ThyroidCancer 甲状腺癌课件

ThyroidCancer

ResearchPresentationJasonM.Leibowitz,MDJune25,2009Preceptor:MarciaS.Brose,MDPhDOtorhinolaryngology:HeadandNeckSurgeryatPENNExcellenceinPatientCare,EducationandResearchsince1870OverviewBackgroundHypothesisMethodsResultsDiscussionConclusions&FutureDirectionsThyroidCancerintheUnitedStatesThyroidcanceristhe

mostcommon

endocrineneoplasm.Thyroidcancerwillbediagnosedin33,550individuals(8070menand25,480women)thisyear.From1997-2004incidenceofthyroidcancerincreasedby6.2%mostlyduetoincreaseddetection.From1985to2004mortalityrateincreasedby0.3%ayear.MolecularChangesinThyroidCancerMolecularPathwayinvolvedinThyroidCancerActivationofMAPKpathwayOncogenicactivationofthispathwayin70%ofallthyroidcancers.BRAFisaserinethreoninekinaseXing,2007.BRAFV600EinThyroidCancer2003:TheBRAFV600Emutationisthemostcommongeneticalterationinthyroidcancer,occurringinabout45%ofsporadicpapillarythyroidcancers(PTCs).V600EBRAFV600EPointmutationin40-45%ofPTCUpregulationofMMP,VEGF-->invasion,angiogenesisSilencingoftumorsuppressivegenes,genesinvolvediniodinetransportBRAFmutationassociatedwithmultiplenegativeprognosticindicators.TargetedTherapyinThyroidcancerLossofdifferentiation(inabilitytotrapRAI),unresectablelesion,leadstopoorprognosisBRAFinhibitorsBAY43-9006(Sorafenib)MultikinaseinhibitorTargetedTherapyandGenotypeK-RASgenemutationandmetastaticcolorectalcarcinoma.RecentresultsfromPhaseII&IIIclinicaltrialsdemonstratethatpatientswithmetastaticcolorectalcancerbenefitfromanti-EGFRtherapy.PatientswithK-RASmutationincodon12&13shouldnotreceiveanti-EGFRtherapysincetheydonotreceiveanybenefit.EGFRandnon-smallcelllungcancer:Epithelialgrowthfactorreceptor10%mutatedinNSCLCEGFRmutationsarepredictorsofTKIsresponsivenessandmayshowalonglastingresponsetoTKIsEXON19DeletionrespondbettertoTKIs.Papillaryvs.FollicularP<0.095FTC=19PTC=24PriorDataConclusionsfrompriordata:ImprovedPFSwithSorafenib.ImprovedPFSofFTCtreatedwithSorafenibwhencomparedtoPTC.OverviewBackgroundHypothesisMethodsResultsDiscussionConclusions&FutureDirectionsHypothesisTherearespecificgenotypes(i.e.BRAFV600E,RASmutations)thatpredictfavorableresponsetotargetedtherapy(Sorafenib).NullHypothesisSpecificgeneticmutationsdonotpredictresponsetotargetedtherapyinthyroidcancer.ResearchPlanTissuesamplescollectedfrompatientswithtreatment-resistantthyroidcancerwithlongtermfollow-up(approximately30patients).Allpatientsreceivedtargetedtherapy(Sorafenib).SampleswithWDTCanalyzedformutationsinBRAFandRASgeneswhenavailable:BRAF-V600ERAS-Exon12,13,61RESULTSOverviewBackgroundHypothesisMethodsResultsDiscussionConclusions&FutureDirectionsResultsofStage1Analysis

N=30M=F=15PTC=17,FTC=9,Other(ATC/PD,MTC):4SamplesanalyzedforBRAFmutation:23/30(76.6%):samplesanalyzedforBRAFmutation4/30(13%):definitegenotypebutquestionedduetophenotype(ATC/PD,MTC)2/30(6%):unabletoamplifyDNAdespitemultiplePCRattempts1/30(3%):pendinganalysis18/30samplesanalyzedforRASmutation,allWTcopiesofthegene

BRAFV600EP<0.02N=13(WT=8,V600E=5)UpdatedgeneticsInourexpandedanalysisto22ptswithWDTC,theeffectisnolongersignificantbutthetrendexists.WearefurtherinvestigatingBRAFcopynumberinthesepatientsp=NSN=22WT=13BRAFV600E=9OverviewBackgroundHypothesisMethodsResultsDiscussionConclusions&FutureDirectionsBRAFV600ECorrelateswithworseSurvival

StateofthemutationinPTC,10/2008THEBRAFconnection

Ciampietal.2005UpdatedgeneticsInourexpandedanalysisto22ptswithWDTC,theeffectisnolongersignificantbutthetrendexists.WearefurtherinvestigatingBRAFcopynumberinthesepatientsp=NSN=22WT=13BRAFV600E=9BRAF(red)x37centromere(green)x3BRAFx47centromerex44copieseach3copieseachTHEBRAFconnection!

PositivePredictor!

Ciampietal,2005.SummaryGoodprogressionfreesurvivalinpatientstreatedwithSorafenib.BRAFV600Eappearstopredictforimprovedoutcomeinpatientstreatedwithsorafenib.BRAFcopynumbergainmayexplainimprovedoutcomeofpatientswithFTCoverpatientswithPTCFutureDirectionsCompletionofgenotypinganalysisofallpatientsEvaluationofcopynumbergainsinWDTCHypothesis:CopynumbergainaccountsforimprovedsurvivalinFTCtreatedwithSorafenibNull:CopynumbergaindoesnotinfluencesurvivalinFTCSelectedSourcesCiampiR,ZhuZ,NikiforovYE.BRAFcopynumbergaininthyroidtumorsdetectedbyfluorescenceinsituhybridization.EndocrinePathology2005;16(2):99-105.CiampiR,NikiforovYE.AlterationsoftheBRAFgeneinthyroidtumors.EndocrinePathology2005;16:3):163-171.Gupta-AbramsonV,TroxelAB,NelloreA,etal.PhaseIITrialofSorafenibinAdvancedThyroidCancer.JournalClinOnc2008;26(29):4714-4719.KundraP,BurmanKD.ThyroidCancerMolecularSignalingPathwaysandUseofTargetedTherapy.EndocMetabClinNAm2007;36:839-853MurerB.TargetedTherapyinNon-SmallCellLungCancer.ArchPathLabMed.2008;132:1573-1575.NikiforovYE.ThyroidCarcinoma:MolecularPathwaysandTherapeutictargets.ModernPathology2008;21:S37-S43.VaskoV,FerrandM,CristofaroJDetal.SpecificPatternofRASOncogeneMuta