转移性结肠癌靶向治疗的未来治疗策略研究课件

1、转移性结肠癌靶向治疗的未来治疗策略研究转移性结肠癌靶向治疗的未来治疗策略研究 作为疗效预测和预后判断的标记物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 Cli

2、n 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*, MS

3、I, 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 le

4、vels, 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 detection2 FISH detection3 Mutations3 Gene levels/polymorphisms1,4 ? KRAS 1 ? EGFR ligands (EGF, heregulin, epiregulin, amphiregulin) 5 ? COX-2 6 ? VEGF 6 1. Livre A, et al. Can

5、cer Res 2006;66:3992 3995; 2. Chung KY, et al. J Clin Oncol 2005;23:18031810; 3. Moroni M, et al. Lancet Oncol 2005;6:279 286; 4. Zhang W, et al. Pharmacogenet Genomics 2006;16:475483; 5. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237; 6. Vallb? hmer D, et al. J Clin Oncol 2005;23:3536 3544 结

6、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法检测的法检测的EGFR基因表达基因表达 ?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 FIS

7、H- TTP (months) C u m u l a t i v e d i s t r i b u t i o n f u n c t i o n C u m u l a t i v e s u r v i v a l f u n c t i o n 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;19:71772

8、3; 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（基因转录（mRNA）水平与生存期无关）水平与生存期无关 a 0 2 4 6 8 EGFR mRNA levels 7.3 months 2.2 months M e

9、d i a n s u r v i v a l ( m o n t h s ) 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. Vallb?hmer 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受体信号传导通路：个性化治疗的合理性 Survival (anti- apoptosis) Gene

10、 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 i

11、nhibitor 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

12、:490 498 VEGF TSP-1 GAPDH T u m o r v o l u m e ( m m 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: 潜在的生物标记物潜在的生物标记物? KRAS基因突变的理论假设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

13、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,

14、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 Panitumum

15、ab 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)

16、 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;67:2643 2648; 3. De Roock W, et al. Ann Oncol 2008;19:508 515; 4. Finocchiaro G, et al. ASCO 2007 (Abstract No. 4021); 5. Di Fiore F, et al. Br J Can

17、cer 2007;96:1166 1169; 6. Khambata-Ford S, et al. J Clin Oncol 2007;25:3230 3237; 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 C h a n g e ( % ) Mutant Pmab + BSC PR (17%) SD

18、(34%) PD (36%) Wild-type Patient Patient BSC alone C h a n g e ( % ) C h a n g e ( % ) 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 C h a n g e ( % ) PR (0%) SD (12%) PD (75%) 160 120 80 40 0 -40 -80 160 120 80 40 0 -40 -80 KRAS基因

19、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 Rooc

20、k 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. Livr

21、e 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 Ov

22、erall survival (OS) a 1.00 0.75 0.50 0.25 0.00 0 10 20 30 S u r v i v a l p r o b a b i l i t y S u r v i v a l p r o b a b i l i t y 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 Li vr

23、e 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: 10.9 22) 10.7 months (95% CI: 8.3 16.3) 5.6 months (95%CI: 2.810.6) S u r v i v a l p r o b a b i l i t y 2 good prognostic factors (wild-type and grad

24、e 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

25、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（得更长的无进展生存期（PFS） High Low EGFR ligand expression 0 20 40 60 80 100 120 140 M e d i a n P F S ( d a y s ) 103.5 days 115.5 days 57 days 57 days n=110, ERB

26、ITUX 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) KRAS status Epiregulin expression

27、 Median PFS (months) Median OS (months) All 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 1

28、00 G/G (n=78) G/C (n=30) C/C (n=4) p=0.097 P a t i e n t s ( % ) 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 E s t i m a t e d P F S p r o b a b i l i t y 0.0 0.1 0.2

29、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 E s t i m a t e d P F S p r o b a b i l i t y 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

30、/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 E s t i m a t e d P F S p r o b a b i l i t y 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

31、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) R e s p o n s e r a t e ( % ) 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 (Abstrac