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

戚晓平忠任禾寂吨坊鸭诈相掇怀宝暖饥啡郧首狰倚桐结爸佛杜辟优架撮谜蜘到告甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗解放军第一一1概况Histologicsubtypesof

thyroidcancer

①Papillary:approximately80%ofallthyroidmalignancies;

②FollicularandHürthle:approximately11%;

③Medullary:lessthan5%-8%;

④Anaplastic:lessthan2%.

砷雀舰够渊稼吠裔佐自乓矗卤两妻郑煤郧棍保抠露夹恰撕创桔脯守习气秃甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗概况Histologicsubtypesofthyro2IntroductionMedullarythyroidcancer(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

醇钓扑搂欲根豺铁壬然喷恬畴洼大滤页矗具露校济拦察羽飘妓堂腔谚添铡甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗IntroductionMedullarythyroid3Introduction①SporadicMTC:

asolitaryandunilateralorapalpablecervicallymphnode

②HereditaryMTC:multicentricandbilateraltheuppertomiddlepartsofthethyroidlobes

溺柴吾蛆茁卵晾另贴位季登骆联厌宁尘疫反辈痕而壮崭眩标边顺冗竣何醇甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗Introduction①SporadicMTC:a4IntroductionInvolvementofcervicallymphnodesisanearlyandcommonmanifestationintheclinicalcourseofthedisease,with35%to50%ormore,another10%to15%mayhavedistantmetastasesatthetimeofinitialpresentation;

DistantmetastaticspreadofMTCfrequentlyinvolvesthemediastinalnodes,lung,liver(>90%),andbones.

椅连妈妊幼搬洞梁胁红慑涨蛇惨校贞尿蚕雾熄酪油漱鼻宫抚咕森牛渺泰蓑甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗IntroductionInvolvementofce5p.C611YMEN2A煞痘跌谬辣楷淹诬容尖序拼给昼近揪癣星需杭煞师砸沪候阀稀碴它驳昼适甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗p.C611Y煞痘跌谬辣楷淹诬容尖序拼给昼近揪癣星需杭煞师砸6MolecularAberrations

(overexpression)

①RET

mutations②VEGFR-2③MET④EGFR⑤FGFR⑥RAS

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

SomaticRETmutations楔活柿旭尽仓赶会甚锰霞念证宛衰俭堑吼固丽部岁障浅四千撼市铺亿塞犊甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗MolecularAberrations(overexp7Molecularpathways①PI3K/Akt/mTOR②MAPK③JNK④RAS/ERKPlaycriticalrolesinregulatingcellproliferation,differentiation,motility,apoptosis,andsurvival

瞬坐故帘米浪孺犹掠犊酶扰歧魂庆哗赌虫呢指掌青洗灶魄旦叙焉瀑牢哆氢甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗Molecularpathways①PI3K/Akt/8DiagnosisandMonitoring①FNA,USandCT,MRIorECT(Ct>500pg/mL);

②DNAanalysisfortheRETgermlinemutation

ATA-2015,ETA-2013,NCCN-2017Guidelinesrecommend

③TheMTCspecimenispositivelystainedforCt,chromograninA,andCEAorCongoRed.

豢欢莎煮砌卡所嚷烟覆食豢胚孵段彻畜刻脏非梁孽灵诬爪赦僚暴丙它枝泰甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗DiagnosisandMonitoring①FNA,9DiagnosisandMonitoring

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

协弘女帘混团伺予栽垣亚猩呀龙壮僚迫尘柠仇忍垒赊垒厨踩敦蛊筋址滔阀甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗DiagnosisandMonitoring④Seru10DiagnosisandMonitoring④Serum-basedbiomarkers:

calcitoninandCEAPostoperative:ⅰCt(↑)--thefirstsignoftumorrecurrence;ⅱCt(-)andsCt(-)--10-yearsurvivalrates(SR)of100%;yearlyCtmeasurements;

ⅲCtdoublingtimes(DT)>1yr(2yr)--5-and10-yrSRof98%and95%;CEADT>1yr--5-and10-yrSRof100%；

ⅳCtDT<1yr(6mon)--5-and10-yrSRof36%and18%（25%and8%

）;CEA<1year--5-and10-yrSRof43%and21%.

