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甲狀腺髓樣癌的分子分型及治療
解放軍第一一七醫(yī)院
戚曉平第1頁(yè),共38頁(yè)。概況Histologicsubtypesof
thyroidcancer
①Papillary:approximately80%ofallthyroidmalignancies;
②FollicularandHürthle:approximately11%;
③Medullary:lessthan5%-8%;
④Anaplastic:lessthan2%.
第2頁(yè),共38頁(yè)。IntroductionMedullarythyroidcancer(MTC)①SporadicMTC:
approximately75%;>50%
somatic
RET
mutations(p.M918T)
-predictapoorprognosis
②HereditaryMTC:
approximately25%;
98%Germline
RET
mutations,MEN2A(~95%)andMEN2B(~5%)
Arisesfromtheneuralcrest-derived,calcitonin-secreting,parafollicularCcellsofthethyroidgland
第3頁(yè),共38頁(yè)。Introduction①SporadicMTC:
asolitaryandunilateralorapalpablecervicallymphnode
②HereditaryMTC:multicentricandbilateraltheuppertomiddlepartsofthethyroidlobes
第4頁(yè),共38頁(yè)。IntroductionInvolvementofcervicallymphnodesisanearlyandcommonmanifestationintheclinicalcourseofthedisease,with35%to50%ormore,another10%to15%mayhavedistantmetastasesatthetimeofinitialpresentation;
DistantmetastaticspreadofMTCfrequentlyinvolvesthemediastinalnodes,lung,liver(>90%),andbones.
第5頁(yè),共38頁(yè)。p.C611YMEN2A第6頁(yè),共38頁(yè)。MolecularAberrations
(overexpression)
①RET
mutations②VEGFR-2③MET④EGFR⑤
FGFR⑥
RAS
(sMTC---56%KRAS+;12%HRAS)(MutationsinRASappeartobemutuallyexclusiveofRETabnormalities)
SomaticRETmutations第7頁(yè),共38頁(yè)。Molecularpathways①PI3K/Akt/mTOR②MAPK③JNK④RAS/ERKPlaycriticalrolesinregulatingcellproliferation,differentiation,motility,apoptosis,andsurvival
第8頁(yè),共38頁(yè)。DiagnosisandMonitoring①FNA,USandCT,MRIorECT(Ct>500pg/mL);
②DNAanalysisfortheRETgermlinemutation
ATA-2015,ETA-2013,NCCN-2017Guidelinesrecommend
③
TheMTCspecimenispositivelystainedforCt,chromograninA,andCEAorCongoRed.
第9頁(yè),共38頁(yè)。DiagnosisandMonitoring
④Serum-basedbiomarkers:
calcitoninandCEA(>50%)Preoperative:ⅰCEA(↑),Ct(-)--poorlydifferentiatedtumors,Rare;
ⅱCt>100pg/mL--predictive–MTC;
ⅲCt>150pg/mL,CEA>30ng/L--regionalspread;
ⅳCt>3000pg/mL,CEA>100ng/L--distantspread.PredictorsofMTCprogress,includingrecurrenceandsurvival
第10頁(yè),共38頁(yè)。DiagnosisandMonitoring④Serum-basedbiomarkers:
calcitoninandCEAPostoperative:ⅰCt(↑)--thefirstsignoftumorrecurrence;ⅱCt(-)andsCt(-)--10-yearsurvivalrates(SR)of100%;yearlyCtmeasurements;
ⅲCtdoublingtimes(DT)>1yr(2yr)--5-and10-yrSR
of98%and95%;CEADT>1yr--5-and10-yrSRof100%;
ⅳCtDT<1yr(6mon)--5-and10-yrSR
of36%and18%(25%and8%
);CEA<1year--5-and10-yrSRof43%and21%.
PredictorsofMTCprogress,includingrecurrenceandsurvival
第11頁(yè),共38頁(yè)。DiagnosisandMonitoring●10-yrSRforpatientswithstagesI,II,III,andIVMTCare100%,93%,71%,and21%,respectively;●SRforpatientswithdistantmetastasesMTCis51%at1yr,26%at5yr,and10%at10yr,respectively.
