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Thankyouforviewingthispresentation.Wewouldliketoremindyouthatthismaterialisthepropertyoftheauthor.ItisprovidedtoyoubytheERSforyourpersonaluseonly,assubmittedbytheauthor.2008bytheauthorThankyouforviewingthispre1HarvestingBiomarkersforEarly

RiskAssessment

Pan-ChyrYangMD,PhD

NationalTaiwanUniversityInstituteofBiomedicalSciencesNationalResearchHealthInstituteHarvestingBiomarkersforEarlWhyLungCancer?WhyNeedBiomarker?Earlymetastasis,poortreatmentoutcomeEastandWestaredifferentPharmacogenomicsofEGFRmutationsPrognosticandpredictivebiomarkersNoveltreatmenttargetsTowardspersonalizedtherapyWhyLungCancer?WhyNeedBiomLungCancerwithEarlyMetastasisFemale,nonsmoker,adenocaDiagnosislate,operable<30%PoortreatmentoutcomeEarlymetastasisLungCancerwithEarlyMetastaEarlyRelapseinStageILungCancerPatientMr.Tseng,67year-oldAdenocarcinomaIBTumorrecur6monthsafteroperationMarch2007Oct2007EarlyRelapseinStageILungGefitnib250mg4weeksPretreatmentTargetTherapyofLungCancerGefitnib250mg4weeksPretreatDelayedDiagnosisandEarlyMetastasisSource:AmericanCancerSociety2006DelayedDiagnosisandEarlyM7LungCancerNaturalHistoryandPersonalizedTherapyTime(m)TumorSize(cm)DiagnosisHighRiskLowRiskLungCancerNaturalHistoryanQualityofLifeandLungCancerTherapyTime(m)QualityofLifeTargetTherapyChemotherapyQualityofLifeandLungCanceBiomarkersDiagnostic:

Diseasediagnosis,classification,monitoringPrognostic:

Estimatingpatients’outcomeindependentoftherapeuticdecisionPredictive:Markersusefultomaketherapeuticdecision

BiomarkersDiagnostic:FourLevelsofBiomarkersGeneGenomeEpigenomeDNAMethylationProteomeProteinTranscriptomeTranscript(Glyco-,Phospho-)ModifiedfromSEQUENOMFourLevelsofBiomarkersGeneG11LungCancerinEastAsia–AUniqueDiseaseTheEastTheWestEtiologySmokerinmaleptsSmokerinfemaleptsFemaleAdenocarcinoma50-60%<10%60-80%80-90%80%30-40%ObjectiveChemotherapyResponse40-70%20-40%MedianSurvivalforAdvancedDisease

(IIIB+IV)12-24m8-12mResponseRatetoEGFR-TKIUnselectedpatientsFirstline30-40%50-70%

<10%

－(ChangA,JThoracicOncol2006)LungCancerinEastAsia–AU18192120C-helixP-loopA-loopDeletions46%L858R(39%)Duplications/insertions(9%)N-lobeC-lobeTransmembraneregionExtracellulardomainRegulatorydomainATPbindingcleftTKdomainDistributionofMutationsinEGFRTKDomain:Meta-analysis(n=1256)18192120C-helixP-loopA-loopDe13LungAdenocaisnotjustonecancer

-EastandWestareDifferent-CaucasiansEastAsiaEGFR(<10%)KRAS(30%)ERBB2(10%)MET(10%)Unknown(Others)EML4-ALKEGFR(30-40%)KRAS(5%)ERBB2(10%)MET(10%)Unknown(Others)EML4-ALKLungAdenocaisnotjustonec14PhaseIITrialsofFirst-lineEGFR-TKIMonotherapyinNSCLCPatientsaNo.evaluableORR,%DCR,%GefitinibEastAsianLeeetal2005Suzukietal2005Kasaharaetal2005Yangetal2008N-smokers,adenoPS0-1PS0-1Enriched54343010661.126.533.350.972.2NR63.382.1CaucasianSpiegeletal2005Recketal2006D’Addario2007PS2-3PS0-1725863458504524ErlotinibGiacconeetal2005Jackmanetal200770yearsold535522.71052.851aAllpatientswereCTna?ve;patientshadstageIII/IVNSCLC,PS0–2unlessspecifiedotherwise;NR,notreportedPhaseIITrialsofFirst-line

N mutR RR PFSOSSutanietal.BJC2006 27 38% 78% 9.4M 15.4MInoueetal.JCO2006 16 33% 75% 9.7MAsahinaetal.BJC2006 16 24% 75% 8.9MYoshidaJTO2007 21 41% 90.5% 7.7MSequistetal.JCO2008 31 35% 58% 8.9M 17.5MYangetal.JCO2008 55 61%69%8.9M24.0MGefitinibinNSCLCwithEGFRMutation

