文版)

THEPATHOLOGIST’SROLEINPERSONALIZEDTREATMENTFORLUNGCANCER

RATIONALEFORNEWADENOCARCINOMACLASSIFICATIONLungcancer–mostfrequentcausemajorcancerincidence/mortalityworldwideAdenocarcinoma–themostcommonhistologicsubtypeWidelydivergentclinical,radiologic,molecular&pathologicspectrumBronchioloalveolarcarcinoma(BAC)–confusingusedmanydifferentwaysdespite99/04WHO;mucinous/nonmucinousRapidevolvingmolecularadvances(EGFR)NSCLCChemotherapy1975-2010NoChemotherapy0%10%0%SingleAgent15%20%10%TwoDrugs25%35%20%ThreeDrugs35%35%20%TwoDrugsplusCetuximab36%47%20%TwoDrugsplusBevacizumab35%51%23%GefitinibEGFRMutation+71%68%35%ResponseRate1YearSurvival2YearSurvival6FEB200211FEB2002ResultswithGefitinib250mgDailyCourtesyofMarkKris,Chief,ThoracicOncology,MSKCCUSA(Erlotinib)vsEastAsia(Gefitinib)

StageIVLungAdenocarcinoma

Results:EGFRMutationPositiveandWT

EGFRMut+EGFRWTResponseRateUSA66%8%EastAsia71%1%ProgFreeSurvivalUSA16mo3moEastAsia10mo2moOverallSurvivalUSAEastAsia28mo>24mo15mo13moJanneProcASCO2010;MokNEJM2009CALGBexon19deletions:54%IPASSexon19deletions:54%CourtesyofMarkKris,Chief,ThoracicOncology,MSKCCInitialGefitinib

IPASSStudyDesignGefitinib

(250mg/day)Carboplatin(AUC5or6)/paclitaxel

(200mg/m2)

3weekly#1:1randomisation

PatientsInitialTreatment

AdenocarcinomaNeverorlightex-smokersPS0-2MeasurablestageIIIB/IVdiseasePrimaryProgression-freesurvival(non-inferiority)SecondaryObjectiveresponserateOverallsurvival

EndpointsMokNEnglJMed361:947-57,2009CourtesyofMarkKris,Chief,ThoracicOncology,MSKCCResultsinEGFRmutationpositiveandnegativepatients(AllAsian,94%NeverSmokers)EGFRmutationpositiveEGFRmutationnegativeHR(95%CI)=0.48(0.36,0.64)

p<0.0001No.eventsgefitinib:97

No.eventsChemo:111Gefitinib(n=132)

Carboplatin/paclitaxel(n=129)

HR(95%CI)=2.85(2.05,3.98)

p<0.0001No.eventsgefitinib:88

No.eventsChemo:701327131113012937721010810304812162024GefitinibC/P0.00.20.40.60.81.0Probabilityofprogression-freesurvivalAtrisk:9142100851410002158048121620240.00.20.40.60.81.0Probabilityofprogression-freesurvivalGefitinib(n=91)

Carboplatin/paclitaxel(n=85)

MonthsMonthsGefitinibCR/PRRate71%CBP/PTXCR/PRRate47%GefitinibCR/PRRate1%CBP/PTXCR/PRRate24%MokNEnglJMed361:947-57,2009ProspectiveTrialsCorrelatingResponsewithEGFRMutationsNAgentResponseRateExon19Exon21Inoue200616Gefitinib75%67%86%Cappuzzo200723Gefitinib65%NRNRPaz-Ares200638Erlotinib82%95%67%Sequist200726Gefitinib62%59%78%Rizvi200921Gefitinib81%90%70%Rosell2009197Gefi/Erloti71%Mok2009132Gefitinib71%NANACourtesyofMarkKris,Chief,ThoracicOncology,MSKCCCourtesyofMarcLadanyi,MSKCCCourtesyofMarcLadanyi,MSKCCMolecularProfilingExplainsTheHeterogeneityofLungAdenocarcinomaandDefinesTargetsforTherapyeAreceptortyrosinekinase(anaplasticlymphomakinase[ALK]fusestotheechinodermmicrotubule-associatedprotein-like4(EML-4)MultiplevariantsofthetranslocationhavebeenidentifiedOncogenic(transformcelllinesandtransgenicmicedeveloplungcancer)Responseafter40dayswith

