甲狀腺髓樣癌的分子分型及治療-課件

甲狀腺髓樣癌的分子分型及治療

解放軍第一一七醫(yī)院

戚曉平甲狀腺髓樣癌的分子分型及治療解放軍第一一概況Histologicsubtypesof

thyroidcancer

①Papillary:approximately80%ofallthyroidmalignancies;

②FollicularandHürthle:approximately11%;

③Medullary:lessthan5%-8%;

④Anaplastic:lessthan2%.

概況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甲狀腺髓樣癌的分子分型及治療-課件MEN2B-denovo

RET

p.M918TMEN2B-denovoRETp.M918TMEN2B-denovo

RET

p.M918TMEN2B-denovoRETp.M918TMEN2A-CLA,RETp.C634R/FMEN2A-CLA,RETp.C634R/F甲狀腺髓樣癌的分子分型及治療-課件SurgicalManagementofMTC

①Theminimumextentofsurgeryisatotalthyroidectomy(TT)withbilateralcentralneckdissection(BiⅥ)

(TT+BiⅥLND);②TTwithipsilaterallateralcompartmentneckdissection;

(Unilaterallateral

LN+,MTCsize>1cm)

(TT+BiⅥ+UniLND)③TTwithbilaterallateralcompartmentneckdissection.(BilateraltumorsorextensiveLN+onthecontralateralside)

(TT+BiⅥ+BiLND)SurgicalManagementofMTC①Th甲狀腺髓樣癌的分子分型及治療-課件SurgicalManagementofMTC***CurrentrecommendationsforthetimingofprophylacticthyroidectomydependsontheriskleveloftheRETmutationinhereditaryMTC(MEN2).

SurgicalManagementofMTCATA-2015GuidelinesrecommendedATA-2015Guidelinesrecommende甲狀腺髓樣癌的分子分型及治療-課件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甲狀腺髓樣癌的分子分型及治療-課件甲狀腺髓樣癌的分子分型及治療

解放軍第一一七醫(yī)院

戚曉平甲狀腺髓樣癌的分子分型及治療解放軍第一一概況Histologicsubtypesof

thyroidcancer

①Papillary:approximately80%ofallthyroidmalignancies;

②FollicularandHürthle:approximately11%;

③Medullary:lessthan5%-8%;

④Anaplastic:lessthan2%.

概況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甲狀腺髓樣癌的分子分型及治療-課件MEN2B-denovo

RET

p.M918TMEN2B-denovoRETp.M918TMEN2B-denovo

RET

p.M918TMEN2B-denovoRETp.M918TMEN2A-CLA,RETp.C634R/FMEN2A-CLA,RETp.C634R/F甲狀腺髓樣癌的分子分型及治療-課件SurgicalManagementofMTC

①Theminimumextentofsurgeryisatotalthyroidectomy(TT)withbilateralcentralneckdissection(BiⅥ)

(TT+BiⅥLND);②TTwithipsilaterallateralcompartmentneckdissection;

(Unilaterallateral

LN+,MTCsize>1cm)

(TT+BiⅥ+UniLND)③TTwithbilaterallateralcompartmentneckdissection.(BilateraltumorsorextensiveLN+onthecontralateralside)

(TT+BiⅥ+BiLND)SurgicalManagementofMTC①Th甲狀腺髓樣癌的分子分型及治療-課件SurgicalManagementofMTC***CurrentrecommendationsforthetimingofprophylacticthyroidectomydependsontheriskleveloftheRETmutationinhereditaryMTC(MEN2).

SurgicalManagementofMTCATA-2015GuidelinesrecommendedATA-2015Guidelinesrecommende甲狀腺髓樣癌的分子分型及治療-課件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