PFS=progression-freesurvival;OS=overallsurvival N mutR RR 16PFSinEGFRmutation-positive

andwild-typepatients(IPASS)EGFRmutation-positiveEGFRwild-typeProbabilityofPFS1.00.20ProbabilityofPFS1.00.20 0 4 8 12 16 20 24 0 4 8 12 16 20 24MonthsMonths132 108 71 31 11 3 0129 103 37 7 2 1 0Atrisk:Gefitinib

C/P91 21 4 2 1 0 0

85 58 14 1 0 0 0Gefitinib(n=132)Carboplatin/paclitaxel(n=129)HR(95%CI)=0.48(0.36,0.64)

p<0.0001Gefitinib(n=91)Carboplatin/paclitaxel(n=85)HR(95%CI)=2.85(2.05,3.98)

p<0.0001IPASSStudyGroupPFSinEGFRmutation-positiveT790M:PrimaryResistancetoGefitinib(ShihJY,etal.NEnglJMed2005)Exon21Exon20L858RT790MLymphocyteDNATumorDNAT790M:PrimaryResistancetoG18AcquiredResistanceinNTUHT790M:14/24(58%)8/11:L858R6/13:Del19C-Metamplification:5/24(21%)2/11:L858R3/13:Del19BothT790M+Metamplification:3(BeanJetal.PNAS2007)C-MetamplificationAcquiredResistanceinNTUHT7919DetectEGFRMutationinTumorandPBbyDNAMassL858R(2573TG)

2573GTT790M(2369CT)unextend23692369CTT/GC/TunextendSensitivity:10copies,QuantifiableSuKYetal2008DetectEGFRMutationinTumor20Genome-WideIdentificationofNovelMarkerforCancerMetastasisEstablishinvitrometastasiscelllinemodelProteomicidentificationofnovelmarkersGenome-wideprofilingofdifferentiallyexpressedmetastasisrelatedgenesCharacterizenovelmetastasis-relatedgenesBiomarkersfordiagnosis,prognosispredictionandtherapyGenome-WideIdentificationof21LungCancerInvasionCellLineModelNo.InvadedCells(ChenJJWetal.CancerRes2001)Medium1Medium2MembraneInvasionCultureLungCancerInvasionCellLine22IVMetastasisAssayinSCIDMiceCL1-0CL1-5IVMetastasisAssayinSCIDMiProteomicsforMetastaticMarkersNM23CL1-0CL1-5ProteomicsforMetastaticMarkMicroarrayandPathwayAnalysis192325413476(CRSD:LiuCCetal.NAR2006)MicroarrayandPathwayAnalysi25molecular-mechanisms-of-cancer-metastasis-in-lung-cancer-肺癌之【課件】RiskScore=0.47NF1+0.51HGF+0.52HMMR+0.52IRF4+0.55ZNF264+0.55ErbB3+0.59STAT2+0.59CPEB4+0.65RNF4+0.75DUSP6+0.92MMD+1.32DLG2-1.09ANXA5-0.84LCK-0.77FRAP1-0.58STAT1(ChenHYetal.NEJM2007)MicroarrayGeneSignatureandLungCancerOutcomeRiskScore=0.47NF1+0.51HGF+0.(YuSLetal.CancerCell2008)miR-137miR-182*miR-372miR-221Let-7aMicroRNASignaturePredictsNSCLCOutcome(YuSLetal.CancerCell200LowriskN=31HighriskN=16AllN=47OverallsurvivalLowriskN=15HighriskN=13AllN=28LowriskN=12HighriskN=25AllN=37MonthsMonthsMonthsRelapse-freesurvivalMonthsMonthsMonthsLowriskN=31HighriskN=16AllN=47LowriskN=15HighriskN=13AllN=28LowriskN=12HighriskN=25AllN=37P=0.044P=0.047P=0.004P=0.031P=0.046P=0.076StageIStageIIStageIIIMicroRNASignatureofNSCLC:SubgroupAnalysis(YuSLetal.CancerCell2008)LowriskN=31HighriskN=16AllNGeneSignatureforLungAdenocarcinomaGenesignaturesforoutcomeprediction