PF-02341066:EML4-ALKTranslocationBaseline40daysafterPF-02341066CourtesyofMarkKris,Chief,ThoracicOncology,MSKCCKwakProcASCO2009Other8%MolecularAlterationsinLungAdenocarcinomainNeverSmokers(22,000/yr)PhamJClinOncol2006ShawJClinOncol2009RielyClinCancerRes2008CourtesyofMarkKris,Chief,ThoracicOncology,MSKCCMolecularCharacteristicsUsedtoSelectPatientsforProtocolsatMSKEGFRBIBW2992Erlotinib+AT-101Erlotinib(Adjuvant)Erlotinib(ECON:Induction+Adjuvant)KRASRibaforolimusGI-4000(G12C,V,D)(Adjuvant)METAmplificationPF-02341066EML4-ALKPF-02341066BRAFAZ6244CourtesyofMarkKris,Chief,ThoracicOncology,MSKCCInAdvancedNSCLC

HISTOLOGYMATTERSPredictiveofresponseEGFRmutation(inadeno)–EGFRTKI’sAdenocaorNSCLC-NOS-pemetrexedPredictiveoftoxicityBevacizumab–contraindicatedinlife-threateninghemorrhageinsquamouscarcinomaInitialTherapyofLungAdvancedAdenocarcinomaAdenocarcinomaNSCLC-NOSEGFRMutationExon19delExon21L858R,L861XExon18G719A/SUnknownEGFRMutationStatusNoEGFRMutationErlotinib/Gefitinib±Pem/Bev/CisPemetrexedBevacizumabCisplatinCourtesyofMarkKris,Chief,ThoracicOncology,MSKCCCourtesyofMarcLadanyi,MSKCCCourtesyofMarcLadanyi,MSKCCMemorialSloan-Kettering

MutationsIdentifiedinLC-MAPMSKCC2009N=1030MutationN%KRAS30629.7EGFR22621.9EML4-ALK22/3017.3BRAF131.3PIK3CA181.7HER220.2MAP2k130.3NRAS20.2CourtesyofMarkKris,Chief,ThoracicOncology,MSKCCPersonalizedLungCancerTherapy

CarehasalwaysbeenpersonalizedbasedonclinicalfactorsAdvancesinthemolecularbiologyoflungcancerhaveidentifieddrivermutationsthatunderlieclinicalfactorsInaddition,specificmutationscanleadtotheselectionofaspecifictherapyThousandsoflungcancersaredrivenbydominantoncogenes.TargetingthemyieldsdramaticresultsCourtesyofMarkKris,Chief,ThoracicOncology,MSKCCMULTIDISCIPLINARYAPPROACHPriorWHOclassifications:bypathologistsDuetoremarkableadvancesinpast10yrs:oncology,molecular,radiology,surgery:needforintegratedmultidisciplinaryapproachInternationalAssociationfortheStudyofLungCancer(IASLC);AmericanThoracicSociety(ATS),EuropeanRespiratorySociety(ERS)Panel:Pathologists,Oncologists,Radiologists,MolecularBiologists,SurgeonsLUNGADENOCARCINOMA

CLASSIFICATIONINSMALLBIOPSYANDCYTOLOGYSPECIMENSNON-SMALLCELLLUNGCANCER:70%PRESENTINADVANCEDSTAGESMALLBIOPSY/CYTOLOGYLUNGCANCERDIAGNOSIS:INUSAOVER130,000CASESIN20092009:ACSestimatesforUSA:219,440LungCancersJemalAetal:CACancerJClin2009:59:22585%NSCLC=186,524(15%SCLC)70%AdvancedStage=130,567Unresectable:Diagnosedbysmallbiopsies/cytologyCLINICAL:KEYMESSAGES

RECOMMENDATIONSWerecommendthatpatientswithadvancedadenocarcinomabetestedforEGFRmutation.EGFRmutationisavalidatedpredictivemarkerforEGFRtyrosinekinaseinhibitors(TKIs)infirstlinetherapyinadvancedlungadenocarcinoma.Strongrecommendation,highqualityevidence.CLINICAL:KEYMESSAGES

