转移性结肠癌靶向治疗的未来治疗策略研究.ppt

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 2006;66:39923995; 2. Sargent DJ, et al. J Clin Oncol 2005;23:20202027; 3. MartnezLpez E, et al. Gastroenterology 1998;114:11801187; 4. Edler D, et al. J Clin Oncol 2002;20:17211728,潜在的结肠癌疗效预测标志物,Meropol NJ, et al. ASCO 2008,*FDA recognized,潜在的EGFR 抑制剂的疗效预测标记物,EGFR1 IHC detection2 FISH detection3 Mutations3 Gene levels/polymorphisms1,4 KRAS1 EGFR ligands (EGF, heregulin, epiregulin, amphiregulin)5 COX-26 VEGF6,1. Livre A, et al. Cancer Res 2006;66:39923995; 2. Chung KY, et al. J Clin Oncol 2005;23:18031810; 3. Moroni M, et al. Lancet Oncol 2005;6:279286; 4. Zhang W, et al. Pharmacogenet Genomics 2006;16:475483; 5. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237; 6. Vallbhmer D, et al. J Clin Oncol 2005;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1821）1,1. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237,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,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 2008;19:717723; 2. Moroni M, et al. Lancet 2005;6:279286; 3. Personeni N, et al. J Clin Oncol 2007;25 (18S) (Abstract No. 10569),扩增基因的表现形式,Albertson DG. Trends Genet 2006;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,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,a39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. Vallbhmer D, et al. J Clin Oncol 2005;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,Yarden Y, Sliwkowski MX. Nat Rev Mol Cell Biol 2001;2:127137; Chakravarti A, et al. Cancer Res 2002;62:43074315; Baselga J. Eur J Cancer 2001;37(Suppl. 4):S16S22; Kawanaka H, et al. Life Sci 2001;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 (mm3),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,Livre A, et al. J Clin Oncol 2008;26:374379,MAPK = 丝裂原激活的蛋白激酶,Fodde R, et al. Nature Rev Cancer 2001;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 2002;62:64516455; 2. Weisenberger DJ, et al. Nat Genet 2006;38:787793; 3. Livre A, et al. Cancer Res 2006;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,1. Livre A, et al. J Clin Oncol 2008;26:374379; 2. Benvenuti S, et al. Cancer Res 2007;67:26432648; 3. De Roock W, et al. Ann Oncol 2008;19:508515; 4. Finocchiaro G, et al. ASCO 2007 (Abstract No. 4021); 5. Di Fiore F, et al. Br J Cancer 2007;96:11661169; 6. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237; 7. Amado RG, et al. J Clin Oncol 2008;26:16261634,靶病灶缩小百分比 可评价KRAS基因状态患者的资料,BSC = Best supportive care; Pmab = panitumumab Amado RG, et al. J Clin Oncol 2008;26:16261634,KRAS基因突变可预测 爱必妥治疗患者的生存期和有效率,1. Livre A, et al. Cancer Res 2006;66:39923995; 2. Di Fiore F, et al. Br J Cancer 2007;96:11661169; 3. De Roock W, et al. Ann Oncol 2008;19:508515; 4. Livre A, et al. J Clin Oncol 2008;26:374379,aIn the combination therapy group (mutant vs wild-type): PFS=12 vs 34 weeks (p=0.016); OS=6.3 vs 10.3 months (p=0.003),KRAS基因突变状态对生存期的影响,1.00,0.75,0.50,0.25,0.00,0,20,40,60,80,100,Time (weeks),p=0.0001,Progression-free survival (PFS)a,Time (months),p=0.026,Overall survival (OS)a,1.00,0.75,0.50,0.25,0.00,0,10,20,30,Survival probability,Survival probability,Wild-type,mutant,an=88,an=88 Livre A, et al. J Clin Oncol 2008;26:374379,KRAS突变状态和爱必妥皮肤毒性与总生存期（OS）的关系,Time (months),1.00,0.75,0.50,0.25,0.00,0,10,20,30,p=0.0008,15.6 months (95% CI: 10.922),10.7 months (95% CI: 8.316.3),5.6 months,(95%CI: 2.810.6),Survival probability,2 good prognostic factors (wild-type and grade 2/3 skin toxicity),0 good prognostic factors (KRAS mutant and grade 0/1 skin toxicity),1 good prognostic factor (wild-type or grade 2/3 skin toxicity),Livre A, et al. AACR Annual Meeting 2007 (Abstract 5671),epiregulin (EREG)和/或amphiregulin (AREG)表达上调可通过与EGFR形成自分泌环路促进肿瘤生长1,a),EGFR配体在CRC中的作用,1. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237,b) 依赖EGFR信号传导通路的肿瘤对爱必妥治疗更加敏感1,EGFR配体高表达可预测爱必妥治疗能够获得更长的无进展生存期（PFS）,High,Low,EGFR ligand expression,0,20,40,60,80,100,120,140,Median PFS (days),103.5 days,115.5 days,57 days,57 days,n=110, ERBITUX monotherapy; DCR=疾病控制率（disease control rate）,EREG,AREG,1. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237,EGFR配体高表达患者的DCR和中位PFS 具有明显优势(EREG p=0.0002; AREG p=0.0001)1,Epiregulin表达水平对KRAS突变型和野生型患者PFS和OS的影响,Tejpar S, et al. ASCO GI 2008 (Abstract No. 411),p0.001,p0.001,Lenz H-J, et al. (unpublished data),COX-2 多态性,COX-2基因多态性与爱必妥疗效的关系,PR,PR,PR,SD,SD,SD,PD,PD,0,10,20,30,40,50,60,70,80,90,100,G/G (n=78),G/C (n=30),C/C (n=4),p=0.097,Patients (%),Nagashima F, et al. ASCO 2007 (Abstract No. 4129),COX-2 765GC 多态性与接受爱必妥治疗mCRC患者的PFS相关,Nagashima F, et al. ASCO 2007 (Abstract No. 4129),COX-2 T+8473C多态性与接受爱必妥治疗mCRC患者的PFS相关,12,抗体依赖性细胞毒作用（ADCC）,Courtesy of Dr Arteaga,FC受体2a和3a的多态性与PFS相关,Zhang W, et al. J Clin Oncol 2007;25:37123718,FC受体3a多态性与爱必妥和bevacizumab的疗效相关（BOND 2）,Lenz H, et al. ASCO GI 2007 (Abstract No. 401),对多个分子生物学标记物的分析,检测多个指标有可能提高预测疗效的效力 PTEN loss1 EGFR ligands2 PI3K mutations3 EGFR gene copy number4,1. Loupakis F, et al ASCO 2008 (Abstract No. 4003); 2. Tejpar S, et al. ASCO GI 2008 (Abstract No. 411) 3. Jhawer M, et al. Cancer Res 2008;68:19531961; 4. Cappuzzo F, et al. Ann Oncol 2008;19:717723,抗EGFR治疗前检测KRAS基因突变状态的四个理由,避免不必要的不良反应 控制不必要的费用 确认能够从治疗中获益的野生型患者 避免治疗对突变型患者的潜在毒性,Committee for Medicinal Products for Human Use (CHMP) gave a positive opinion for ERBITUX May 30, 2008 but only for patients with wild-type