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甲状腺髓样癌的分子分型及治疗
解放军第一一七医院
戚晓平甲状腺髓样癌的分子分型及治疗解放军第一一概况Histologicsubtypesof
thyroidcancer
①Papillary:approximately80%ofallthyroidmalignancies;
②FollicularandHürthle:approximately11%;
③Medullary:lessthan5%-8%;
④Anaplastic:lessthan2%.
概况HistologicsubtypesofthyroIntroductionMedullarythyroidcancer(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
IntroductionMedullarythyroidIntroduction①SporadicMTC:
asolitaryandunilateralorapalpablecervicallymphnode
②HereditaryMTC:multicentricandbilateraltheuppertomiddlepartsofthethyroidlobes
Introduction①SporadicMTC:aIntroductionInvolvementofcervicallymphnodesisanearlyandcommonmanifestationintheclinicalcourseofthedisease,with35%to50%ormore,another10%to15%mayhavedistantmetastasesatthetimeofinitialpresentation;
DistantmetastaticspreadofMTCfrequentlyinvolvesthemediastinalnodes,lung,liver(>90%),andbones.
IntroductionInvolvementofcep.C611YMEN2Ap.C611YMolecularAberrations
(overexpression)
①RET
mutations②VEGFR-2③MET④EGFR⑤
FGFR⑥
RAS
(sMTC---56%KRAS+;12%HRAS)(MutationsinRASappeartobemutuallyexclusiveofRETabnormalities)
SomaticRETmutationsMolecularAberrations(overexpMolecularpathways①PI3K/Akt/mTOR②MAPK③JNK④RAS/ERKPlaycriticalrolesinregulatingcellproliferation,differentiation,motility,apoptosis,andsurvival
Molecularpathways①PI3K/Akt/DiagnosisandMonitoring①FNA,USandCT,MRIorECT(Ct>500pg/mL);
②DNAanalysisfortheRETgermlinemutation
ATA-2015,ETA-2013,NCCN-2017Guidelinesrecommend
③
TheMTCspecimenispositivelystainedforCt,chromograninA,andCEAorCongoRed.
DiagnosisandMonitoring①FNA,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
DiagnosisandMonitoring④SeruDiagnosisandMonitoring④Serum-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
DiagnosisandMonitoring④SerumDiagnosisandMonitoring●10-yrSRforpatientswithstagesI,II,III,andIVMTCare100%,93%,71%,and21%,respectively;●SRforpatientswithdistantmetastasesMTCis51%at1yr,26%at5yr,and10%at10yr,respectively.
●DiagnosisandMonitoring●10-yrATA-2015GuidelinesrecommendedATA-2015Guidelinesrecommende甲状腺髓样癌的分子分型及治疗-课件MEN2B-denovo
RET
p.M918TMEN2B-denovoRETp.M918TMEN2B-denovo
RET
p.M918TMEN2B-denovoRETp.M918TMEN2A-CLA,RETp.C634R/FMEN2A-CLA,RETp.C634R/F甲状腺髓样癌的分子分型及治疗-课件SurgicalManagementofMTC
①Theminimumextentofsurgeryisatotalthyroidectomy(TT)withbilateralcentralneckdissection(BiⅥ)
(TT+BiⅥLND);②TTwithipsilaterallateralcompartmentneckdissection;
(Unilaterallateral
LN+,MTCsize>1cm)
(TT+BiⅥ+UniLND)③TTwithbilaterallateralcompartmentneckdissection.(BilateraltumorsorextensiveLN+onthecontralateralside)
(TT+BiⅥ+BiLND)SurgicalManagementofMTC①Th甲状腺髓样癌的分子分型及治疗-课件SurgicalManagementofMTC***CurrentrecommendationsforthetimingofprophylacticthyroidectomydependsontheriskleveloftheRETmutationinhereditaryMTC(MEN2).
