甲状腺髓样癌的分子分型及治疗.ppt

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,概况,Histologic subtypes of thyroid cancer Papillary: approximately 80% of all thyroid malignancies; Follicular and Hrthle: approximately 11%; Medullary: less than 5%-8% ; Anaplastic: less than 2%.,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,Introduction,Medullary thyroid cancer (MTC) Sporadic MTC: approximately 75%; 50% somatic RET mutations (p.M918T) -predict a poor prognosis Hereditary MTC: approximately 25%; 98% Germline RET mutations, MEN 2A (95%) and MEN 2B (5%) Arises from the neural crest-derived, calcitonin-secreting, parafollicular C cells of the thyroid gland,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,Introduction,Sporadic MTC: a solitary and unilateral or a palpable cervical lymph node Hereditary MTC: multicentric and bilateral the upper to middle parts of the thyroid lobes,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,Introduction,Involvement of cervical lymph nodes is an early and common manifestation in the clinical course of the disease, with 35% to 50% or more, another 10% to 15% may have distant metastases at the time of initial presentation; Distant metastatic spread of MTC frequently involves the mediastinal nodes, lung, liver (90%), and bones.,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,p.C611Y MEN2A,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,Molecular Aberrations (overexpression ), RET mutations VEGFR-2 MET EGFR FGFR RAS (sMTC-56% KRAS+;12%HRAS) (Mutations in RAS appear to be mutually exclusive of RET abnormalities),Somatic RET mutations,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,Molecular pathways, PI3K/Akt/mTOR MAPK JNK RAS/ERK Play critical roles in regulating cell proliferation, differentiation, motility, apoptosis, and survival,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,Diagnosis and Monitoring, FNA,US and CT, MRI or ECT (Ct 500 pg/mL); DNA analysis for the RET germline mutation ATA-2015, ETA-2013, NCCN-2017 Guidelines recommend The MTC specimen is positively stained for Ct, chromogranin A, and CEA or Congo Red.,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,Diagnosis and Monitoring,Serum-based biomarkers: calcitonin and CEA (50%) Preoperative: CEA(), Ct (-)-poorly differentiated tumors, Rare; Ct 100 pg/mL-predictive MTC; Ct 150 pg/mL, CEA 30 ng/L-regional spread; Ct 3000 pg/mL, CEA 100 ng/L-distant spread.,Predictors of MTC progress, including recurrence and survival,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,Diagnosis and Monitoring,Serum-based biomarkers: calcitonin and CEA Postoperative: Ct ()- the first sign of tumor recurrence; Ct (-) and sCt (-) -10-year survival rates (SR) of 100%; yearly Ct measurements; Ct doubling times (DT) 1 yr (2yr)- 5- and 10-yr SR of 98% and 95%; CEA DT 1 yr - 5- and 10-yr SR of 100%； Ct DT 1 yr (6mon)- 5- and 10-yr SR of 36% and 18% （25% and 8% ）; CEA 1 year - 5- and 10-yr SR of 43% and 21%.,Predictors of MTC progress, including recurrence and survival,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,Diagnosis and Monitoring,10-yr SR for patients with stages I, II, III, and IV MTC are 100%, 93%, 71%, and 21%, respectively; SR for patients with distant metastases MTC is 51% at 1 yr, 26% at 5 yr, and 10% at 10 yr, 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,ATA-2015 Guidelines recommended,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,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,MEN2B-de novo 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-de novo 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,MEN2A-CLA, RET p.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,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,Surgical Management of MTC,The minimum extent of surgery is a total thyroidectomy (TT) with bilateral central neck dissection (Bi) (TT+BiLND); TT with ipsilateral lateral compartment neck dissection; (Unilateral lateral LN+, MTC size 1 cm) (TT+Bi+UniLND) TT with bilateral lateral compartment neck dissection. (Bilateral tumors or extensive LN+ on the contralateral side) (TT+Bi+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,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,Surgical Management of MTC,*Current recommendations for the timing of prophylactic thyroidectomy depends on the risk level of the RET mutation in hereditary MTC (MEN 2).,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,ATA-2015 Guidelines recommended,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,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,Surgical Management of MTC, ATA-D (HST)-MEN 2B 1yr, TT + Bi LND; ATA-AC (MODH)-MEN 2A basal Ct 40 pg/mL, TT without Bi LND is adequate. (Ct 60 ng/L, Elisei R, et al ; Ct 70 ng/L, Qi XP, et al ),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,Female, 5.5yr; p.C634Y; bilateral MTC; DFS 6yr,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,Residual and Recurrent Disease,Residual and Recurrent : approximately 50%-80%, postoperation Ct 150 pg/ml, higher probability of distant metastatic disease; US, 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,Residual and Recurrent Disease,Cytoreductive (Salvage ) surgery Reduced Ct levels in many patients; Normalization of the Ct levels in up to about 1/3 of patients; The risk of surgical complications,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,Medical Management of Advanced Metastatic Disease, Cytotoxic chemotherapy in limited patients with rapidly progressive disease minimal benefit Radionuclide therapy I-131 responses only about 30% to 35%, Somatostatin analogs octreotide,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,Medical Management of Advanced Metastatic Disease,Targeted therapy,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,Tyrosine kinase receptors and downstream effectors,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,Medical Management of Advanced Metastatic Disease,Targeted therapy Tyrosine kinase inhibitors(TKIs)- RET, EGFR, VEGFR, and FGFR, MET,Two small-molecule TKIs, vandetanib (Apr 2011) and cabozantinib(Nov 2012), are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival (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,Medical Management of Advanced Metastatic Disease,Vandetanib-RET, EGFR, VEGFR and EGFR two phase 2 (hereditary only) dose daily 300 mg 100 mg PR 20% 16% stable disease 53% 53% median PFS 27.9 months 24 weeks phase 3 in 331 patients (H-S-MTC) 300mg/d; objective response rate (ORR) 45%; median PFS 30.5 months.,QT prolongation (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,Medical Management of Advanced Metastatic Disease,Cabozantinib-RET, VEGFR and c-MET less suitable for elderly patients for whom the prevalence of cardiovascular risk factors The estimated median PFS with vandetanib is numerically longer than with cabo