抗EGFR治疗结直肠癌疗效的潜在预测标记.ppt

抗EGFR治疗结直肠癌疗效的潜在预测标记,浙江大学医学院附属第一医院肿瘤中心化疗科徐农,肿瘤治疗,疗效,毒性,选择,EGFR状态作为结直肠癌的预后因素,82%的结直肠癌EGFR有不同程度的表达,Nicholsonetal.EurJCancer2019;37(Suppl.4):S915,Frequency(%)ofstudiesshowinganassociationbetweenincreasedEGFRlevelanddecreasedsurvival,预测抗EGFR疗效指标,皮疹检测EGFR状态EGFR蛋白表达IHC基因表达FISH基因突变基因水平基因考贝数检测EGFR激活EGFR配体EGFR磷酸化KRAS,其他信号通路PTEN失活VEGF基因表达P21丢失STAT3激活胚系基因多态性EGFR基因多态性（CA双核苷酸重复序列）FcR多态性（FcRIIa131位点和FcRIIIa158位点）cyclinD1A870G和EGFA61G的多态性Cox-2的G765C多态性,临床预测标记,痤疮样皮疹,痤疮样皮疹是抗EGFR靶向药物常见的不良反应，并呈剂量依赖性。抑制EGFR介导的信号通路-抑制生长、促进凋亡、-抑制细胞迁移-增加细胞黏附和分化-刺激炎症进而影响角质化细胞导致特有的皮肤表现,抗EGFR治疗所致皮肤反应,123456789,抗EGFR治疗所致皮肤反应,Descriptionofseverecases,后炎症效应,痤疮样皮疹,甲沟炎,皮肤干燥,Topicalantiacnecreams(dryingeffect)tetracyclinesantihistamines,Pruritus,Pulsedyelaser,Emollients,Hydrocolloiddressingorpropyleneglycolacetylsalicyl,Antisepticsoaks,silvernitrate(pyogenicgranuloma),皲裂,SegaertS,etal.AnnOncol.2019;16:1425-1433.,TherapySuggestions,西妥昔单抗治疗皮疹与生存期关系,1.SaltzL,etal.ProcASCO.2019.2.SaltzL,etal.JClinOncol.2019;22:1201-1208.3.CunninghamD,etal.NEnglJMed.2019;351:337-345.4.VanCutsemE,etal.EORTC/NCIGeneva.2019.5.XiongH,etal.JClinOncol.2019;22:2610-2616.6.KiesMS,etal.ProcASCO.2019.,0,Noreaction,Grade2,Grade1,Grade3,Survival(Months),16,12,8,4,CRC9923Saltz(2019)1,CRC0141Saltz(2019)2,CRCBONDCunningham3,CRCVanCutsem(2019)4,PancreaticXiong(2019)5,SCCHNKies(2019)6,*Therewerenograde4skinreactions.,VanCutsemE,etal.ASCO2019.Abstract4000.,Skinreactiongrade0or1(n=244),0.0,2.5,5.0,7.5,10.0,12.5,15.0,17.5,20.0,PFSTime(Months),1.00,0.75,0.50,0.25,0.00,PFSEstimate,Skinreactiongrade2(n=243),Skinreactiongrade3*(n=112),11.3months,5.4months,9.4months,CRYSTAL:PFSbyOn-StudySkinReactions:Cetuximab+FOLFIRI,皮肤毒性与肿瘤疗效的机理,一些研究者提出假设，皮疹是西妥昔单抗与受体结合饱和程度的替代标志获得所需皮肤毒性的靶向剂量就能进一步提高该药物的疗效证实假说，进行了一项随机多中心I、II期研究（EVEREST试验）另一种假说的解释是皮肤毒性的预测价值可能与个体间胚系遗传多态性有关,TejparS,etal.ASCO2019.Abstract4037.,PatientswithEGFR-positivemCRCfailingirinotecan-basedtherapy(N=166),ArmA:Irinotecan+standard-doseCetuximab250mg/m2/week,ArmB:Irinotecan+dose-escalated*Cetuximabdoseincreasesof50mg/m2q2wuptomaximum500mg/m2/wk,ArmC:Irinotecan+standard-doseCetuximab250mg/m2/week,Day1,Day22,Grade1rash(n=89),Grade2rash(n=77),*Doseescalatedby50mg/m2/weekuntilgrade2toxicity,tumorresponse,ordosereaches500mg/m2.,EVEREST:StudyDesign,Cetuximab400mg/m2initialdosethen250mg/m2/wk+Irinotecan(180mg/m2q2w),Noteligibleforrandomization,randomization,TejparS,etal.ASCO2019.Abstract4037.,ArmC(StandardDose),ArmC(StandardDose),ResponseRate,PFS,Months,Response(%),ArmA(FixedDose),ArmB(DoseEscalation),ArmA(FixedDose),ArmB(DoseEscalation),0,5,10,15,20,25,30,35,0,1,2,3,4,5,6,EVERESTPhaseI/IICetuximabinmCRCStudy:PreliminaryResults,EGFR表达状态,EGFR表达(IHC),EGFR突变,与NSCLC相反,体细胞EGFR基因突变在结直肠癌患者中罕见不论EGFR基因状态是野生型还是突变型,抗EGFR治疗都有效,Khambata-FordS,etal.JClinOncol.2019;25:3230-3237.TsuchihashiZ,etal.NEnglJMed.2019;353:208-209.,EGFR基因拷贝数,Metastaticcolorectalcancerpatientstreatedwithcetuximaborpanitumumab(N=31)screenedforEGFRcopynumberandmutationprofileObjectiveresponse(n=10)Stableorprogressivedisease(n=21),MoroniM,etal.LancetOncol.2019;6:279-286.,89.9,4.8,0,20,40,60,80,100,Objectiveresponders,Nonresponders,IncreasedEGFRCopyNumberbyFISH(%),P0.0001,EGFRFISH表达,Retrospectiveanalysessuggestacorrelationbetweenanti-EGFRtherapyandEGFRgenecopynumbersbyFISH2,3Methodologyissuesfortranslationintoclinicalpractice4,CetuximabTreatmentofmCRC(n=85)1,1.CappuzzoF,etal.AnnOncol.2019;Epub.2.MoroniM,etal.Lancet2019;6:279-286.3.Sartore-BianchiA,etal.JClinOncol.2019;25:3238-3245.4.PersoneniN,etal.JClinOncol.2019;25:18S.Abstract10569.,6.6,11.3,3.5,8.5,0,4,8,12,16,TTP,OS,Months,EGFRFISH+,EGFRFISH-,P=.02,P=.8,100,70,30,0,20,40,60,80,100,2.47,2.47,CR+PR,PD+SD,100,32,0,20,40,60,80,100,43%,43%,68,P=.0009,P=.0007,Patients(%),Patients(%),EGFRgenecopynumber,Chromosome7polysomyoramplification,EGFR基因拷贝数,Sartore-BianchiA,etal.JClinOncol.2019;25:3238-3245.,Survival,responseoutcomesonpanitumumabassociatedwithEGFRgenecopynumber,EGFR磷酸化（激活）,MeasuringEGFRphosphorylationbyimmunohistochemistrymaypredicthigherresponseratesMajormethodologicalissuesfortranslationintoclinicalpractice,pEGFR7(n=7),pEGFR7(n=13),0,20,40,60,80,100,DiseaseControlRate(%),100,54,P=0.05,LevelofEGFRPhosphorylation,PersoneniN,etal.SeminOncol.2019;32:S59-S62.,EGFR配体表达:APredictorforIncreasedPFS?,EGFRLigandExpression,High,Low,0,20,40,60,80,100,120,140,MedianPFS(Days),103.5days,115.5days,57days,57days,EREG(P=.0002),AREG(P=.0002),n=110,cetuximabmonotherapy.,Khambata-FordS,etal.JClinOncol2019;25:3230-3237.,EREG:epireulin表皮调节素,AREG:amphiregulin双调蛋白,AssociationofPFSandOSwiththebaselineexpressionlevelofepiregulin(EREG),VanCutsemE,etal.WCGIC2019.Abstract0034.,EVEREST研究:表皮调节素,PFS,Survival,HighLow,1.00.20.0,0100200300400500,0200