《转移性结肠癌靶向治疗的未来治疗策略研究.ppt》由会员分享，可在线阅读，更多相关《转移性结肠癌靶向治疗的未来治疗策略研究.ppt（33页珍藏版）》请在三一文库上搜索。
1、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
2、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
3、 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
4、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
5、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;6:2
6、79286; 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,0,2,4,6,8,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=
7、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
8、;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 I
9、EC-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
10、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;26:3
11、74379; 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
12、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 Onc
13、ol 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
14、,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
15、% 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,
16、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
17、,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
18、 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
19、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)
20、,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
21、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 KRAS tumors1,1. Committee for Medicinal Products for Human Use post-authorisation
22、summary of positive opinion for ERBITUX 2008. Doc.Ref. EMEA/CHMP/280402/2008,KRAS基因状态的应用,前瞻性研究已经验证了KRAS、epiregulin和amphiregulin基因表达的意义1,2 EGFR抑制剂能够提高以下患者的有效率： KRAS野生型 Epiregulin和amphiregulin高表达 KRAS野生型和突变型已经确定为预测标记物1,3 KRAS突变的肿瘤患者可能适合新药治疗,1. Livre A, et al. Cancer Res 2006;66:39923995; 2. Khambata-F
23、ord S, et al. J Clin Oncol 2007;25:32303237; 3. Yuen ST, et al. Cancer Res 2002;62:64516455,展 望,爱必妥可以提高KRAS野生型患者的有效率1 重要的是，爱必妥治疗有效率的提高能够增加R0切除2 KRAS基因检测是mCRC个体化治疗的第一步 KRAS野生型和突变型患者中的深入研究能够进一步明确其他疗效预测标记物和预后判断标记物,1. Livre A, et al. Cancer Res 2006;66:39923995; 2. Folprecht G, et al. Ann Oncol 2006;17:450456,