甲狀腺髓樣癌的分子分型及治療

1、甲狀腺髓樣癌的分子分型及治療,解放軍第一一七醫(yī)院 戚曉平,概況,Histologic subtypes of thyroid cancer ①Papillary: approximately 80% of all thyroid malignancies; ②Follicular and Hürthle: approximately 11%; ③Medullary: less

2、 than 5%-8% ;④Anaplastic: less than 2%.,Introduction,Medullary thyroid cancer (MTC)①Sporadic MTC: approximately 75%; > 50% somatic RET mutations (p.M918T)

3、 -predict a poor prognosis ②Hereditary MTC: approximately 25%; 98% Germline RET mutations, MEN 2A (~95%) and MEN 2B (~5%) Arises from the neural crest-derived, calcitonin-s

4、ecreting, parafollicular C cells of the thyroid gland,Introduction,①Sporadic MTC: a solitary and unilateral or a palpable cervical lymph node ②Hereditary MTC: multicentric and bilater

5、al 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

6、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.,p.C

7、611YMEN2A,Molecular Aberrations (overexpression ),① RET mutations ② VEGFR-2 ③ MET ④ EGFR⑤ FGFR⑥ RAS (sMTC---56% KRAS+;12%HRAS)(Mutations in RAS appear to be mutually exclusive of RET abnormalities),Somatic RE

8、T mutations,Molecular pathways,① PI3K/Akt/mTOR ② MAPK ③ JNK ④ RAS/ERKPlay critical roles in regulating cell proliferation, differentiation, motility, apoptosis, and survival,Diagnosis and Monitoring,① FNA,US and CT

9、, MRI or ECT (Ct >500 pg/mL);② DNA analysis for the RET germline mutation ATA-2015, ETA-2013, NCCN-2017 Guidelines recommend ③ The MTC specimen is positively stained for Ct, chromogranin A, and CEA or C

10、ongo Red.,Diagnosis and Monitoring,④Serum-based biomarkers: calcitonin and CEA (>50%)Preoperative: ⅰ CEA(↑), Ct (-)--poorly differentiated tumors, Rare;

11、 ⅱ Ct >100 pg/mL--predictive –MTC; ⅲ Ct > 150 pg/mL, CEA > 30 ng/L--regional spread; ⅳ Ct > 3000 pg/mL, CEA > 100 ng/L--distant spread.,Predictors of MTC progress

12、, including recurrence and survival,Diagnosis and Monitoring,④Serum-based biomarkers: calcitonin and CEAPostoperative: ⅰ Ct (↑)-- the first sign of tumor re

13、currence; ⅱ Ct (-) and sCt (-) --10-year survival rates (SR) of 100%; yearly Ct measurements; ⅲ Ct doubling times (DT) > 1 yr (2yr)-- 5- and 10-yr SR of 98% and 95%; CEA DT > 1 yr --

14、 5- and 10-yr SR of 100%； ⅳ 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

15、and survival,Diagnosis and Monitoring,●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

16、% at 10 yr, respectively.,●,ATA-2015 Guidelines recommended,,,MEN2B-de novo RET p.M918T,MEN2B-de novo RET p.M918T,MEN2A-CLA, RET p.C634R/F,Surgical Management of MTC,①The minimum extent of surgery is a total thyroidectom

17、y (TT) with bilateral central neck dissection (BiⅥ) (TT+BiⅥLND);②TT with ipsilateral lateral compartment neck dissection; (Unilateral lateral LN+, MTC size > 1 cm) (TT+BiⅥ+UniLND)③ TT wi

18、th bilateral lateral compartment neck dissection. (Bilateral tumors or extensive LN+ on the contralateral side) (TT+BiⅥ+BiLND),Surgical Management of MTC,***Current recommendations for t

19、he timing of prophylactic thyroidectomy depends on the risk level of the RET mutation in hereditary MTC (MEN 2).,ATA-2015 Guidelines recommended,Surgical Management of MTC,● ATA-D (HST)-MEN 2B

20、 >1yr, TT + BiⅥ LND; ● ATA-A~C (MOD~H)-MEN 2A basal Ct < 40 pg/mL, TT without BiⅥ LND is adequate. (Ct < 60 ng/L, Elisei R, et al ; Ct < 70 ng/L, Qi XP, et al ),,,,Female, 5.5yr; p.C634Y; bila

21、teral MTC; DFS 6yr,Residual and Recurrent Disease,Residual and Recurrent : approximately 50%-80%, postoperationⅰCt 150 pg/ml, higher probability of distant metastatic disease;ⅲ US,

22、CT/MRI;,,Residual and Recurrent Disease,Cytoreductive (Salvage ) surgery ⅰ Reduced Ct levels in many patients; ⅱ Normalization of the Ct levels in up to about 1/3 of patients;ⅲ The risk of surgical complications↑,Medi

23、cal Management of Advanced Metastatic Disease,① Cytotoxic chemotherapy in limited patients with rapidly progressive disease minimal benefit ② Radionuclide therapy I-131 responses only about 30% to 35%,

24、③ Somatostatin analogs octreotide,Medical Management of Advanced Metastatic Disease,④Targeted therapy,Tyrosine kinase receptors and downstream effectors,Medical Management of Advanced Metastatic Disease,④Targeted t

25、herapy 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 advanc

26、ed or progressive MTC and provide significant increases in progression-free survival (PFS).,Medical Management of Advanced Metastatic Disease,●Vandetanib--RET, EGFR, VEGFR and EGFRⅰtwo phase 2 (hereditary only) dose

27、daily 300 mg 100 mgPR 20% 16%stable disease 53% 53%median PFS 27.9 months >24 we

28、eksⅱphase 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%)….,Medical Management of Ad

29、vanced 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

30、than with cabozantinib,Choice: The patient’s comorbid conditions and the toxicity profile that the patient is willing to bear,Medical Management of Advanced Metastatic Disease,●other small-molecule kinase inhibitors

31、 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 u