腫瘤異質(zhì)性對NSCLC靶向治療原繼發(fā)耐藥的影響

?腫瘤遺傳異質(zhì)性概念?腫瘤內(nèi)異質(zhì)性與NSCLC靶向治療原發(fā)耐藥?腫瘤內(nèi)異質(zhì)性與NSCLC靶向治療繼發(fā)耐藥tyhinindividualtyhinindividualtumors的基礎(chǔ)neityrogeneityl時(shí)間遺傳異質(zhì)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)?肺癌干細(xì)胞或者肺癌發(fā)生細(xì)胞遺傳物質(zhì)的高度可塑性、適應(yīng)性和多變性(essentialfactor).?腫瘤細(xì)胞所處的特定的微環(huán)境導(dǎo)致異質(zhì)性的產(chǎn)生.肺癌細(xì)胞的斷適應(yīng)環(huán)境，繼態(tài)變化過程?動態(tài)改變是腫瘤遺傳異質(zhì)性的重要特點(diǎn)?腫瘤遺傳異質(zhì)性概念?腫瘤內(nèi)異質(zhì)性與NSCLC靶向治療原發(fā)耐藥?腫瘤內(nèi)異質(zhì)性與NSCLC靶向治療繼發(fā)耐藥OhashiKetalJClinOncol3;31:1070-1080.亡誘導(dǎo)失?。涸l(fā)腫瘤BIM低表達(dá)與EGFR-TKI治療后更短的PFS相關(guān)瘤異質(zhì)性：–EGFR/ALK變異與野生型細(xì)胞克隆并存–EGFR/ALK敏感性變異與耐藥基因并存?ALK/ROS1/RET/HER2/KRAS/NRAS/PIK3CA/AKT1/BRAF/MEK1?29%的原發(fā)耐藥肺癌有HGF過表達(dá)–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研究研究名稱EGFRorALK檢測方法EGFR雙突變發(fā)生率Zhangetal,MolecularZhangetal,MolecularALK,DS檢測EGFRHIHCALKISHALKDSlCCREGFRALKtsequenomeEGFRRtalCCRISHALKDSawetalJCOISHALKDSEGFR亞裔患者的雙突變研究(2014CCR)：18.6%ALK陽性患者合ancerResMarALK陽性NSCLC表現(xiàn)出驅(qū)動突變的高度瘤ALK/ALK/EGFRALK瘤內(nèi)異質(zhì)性耐藥ClinCancerResMar8(5):1472-82JClinOncol.2015Nov10;33(32):3701-9?腫瘤遺傳異質(zhì)性概念?腫瘤內(nèi)異質(zhì)性與NSCLC靶向治療原發(fā)耐藥?腫瘤內(nèi)異質(zhì)性與NSCLC靶向治療繼發(fā)耐藥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?腫瘤遺傳異質(zhì)性概念?腫瘤內(nèi)異質(zhì)性與NSCLC靶向治療原發(fā)耐藥?腫瘤內(nèi)異質(zhì)性與NSCLC靶向治療繼發(fā)耐藥StrategyfortacklinggeneticheterogeneityLancetoncol2012;13(4):e178-85.血液檢測帶來的突破:血漿循環(huán)腫瘤細(xì)胞(CTC)&ctDNAnnalneitytoring--tumortoring--tumorexosome/microvesicles--normaltissueapoptosistRevClinOncol耐藥”樹，建立外周血動態(tài)、定量、多McMETT?耐藥檢測體系實(shí)現(xiàn)對耐藥的實(shí)時(shí)監(jiān)測EGFRsensitivmutationwithrareT790MclonesinT790MpositiveinctDNA