(BeerD.NatureMed2002,BianchiF.JCI2007,SunZ.JCO2008,LauSK.JCO2007,PottiA.NEJM2006,ChenHY.NEJM2007,etc)Minimaloverlap,non-celltypespecific,differentstatisticalmethod,lackofindependentvalidationLarge,training-testing,multi-site,blindvalidationMolecularinformationusefulforriskpredictionofearlystagelungcancer

(SheddenKetal.NatureMed2008)CombinemultiplelevelsofbiomarkersDNA,mRNAbiomarkersmicroRNA(YuSLetal.CancerCell2008)DNAmethylation(BrockMetal.NEJM2008)Proteomics,Glycoproteome

GeneSignatureforLungAdenoc30InteractionNetworksofIndependentPrognosticGeneSets(LauSKetal.JCO2007)InteractionNetworksofIndepeCombinationofGeneExpressionandMicroRNASignaturesandLungCancerOutcomeNone(n=24)Twosignatures(n=30)Anyonesignature(n=39)P<0.0001Three-yearsurvival:None:0.91Anyonesignature:0.61Twosignatures:0.16MonthsOverallsurvivalSignatures:Gene:ChenHYetal,NEJM2007microRNA:YuSLetal,CancerCell2008CombinationofGeneExpressionClaudin-1isDown-regulatedinLungAdenocarcinomaCLDN1IHCstainingAdenocarcinomaCLDN1positivestainingNormalbronchialepitheliumSquamouscellcarcinomaAdenocarcinomanegativestaining(ChaoYCetal,AJRCCM2008)Claudin-1isDown-regulatedin33Claudin-1andSurvivalofLungAdenocarcinomaLowCLDN1(n=32)Time(month)Overall

Survivalp=0.027

HighCLDN1(n=32)Overall

SurvivalTime(month)CLDN1Negative(n=34)CLDN1Positive(n=33)p=0.024CLDN1protein:IHCstainingCLDN1mRNA:RealtimePCR

(anindependentcohort)(ChaoYCetal,AJRCCM2008)Claudin-1andSurvivalofLung34Claudin-1InhibitsCancerCellMigration/DissociationCL1-5/GFP-CLDN1EGFPCL1-5/EGFPPhase(ChaoYCetal,AJRCCM2008)Claudin-1InhibitsCancerCell35StrategyTowardsPersonalized

TherapyofLungCancer

ScreeningEarlydetectionDiagnosisstagingInoperableOperableRiskgenes,SNPsClinicaltrial,SpiralCT,othersNewstagingsystem:TNMCMicrometastasisPredictoutcome&metastasisChemopreventionClinicaltrialPredictchemotherapyresponse(ERCC1,RRM1)Targettherapy(EGFR)ClinicaltrialClinicalnetworkBiomarkersNewmethodsGeneSignatureBiomarkersStrategyTowardsPersonalized36ConclusionGenomicandproteomictoolsfacilitatetheidentificationofnovellungcancerbiomarkersLungadenocarcinomaisadistinctdiseasegroupwithspecificpharmacogenomicsPrognosticandpredictivemarkersareusefulforpersonalizedtherapyoflungcancerTranslationalresearchtovalidatebiomarkersforclinicalapplicationConclusionGenomicandproteomi5-GeneSignatureforNSCLCSTAT1:GrowtharrestandapoptosisLCK:lymphocyte-specificproteintyrosinekinase,regulatecancercellmotilityandTcellactivationERBB3:v-erb-b2avainerythroblasticleukemiaviraloncogenehomolog3,memberofEGFR-TKMMD:Monocyte-to-macrophagedifferentiationproteinDUSP6:Dual-specificityphosphatase6InactivateERK2,suppresstumorandapoptosis5-GeneSignatureforNSCLCSTAT

Thankyouforviewingthispresentation.Wewouldliketoremindyouthatthismaterialisthepropertyoftheauthor.ItisprovidedtoyoubytheERSforyourpersonaluseonly,assubmittedbytheauthor.2008bytheauthorThankyouforviewingthispre39HarvestingBiomarkersforEarly