STATEMENTSOFFACTAdenocarcinomahistologyisastrongpredictorforoutcometopemetrexedtherapyinadvancedstagepatients.Distinctionbetweenadenocarcinomaorothernon-smallcellhistologiesandsquamouscellcarcinomaisimportantbecauseofpotentiallife-threateninghemorrhageinpatientswithsquamouscellcarcinomawhoreceivebevacizumabtherapy.SQUAMOUSCELLCARCINOMAADENOCARCINOMATTF-1NoclearADCorSQCCmorphology:NSCLC-NOSPOSITIVEBIOPSY(FOB,TBBx,Core,SLBx)ClassicMorphology:SQCCKeratinization,pearlsand/orintercellularbridgesNEmorphology,smallcells,nonucleoli,NEIHC+,TTF-1+/-,CK+SCLCNSCLCNOSSQCCmarker+veADCmarker+/orMucin-vePOSITIVECYTOLOGY(effusion,aspirate,washings,brushings)IHC–veandMucin-veHistology:Lepidic,papillary,and/oracinararchitecture(s)Cytology:3-Darrangements,delicatefoamy/vacuolated(translucent)cytoplasm,FinenuclearchromatinandoftenprominentnucleoliNucleiareofteneccentricallysituatedClassicmorphology:ADCADCmarkerand/orMucin+ve;SQCCmarker-veSTEP1STEP2NSCLC,favorSQCCNSCLC,favorADCNEmorphology,largecells,NEIHC+NSCLC,?LCNEC

Molecularanalysis:e.g.EGFRmutation†ApplyancillarypanelofOneSQCCandoneADCmarker+/ORMucinIftumortissueinadequateformoleculartesting,discussneedforfurthersampling-backtoStep1STEP3ADCmarkerorMucin+ve;aswellasSQCCmarker+veNSCLC,NOS,possibleadenosquamouscaNoclearADCorSQCCmorphology:NSCLC-NOSPOSITIVEBIOPSY(FOB,TBBx,Core,SLBx)ClassicMorphology:SQCCKeratinization,pearlsand/orintercellularbridgesNEmorphology,smallcells,nonucleoli,NEIHC+,TTF-1+/-,CK+SCLCNSCLCNOSSQCCmarker+veADCmarker+/orMucin-vePOSITIVECYTOLOGY(effusion,aspirate,washings,brushings)IHC–veandMucin-veHistology:Lepidic,papillary,and/oracinararchitecture(s)Cytology:3-Darrangements,delicatefoamy/vacuolated(translucent)cytoplasm,FinenuclearchromatinandoftenprominentnucleoliNucleiareofteneccentricallysituatedClassicmorphology:ADCADCmarkerand/orMucin+ve;SQCCmarker-veSTEP1STEP2NSCLC,favorSQCCNSCLC,favorADCNEmorphology,largecells,NEIHC+NSCLC,?LCNEC

Molecularanalysis:e.g.EGFRmutation†ApplyancillarypanelofOneSQCCandoneADCmarker+/ORMucinIftumortissueinadequateformoleculartesting,discussneedforfurthersampling-backtoStep1STEP3DiffuseADCmarkerorMucin+ve;aswellasSQCCmarker+veNSCLC,NOS,possibleadenosquamouscaIMMUNOHISTOCHEMICALMARKERSADENOCARCINOMATTF-1(best),Napsin,PE-10SQUAMOUSCARCINOMAP63(best),CK5/6,34βE12Desmocolin-3(needmoretesting)Cocktails–nuclear/cytoplasmicantibodiesAdenoca–TTF-1/NapsinSquamous–p63/CK5/6SUGGESTEDTERMINOLOGY

NSCLC:SMALLBIOPSIES/CYTOLOGYLightmicroscopy–cleardifferentiationSquamousCellCarcinomaorAdenocarcinomaLightmicroscopy–NSCLC-NOS–doIHCClearIHCdifferentiationNon-smallcellcarcinoma,favorsquamouscellcarcinoma(IHC:positivesquamous,negativeadeno)Non-smallcellcarcinoma,favoradenocarcinoma(IHC:positiveadeno,negativesquamous)IHCnegativeornotclear:NSCLC-NOSAllstainingnegativeConflictingstaining(bothadeno&squamousIHC)NSCLC-NOS

BYLIGHTMICROSCOPYNSCLC–FAVORADENOCARCINOMAP63TTF-1NSCLC–FAVORADENOCARCINOMATOUCHPREPCYTOLOGYNSCLC-NOS,FAVORADENOCARCINOMA

