甲状腺髓样癌的分子分型及治疗.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,HistologicsubtypesofthyroidcancerPapillary:approximately80%ofallthyroidmalignancies;FollicularandHrthle:approximately11%;Medullary:lessthan5%-8%;Anaplastic:lessthan2%.,Introduction,Medullarythyroidcancer(MTC)SporadicMTC:approximately75%;50%somaticRETmutations(p.M918T)-predictapoorprognosisHereditaryMTC:approximately25%;98%GermlineRETmutations,MEN2A(95%)andMEN2B(5%)Arisesfromtheneuralcrest-derived,calcitonin-secreting,parafollicularCcellsofthethyroidgland,Introduction,SporadicMTC:asolitaryandunilateralorapalpablecervicallymphnodeHereditaryMTC:multicentricandbilateraltheuppertomiddlepartsofthethyroidlobes,Introduction,Involvementofcervicallymphnodesisanearlyandcommonmanifestationintheclinicalcourseofthedisease,with35%to50%ormore,another10%to15%mayhavedistantmetastasesatthetimeofinitialpresentation;DistantmetastaticspreadofMTCfrequentlyinvolvesthemediastinalnodes,lung,liver(90%),andbones.,p.C611YMEN2A,MolecularAberrations(overexpression),RETmutationsVEGFR-2METEGFRFGFRRAS(sMTC-56%KRAS+;12%HRAS)(MutationsinRASappeartobemutuallyexclusiveofRETabnormalities),SomaticRETmutations,Molecularpathways,PI3K/Akt/mTORMAPKJNKRAS/ERKPlaycriticalrolesinregulatingcellproliferation,differentiation,motility,apoptosis,andsurvival,DiagnosisandMonitoring,FNA,USandCT,MRIorECT(Ct500pg/mL);DNAanalysisfortheRETgermlinemutationATA-2019,ETA-2019,NCCN-2019GuidelinesrecommendTheMTCspecimenispositivelystainedforCt,chromograninA,andCEAorCongoRed.,DiagnosisandMonitoring,Serum-basedbiomarkers:calcitoninandCEA(50%)Preoperative:CEA(),Ct(-)-poorlydifferentiatedtumors,Rare;Ct100pg/mL-predictiveMTC;Ct150pg/mL,CEA30ng/L-regionalspread;Ct3000pg/mL,CEA100ng/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%;CEADT1yr-5-and10-yrSRof100%；CtDT1yr,TT+BiLND;ATA-AC(MODH)-MEN2AbasalCt40pg/mL,TTwithoutBiLNDisadequate.(Ct60ng/L,EliseiR,etal;Ct24weeksphase3in331patients(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:Thepatientscomorbidconditionsandthetoxicityprofilethatthepatientiswillingtobear,MedicalManagementofAdvancedMetastaticDisease,othersmall-moleculekinaseinhibitorssunitinib,sorafenib,andpazopanibOthertargetedtreatmentsmammaliantargetofrapamycin(mTOR)inhibitor-everolimus,Prevention-PD/PGD,Preimplant