转移性结肠癌靶向治疗的未来治疗策略研究

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 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 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 18 21） 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 0 10 20 p=0.05 EGFR FISH+ EGFR FISH- TTP (months) Cumulative distribution function Cumulative survival function 0 10 20 30 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 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 8 EGFR mRNA levels 7.3 months 2.2 monthsMedian 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 Survival (anti- apoptosis) Gene transcription Cell-cycle progression MYC MYC Cyclin D1 FOSJUN PP Cyclin D1 Angiogenesis Invasion andmetastasis Chemotherapy/ radiotherapy resistance Proliferation/ maturation MAPK MEK RAS RAFSOS GRB2 PTEN AKT STAT P13K pY pY Ligand: AREG/EREG Target for EGFR-ERBITUX EGFR-TKTarget for EGFT-TK inhibitor pY 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-18RAS-3RAS-4IEC-18SRC-3SRC-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 Livre A, et al. J Clin Oncol 2008;26:374379MAPK = 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 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 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 Change (%) Mutant Pmab + BSC PR (17%) SD (34%) PD (36%) Wild-type Patient Patient BSC alone Change (%) Change (%) Patient Patient PR (0%) SD (12%) PD (70%) PR (0%) SD (8%) PD (60%) 160 120 80 40 0 -40 -80 160 120 80 40 0 -40 -80 Change (%) PR (0%) SD (12%) PD (75%) 160 120 80 40 0 -40 -80 160 120 80 40 0 -40 -80 KRAS基因突变可预测 爱必妥治疗患者的生存期和有效率 Reference No. of patients KRAS mutant (%) Objective response rate (%) Wild-type vs mutant (KRAS-evaluable population) All patients KRAS mutant PFS (weeks) OS (months) Livre A, et al.1 30 43 37 0 16.3 vs 6.9 (p=0.016) Di Fiore F, et al.2 59 37 20 0 23.9 vs 13.0 (p=0.015) De Roock W, et al.3,a 113 41 25 0 24.0 vs 12.0 (p=0.074) 9.9 vs 6.3 (p=0.020) Livre A, et al. 89 27 29 0 31.4 vs 10.1 (p=0.0001) 14.3 vs 10.1 (p=0.026) 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 KRAS wild-type KRAS mutant Median PFS (95% CI), weeks Median OS (95% CI), months 31.4 (19.436) 14.3 (9.420) 10.1 (816) 10.1 (5.113) 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) a) 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) ERBITUX 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=0.5233 30 45.9 Overall 18 36 Wild-type 0.5233 36 65.4 Overall 24 44.3 Mutant 0.5233 12 29.1 Overall 12 24.3 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) Months since start of ERBITUX treatment Estimated PFS probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 3 6 9 12 Log-rank p-value=0.031 G/G (n=87) G/C (n=34) C/C (n=4) COX-2 T+8473C多态性与接受爱必妥治疗 mCRC患者的 PFS相关 12 Estimated PFS probability Months since start of ERBITUX treatment 1.0 0.9 0.8 0.7 0.6 0.0 0 3 6 9 0.5 0.4 0.3 0.2 0.1 C/C (n=19)T/T (n=58) T/C (n=48) Log-rank p-value=0.003 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 Estimated PFS probability 1.0 0.9 0.8 0.7 0.6 0.0 Months since start of ERBITUX therapy 0 3 6 9 12 0.5 0.4 0.3 0.2 0.1 FC 2A: H/H pr H/R and FC 3A F/F or F/V (n=22) Log-rank p-value=0.004 FC 2A: R/R or FC 3A V/V (n=13) 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) Response rate (%) 60 50 40 30 20 0 FC receptor 3a F/F (n=9) V/F (n=12) V/V (n=12) 10 Fishers exact test p=0.054 Response in patients treated with ERBITUX/bevacizumab 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.