BYLIGHTMICROSCOPYEGFRmutation-negativeExon19deletionExon21L858RmutationKRASmutation-positiveG12VResultsfavoradenocarcinomaEGFRMUTATIONTESTINGADENO-CARCINOMABYHISTOLOGYNSCLCFAVORADENOPosTTF-1+/ormucin;Negp63NSCLC–NOS(possibleadenosquamous)(DiffuseposTTF-1+/ormucin;Posp63)NSCLC-NOS(NegTTF-1,mucin&p63)NOEGFRMUTATIONTESTINGSQUAMOUSCARCINOMABYHISTOLOGYNSCLC,FAVORSQUAMOUSCA(p63pos;TTF-1&/orMucinneg)STRATEGY:MAXIMIZENUMBEROFPATIENTSELIGIBLEFOREGFRMUTATIONTESTINGORFORPEMETREXEDORBEVACIZUMABTHERAPYPHASEIIISTUDYCOMPARINGCISPLATINPLUSGEMCITABINEWITHCISPLATIN&PEMETREXEDINADVANCEDNSCLCScagliottiG,etal:JCO26:3543-51,2008ALLDIAGNOSES–BYLIGHTMICROSCOPYNOIMMUNOSTAINSBEWAREOFCLAIMSTHATMOLECULARTECHNIQUESOROTHERLABORATORYTESTSPROVIDEANYADVANTAGETOHISTOLOGYTheonlyvalidationofhistologyforEGFRmutation/TKI’s,PemetrexedandBevucizumabisbylightmicroscopyaloneNoneofthesetests–evenIHCand/ormucinstainsarevalidatedinclinicaltrialsSomeemergingdatageneratedbycompaniesandcommercialtestsofferedbasedonsuchdataareseriouslyflawedADENOCARCINOMACLASSIFICATIONINRESECTIONSPECIMENSPATHOLOGY:KEYMESSAGES

RECOMMENDATIONSWerecommenddiscontinuinguseofterm“BAC”.Strongrecommendation,highqualityevidence.Werecommendanewconceptof“Adenocarcinomainsitu”(AIS)todefinepatientswhohavenear100%diseasespecificsurvival,ifcompletelyresected.Strongrecommendation,moderatequalityevidence.IASLC/ATS/ERSADENOCARCINOMACLASSIFICATION

PREINVASIVELESIONSATYPICALADENOMATOUSHYPERPLASIAADENOCARCINOMAINSITU(formerlyBACpattern)†non-mucinousmucinousMINIMALLYINVASIVEADENOCARCINOMA(alepidicpredominanttumorwith<=5mminvasion)INVASIVEADENOCARCINOMA†Sizeshouldbespecified.AISshouldbe<=3cmandcompletelysampledhistologicallADENOCARCINOMAINSITU

NONMUCINOUSMINIMALLYINVASIVEADENOCA

NONMUCINOUSIASLC/ATS/ERSADENOCARCINOMACLASSIFICATIONINVASIVEADENOCARCINOMALepidicpatternpredominant(formerlynon-mucinousBACpattern)AcinarpatternpredominantPapillarypatternpredominantMicropapillarypattern,predominantSolidpatternpredominant

(Comprehensivehistologicsubtyping:semiquantitativeassessmentofpatternsin5-10%increments)

TravisWD,etal;JournalofThoracicOncology,inpressLEPIDICPREDOMINANTOLDBACCONCEPT

FIVEPLACESINNEWCLASSIFICATIONAdenocarcinomainsitu(AIS)whichcanbenon-mucinousandrarelymucinousMinimallyinvasiveadenocarcinomaInvasiveadenocarcinomawithpredominantnonmucinouslepidicpatternInvasiveadenocarcinomawithlessthanpredominantnonmucinouslepidicpattern(probablymostformerlyclinicallyadvancedadenocarcinomaswithBACpattern)MucinousadenocarcinomawithlepidicpatternACINARPAPILLARYMICRO-

PAPILLARYSOLIDWITHMUCINDPASSTAINFREQUENCYOFAIS,MIA,LEPIDICPREDOMINANTADENOCA

514MSKCCSTAGE1CASESAIS,MIA,LPNM,ONLY7.4%OFALLSTAGEIADENOCAYoshizawaA,etalSTAGEIADENOCARCINOMA(N=514)