400600800,HighLow,P=.013,P=.00033,Time(Days),Time(Days),ProofofPFS,ProofofOS,1.00.20.0,KRAS突变,预测西妥昔单抗疗效的生物学指标,RAS是细胞内信号传导途径中的“下游区”的一种信号传导蛋白，对细胞的生长，存活和分化等功能具有重要影响,K-RAS基因,KRAS基因突变时，不管EGFR是否活化，KRAS蛋白（p21ras）激活,KRAS基因突变是早期事件，结直肠患者发生率4045%,KRAS突变总体与预后差有关,KRAS突变患者西妥昔单抗治疗生存期明显缩短,30mCRCpatientstreatedwithcetuximab43%withKRASmutationKRASmutationobservedin0%of11responders68%of19nonrespondersP=.0003,LievreA,etal.CancerRes.2019;66:3992-3995.,6.3,16.9,0,5,10,15,20,MedianSurvival(months),MutatedKRAS,WildtypeKRAS,P=.016,PredictiveRoleofKRASinCRC,P=.003,Khambata-FordS,etal.JClinOncol.2019;25:3230-3237.,11,51,89,46,0,20,40,60,80,100,DiseaseControlGroup,Patients(%),MutantatKRAScodon12or13,Wild-typeKRAS,Nonresponders,Single-ArmStudies:KRASasaBiomarkerforEGFRInhibitors,KRASStatusandResponsetoPanitumumab:PhaseIIITrialAnalysis,AmadoRG,etal.GICancersSymposium2019.Abstract278.JClinOncol2019,26,1626,Panitumumab6mg/kgevery2weeks+BestSupportiveCare(n=231),BestSupportiveCare*(n=232),ColorectalcancerpatientsstratifiedbyECOG0-1vs2andregion(N=463),*Optionalcrossovertopanitumumabupondiseaseprogression.,PFSbyKRASStatusandTreatment,AmadoRG,etal.GICancersSymposium2019.Abstract278.JClinOncol2019,26,1626,TherelativeeffectofpanitumumabvsbestsupportivecarewassignificantlygreaterinpatientswithWTvsmutantKRASThequantitative-interactiontestcomparingthemagnitudeoftherelativetreatmenteffectonPFSbetweenWTandmutantKRASwasstatisticallysignificant(P.0001)PFSwassignificantlygreaterforpanitumumabtreatmentcomparedwithbestsupportivecareintheWTKRASgroup(stratifiedlog-ranktest:P.0001).,MutantKRAS,WTKRAS,Pmab+BSC,BSCalone,7.4,7.3,HR:0.99(95%CI:0.73-1.36),ProportionEventFree,Weeks,0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,4,8,12,16,20,24,28,32,36,40,44,48,52,HR:0.45(95%CI:0.34-0.59)Stratifiedlog-ranktest:Pgrade2toxicity,tumorresponse,ordosereaches500mg/m2.,EVEREST:StudyDesign,Cetuximab400mg/m2initialdosethen250mg/m2/wk+Irinotecan(180mg/m2q2w),Noteligibleforrandomization,randomization,EVEREST:PFS(ITTPopulation),0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,Days,PFSEstimate,800,P.0001,KRASmutant,WTKRAS,KRASmutationpresent,83days(95%CI:75.9-90.2),173days(95%CI:141.3-204.7),TejparS,etal.ASCO2019.Abstract4001.Reproducedwithpermission.,EVEREST:PFSbyTreatmentGroupandKRASStatus,0.0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,800,0