●第12頁(yè),共38頁(yè)。ATA-2015Guidelinesrecommended第13頁(yè),共38頁(yè)。第14頁(yè),共38頁(yè)。MEN2B-denovo
RET
p.M918T第15頁(yè),共38頁(yè)。MEN2B-denovo
RET
p.M918T第16頁(yè),共38頁(yè)。MEN2A-CLA,RETp.C634R/F第17頁(yè),共38頁(yè)。第18頁(yè),共38頁(yè)。SurgicalManagementofMTC
①Theminimumextentofsurgeryisatotalthyroidectomy(TT)withbilateralcentralneckdissection(BiⅥ)
(TT+BiⅥLND);②TTwithipsilaterallateralcompartmentneckdissection;
(Unilaterallateral
LN+,MTCsize>1cm)
(TT+BiⅥ+UniLND)③TTwithbilaterallateralcompartmentneckdissection.(BilateraltumorsorextensiveLN+onthecontralateralside)
(TT+BiⅥ+BiLND)第19頁(yè),共38頁(yè)。第20頁(yè),共38頁(yè)。SurgicalManagementofMTC***CurrentrecommendationsforthetimingofprophylacticthyroidectomydependsontheriskleveloftheRETmutationinhereditaryMTC(MEN2).
第21頁(yè),共38頁(yè)。ATA-2015Guidelinesrecommended第22頁(yè),共38頁(yè)。第23頁(yè),共38頁(yè)。SurgicalManagementofMTC●ATA-D(HST)-MEN2B
>1yr,TT+BiⅥLND;
●ATA-A~C(MOD~H)-MEN2A
basalCt<40pg/mL,TTwithoutBiⅥLNDisadequate.(Ct
<60ng/L,EliseiR,etal
;Ct
<70ng/L,QiXP,etal)第24頁(yè),共38頁(yè)。Female,5.5yr;p.C634Y;bilateralMTC;DFS6yr第25頁(yè),共38頁(yè)。ResidualandRecurrentDisease
ResidualandRecurrent:approximately50%-80%,postoperationⅰCt<150pg/ml,residualdiseaseinthethyroidbedordraininglymphnodes;ⅱCt>150pg/ml,higherprobabilityofdistantmetastaticdisease;ⅲUS,CT/MRI;
第26頁(yè),共38頁(yè)。ResidualandRecurrentDiseaseCytoreductive(Salvage)surgery
ⅰReducedCtlevelsinmanypatients;ⅱNormalizationoftheCtlevelsinuptoabout1/3ofpatients;ⅲTheriskofsurgicalcomplications↑
第27頁(yè),共38頁(yè)。MedicalManagementofAdvancedMetastaticDisease
①Cytotoxicchemotherapyinlimitedpatientswithrapidlyprogressivedisease
minimalbenefit
②RadionuclidetherapyI-131responsesonlyabout30%to35%,
③Somatostatinanalogsoctreotide
第28頁(yè),共38頁(yè)。MedicalManagementofAdvancedMetastaticDisease④Targetedtherapy第29頁(yè),共38頁(yè)。
Tyrosinekinasereceptorsanddownstreameffectors第30頁(yè),共38頁(yè)。MedicalManagementofAdvancedMetastaticDisease④Targetedtherapy
Tyrosinekinaseinhibitors(TKIs)--
RET,EGFR,VEGFR,andFGFR,MET
Twosmall-moleculeTKIs,vandetanib(Apr2011)andcabozantinib(Nov2012),arecurrentlyavailableasapprovedagentsforthetreatmentofadvancedorprogressiveMTCandprovidesignificantincreasesinprogression-freesurvival(PFS).
第31頁(yè),共38頁(yè)。MedicalManagementofAdvancedMetastaticDisease●Vandetanib--RET,EGFR,VEGFRandEGFRⅰtwophase2(hereditaryonly)
dosedaily300mg100mgPR20%16%stabledisease53%53%medianPFS27.9months>24weeksⅱphase3in331patients
(H-S-MTC)300mg/d;objectiveresponserate(ORR)45%;medianPFS30.5months.
QTprolongation(14%),diarrhea(56%),rash(45%),hypertension(32%),headache(26%)….第32頁(yè),共38頁(yè)。MedicalManagementofAdvancedMetastaticDisease●Cabozantinib--RET,VEGFRandc-MET
lesssuitableforelderlypatientsforwhomtheprevalenceofcardiovascularriskfactors
TheestimatedmedianPFSwithvandetanibisnumericallylongerthanwithcabozantinib
Choice:
Thepatient’scomorbidconditionsandthetoxicity
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