RECURRENCE-FREESURVIVAL(RFS)BYIASLCHISTOLOGICTYPEYoshizawaA,etalHistologicType(N)5YearRFS%AIS(1)100MIA(8)100LepidicNM(29)89Papillary(143)83Acinar(232)85MucinousAdca(13)76Solid(67)71Micropapillary(12)64Colloid(9)71P=0.003STAGEIADENOCARCINOMA(N=514)

RECURRENCE-FREESURVIVAL(RFS)BYIASLCHISTOLOGICTYPEYoshizawaA,etalHistologicType(N)5YearRFS%AIS(1)100MIA(8)100LepidicNM(29)89Papillary(143)83Acinar(232)85MucinousAdca(13)76Solid(67)71Micropapillary(12)64Colloid(9)71P=0.003AIS,MIASTAGEIADENOCARCINOMA(N=514)

RECURRENCE-FREESURVIVAL(RFS)BYIASLCHISTOLOGICTYPEYoshizawaA,etalHistologicType(N)5YearRFS%AIS(1)100MIA(8)100LepidicNM(29)89Papillary(143)83Acinar(232)85MucinousAdca(13)76Solid(67)71Micropapillary(12)64Colloid(9)71P=0.003Lepidic,Papillary&AcinarPredominantAIS,MIASTAGEIADENOCARCINOMA(N=514)

RECURRENCE-FREESURVIVAL(RFS)BYIASLCHISTOLOGICTYPEYoshizawaA,etalHistologicType(N)5YearRFS%AIS(1)100MIA(8)100LepidicNM(29)89Papillary(143)83Acinar(232)85MucinousAdca(13)76Solid(67)71Micropapillary(12)64Colloid(9)71P=0.003Micropapillary&SolidPredominantColloid,MucinousAdAIS,MIALepidic,Papillary&AcinarPredominantSTAGEIADENOCARCINOMA(N=514)

RECURRENCE-FREESURVIVAL(RFS)BYIASLCHISTOLOGICTYPEYoshizawaA,etalHistologicType(N)5YearRFS%AIS/MIA(9)100LepidicNM,Papillary,Acinar(404)85MucinousAdca,Colloid,Solid,Micropapillary(101)71P<0.001IASLC/ATS/ERSADENOCARCINOMACLASSIFICATIONMucinousadenocarcinoma(formerlymucinousBACpattern)ColloidadenocarcinomaFetaladenocarcinoma(lowandhighgrade)EntericadenocarcinomaVARIANTSTravisWD,etal;JournalofThoracicOncology,inpressMUCINOUSADENOCARCINOMAMUCINOUSADENOCARCINOMASTAGEIADENOCARCINOMA(N=514)

RFSBYNONMUCINOUSLEPIDICvs.MUCINOUSADCAHistologicType(N)5YearRFS%LepidicNM(29)89MucinousAdca(13)76YoshizawaA,etalP=0.034CLASSIFICATIONINALOWRESOURCESETTINGPathology:Intheabsenceofmolecular,immunohistochemicalorhistochemicaltesting,thediagnosisandsubclassificationoflungadenocarcinomaisbasedpurelyonlightmicroscopicevaluationofpathologicmaterial.Clinical,Radiology,Surgery:Evaluation&Rxofpatientswithlungadenocarcinomashouldbenodifferentifthediagnosiswereestablishedintheabsenceofspecialtechniques.IMPLICATIONSOFNEWCLASSIFICATIONANDOURDATAFORTNMSTAGINGInbreastcancer,thesizeT-factorismeasuredbasedonlyonthesizeoftheinvasivecomponent(excludingthesizeoftheCIScomponent)WesoughttoexamineifinourStageItumors,thetumorsizeTfactormayneedtobeadjustedfromtotaltumorsizetoonlythesizeoftheinvasivecomponent.STAGE1ADENOCARCINOMA

StandardGrossSize

T1a<=2cmvs.T1b>2-3cmYoshizawaA,etalStage(N)5YearRFS%T1a(258)89T1b(152)83P=0.095STAGE1ADENOCARCINOMA

Sizeadjustedby%invasion(notinsitu)

T1a<=2cmvs.T1b>2-3cmP=0.001Stage(N)5YearRFS%