RiskAssessment

Pan-ChyrYangMD,PhD

NationalTaiwanUniversityInstituteofBiomedicalSciencesNationalResearchHealthInstituteHarvestingBiomarkersforEarlWhyLungCancer?WhyNeedBiomarker?Earlymetastasis,poortreatmentoutcomeEastandWestaredifferentPharmacogenomicsofEGFRmutationsPrognosticandpredictivebiomarkersNoveltreatmenttargetsTowardspersonalizedtherapyWhyLungCancer?WhyNeedBiomLungCancerwithEarlyMetastasisFemale,nonsmoker,adenocaDiagnosislate,operable<30%PoortreatmentoutcomeEarlymetastasisLungCancerwithEarlyMetastaEarlyRelapseinStageILungCancerPatientMr.Tseng,67year-oldAdenocarcinomaIBTumorrecur6monthsafteroperationMarch2007Oct2007EarlyRelapseinStageILungGefitnib250mg4weeksPretreatmentTargetTherapyofLungCancerGefitnib250mg4weeksPretreatDelayedDiagnosisandEarlyMetastasisSource:AmericanCancerSociety2006DelayedDiagnosisandEarlyM45LungCancerNaturalHistoryandPersonalizedTherapyTime(m)TumorSize(cm)DiagnosisHighRiskLowRiskLungCancerNaturalHistoryanQualityofLifeandLungCancerTherapyTime(m)QualityofLifeTargetTherapyChemotherapyQualityofLifeandLungCanceBiomarkersDiagnostic:

Diseasediagnosis,classification,monitoringPrognostic:

Estimatingpatients’outcomeindependentoftherapeuticdecisionPredictive:Markersusefultomaketherapeuticdecision

BiomarkersDiagnostic:FourLevelsofBiomarkersGeneGenomeEpigenomeDNAMethylationProteomeProteinTranscriptomeTranscript(Glyco-,Phospho-)ModifiedfromSEQUENOMFourLevelsofBiomarkersGeneG49LungCancerinEastAsia–AUniqueDiseaseTheEastTheWestEtiologySmokerinmaleptsSmokerinfemaleptsFemaleAdenocarcinoma50-60%<10%60-80%80-90%80%30-40%ObjectiveChemotherapyResponse40-70%20-40%MedianSurvivalforAdvancedDisease

(IIIB+IV)12-24m8-12mResponseRatetoEGFR-TKIUnselectedpatientsFirstline30-40%50-70%

<10%

－(ChangA,JThoracicOncol2006)LungCancerinEastAsia–AU18192120C-helixP-loopA-loopDeletions46%L858R(39%)Duplications/insertions(9%)N-lobeC-lobeTransmembraneregionExtracellulardomainRegulatorydomainATPbindingcleftTKdomainDistributionofMutationsinEGFRTKDomain:Meta-analysis(n=1256)18192120C-helixP-loopA-loopDe51LungAdenocaisnotjustonecancer

-EastandWestareDifferent-CaucasiansEastAsiaEGFR(<10%)KRAS(30%)ERBB2(10%)MET(10%)Unknown(Others)EML4-ALKEGFR(30-40%)KRAS(5%)ERBB2(10%)MET(10%)Unknown(Others)EML4-ALKLungAdenocaisnotjustonec52PhaseIITrialsofFirst-lineEGFR-TKIMonotherapyinNSCLCPatientsaNo.evaluableORR,%DCR,%GefitinibEastAsianLeeetal2005Suzukietal2005Kasaharaetal2005Yangetal2008N-smokers,adenoPS0-1PS0-1Enriched54343010661.126.533.350.972.2NR63.382.1CaucasianSpiegeletal2005Recketal2006D’Addario2007PS2-3PS0-1725863458504524ErlotinibGiacconeetal2005Jackmanetal200770yearsold535522.71052.851aAllpatientswereCTna?ve;patientshadstageIII/IVNSCLC,PS0–2unlessspecifiedotherwise;NR,notreportedPhaseIITrialsofFirst-line

N mutR RR PFSOSSutanietal.BJC2006 27 38% 78% 9.4M 15.4MInoueetal.JCO2006 16 33% 75% 9.7MAsahinaetal.BJC2006 16 24% 75% 8.9MYoshidaJTO2007 21 41% 90.5% 7.7MSequistetal.JCO2008 31 35% 58% 8.9M 17.5MYangetal.JCO2008 55 61%69%8.9M24.0MGefitinibinNSCLCwithEGFRMutation

PFS=progression-freesurvival;OS=overallsurvival N mutR RR 54PFSinEGFRmutation-positive

andwild-typepatients(IPASS)EGFRmutation-positiveEGFRwild-typeProbabilityofPFS1.00.20ProbabilityofPFS1.00.20 0 4 8 12 16 20 24 0 4 8 12 16 20 24MonthsMonths132 108 71 31 11 3 0129 103 37 7 2 1 0Atrisk:Gefitinib

