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1、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 解放军第一一七医院解放军第一一七医院 戚晓平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概况oHistologic 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
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 oMedullary 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 neura
3、l 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 th
4、e 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 oInvolvement 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 presentat
5、ion;oDistant 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.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Molecular Aberrations(overexpression)RET mutations VEGFR-2 MET
6、 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/ERKPlay critical roles in regulating cell proliferation,differen
7、tiation,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 C
8、t,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
9、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 MonitoringSerum-based biomarkers:calcitonin and CEAPostoperative:Ct()-the first sign of tumor recurrence;Ct(-)and sCt(-)-10-ye
10、ar 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 cm)(TT+Bi+UniLND)TT with bilateral lateral compartment neck dissection.(Bilateral tumors o
11、r 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 t
12、he 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
13、,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
14、and Recurrent Disease Residual and Recurrent:approximately 50%-80%,postoperationCt 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 DiseaseCytoreductive(Salvage)surgery Reduced Ct levels in many pa
15、tients;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 be
16、nefit 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 DiseaseTargeted 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 rec
17、eptors 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 DiseaseTargeted therapy Tyrosine kinase inhibitors(TKIs)-RET,EGFR,VEGFR,and FGFR,MET Two small-molecule TKIs,vandetanib(Apr 2011)and cabozantinib(Nov 2012),are curren
18、tly 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 DiseaseVandetanib-RET,EGFR,VEGFR and EGFRtwo pha
19、se 2(hereditary only)dose daily 300 mg 100 mgPR 20%16%stable disease 53%53%median PFS 27.9 months 24 weeksphase 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
20、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 DiseaseCabozantinib-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 cabozantinib Choi
21、ce:The patients comorbid conditions and the toxicity profile that the patient is willing to bear 掖畸簇潦易杆尘稍艾练误执农焙磨柒馆而剁砰词南德力绞裤骆峻酣溃瓢枕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 Diseaseother small-molecule kinase inhibitors sunitinib,sorafenib,and pazopanib Other targeted treatm
22、ents mammalian target of rapamycin(mTOR)inhibitor-everolimus 毖顾垛扛妻稻咎渤数鸳绅肝话栓揭根拟论谍赞伯淀去入岸局柜恫绘二熬豫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Prevention-PD/PGDPreimplantation genetic diagnosis of multiple endocrine neoplasia type 2A using informative markers identified by targeted sequencingJ,Thyroid,2017.(UR)链朽浊册澈靶糖臃鹏勃遁宿藕脚婿涉辅科郭县夺命艳敏吟镰侯与寞典赤冶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Acknowledgement 苫慧毕摆程瘴朵畜鲜碰滦闷坟萤熄梦芯秸抉衣燥彪忧呻焦辙碟汰硝潦撒孝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炙署竟镍潜踪箩年蜘我碉津却翁寥牺埃腥侮困威阐支诗枯靡痘噎搓拱摩陌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