肺癌驱动基因研究总结

非小细胞肺癌驱动基因研究吴一龙广东省肺癌研究所广东省人民医院广东省医学科学院2Treatmentselectionismovingfromhistology-basedtotargetingoncogenicdriversFigure:MassachusettsGeneralHospital,dataonfile.HornL,PaoW.JClinOncol.2009;26:4232–4235.KRASEGFRBRAFHER2PIK3CAALKMETUnknown1999Histology-drivenselection2010Targetingoncogenicdrivers**IncidenceofmutationsinadenocarcinomaprovidedasanexampleNon-squamousEvolutionofNSCLCtreatmentSquamousEGFRWTEGFRMuSquamousEGFRMuKRASMuALK+Othernon-squamousWTSquamous2008TodayCurrentStandardofNSCLCCareAdenocarcinomaSquamous-cellcarcinomaLargecellcarcinomaNSCLC肿瘤驱动基因KrisMG,etal.ASCO2011.CRA7506.JohnsonBE,etal.IASLCWCLC2011.AbstractO16.01.MassachusettsGeneralHospital,dataonfile;HornL,PaoW.JClinOncol2009;26:4232–4235.K-rasEGFRB-rafHer2PIK3CAALKMETUnknownUnknown2010：7类肿瘤驱动基因，未知55%NRASMEK1HER2PIK3CAMETAMPNomutationdetectedKRAS(22%)EGFR(17%)EML4-ALK(7%)Doublemutants(3%)BRAF(2%)AKT12011：10类肿瘤驱动基因，未知46%EGFR28%PTEN10%STK118%EML4-ALK6%KRAS5%c-MET5%PIK3CA4%BRAF2%DDR21%FGER20.6%unknown30%NSCLCFrequencyofdrivergenesinsubgroupsofNSCLCinChineseAnSJ,WuYL.PLoSOneJune2012FrequencyofdrivergenesinsubgroupsofNSCLCinChineseAnSJ,WuYL.PLoSOneJune201291%抗肿瘤药物的敏感性与基因变异相关分析了130种抗肿瘤药物与肿瘤基因变异之间的关系，证实91%(118/130)的抗肿瘤药物敏感性与至少一种基因变异相关GarnettMJ,etal.Nature2012;483:570-577.SignificantlyMutatedGenesinSquamousCellLungCancerGovindanetal.TheCancerGenomeAtlas(TCGA)Project.2012ASCO178/500鳞癌完成分析GeneEventTypeFrequencyCDKN2ADeletion/Mutation/Methylation72%PI3KCAMutation16%PTENMutation/Deletion15%FGFR1Amplification15%EGFRAmplification9%PDGFRAAmplification/Mutation9%CCND1Amplification8%DDR2Mutation4%BRAFMutation4%ERBB2Amplification4%FGFR2Mutation3%TherapeutictargetsinsquamouscelllungcarcinomaGovindanRetal.ASCO2012第一个有临床意义的NSCLC驱动基因：EGFREGFRmutant1stlinetrials:PFSandOSPFSOSEGFRTKI组化疗组HREGFRTKI组化疗组HRGefitinibtrialsIPASS*1(n=261)9.56.30.48p0.00121.621.91.00(0.76-1.33)NEJ0022N=19410.85.40.36P0.00127.726.60.89(0.63-1.24)WJTOG34053N=1729.26.30.49P0.000136391.19(0.77-1.83)ErlotinibtrialsOPTIMAL4N=15413.74.60.16p0.000122.728.81.04(0.69-1.58)EURTAC5N=17410.45.40.47p0.000119.319.51.04(0.65-1.68)#AfatinibtrialLUX-LUNG-3N=34513.66.90.47p0.0001PlaceboErlotinib150mg/dayPreviouslyuntreatedstageIIIB/IVNSCLC,PS0/1(n=451)RPDGemcitabine1,250mg/m2(d1,8)+carboplatinAUC=5orcisplatin75mg/m2(d1)+placebo(d15–28);q4wksx6cyclesGC-placebo(n=225)Gemcitabine1,250mg/m2(d1,8)+carboplatinAUC=5orcisplatin75mg/m2(d1)+erlotinib150mg/day(d15–28);q4wksx6cyclesGC-erlotinib(n=226)PDStudytreatmentMaintenancephaseScreeningErlotinib150mg/dayPrimaryendpoint:PFSwithIRCconfirmationSecondaryendpoints:subgroupanalyses,OSinallpatientsandsubgroups,ORR,durationofresponse,TTP,NPRat16weeks,safety,QoLFASTACT-2(MO22201;CTONG0902)studydesignNSCLC=non-smallcelllungcancer;PS=performancestatus;PD=diseaseprogression;AUC=areaunderthecurve;q4wks=every4weeks;IRC=independentreviewcommittee;OS=overallsurvival;ORR=objectiveresponserate;TTP=timetoprogression;NPR=non-progressionrate;QoL=qualityoflife1:1;stratifiedbystage,histology,smokingstatusandchemoregimenPFSaccordingtoIRCPFSprobabilityTime(months)0222426281816126201410842Patientsremaining225Placebo12351341951791792001.00.80.60.40.207.410.0HR=0.58(0.46–0.72)Log-rankp0.0001226Erlotinib4376151599311417720011731032914110Erlotinib(n=226)Placebo(n=225)Mok,Wuetal.ASCO2012PFSandOSinEGFRMut+subgroup(22Jun2012)1.00.80.60.40.20Time(months)PFSprobability1.00.80.60.40.20bTime(months)OSprobability048121620242832048121620242832366.916.820.631.4Erlotinib(n=49)Placebo(n=48)HR=0.48(0.27–0.84)p=0.0092Erlotinib(n=49)Placebo(n=48)HR=0.25(0.16–0.39)p0.0001PFSOSE4946423325191160P483516542210E494846454133241530P48484336262414600Mok,ESMO2012CTONG9021.00.80.60.40.20PFSandOSinpatientswithEGFRWTandERCC1IHC+status(22Jun2012)Time(months)PFSprobability1.00.80.60.40.20Time(months)PFSOSOSprobability04824329.518.4Erlotinib(n=20)Placebo(n=17)HR=0.32(0.14–0.69)p=0.0024Erlotinib(n=20)Placebo(n=17)HR=0.55(0.27–1.12)p=0.0941016284.67.54812242012162028E2013732210P178200000E20161515138630P17139631000CTONG902Mok,ESMO2012OSinITTpopulation(22Jun2012)15.218.3Erlotinib(n=226)Placebo(n=225)HR=0.79(95%CI0.64–0.99)p=0.0420OSprobabilityTime(months)1.00.80.60.40.2003836343230282624222018161412108642E2262192021911761651541381291149885685239239610P225218206185168156138120103927868533724136400Mok,ESMO2012Mok,ESMO2012TarcevaT790Mpresent(n=21)TarcevaT790Mabsent(n=43)ChemotherapyT790Mpresent(n=26)ChemotherapyT790Mabsent(n=33)EURTACResults:PFSbybaselineT790MstatusPFSprobability1.00.80.60.40.20Time(months)03691215182124273033364.56.38.812.1RosellR,etal.JClinOncol2012;30(Suppl.15PtI):485s(Abs.7522)NatureMedicine18(8):521,2012EURTACBiomarkerStudy•95patientsfromEURTAC(EGFRMutation)withavailablesamples•Biomarkers:ELM4ALK,T790M,TP53,BIM16%detectedbyPCR38%detected24%mutation31%highBEAMlevelBestsurvivalinEGFRmutantsreceivingerlotinib:T790M+iveandBIMhigh:40+months疗效持续时间：基线到首次PD时间；肿瘤负荷：靶病灶倍增时间和非靶病灶评分（4分）：病变进展、新出现胸内病变、新出现胸外病变、恶性胸腔积液症状评分：无症状（0）、原有症状稳定（1）、症状恶化（2）YangJJ,ChenHJ,WuYL,etal.LungCancerOnLine17Oct2012NSCLC驱动基因EML4-ALK融合基因PROFILE100