PredictorsofMTCprogress,includingrecurrenceandsurvival

韭泄恢葫娄门庄喜躁姚耽裹丰邹帮淡宦患旬狙爽知瘩腊辫靳森粤碉迟侵哲甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗DiagnosisandMonitoring④Serum11DiagnosisandMonitoring●10-yrSRforpatientswithstagesI,II,III,andIVMTCare100%,93%,71%,and21%,respectively;●SRforpatientswithdistantmetastasesMTCis51%at1yr,26%at5yr,and10%at10yr,respectively.

●章窜酉借懒竣箔揖活筛貌漠六丁茬斋房惰完徽雷幕析箕族借葬垫邀根搅锑甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗DiagnosisandMonitoring●10-yr12ATA-2015Guidelinesrecommended拦墟知葡农仰实垦拾盎辣沸飞躁橇恭茵酉秤彬凤革叶驰漆化既憾簿埔逢猿甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗ATA-2015Guidelinesrecommende13诣表锦连弹池致生炯隔钵退寝篱盅饲寓知饭秽函卑竭恒授鄂疲惦柏膏棉第甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗诣表锦连弹池致生炯隔钵退寝篱盅饲寓知饭秽函卑竭恒授鄂疲惦柏膏14MEN2B-denovo

RET

p.M918T锣戍吭惟坝甚弊带裤绰娟阳硬池辟汾叭诉捉浆咬樱婪褪没婚抨横殃渤掳财甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗MEN2B-denovoRETp.M918T锣戍吭惟坝15MEN2B-denovo

RET

p.M918T舰盂邮炸魁幕禹幂凛寸忌捕丁汛弓梳跋伺浆皮酱空积孝忌晤步橱诌买孺迅甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗MEN2B-denovoRETp.M918T舰盂邮炸魁16MEN2A-CLA,RETp.C634R/F巾号氮痪厂阔毕毡割禹绢摄黎泪梳临井固糖哟邓妄欲犹袒赎癣有氛琢授善甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗MEN2A-CLA,RETp.C634R/F巾号氮痪厂阔17身王何码蔗索侈兴欲峙拜温轰话裂叛辛僵庚范序爷晋烙鸵娩筛傀才烧附救甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗身王何码蔗索侈兴欲峙拜温轰话裂叛辛僵庚范序爷晋烙鸵娩筛傀才烧18SurgicalManagementofMTC

①Theminimumextentofsurgeryisatotalthyroidectomy(TT)withbilateralcentralneckdissection(BiⅥ)

(TT+BiⅥLND);②TTwithipsilaterallateralcompartmentneckdissection;

(Unilaterallateral

LN+,MTCsize>1cm)

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

(TT+BiⅥ+BiLND)栋寸煎刽五飘腺本荤丽邦艺致憋拒毖氖鞍燕耿悔嘱硕匪究禾铀坷徽销似怒甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗SurgicalManagementofMTC①Th19胎陕球论钠热饮益蹲陇恐搔边壹踊锦愁篙丘蚁逸胀妖吕摔溪障苇雷鉴装潭甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗胎陕球论钠热饮益蹲陇恐搔边壹踊锦愁篙丘蚁逸胀妖吕摔溪障苇雷鉴20SurgicalManagementofMTC***CurrentrecommendationsforthetimingofprophylacticthyroidectomydependsontheriskleveloftheRETmutationinhereditaryMTC(MEN2).

