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Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,07/23/2007,QRM Merck Serono,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,07/23/2007,QRM Merck Serono,*,Investigating future treatment strategies with targeted therapy in mCRC,Heinz-Josef Lenz,University of Southern California,USC/Norris Comprehensive Cancer Center Los Angeles,USA,作为疗效预测和预后判断的标记物,疗效预测标记物：,能够预测某种特定治疗方式疗效的标记物,KRAS,基因突变导致肿瘤对,EGFR,抑制剂抵抗,预后判断标记物：,在不考虑治疗因素的情况下能够判断患者结局的标记物,18,号染色体长臂（,18q,）缺失,某些分子标记物具有上述两种作用,胸腺嘧啶合成酶（,Thymidylate synthase,）表达,1.Livre A,et al.Cancer Res 2019;66:39923995;,2.Sargent DJ,et al.J Clin Oncol 2019;23:20202027;,3.Mart,nezLpez,E,et al.Gastroenterology 2019;114:11801187;4.Edler D,et al.J Clin Oncol 2019;20:17211728,潜在的结肠癌疗效预测标志物,Meropol NJ,et al.ASCO 2019,药物,标记物,Fluoropyrimidines,TS,DPD*,TP,MSI,MTHFR expression/polymorphisms,Irinotecan,UGT polymorphisms*,MSI,transporter polymorphisms,Oxaliplatin,ERCC1,GST P1,XPD expression,transporter polymorphisms,EGFR antibodies,Gene amplification/polymorphism,RAS mutation,BRAF mutation,ligand expression,PTEN expression,VEGF levels,VEGF inhibitors,VEGF polymorphisms,ICAM polymorphisms/levels,E-selectin levels,HIF1,Glut-1,VEGFR gene expression,General,Circulating tumor cells,*,FDA recognized,潜在的,EGFR,抑制剂的疗效预测标记物,EGFR,1,IHC detection,2,FISH detection,3,Mutations,3,Gene levels/polymorphisms,1,4,KRAS,1,EGFR ligands(EGF,heregulin,epiregulin,amphiregulin),5,COX-2,6,VEGF,6,1.,Livre A,et al.Cancer Res 2019;66:39923995;2.Chung KY,et al.J Clin Oncol 2019;23:18031810;,3.Moro,ni M,et al,.Lancet Oncol 2019;6:279286;4.Zhang W,et al.Pharmacogenet Genomics 2019;16:475483;,5.,Khambata-Ford S,et al.J Clin Oncol 2019;25:32303237;,6.Vallb,hmer D,et al.J Clin Oncol 2019;23:35363544,结直肠癌（,CRC,）少见,EGFR,基因突变,结直肠癌（,CRC,）肿瘤标本中很少见,EGFR,基因突变,对爱必妥单药治疗转移性结直肠癌（,mCRC,）临床试验中,110,例活检标本进行的研究未发现,EGFR,基因突变（外显子,18,21,）,1,1.Khambata-Ford S,et al.J Clin Oncol 2019;25:3230,3237,FISH,法检测的,EGFR,基因表达,回顾性研究：,FISH,法检测的,EGFR,表达水平,有可能,预测爱必妥疗效,1,2,但近期的一项研究并未发现,EGFR,表达水平与疗效之间的具有相关性,3,01020,p=0.05,EGFR FISH+,EGFR FISH-,TTP(months),Cumulative distribution function,Cumulative survival function,0102030,p=0.7,EGFR FISH-,EGFR FISH+,Survival time(months),爱必妥治疗,mCRC,（,n=85,）,0.0,0.2,0.4,0.6,0.8,1.0,0.0,0.2,0.4,0.6,0.8,1.0,1.Cappuzzo F,et al.Ann Oncol 2019;19:717,723,;2.Moroni M,et al.Lancet 2019;6:279,286;3.Personeni N,et al.J Clin Oncol 2019;25(18S)(Abstract No.10569),扩增基因的表现形式,Albertson DG.Trends Genet 