甲状腺髓样癌的分子分型及治疗ppt课件

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 戚晓平概略概略o Histologic subtypes of thyroid cancer o Papillary: approximately 80% of all thyroid malignancies; o Follicular and Hrthle: approximately 11%; o Medullary: less than 5%-8% ;o Anaplastic: less than 2%. Introduction o Medullary thyroid cancer (MTC)o Spora

2、dic MTC: approximately 75%; o 50% somatic RET mutations (p.M918T)o -predict a poor prognosis o Hereditary MTC: approximately 25%; o 98% Germline RET mutations, MEN 2A (95%) and MEN 2B (5%) o o Arises from the neural crest-derived, calcitonin-secreting, parafollicular C cells of the thyroid gland Int

3、roduction 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 Introduction oInvolvement of cervical lymph nodes is an early and common manifestation in the clinical course of the disease,

4、with 35% to 50% or more, another 10% to 15% 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 FG

5、FR RAS (sMTC-56% KRAS+;12%HRAS)(Mutations in RAS appear 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 Monitorin

6、g FNA,US and CT, MRI or ECT (Ct 500 pg/mL); DNA analysis for the RET germline mutation ATA-2019, ETA-2019, NCCN-2019 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%)Preo

7、perative: 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 Diagnosis and MonitoringSerum-based biomarkers: calcitonin and

8、 CEAPostoperative: 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% （

9、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)Surgical Management of MTC*Current recommendations for the timing of prophylactic thyroidectomy depends on the risk level of the RE

10、T mutation in hereditary MTC (MEN 2). ATA-2019 Guidelines recommendedSurgical 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 )Female, 5.5yr; p.C634Y; bilateral MTC;

11、DFS 6yrResidual and Recurrent Disease Residual and Recurrent : approximately 50%-80%, postoperationCt 150 pg/ml, higher probability of distant metastatic disease; US, CT/MRI;Residual and Recurrent DiseaseCytoreductive (Salvage ) surgery Reduced Ct levels in many patients; Normalization of the Ct lev

12、els in up to about 1/3 of patients; The risk of surgical complications 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 octreo

13、tide Medical Management of Advanced Metastatic DiseaseTargeted therapyTyrosine kinase receptors and downstream effectors Medical Management of Advanced Metastatic DiseaseTargeted therapy Tyrosine kinase inhibitors(TKIs)- RET, EGFR, VEGFR, and FGFR, MET Two small-molecule TKIs, vandetanib (Apr 2019)

14、and cabozantinib(Nov 2019), are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival (PFS). Medical Management of Advanced Metastatic DiseaseVandetanib-RET, EGFR, VEGFR and EGFRtwo phase 2 (hereditary o

15、nly) 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%;median PFS 30.5 months. QT prolongation (14%),diarrhea (56%), rash (45%), hypertension (32%), headache (26%).Medical Management of A

16、dvanced Metastatic DiseaseCabozantinib-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 Medical Management of Advanced Metastatic Diseaseother small-molecule kinase inhibitors sunitinib, sorafenib, and pazopanib Other target