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%.Introduction o Medullary thyroid cancer(MTC)Sporadic MTC:
2、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 Introduction Sporadic MTC:a solitary
3、and unilateral or a palpable cervical lymph node Hereditary MTC:multicentric and bilateral the upper to middle parts of the thyroid lobes 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 1
4、5%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.p.C611YMEN2AMolecular Aberrations(overexpression)RET mutations VEGFR-2 MET EGFR FGFR RAS (sMTC-56%KRAS+;12%HRAS)(Mutations in RAS ap
5、pear to be mutually exclusive of RET abnormalities)Somatic RET mutationsMolecular 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 f
6、or 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.Diagnosis and Monitoring Serum-based biomarkers:calcitonin and CEA(50%)Preoperative:CEA(),Ct(-)-poorly differentiated tumors,Rare;Ct 100 pg/
7、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 Diagnosis and MonitoringSerum-based biomarkers:calcitonin and CEAPostoperative:Ct()-the first sign of tumor recurrence;Ct(-)and sCt(-)-10-
8、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
9、 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 recommendedSurgical Management of MTC ATA-D(HST)-MEN 2B 1
10、yr,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 6yrResidual and Recurrent Disease Residual and Recurrent:approximately 50%-80%,postoperationCt 150 pg/ml,higher probability of dis
11、tant metastatic disease;US,CT/MRI;Residual 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 Medical Management of Advanced Metastatic Disease Cytotoxic chemotherapy i
12、n 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 DiseaseTargeted therapyTyrosine kinase receptors and downstream effectors Medical Management of Adva
13、nced 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 progressive MTC and provide significant increases in
14、 progression-free survival(PFS).Medical 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 331 patients(H-S-MTC)300mg/d;objective response rate(ORR)45%;
15、median PFS 30.5 months.QT prolongation(14%),diarrhea(56%),rash(45%),hypertension(32%),headache(26%).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 wit
16、h 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 Diseaseother small-molecule kinase inhibitors sunitinib,sorafenib,and pazopanib Other targeted treatments mammalian target of rapamycin(mTOR)inhibitor-everolimus Prevention-PD/PGDPreimplantation genetic diagnosis of multiple endocrine neoplasia type 2A using informative markers identified by targeted sequencingJ,Thyroid,2017.(UR)Acknowledgement