2019;22:447455,双微染色体,染色体区域扩增,在基因组内广泛分布,EGFR,基因转录（,mRNA,）水平与生存期无关,a,0,2,4,6,8,EGFR mRNA levels,7.3 months,2.2 months,Median survival(months),95%CI:4.413.5 months,95%CI:1.74.5 months,p=0.09,a,39,例伊诺替康和奥沙利铂耐药的,mCRC,接受 爱必妥单药治疗,Low,High,1.Vallb,hmer D,et al.J Clin Oncol 2019;23:35363544,EGFR,基因表达水平与爱必妥治疗后患者的生存期无明显相关性（小样本研究）,1,EGF,受体信号传导通路：个性化治疗的合理性,Survival(anti-apoptosis),Gene transcription,Cell-cycle progression,MYC,MYC,Cyclin D1,FOS,JUN,P,P,Cyclin D1,Angiogenesis,Invasion and,metastasis,Chemotherapy/radiotherapy resistance,Proliferation/maturation,MAPK,MEK,RAS,RAF,SOS,GRB2,PTEN,AKT,STAT,P13K,pY,pY,Ligand:AREG/EREG,Target for EGFR-ERBITUX,EGFR-TK,Target for EGFT-TK inhibitor,pY,Yarden Y,Sliwkowski MX.,Nat Rev Mol Cell Biol,2019;2:127137;Chakravarti A,et al.Cancer Res 2019;62:43074315;Baselga J.Eur J Cancer 2019;37(Suppl.4):S16S22;Kawanaka H,et al.Life Sci 2019;69:30193033,2000 American Association for Cancer Research,Rak J,et al.Cancer Res 2000;60:490498,VEGF,TSP-1,GAPDH,IEC-18,RAS-3,RAS-4,IEC-18,SRC-3,SRC-4,Tumor volume(mm,3,),2500,2000,1500,1000,500,0,Time(days),0,5,10,15,20,25,IEC-18,IEC-18/4A,IEC-184B,RAS-3,RAS-4,SRC-3,SRC-4,VEGF:,潜在的生物标记物,?,KRAS,基因突变的理论假设,KRAS,基因突变能够激活下游,RAS/MAPK,信号传导通路，这种激活无需配体诱导的,EGFR,激活,导致爱必妥耐药,KRAS,基因突变预测爱必妥疗效和判断,mCRC,预后的作用有待证实,Li,vre A,et al.J Clin Oncol 2019;26:374,379,MAPK=,丝裂原激活的蛋白激酶,Fodde R,et al.Nature Rev Cancer 2019;1:5567,40%,的,CRC,具有,KRAS,基因突变,KRAS,基因突变是,CRC,发生的早期事件,KRAS,基因突变并非,CRC,的孤立事件,KRAS,突变与,BRAF,突变相联系，后者与,CpG,岛甲基化表型（,CIMP,）,1,，,2,有关,KRAS,突变与,PI3K,突变相关,3,1.Yuen ST,et al.Cancer Res 2019;62:64516455;2.Weisenberger DJ,et al.Nat Genet 2019;38:787793;,3.,Livre A,et al.Cancer Res 2019;66:39923995,KRAS,基因突变者,EGFR,抑制剂的疗效差对化疗耐药,mCRC,进行的回顾性分析,Reference,Treatment,No.of patients(wild-type:mutant),Objective response,n(%),Wild-type,Mutant,Livre A,et al.,1,ERBITUX CT,89(65:24),26(40),0(0),Benvenuti S,et al.,2,Panitumumab or ERBITUX or ERBITUX+CT,48(32:16),10(31),1(6),De Roock W,et al.,3,ERBITUX or ERBITUX+irinotecan,113(67:46),27(41),0(0),Finocchiaro G,et al.,4,ERBITUX CT,81(49:32),13(27),2(6),Di Fiore F,et al.,5,ERBITUX+CT,59(37:22),12(32),0(0),Khambata-Ford S,et al.,6,ERBITUX,80(50:30),5(10),0(0),Amado RG,et al.,7,Panitumumab,208(124:84),21(17),0(0),1.,Livre A,et al.J Clin Oncol 2019;26:374379;2.,Benvenuti S,et al.Cancer Res 2019;67:26432648;3.,De Roock W,et al.Ann Oncol 2019;19:508515;,4.,Finocchiaro G,et al.ASCO 2019(Abstract No.4021);5.,Di Fiore F,et al.Br J Cancer 2019;96:11661169;6.,K
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