甲状腺髓样癌的分子分型及治疗ppt课件.ppt

甲状腺髓样癌的分子分型及治疗 解放军第一一七医院戚晓平 概况 Histologicsubtypesofthyroidcancer Papillary approximately80 ofallthyroidmalignancies FollicularandH rthle approximately11 Medullary lessthan5 8 Anaplastic lessthan2 Introduction Medullarythyroidcancer MTC SporadicMTC approximately75 50 somaticRETmutations p M918T predictapoorprognosis HereditaryMTC approximately25 98 GermlineRETmutations MEN2A 95 andMEN2B 5 Arisesfromtheneuralcrest derived calcitonin secreting parafollicularCcellsofthethyroidgland Introduction SporadicMTC asolitaryandunilateralorapalpablecervicallymphnode HereditaryMTC multicentricandbilateraltheuppertomiddlepartsofthethyroidlobes Introduction Involvementofcervicallymphnodesisanearlyandcommonmanifestationintheclinicalcourseofthedisease with35 to50 ormore another10 to15 mayhavedistantmetastasesatthetimeofinitialpresentation DistantmetastaticspreadofMTCfrequentlyinvolvesthemediastinalnodes lung liver 90 andbones p C611YMEN2A MolecularAberrations overexpression RETmutations VEGFR 2 MET EGFR FGFR RAS sMTC 56 KRAS 12 HRAS MutationsinRASappeartobemutuallyexclusiveofRETabnormalities SomaticRETmutations Molecularpathways PI3K Akt mTOR MAPK JNK RAS ERKPlaycriticalrolesinregulatingcellproliferation differentiation motility apoptosis andsurvival DiagnosisandMonitoring FNA USandCT MRIorECT Ct 500pg mL DNAanalysisfortheRETgermlinemutationATA 2015 ETA 2013 NCCN 2017Guidelinesrecommend TheMTCspecimenispositivelystainedforCt chromograninA andCEAorCongoRed DiagnosisandMonitoring Serum basedbiomarkers calcitoninandCEA 50 Preoperative CEA Ct poorlydifferentiatedtumors Rare Ct 100pg mL predictive MTC Ct 150pg mL CEA 30ng L regionalspread Ct 3000pg mL CEA 100ng L distantspread PredictorsofMTCprogress includingrecurrenceandsurvival DiagnosisandMonitoring Serum basedbiomarkers calcitoninandCEAPostoperative Ct thefirstsignoftumorrecurrence Ct andsCt 10 yearsurvivalrates SR of100 yearlyCtmeasurements Ctdoublingtimes DT 1yr 2yr 5 and10 yrSRof98 and95 CEADT 1yr 5 and10 yrSRof100 CtDT 1yr 6mon 5 and10 yrSRof36 and18 25 and8 CEA 1year 5 and10 yrSRof43 and21 PredictorsofMTCprogress includingrecurrenceandsurvival DiagnosisandMonitoring 10 yrSRforpatientswithstagesI II III andIVMTCare100 93 71 and21 respectively SRforpatientswithdistantmetastasesMTCis51 at1yr 26 at5yr and10 at10yr respectively ATA 2015Guidelinesrecommended MEN2B denovoRETp M918T MEN2B denovoRETp M918T MEN2A CLA RETp C634R F SurgicalManagementofMTC Theminimumextentofsurgeryisatotalthyroidectomy TT withbilateralcentralneckdissection Bi TT Bi LND TTwithipsilaterallateralcompartmentneckdissection UnilaterallateralLN MTCsize 1cm TT Bi UniLND TTwithbilaterallateralcompartmentneckdissection BilateraltumorsorextensiveLN onthecontralateralside TT Bi BiLND SurgicalManagementofMTC CurrentrecommendationsforthetimingofprophylacticthyroidectomydependsontheriskleveloftheRETmutationinhereditaryMTC MEN2 ATA 2015Guidelinesrecommended SurgicalManagementofMTC ATA D HST MEN2B 1yr TT Bi LND ATA A C MOD H MEN2AbasalCt 40pg mL TTwithoutBi LNDisadequate Ct 60ng L EliseiR etal Ct 70ng L QiXP etal Female 5 5yr p C634Y bilateralMTC DFS6yr ResidualandRecurrentDisease ResidualandRecurrent approximately50 80 postoperation Ct150pg ml higherprobabilityofdistantmetastaticdisease US CT MRI ResidualandRecurrentDisease Cytoreductive Salvage surgery ReducedCtlevelsinmanypatients NormalizationoftheCtlevelsinuptoabout1 3ofpatients Theriskofsurgicalcomplications MedicalManagementofAdvancedMetastaticDisease Cytotoxicchemotherapyinlimitedpatientswithrapidlyprogressivediseaseminimalbenefit RadionuclidetherapyI 131responsesonlyabout30 to35 Somatostatinanalogsoctreotide MedicalManagementofAdvancedMetastaticDisease Targetedtherapy Tyrosinekinasereceptorsanddownstreameffectors MedicalManagementofAdvancedMetastaticDisease TargetedtherapyTyrosinekinaseinhibitors TKIs RET EGFR VEGFR andFGFR MET Twosmall moleculeTKIs vandetanib Apr2011 andcabozantinib Nov2012 arecurrentlyavailableasapprovedagentsforthetreatmentofadvancedorprogressiveMTCandprovidesignificantincreasesinprogression freesurvival PFS MedicalManagementofAdvancedMetastaticDisease Vandetanib RET EGFR VEGFRandEGFR twophase2 hereditaryonly dosedaily300mg100mgPR20 16 stabledisease53 53 medianPFS27 9months 24weeks phase3in331patients H S MTC 300mg d objectiveresponserate ORR 45 medianPFS30 5months QTprolongation 14 diarrhea 56 rash 45 hypertension 32 headache 26 MedicalManagementofAdvancedMetastaticDisease Cabozantinib RET VEGFRandc METlesssuitableforelderlypatientsforwhomtheprevalenceofcardiovascularriskfactorsTheestimatedmedianPFSwithvandetanibisnumericallylongerthanwithcabozantinib Choice Thepatient scomorbidconditionsandthetoxicityprofilethatthepatientiswillingtobear MedicalManagementofAdvancedMetastaticDisease othersmall moleculekinaseinhibitorssunitinib sorafenib andpazo