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 戚晓平戚晓平甲状腺髓样癌的分子分型及治疗1概况概况o 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%.甲状腺髓样癌的分子分型及治疗2Introduction o Medullary th
2、yroid 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 甲状腺髓样癌的
3、分子分型及治疗3Introduction 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 甲状腺髓样癌的分子分型及治疗4Introduction oInvolvement of cervical lymph nodes is an early and common manifestation in the clinical
4、 course of the disease,with 35%to 50%or more,another 10%to 15%may have distant metastases at the time of initial presentation;oDistant metastatic spread of MTC frequently involves the mediastinal nodes,lung,liver(90%),and bones.甲状腺髓样癌的分子分型及治疗5p.C611YMEN2A甲状腺髓样癌的分子分型及治疗6Molecular Aberrations(overexpr
5、ession)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甲状腺髓样癌的分子分型及治疗7Molecular pathways PI3K/Akt/mTOR MAPK JNK RAS/ERKPlay critical roles in regulating cell proliferation,differentiation,motil
6、ity,apoptosis,and survival 甲状腺髓样癌的分子分型及治疗8Diagnosis 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.甲状腺髓样癌的分子分型及治疗9Diagn
7、osis 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 甲状腺
8、髓样癌的分子分型及治疗10Diagnosis and MonitoringSerum-based biomarkers:calcitonin and CEAPostoperative: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%；
9、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 or extensive LN+on the contralateral side)(TT+Bi+BiLND)甲状腺髓样癌的分子分型及治疗19甲状腺髓样癌的分子分型及治疗20Surgical Management of MTC*Current recommendations for the ti
10、ming of prophylactic thyroidectomy depends on the risk level of the RET mutation in hereditary MTC(MEN 2).甲状腺髓样癌的分子分型及治疗21ATA-2015 Guidelines recommended甲状腺髓样癌的分子分型及治疗22甲状腺髓样癌的分子分型及治疗23Surgical 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
11、is adequate.(Ct 60 ng/L,Elisei R,et al;Ct 70 ng/L,Qi XP,et al)甲状腺髓样癌的分子分型及治疗24Female,5.5yr;p.C634Y;bilateral MTC;DFS 6yr甲状腺髓样癌的分子分型及治疗25Residual and Recurrent Disease Residual and Recurrent:approximately 50%-80%,postoperationCt 150 pg/ml,higher probability of distant metastatic disease;US,CT/MRI;甲状腺
12、髓样癌的分子分型及治疗26Residual and Recurrent DiseaseCytoreductive(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 甲状腺髓样癌的分子分型及治疗27Medical Management of Advanced Metastatic Disease Cytotoxic chemotherapy in lim
13、ited patients with rapidly progressive disease minimal benefit Radionuclide therapy I-131 responses only about 30%to 35%,Somatostatin analogs octreotide 甲状腺髓样癌的分子分型及治疗28Medical Management of Advanced Metastatic DiseaseTargeted therapy甲状腺髓样癌的分子分型及治疗29Tyrosine kinase receptors and downstream effectors
14、 甲状腺髓样癌的分子分型及治疗30Medical 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 currently available as approved agents for the treatment of advanced or progressi
15、ve MTC and provide significant increases in progression-free survival(PFS).甲状腺髓样癌的分子分型及治疗31Medical Management of Advanced Metastatic DiseaseVandetanib-RET,EGFR,VEGFR and EGFRtwo phase 2(hereditary only)dose daily 300 mg 100 mgPR 20%16%stable disease 53%53%median PFS 27.9 months 24 weeksphase 3 in 33
16、1 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%).甲状腺髓样癌的分子分型及治疗32Medical Management of Advanced Metastatic DiseaseCabozantinib-RET,VEGFR and c-MET less suitable for elderly patients for whom
17、 the prevalence of cardiovascular risk factors The estimated median PFS with vandetanib is numerically longer than with cabozantinib Choice:The patients comorbid conditions and the toxicity pro the patient is willing to bear 甲状腺髓样癌的分子分型及治疗33Medical Management of Advanced Metastatic Diseaseother smal
18、l-molecule kinase inhibitors sunitinib,sorafenib,and pazopanib Other targeted treatments mammalian target of rapamycin(mTOR)inhibitor-everolimus 甲状腺髓样癌的分子分型及治疗34Prevention-PD/PGDPreimplantation genetic diagnosis of multiple endocrine neoplasia type 2A using informative markers identified by targeted sequencingJ,Thyroid,2017.(UR)甲状腺髓样癌的分子分型及治疗35Acknowledgement 甲状腺髓样癌的分子分型及治疗36甲状腺髓样癌的分子分型及治疗37
