【文档说明】甲状腺髓样癌的分子分型及治疗教学课件.ppt，共(37)页，9.185 MB，由小橙橙上传

转载请保留链接：https://www.ichengzhen.cn/view-249415.html

以下为本文档部分文字说明：

甲状腺髓样癌的分子分型及治疗1概况Histologicsubtypesofthyroidcancer①Papillary:approximately80%ofallthyroidmalignancies;②FollicularandHürthle:approxima

tely11%;③Medullary:lessthan5%-8%;④Anaplastic:lessthan2%.2IntroductionMedullarythyroidcancer(MTC)①Sporadi

cMTC:approximately75%;>50%somaticRETmutations(p.M918T)-predictapoorprognosis②HereditaryMTC:approximately25%;98%Germli

neRETmutations,MEN2A(~95%)andMEN2B(~5%)Arisesfromtheneuralcrest-derived,calcitonin-secreting,parafollicularCcellsofthethyroidgland3Introduc

tion①SporadicMTC:asolitaryandunilateralorapalpablecervicallymphnode②HereditaryMTC:multicentricandbilateraltheuppertomiddlepartsofthet

hyroidlobes4IntroductionInvolvementofcervicallymphnodesisanearlyandcommonmanifestationintheclinicalcourseofthedisease,with35

%to50%ormore,another10%to15%mayhavedistantmetastasesatthetimeofinitialpresentation;DistantmetastaticspreadofMTCfrequentlyinvol

vesthemediastinalnodes,lung,liver(>90%),andbones.5p.C611YMEN2A6MolecularAberrations(overexpression)①RETmutations②VEGFR-2③M

ET④EGFR⑤FGFR⑥RAS(sMTC---56%KRAS+;12%HRAS)(MutationsinRASappeartobemutuallyexclusiveofRETabnormalities)Soma

ticRETmutations7Molecularpathways①PI3K/Akt/mTOR②MAPK③JNK④RAS/ERKPlaycriticalrolesinregulatingcellproliferation,differentiation,motilit

y,apoptosis,andsurvival8DiagnosisandMonitoring①FNA,USandCT,MRIorECT(Ct>500pg/mL);②DNAanalysisfortheRETgermlinemutationA

TA-2015,ETA-2013,NCCN-2017Guidelinesrecommend③TheMTCspecimenispositivelystainedforCt,chromograninA,andCEAorCongoRed.9Di

agnosisandMonitoring④Serum-basedbiomarkers:calcitoninandCEA(>50%)Preoperative:ⅰCEA(↑),Ct(-)--poorlydifferentiatedtumors,Rare;ⅱCt>100pg/mL--predicti

ve–MTC;ⅲCt>150pg/mL,CEA>30ng/L--regionalspread;ⅳCt>3000pg/mL,CEA>100ng/L--distantspread.PredictorsofMTCprogress,includin

grecurrenceandsurvival10DiagnosisandMonitoring④Serum-basedbiomarkers:calcitoninandCEAPostoperative:ⅰCt(↑)--thefirstsignoftum

orrecurrence;ⅱCt(-)andsCt(-)--10-yearsurvivalrates(SR)of100%;yearlyCtmeasurements;ⅲCtdoublingtimes(DT)>1yr(2yr)--5-and10-yrS

Rof98%and95%;CEADT>1yr--5-and10-yrSRof100%；ⅳCtDT<1yr(6mon)--5-and10-yrSRof36%and18%（25%and8%）;CEA<1year--

5-and10-yrSRof43%and21%.PredictorsofMTCprogress,includingrecurrenceandsurvival11DiagnosisandMonitoring●10-yrSRforpatientswithstagesI,II,III,andIVMT

