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1、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,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%.,Introduction,Medullary thyroid cancer(MTC)Sporadic MTC:approximately 75%;50%somatic
2、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,Introduction,Sporadic MTC:a solitary and unilateral or a palpable
3、cervical lymph node Hereditary MTC:multicentric and bilateral the upper to middle parts of the thyroid lobes,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
4、at the time of initial presentation;Distant metastatic spread of MTC frequently involves the mediastinal nodes,lung,liver(90%),and bones.,p.C611YMEN2A,Molecular Aberrations(overexpression),RET mutations VEGFR-2 MET EGFR FGFR RAS(sMTC-56%KRAS+;12%HRAS)(Mutations in RAS appear to be mutually exclusive
5、 of RET abnormalities),Somatic RET mutations,Molecular pathways,PI3K/Akt/mTOR MAPK JNK RAS/ERKPlay critical roles in regulating cell proliferation,differentiation,motility,apoptosis,and survival,Diagnosis and Monitoring,FNA,US and CT,MRI or ECT(Ct 500 pg/mL);DNA analysis for the RET germline mutatio
6、n ATA-2015,ETA-2013,NCCN-2017 Guidelines recommend The MTC specimen is positively stained for Ct,chromogranin A,and CEA or Congo Red.,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 p
7、g/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,Diagnosis and Monitoring,Serum-based biomarkers:calcitonin and CEAPostoperative:Ct()-the first sign of tumor recurrence;Ct(-)and sCt(-)-10-year survival rates(SR)o
8、f 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,Diagnosis and Mo
9、nitoring,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.,ATA-2015 Guidelines recommended,MEN2B-de novo RET p.M918T,MEN2B-de novo RET p.M918T,MEN2A-CLA,RET p.
10、C634R/F,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 dis
11、section.(Bilateral tumors or extensive LN+on the contralateral side)(TT+Bi+BiLND),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).,ATA-2015 Guidelines recommended,Surgical Manageme
12、nt 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),Female,5.5yr;p.C634Y;bilateral MTC;DFS 6yr,Residual and Recurrent Disease,Residual and Recurrent:approximately 50%-80%,postoperationCt 150
13、pg/ml,higher probability of distant metastatic disease;US,CT/MRI;,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,Medical Management of Advanced Metastatic
14、 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,Medical Management of Advanced Metastatic Disease,Targeted therapy,Tyrosine kinase receptors and downstream e
15、ffectors,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
16、and provide significant increases in progression-free survival(PFS).,Medical Management of Advanced Metastatic Disease,Vandetanib-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 331 patients(H-S-MTC)30
17、0mg/d;objective response rate(ORR)45%;median PFS 30.5 months.,QT prolongation(14%),diarrhea(56%),rash(45%),hypertension(32%),headache(26%).,Medical Management of Advanced Metastatic Disease,Cabozantinib-RET,VEGFR and c-MET less suitable for elderly patients for whom the prevalence of cardiovascular
18、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,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,Prevention-PD/PGD,Preimplantation genetic diagnosis of multiple endocrine neoplasia type 2A using informative markers identified by targeted sequencingJ,Thyroid,2017.(UR),Acknowledgement,
