甲状腺髓样癌的分子分型及治疗优质课件

概况概况oHistologic 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%.概况Histologic subtypes of thyro1Introduction oMedullary thyroid cancer(MTC)Sporadic MTC: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 Medullary thyroid2Introduction 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 Sporadic MTC:a3Introduction 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 distant metastases at the time of initial presentation;oDistant metastatic spread of MTC frequently involves the mediastinal nodes,lung,liver(90%),and bones.Introduction Involvement of ce4p.C611YMEN2Ap.C611Y5Molecular Aberrations(overexpression)RET mutations VEGFR-2 MET EGFR FGFR RAS (sMTC-56%KRAS+;12%HRAS)(Mutations in RAS appear to be mutually exclusive of RET abnormalities)Somatic RET mutationsMolecular Aberrations(overexp6Molecular pathways PI3K/Akt/mTOR MAPK JNK RAS/ERKPlay critical roles in regulating cell proliferation,differentiation,motility,apoptosis,and survival Molecular pathways PI3K/Akt/7Diagnosis and Monitoring FNA,US and CT,MRI or ECT(Ct 500 pg/mL);DNA analysis for 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 FNA,8Diagnosis and Monitoring Serum-based biomarkers:calcitonin and CEA(50%)Preoperative: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 Monitoring Seru9Diagnosis and MonitoringSerum-based biomarkers:calcitonin and 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%（25%and 8%）;CEA 3000 pg/mL,CEA 100 ng/L-distant spread.SR for patients with distant metastases MTC is 51%at 1 yr,26%at 5 yr,and 10%at 10 yr,respectively.Predictors of MTC progress,including recurrence and survivalin limited patients with rapidly progressive disease minimal benefitapproximately 50%-80%,postoperationPreoperative:Prevention-PD/PGDPrevention-PD/PGDATA-2015 Guidelines recommended Reduced Ct levels in many patients;Surgical Management of MTC17Surgical 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 dissection.(Bilateral tumors or extensive LN+on the contralateral side)(TT+Bi+BiLND)Surgical Management of MTC Th18甲状腺髓样癌的分子分型及治疗优质课件19Surgical 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).Surgical Management of MTC20ATA-2015 Guidelines recommendedATA-2015 Guidelines recommende21甲状腺髓样癌的分子分型及治疗优质课件22Surgical 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)Surgical Management of MTC AT23Female,5.5yr;p.C634Y;bilateral MTC;DFS 6yrFemale,5.5yr;p.C634Y;bilate24Residual 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 Disease25Residual 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 Residual and Recurrent Disease26Predictors of MTC progress,including recurrence and survivalATA-2015,ETA-2013,NCCN-2017 Guidelines recommendTwo 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 progression-free survival(PFS).other small-molecule kinase inhibitors sunitinib,sorafenib,and pazopanibDiagnosis and MonitoringThe minimum extent of surgery is a total thyroidectomy(TT)with bilateral central neck dissection(Bi)(TT+BiLND);Medullary thyroid cancer(MTC)IntroductionThe minimum extent of surgery is a total thyroidectomy(TT)with bilateral central neck dissection(Bi)(TT+BiLND);Residual and Recurrent DiseaseFollicular and Hrthle:approximately 11%;Acknowledgement1yr,TT+Bi LND;Diagnosis and MonitoringCt 150 pg/ml,higher probability of distant metastaticTyrosine kinase receptors and downstream effectorsTwo 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 progression-free survival(PFS).Residual and Recurrent DiseaseInvolvement 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 at the time of initial presentation;50%somatic RET mutations(p.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 octreotide Predictors of MTC progress,in27Medical Management of Advanced Metastatic DiseaseTargeted therapyMedical Management of Advanced28Tyrosine kinase receptors and downstream effectors Tyrosine kinase receptors and29Medical 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 provide significant increases in progression-free survival(PFS).Medical Management of Advanced30Medical 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%;median PFS 30.5 months.QT prolongation(14%),diarrhea(56%),rash(45%),hypertension(32%),headache(26%).Medical Management of Advanced31Medical 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 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 Advanced32Medical Management of Advanced Metastatic Diseaseother small-molecule kinase inhibitors sunitinib,sorafenib,and pazopanib Other targeted treatments mammalian target of rapamycin(mTOR)inhibitor-everolimus Medical Management of Advanced33Prevention-PD/PGDPreimplantation genetic diagnosis of multiple endocrine neoplasia type 2A using informative markers identified by targeted sequencingJ,Thyroid,2017.(UR)Prevention-PD/PGDPreimplantat34Acknowledgement Acknowledgement 35甲状腺髓样癌的分子分型及治疗优质课件36