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 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%.2 Introduction o Medullary thyroid cancer(MTC)Sporadic MTC:approximately 75%;50%
2、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
3、 palpable cervical lymph node Hereditary MTC:multicentric and bilateral the upper to middle parts of the thyroid lobes 4 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 distan
4、t metastases at the time of initial presentation;oDistant metastatic spread of MTC frequently involves the mediastinal nodes,lung,liver(90%),and bones.5 p.C611YMEN2A6 Molecular Aberrations(overexpression)RET mutations VEGFR-2 MET EGFR FGFR RAS (sMTC-56%KRAS+;12%HRAS)(Mutations in RAS appear to be mu
5、tually exclusive of RET abnormalities)Somatic RET mutations7 Molecular pathways PI3K/Akt/mTOR MAPK JNK RAS/ERKPlay 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 RE
6、T 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-pred
7、ictive 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 MonitoringSerum-based biomarkers:calcitonin and CEAPostoperative:Ct()-the first sign of tumor recurrence;Ct(-)and sCt(-)-10-year
8、 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
9、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 recommended22 23 Surgical Management of MTC ATA-D(HS
10、T)-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 6yr25 Residual and Recurrent Disease Residual and Recurrent:approximately 50%-80%,postoperationCt 150 pg/ml,higher p
11、robability of distant metastatic disease;US,CT/MRI;26 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 27 Medical Management of Advanced Metastatic Disease C
12、ytotoxic 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 DiseaseTargeted therapy29 Tyrosine kinase receptors and downstream effecto
13、rs 30 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 currently available as approved agents for the treatment of advanced or progressive MTC and
14、provide significant increases in progression-free survival(PFS).31 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
15、/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 DiseaseCabozantinib-RET,VEGFR and c-MET less suitable for elderly patients for whom the prevalence of cardiovascular ris
16、k 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 Diseaseother small-molecule kinase inhibitors sunitinib,so
17、rafenib,and pazopanib Other targeted treatments mammalian target of rapamycin(mTOR)inhibitor-everolimus 34 Prevention-PD/PGDPreimplantation genetic diagnosis of multiple endocrine neoplasia type 2A using informative markers identified by targeted sequencingJ,Thyroid,2017.(UR)35 Acknowledgement 36 37
