肿瘤异质性对NSCLC靶向治疗原继发耐药的影响

•肿瘤遗传异质性概念•肿瘤内异质性与NSCLC靶向治疗原发耐药•肿瘤内异质性与NSCLC靶向治疗继发耐药tyhinindividualtyhinindividualtumors的基础neityrogeneityl时间遗传异质性logy果alOncologist34.90%34.90% 23.10%pre-chemopost-chemo0%plasmaplasmatissueBai,etal.J.Clin.Oncol,2012,30(25):3077-83.Sequistetal.TranslationalMed.2011AfterAfter3monthsofAfter15monthsceritinibofceritinibAfter2monthsofcrizotinibAfter34monthstinibEML4–ALKgenotypeWTS1206YG1202RCancerDiscov4Jun;4(6):662-73NEnglJMedJan7;374(1):54-61 (Potentialexplanationoftumorgeneticheterogeneity)•肺癌干细胞或者肺癌发生细胞遗传物质的高度可塑性、适应性和多变性(essentialfactor).•肿瘤细胞所处的特定的微环境导致异质性的产生.肺癌细胞的断适应环境，继态变化过程•动态改变是肿瘤遗传异质性的重要特点•肿瘤遗传异质性概念•肿瘤内异质性与NSCLC靶向治疗原发耐药•肿瘤内异质性与NSCLC靶向治疗继发耐药OhashiKetalJClinOncol3;31:1070-1080.亡诱导失败：原发肿瘤BIM低表达与EGFR-TKI治疗后更短的PFS相关瘤异质性：–EGFR/ALK变异与野生型细胞克隆并存–EGFR/ALK敏感性变异与耐药基因并存•ALK/ROS1/RET/HER2/KRAS/NRAS/PIK3CA/AKT1/BRAF/MEK1•29%的原发耐药肺癌有HGF过表达–其他OhashiKetalJClinOncol3;31:1070-1080.testighabundance++undance++GroupW(Wild-typeEGFR)NN51183122nd/3rdlinenib2nd/3rdlinenibZhouetal,JCO.2011;29(24):3316-21Zhou,etal.J.Clin.Oncol,2011ietalPLOSone研究研究名称EGFRorALK检测方法EGFR双突变发生率Zhangetal,MolecularZhangetal,MolecularALK,DS检测EGFRHIHCALKISHALKDSlCCREGFRALKtsequenomeEGFRRtalCCRISHALKDSawetalJCOISHALKDSEGFR亚裔患者的双突变研究(2014CCR)：18.6%ALK阳性患者合ancerResMarALK阳性NSCLC表现出驱动突变的高度瘤ALK/ALK/EGFRALK瘤内异质性耐药ClinCancerResMar8(5):1472-82JClinOncol.2015Nov10;33(32):3701-9•肿瘤遗传异质性概念•肿瘤内异质性与NSCLC靶向治疗原发耐药•肿瘤内异质性与NSCLC靶向治疗继发耐药linLungCancer未知……NaturemedicineAcquiredEGFRC797SmutationmediatesresistancetoAZD9291innon–smallcelllungcancerharboringEGFRT790McfDNA20-genepanelCTCCALK-dominantmechanismsofresistanceALKnon-dominantmechanismsofresistancePartiallyALKdependentALKindependentNatRevClinOncolAug;11(8):473-81•Mostresistant:G1202RNatRevClinOncol.2012Apr3;9(5):268-77NatRevClinOncolAug;11(8):473-81tinibentALKstatusattimeofresistanceALKstatusattimeofesistance123456789ngtinibALKstatusattimeofresistanceALKstatusattimeofbresistance12CancerDiscov4Jun;4(6):662-73JThoracOncol.2014Dec;9(12):1821-5JThoracOncol.2014Apr;9(4):549-53•肿瘤遗传异质性概念•肿瘤内异质性与NSCLC靶向治疗原发耐药•肿瘤内异质性与NSCLC靶向治疗继发耐药StrategyfortacklinggeneticheterogeneityLancetoncol2012;13(4):e178-85.血液检测带来的突破:血浆循环肿瘤细胞(CTC)&ctDNAnnalneitytoring--tumortoring--tumorexosome/microvesicles--normaltissueapoptosistRevClinOncol耐药”树，建立外周血动态、定量、多McMETT?耐药检测体系实现对耐药的实时监测EGFRsensitivmutationwithrareT790MclonesinT790MpositiveinctDNA