Care100%,93%,71%,and21%,respectively;●SRforpatientswithdistantmetastasesMTCis51%at1yr,26%at5yr,and10%at10yr,respe

ctively.●12ATA-2015Guidelinesrecommended1314MEN2B-denovoRETp.M918T15MEN2B-denovoRETp.M918T16MEN2A-CLA,RETp.C634R/F1718SurgicalManagem

entofMTC①Theminimumextentofsurgeryisatotalthyroidectomy(TT)withbilateralcentralneckdissection(BiⅥ)(TT+B

iⅥLND);②TTwithipsilaterallateralcompartmentneckdissection;(UnilaterallateralLN+,MTCsize>1cm)(TT+BiⅥ+UniLND)③TTw

ithbilaterallateralcompartmentneckdissection.(BilateraltumorsorextensiveLN+onthecontralateralside)(TT+BiⅥ+BiLND)1920SurgicalMa

nagementofMTC***CurrentrecommendationsforthetimingofprophylacticthyroidectomydependsontheriskleveloftheRETmutationinheredita

ryMTC(MEN2).21ATA-2015Guidelinesrecommended2223SurgicalManagementofMTC●ATA-D(HST)-MEN2B>1yr,TT+BiⅥLND;●ATA-A~C(MOD~H)-MEN2Abasal

Ct<40pg/mL,TTwithoutBiⅥLNDisadequate.(Ct<60ng/L,EliseiR,etal;Ct<70ng/L,QiXP,etal)24Female,5.5yr;p.C634Y;

bilateralMTC;DFS6yr25ResidualandRecurrentDiseaseResidualandRecurrent:approximately50%-80%,postoperationⅰCt<150

pg/ml,residualdiseaseinthethyroidbedordraininglymphnodes;ⅱCt>150pg/ml,higherprobabilityofdistantmetastaticdi

sease;ⅲUS,CT/MRI;26ResidualandRecurrentDiseaseCytoreductive(Salvage)surgeryⅰReducedCtlevelsinmanypatients;ⅱNormalizationoftheCtl

evelsinuptoabout1/3ofpatients;ⅲTheriskofsurgicalcomplications↑27MedicalManagementofAdvancedMetastaticDisease①Cytot

oxicchemotherapyinlimitedpatientswithrapidlyprogressivediseaseminimalbenefit②RadionuclidetherapyI-131re

sponsesonlyabout30%to35%,③Somatostatinanalogsoctreotide28MedicalManagementofAdvancedMetastaticDisease④Targetedtherapy29Tyrosinekinaserecept

orsanddownstreameffectors30MedicalManagementofAdvancedMetastaticDisease④TargetedtherapyTyrosinekinaseinhibitors(TKIs)--RET,EGFR,VEGFR,andFGFR,MET

Twosmall-moleculeTKIs,vandetanib(Apr2011)andcabozantinib(Nov2012),arecurrentlyavailableasapprovedagentsforthetreatmentofadvancedorprogressiv

eMTCandprovidesignificantincreasesinprogression-freesurvival(PFS).31MedicalManagementofAdvancedMetastaticDisease●Vand

etanib--RET,EGFR,VEGFRandEGFRⅰtwophase2(hereditaryonly)dosedaily300mg100mgPR20%16%stabledisease53%53%medianPFS27.9months>24wee

ksⅱphase3in331patients(H-S-MTC)300mg/d;objectiveresponserate(ORR)45%;medianPFS30.5months.QTprolongation(14%),diarrhea(56%),rash

(45%),hypertension(32%),headache(26%)….32MedicalManagementofAdvancedMetastaticDisease●Cabozantinib--RET,VEGFRandc-METl

esssuitableforelderlypatientsforwhomtheprevalenceofcardiovascularriskfactorsTheestimatedmedianPFSwithvandetanibisnumericallylongertha

nwithcabozantinibChoice:Thepatient’scomorbidconditionsandthetoxicityprofilethatthepatientiswillingtobear33MedicalMa

nagementofAdvancedMetastaticDisease●othersmall-moleculekinaseinhibitorssunitinib,sorafenib,andpazopanib●Othertargetedtreatmentsmammalian

targetofrapamycin(mTOR)inhibitor-everolimus34Prevention-PD/PGDPreimplantationgeneticdiagnosisofmultipleendocrineneoplasiatype2Ausinginform

ativemarkersidentifiedbytargetedsequencing[J],Thyroid,2017.(UR)35Acknowledgement3637