甲狀腺髓樣癌的分子分型及治療

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