SurgicalManagementofMTCATA-2015GuidelinesrecommendedATA-2015Guidelinesrecommende甲状腺髓样癌的分子分型及治疗-课件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)SurgicalManagementofMTC●ATFemale,5.5yr;p.C634Y;bilateralMTC;DFS6yrFemale,5.5yr;p.C634Y;bilateResidualandRecurrentDisease
ResidualandRecurrent:approximately50%-80%,postoperationⅰCt<150pg/ml,residualdiseaseinthethyroidbedordraininglymphnodes;ⅱCt>150pg/ml,higherprobabilityofdistantmetastaticdisease;ⅲUS,CT/MRI;
ResidualandRecurrentDiseaseResidualandRecurrentDiseaseCytoreductive(Salvage)surgery
ⅰReducedCtlevelsinmanypatients;ⅱNormalizationoftheCtlevelsinuptoabout1/3ofpatients;ⅲTheriskofsurgicalcomplications↑
ResidualandRecurrentDiseaseMedicalManagementofAdvancedMetastaticDisease
①Cytotoxicchemotherapyinlimitedpatientswithrapidlyprogressivedisease
minimalbenefit
②RadionuclidetherapyI-131responsesonlyabout30%to35%,
③Somatostatinanalogsoctreotide
MedicalManagementofAdvancedMedicalManagementofAdvancedMetastaticDisease④TargetedtherapyMedicalManagementofAdvanced
Tyrosinekinasereceptorsanddownstreameffectors
TyrosinekinasereceptorsandMedicalManagementofAdvancedMetastaticDisease④Targetedtherapy
Tyrosinekinaseinhibitors(TKIs)--
RET,EGFR,VEGFR,andFGFR,MET
Twosmall-moleculeTKIs,vandetanib(Apr2011)andcabozantinib(Nov2012),arecurrentlyavailableasapprovedagentsforthetreatmentofadvancedorprogressiveMTCandprovidesignificantincreasesinprogression-freesurvival(PFS).
MedicalManagementofAdvancedMedicalManagementofAdvancedMetastaticDisease●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%)….MedicalManagementofAdvancedMedicalManagementofAdvancedMetastaticDisease●Cabozantinib--RET,VEGFRandc-MET
lesssuitableforelderlypatientsforwhomtheprevalenceofcardiovascularriskfactors
TheestimatedmedianPFSwithvandetanibisnumericallylongerthanwithcabozantinib
Choice:
Thepatient’scomorbidconditionsandthetoxicityprofilethatthepatientiswillingtobear
MedicalManagementofAdvancedMedicalManagementofAdvancedMetastaticDisease●othersmall-moleculekinaseinhibitorssunitinib,sorafenib,andpazopanib
●Othertargetedtreatments
mammaliantargetofrapamycin(mTOR)inhibitor-everolimus
MedicalManagementofAdvanced
Prevention-PD/PGDPreimplantationgeneticdiagnosisofmultipleendocrineneoplasiatype2Ausinginformativemarkersidentifiedbytargetedsequencing[J],Thyroid,2017.(UR)
Prevention-PD/PGDPreimplantatAcknowledgementAcknowledgement甲状腺髓样癌的分子分型及治疗-课件甲状腺髓样癌的分子分型及治疗
解放军第一一七医院
戚晓平甲状腺髓样癌的分子分型及治疗解放军第一一概况Histologicsubtypesof
thyroidcancer
①Papillary:approximately80%ofallthyroidmalignancies;
②FollicularandHürthle:approximately11%;
③Medullary:lessthan5%-8%;
④Anaplastic:lessthan2%.
概况HistologicsubtypesofthyroIntroductionMedullarythyroidcancer(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
IntroductionMedullarythyroidIntroduction①SporadicMTC:
asolitaryandunilateralorapalpablecervicallymphnode
②HereditaryMTC:multicentricandbilateraltheuppertomiddlepartsofthethyroidlobes
Introduction①SporadicMTC:aIntroductionInvolvementofcervicallymphnodesisanearlyandcommonmanifestationintheclinicalcourseofthedisease,with35%to50%ormore,another10%to15%mayhavedistantmetastasesatthetimeofinitialpresentation;
DistantmetastaticspreadofMTCfrequentlyinvolvesthemediastinalnodes,lung,liver(>90%),andbones.
