甲状腺髓样癌分子分型及治疗

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,甲状腺髓样癌的分子分型及治疗,1,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%.,2,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,3,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,4,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.,5,p.C611Y,MEN2A,6,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,7,Molecular pathways, PI3K/Akt/mTOR, MAPK, JNK, RAS/ERK,Play critical roles in regulating cell proliferation, differentiation, motility, apoptosis, and survival,8,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.,9,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,10,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 cm) (TT+Bi+UniLND), TT with bilateral lateral compartment neck dissection.,(Bilateral tumors or extensive LN+ on the contralateral side) (TT+Bi+BiLND),19,20,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).,21,ATA-2015 Guidelines recommended,22,23,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 ),24,Female, 5.5yr; p.C634Y; bilateral MTC; DFS 6yr,25,Residual and Recurrent Disease,Residual and Recurrent :,approximately 50%-80%, postoperation,Ct 150 pg/ml, higher probability of distant metastatic,disease;, US, CT/MRI;,26,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,27,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,28,Medical Management of Advanced Metastatic Disease,Targeted therapy,29,Tyrosine kinase receptors and downstream effectors,30,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).,31,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%).,32,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 cabozantinib,Choice: The patients comorbid conditions and the toxicity profile that the patient is willing to bear,33,Medical Management of Advanced Metastatic Disease,other small-molecule kinase inhibitors sunitinib, sorafenib, and pazopanib,Other targeted treatments,mammalian target of rapamycin (mTOR) inhibitor -everolimus,34,Prevention-PD/PGD,Preimplantation genetic diagnosis of multiple endocrine neoplasia type 2A using informative markers identified by targeted sequencingJ, Thyroid, 2017. (UR),35,Acknowledgement,36,37,