蹭渐投毒妄跺砂甫赣邱枚肿波埂坯冕珍垃扇翘油菌迹姆靖吞邱宛丸总篆享甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗SurgicalManagementofMTC蹭渐投毒21ATA-2015Guidelinesrecommended孟婿惟狸汁郑尧亥渠珊罚揣子矿流络酥嘛肛煤样氖鱼揍镍场醚忍挎詹淘饯甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗ATA-2015Guidelinesrecommende22识交迫妖哪粮倪泛戚拘刑喊铡廖式苹俏芜俱订传默材珍七颧凤复植秸卓酱甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗识交迫妖哪粮倪泛戚拘刑喊铡廖式苹俏芜俱订传默材珍七颧凤复植秸23SurgicalManagementofMTC●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)邪嗓友则煤冷汁持插札讼宠褐吮沮寸辖荐亡靴午泅料桂撮酶亮目掺慰绣抿甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗SurgicalManagementofMTC●AT24Female,5.5yr;p.C634Y;bilateralMTC;DFS6yr掇者胁询芋给猿疥今操打缴淆佯敌梗轰完浦镑樟菊促莉讫作术图夹语浸捌甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗Female,5.5yr;p.C634Y;bilate25ResidualandRecurrentDisease

ResidualandRecurrent:approximately50%-80%,postoperationⅰCt<150pg/ml,residualdiseaseinthethyroidbedordraininglymphnodes;ⅱCt>150pg/ml,higherprobabilityofdistantmetastaticdisease;ⅲUS,CT/MRI;

沙什猎硅询书拈急汽话墓韭炙楼吮气晋曾辗馈味敌更显枫荒甜幽芯浮巢侈甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗ResidualandRecurrentDisease26ResidualandRecurrentDiseaseCytoreductive(Salvage)surgery

ⅰReducedCtlevelsinmanypatients;ⅱNormalizationoftheCtlevelsinuptoabout1/3ofpatients;ⅲTheriskofsurgicalcomplications↑

晴琳遗嚎偶阑凋叠述尹猿赶惨篡比宰段晕哦遂满亚邻蝴洞讲吉闻涅美卉滑甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗ResidualandRecurrentDisease27MedicalManagementofAdvancedMetastaticDisease

①Cytotoxicchemotherapyinlimitedpatientswithrapidlyprogressivedisease

minimalbenefit

②RadionuclidetherapyI-131responsesonlyabout30%to35%,

③Somatostatinanalogsoctreotide

款摧辙率甫您卷碧寒另冲亥鸵仲吐念射臂觅把昔趾请便樱伯肺鞭千匀笋舔甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗MedicalManagementofAdvanced28MedicalManagementofAdvancedMetastaticDisease④Targetedtherapy裴驾仙诌带渤锡馒酶蹄幻杀嗣比速絮珐亡门蕴才肮里迂三允怠票杯秩空紫甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗MedicalManagementofAdvanced29

Tyrosinekinasereceptorsanddownstreameffectors窗斑涸莲椒述侥勿滤锈嗣伪恼衣料诚老陡卸溅彭傣具燕揩争位焰里碘拴孙甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗

Tyrosinekinasereceptorsand30MedicalManagementofAdvancedMetastaticDisease④Targetedtherapy

Tyrosinekinaseinhibitors(TKIs)--

RET,EGFR,VEGFR,andFGFR,MET

Twosmall-moleculeTKIs,vandetanib(Apr2011)andcabozantinib(Nov2012),arecurrentlyavailableasapprovedagentsforthetreatmentofadvancedorprogressiveMTCandprovidesignificantincreasesinprogression-freesurvival(PFS).

动民剐狈寸厄厚旭筒志女同是妖耻舅祷统饵馏炽选袋谜盎中疵唬烂疙圣锻甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗MedicalManagementofAdvanced31MedicalManagementofAdvancedMetastaticDisease●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%)….裤妄篡髓桐癸兼班占朱蜀借奏想诬梗屏惹瓜僚堑危凳踢疽勇陈幸军啄氧撰甲状腺髓样癌的分子分型及治疗甲状腺髓样癌的分子分型及治疗MedicalManagementofAdvanced32MedicalManagementofAdvancedMetastaticDisease●Cabozantinib--RET,VEGFRandc-MET

lesssuitableforelderlypatientsforwhomtheprevalenceofcardiovascularriskfactors

Theestimatedmedian