IntroductionInvolvementofcep.C611YMEN2Ap.C611YMolecularAberrations
(overexpression)
①RET
mutations②VEGFR-2③MET④EGFR⑤
FGFR⑥
RAS
(sMTC---56%KRAS+;12%HRAS)(MutationsinRASappeartobemutuallyexclusiveofRETabnormalities)
SomaticRETmutationsMolecularAberrations(overexpMolecularpathways①PI3K/Akt/mTOR②MAPK③JNK④RAS/ERKPlaycriticalrolesinregulatingcellproliferation,differentiation,motility,apoptosis,andsurvival
Molecularpathways①PI3K/Akt/DiagnosisandMonitoring①FNA,USandCT,MRIorECT(Ct>500pg/mL);
②DNAanalysisfortheRETgermlinemutation
ATA-2015,ETA-2013,NCCN-2017Guidelinesrecommend
③
TheMTCspecimenispositivelystainedforCt,chromograninA,andCEAorCongoRed.
DiagnosisandMonitoring①FNA,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
DiagnosisandMonitoring④SeruDiagnosisandMonitoring④Serum-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
DiagnosisandMonitoring④SerumDiagnosisandMonitoring●10-yrSRforpatientswithstagesI,II,III,andIVMTCare100%,93%,71%,and21%,respectively;●SRforpatientswithdistantmetastasesMTCis51%at1yr,26%at5yr,and10%at10yr,respectively.
●DiagnosisandMonitoring●10-yrATA-2015GuidelinesrecommendedATA-2015Guidelinesrecommende甲状腺髓样癌的分子分型及治疗-课件MEN2B-denovo
RET
p.M918TMEN2B-denovoRETp.M918TMEN2B-denovo
RET
p.M918TMEN2B-denovoRETp.M918TMEN2A-CLA,RETp.C634R/FMEN2A-CLA,RETp.C634R/F甲状腺髓样癌的分子分型及治疗-课件SurgicalManagementofMTC
①Theminimumextentofsurgeryisatotalthyroidectomy(TT)withbilateralcentralneckdissection(BiⅥ)
(TT+BiⅥLND);②TTwithipsilaterallateralcompartmentneckdissection;
(Unilaterallateral
LN+,MTCsize>1cm)
(TT+BiⅥ+UniLND)③TTwithbilaterallateralcompartmentneckdissection.(BilateraltumorsorextensiveLN+onthecontralateralside)
(TT+BiⅥ+BiLND)SurgicalManagementofMTC①Th甲状腺髓样癌的分子分型及治疗-课件SurgicalManagementofMTC***CurrentrecommendationsforthetimingofprophylacticthyroidectomydependsontheriskleveloftheRETmutationinhereditaryMTC(MEN2).
SurgicalManagementofMTCATA-2015GuidelinesrecommendedATA-2015Guidelinesrecommende甲状腺髓样癌的分子分型及治疗-课件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)SurgicalManagementofMTC●ATFemale,5.5yr;p.C634Y;bilateralMTC;DFS6yrFemale,5.5yr;p.C634Y;bilateResidualandRecurrentDisease
ResidualandRecurrent:approximately50%-80%,postoperationⅰCt<150pg/ml,residualdiseaseinthethyroidbedordraininglymphnodes;ⅱCt>150pg/ml,higherprobabilityofdistantmetastaticdisease;ⅲUS,CT/MRI;
ResidualandRecurrentDiseaseResidualandRecurrentDiseaseCytoreductive(Salvage)surgery
ⅰReducedCtlevelsinmanypatients;ⅱNormalizationoftheCtlevelsinuptoabout1/3ofpatients;ⅲTheriskofsurgicalcomplications↑
ResidualandRecurrentDiseaseMedicalManagementofAdvancedMetastaticDisease
①Cytotoxicchemotherapyinlimitedpatientswithrapidlyprogressivedisease
minimalbenefit
②RadionuclidetherapyI-131responsesonlyabout30%to35%,
③Somatostatinanalogsoctreotide
MedicalManagementofAdvancedMedicalManagementofAdvancedMetastaticDisease④TargetedtherapyMedicalManagementofAdvanced
Tyrosinekinasereceptorsanddownstreameffectors
TyrosinekinasereceptorsandMedicalManagementofAdvancedMetastaticDisease④Targetedtherapy
Tyrosinekinaseinhibitors(TKIs)--
RET,EGFR,VEGFR,andFGFR,MET
Twosmall-moleculeTKIs,vandetanib(Apr2011)andcabozantinib(Nov2012),arecurrentlyavailableasapprovedagentsforthet
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