.0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,800,0.0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,800,Days,Days,Days,KRASmutant,WTKRAS,Control,KRASmutationpresent,P=.014,KRASmutant,WTKRAS,DoseEscalation,KRASmutationpresent,KRASmutant,WTKRAS,Nonrandomized,KRASmutationpresent,P.001,P=.020,TejparS,etal.ASCO2019.Abstract4001.Reproducedwithpermission.,PFSEstimate,PFSEstimate,PFSEstimate,CAIRO2StudyoftheDutchColorectalGroup(DCCG):Schema,Stratifiedbypreviousadjuvantchemotherapy,serumLDH,numberofaffectedorgans,andinstitution,Patientswithadvancedcolorectalcancer,withnoprevioussystemictreatmentforadvanceddisease,andWHOperformancescore0-1(N=755),ArmACycles1-6Capecitabine1000mg/m2BIDonDays1-14+Oxaliplatin130mg/m2onDay1+Bevacizumab7.5mg/kgonDay1Cycles7andbeyondCapecitabine1250mg/m2BIDonDays1-14+Bevacizumab7.5mg/kgonDay1(n=368),ArmB*Capecitabine,Oxaliplatin,Bevacizumabasabove+Cetuximab400mg/m2initialdosethen250mg/m2weekly(n=368),Punt,etal.ASCO2019.Abstract4011.,Primaryendpoint:PFSSecondaryendpoints:OS,responserate,toxicity,qualityoflife,*3-wkcycles.,CAIRO2:ImpactofKRASonPFS/OS,KRAS突变率39.1%（196/501）,其他信号通路,PTEN磷酸酯酶和肿瘤抑癌蛋白,调节PI-3K-Akt信号通路40%的结直肠癌PTEN表达下降，与PTEN突变或缺失有关,Romagnanietal.GastrointestinalCancersSymposium2019abstract427,n=10,n=17,0,20,40,60,80,100,有效,PTEN表达,P=0.001,Patients(%),无效,35,100,上调VEGF和其他血管发生介质,A431鳞状细胞癌移植瘤模型EGFR过表达的体内实验提示，通过增加EGFR产物能够诱导西妥昔单抗的获得性耐药Ciardiello等提示对西妥昔单抗或吉非替尼耐药的结肠癌细胞株活化的磷酸MAPK、COX-2表达和VEGF增高510倍Vallbohmer的研究也表明，在39例转移性结直肠中，用定量PCR检测发现，肿瘤内VEGF基因低表达与西妥昔单抗治疗疗效有关,Viloria-Petitetal.CancerRes2019;61:50905101Ciardielloetal.ClinCancerRes2019;10:784793Vallbohmeretal.JClinOncol2019;23:35363544.,p21,Ogino的研究提示结直肠癌p21表达，尤其伴有p53突变，是预测化疗加吉非替尼耐药的指标,Oginoetal.ClinCancerRes2019;11:66506656,0,20,40,60,80,100,有效率(%),25,67,0,20,40,60,80,100,Patients(%),9,68,P=0.05,p21丢失,p21表达阳性,P=0.005,p21表达丢失伴野生型p53,p21表达伴p53突变,STAT3激活,在EVEREST研究中，用IHC检测pSTAT3，初步结果显示西妥昔单抗治疗有效患者的STAT磷酸化程度轻度升高,Spanoetal.EurJCancer2019;42:26682670.,胚系基因多态性预测指标,EGFR基因多态性EGFRG+497AEGFA+61G,0,0.4,0.8,1.2,2,PFS(月),1.3,1.8,0,0.4,0.8,1.2,1.6,2,1.2,1.4,P=0.0017,EGFRG+497A,EGFR+497GG,P=0.042,EGF+61GG,EGF+61A-allele,PFS(月),1.6,Lurjeetal.submittedforpublication,130例MCRC患者cetuximab治疗回顾研究(IMCL-0144),FcR多态性,39例转移性CRC患者IgG1mAb的片段c能诱导ADCC,ZhangW,etal.JClinOncol.2019;25:3712-3718.,Log-rankP=0.004,FCGR2AH/HorH/RandFCGR3AF/ForF/V(n=22),FCGR2