C/P91 21 4 2 1 0 0

85 58 14 1 0 0 0Gefitinib(n=132)Carboplatin/paclitaxel(n=129)HR(95%CI)=0.48(0.36,0.64)

p<0.0001Gefitinib(n=91)Carboplatin/paclitaxel(n=85)HR(95%CI)=2.85(2.05,3.98)

p<0.0001IPASSStudyGroupPFSinEGFRmutation-positiveT790M:PrimaryResistancetoGefitinib(ShihJY,etal.NEnglJMed2005)Exon21Exon20L858RT790MLymphocyteDNATumorDNAT790M:PrimaryResistancetoG56AcquiredResistanceinNTUHT790M:14/24(58%)8/11:L858R6/13:Del19C-Metamplification:5/24(21%)2/11:L858R3/13:Del19BothT790M+Metamplification:3(BeanJetal.PNAS2007)C-MetamplificationAcquiredResistanceinNTUHT7957DetectEGFRMutationinTumorandPBbyDNAMassL858R(2573TG)

2573GTT790M(2369CT)unextend23692369CTT/GC/TunextendSensitivity:10copies,QuantifiableSuKYetal2008DetectEGFRMutationinTumor58Genome-WideIdentificationofNovelMarkerforCancerMetastasisEstablishinvitrometastasiscelllinemodelProteomicidentificationofnovelmarkersGenome-wideprofilingofdifferentiallyexpressedmetastasisrelatedgenesCharacterizenovelmetastasis-relatedgenesBiomarkersfordiagnosis,prognosispredictionandtherapyGenome-WideIdentificationof59LungCancerInvasionCellLineModelNo.InvadedCells(ChenJJWetal.CancerRes2001)Medium1Medium2MembraneInvasionCultureLungCancerInvasionCellLine60IVMetastasisAssayinSCIDMiceCL1-0CL1-5IVMetastasisAssayinSCIDMiProteomicsforMetastaticMarkersNM23CL1-0CL1-5ProteomicsforMetastaticMarkMicroarrayandPathwayAnalysis192325413476(CRSD:LiuCCetal.NAR2006)MicroarrayandPathwayAnalysi63molecular-mechanisms-of-cancer-metastasis-in-lung-cancer-肺癌之【課件】RiskScore=0.47NF1+0.51HGF+0.52HMMR+0.52IRF4+0.55ZNF264+0.55ErbB3+0.59STAT2+0.59CPEB4+0.65RNF4+0.75DUSP6+0.92MMD+1.32DLG2-1.09ANXA5-0.84LCK-0.77FRAP1-0.58STAT1(ChenHYetal.NEJM2007)MicroarrayGeneSignatureandLungCancerOutcomeRiskScore=0.47NF1+0.51HGF+0.(YuSLetal.CancerCell2008)miR-137miR-182*miR-372miR-221Let-7aMicroRNASignaturePredictsNSCLCOutcome(YuSLetal.CancerCell200LowriskN=31HighriskN=16AllN=47OverallsurvivalLowriskN=15HighriskN=13AllN=28LowriskN=12HighriskN=25AllN=37MonthsMonthsMonthsRelapse-freesurvivalMonthsMonthsMonthsLowriskN=31HighriskN=16AllN=47LowriskN=15HighriskN=13AllN=28LowriskN=12HighriskN=25AllN=37P=0.044P=0.047P=0.004P=0.031P=0.046P=0.076StageIStageIIStageIIIMicroRNASignatureofNSCLC:SubgroupAnalysis(YuSLetal.CancerCell2008)LowriskN=31HighriskN=16AllNGeneSignatureforLungAdenocarcinomaGenesignaturesforoutcomeprediction

(BeerD.NatureMed2002,BianchiF.JCI2007,SunZ.JCO2008,LauSK.JCO2007,PottiA.NEJM2006,ChenHY.NEJM2007,etc)Minimaloverlap,non-celltypespecific,differentstatisticalmethod,lackofindependentvalidationLarge,training-testing,multi-site,blindvalidationMolecularinformationusefulforriskpredictionofearlystagelungcancer

(SheddenKetal.NatureMed2008)CombinemultiplelevelsofbiomarkersDNA,mRNAbiomarkersmicroRNA(YuSLetal.CancerCell2008)DNAmethylation(BrockMetal.NEJM2008)Proteomics,Glycoproteome

GeneSignatureforLungAdenoc68InteractionNetworksofIndependentPrognosticGeneSets(LauSKetal.JCO2007)InteractionNetworksofIndepeCombinationofGeneExpressionandMicroRNASignaturesandLungCancerOutcomeNone(n=24)Twosignatures(n=30)Anyonesignature(n=39)P<0.0001Three-yearsurvival:None:0.91Anyonesignature:0.61Twosignatures:0.16MonthsOverallsurvivalSignatures:Gene:ChenHYetal,NEJM2007micr

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