转移性结肠癌靶向治疗的未来治疗策略研究课件

1、Investigating future treatment strategies with targeted therapy in mCRCHeinz-Josef LenzUniversity of Southern CaliforniaUSC/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

2、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Fluoropyrim

3、idinesTS, DPD*, TP, MSI, MTHFR expression/polymorphismsIrinotecanUGT polymorphisms*, MSI, transporter polymorphismsOxaliplatinERCC1, GST P1, XPD expression, transporter polymorphismsEGFR antibodiesGene amplification/polymorphism, RAS mutation, BRAF mutation, ligand expression, PTEN expression, VEGF

4、levelsVEGF inhibitorsVEGF polymorphisms, ICAM polymorphisms/levels, E-selectin levels, HIF1, Glut-1, VEGFR gene expressionGeneralCirculating tumor cells*FDA recognized潜在的EGFR 抑制剂的疗效预测标记物EGFR1IHC detection2FISH detection3Mutations3Gene levels/polymorphisms1,4 KRAS1EGFR ligands (EGF, heregulin, epireg

5、ulin, amphiregulin)5 COX-26VEGF61. 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. Val

6、lbhmer 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）11. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237FISH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301020p=0.0

7、5EGFR FISH+EGFR FISH-TTP (months)Cumulative distribution functionCumulative survival function0102030p=0.7EGFR FISH-EGFR FISH+Survival time (months)爱必妥治疗mCRC （n=85）0.00.20.40.60.81.00.00.20.40.60.81.01. Cappuzzo F, et al. Ann Oncol 2008;19:717723; 2. Moroni M, et al. Lancet 2005;6:279286; 3. Personen

8、i 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 2000 American Association for Cancer Research Rak J, et al. Cancer Res 2000;60:490498VEGFTSP-1GAPDHIEC-18RAS-3RAS-4IEC-18SRC-3SRC-4Tumor volume (mm3)2500200015001000500

9、0Time (days)0510152025IEC-18IEC-18/4AIEC-184BRAS-3RAS-4SRC-3SRC-4VEGF: 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;1:556740%的CRC具有KRAS基因突变K

10、RAS基因突变是CRC发生的早期事件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;26:16261634Change (%)MutantPmab+ BSCPR (17%)SD (34%)PD (36%)Wild-typePatientPatientBSCaloneChange (%)Change (%)PatientPatientPR (0%)SD (12%)PD (70%)PR (0%)SD (8%)PD (60%)160120

11、80400-40-8016012080400-40-80Change (%)PR (0%)SD (12%)PD (75%)16012080400-40-8016012080400-40-80KRAS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 patientsKRAS mutant (%)Objective responserate (%) Wild-type vs mutant (KRAS-evaluable population)All patientsKRAS mutantPFS (weeks)OS (months) Livre A, et al.130

12、4337016.3 vs 6.9 (p=0.016) Di Fiore F, et al.2 593720023.9 vs 13.0 (p=0.015)De Roock W, et al.3,a1134125024.0 vs 12.0 (p=0.074)9.9 vs 6.3 (p=0.020) Livre A, et al. 892729031.4 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 20

13、07;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1.000.750.500.250.00020406080100Time (weeks)p=0.0001Pro

14、gression-free survival (PFS)aTime (months)p=0.026Overall survival (OS)a1.000.750.500.250.000102030Survival probabilitySurvival probabilityKRAS wild-typeKRAS mutantMedian PFS (95% CI), weeks Median OS (95% CI), months31.4 (19.436)14.3 (9.420)10.1 (816)10.1 (5.113)Wild-typemutantan=88an=88 Livre A, et

15、 al. J Clin Oncol 2008;26:374379KRAS突变状态和爱必妥皮肤毒性与总生存期（OS）的关系Time (months)1.000.750.500.250.000102030p=0.000815.6 months (95% CI: 10.922) 10.7 months (95% CI: 8.316.3) 5.6 months(95%CI: 2.810.6)Survival probability2 good prognostic factors (wild-type and grade 2/3 skin toxicity) 0 good prognostic fac

16、tors (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)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）HighLowEGFR ligand expression020406080100120140Median PFS (days)103.5 days115.5 days57days57daysn=11

17、0, ERBITUX monotherapy; DCR=疾病控制率（disease control rate）EREGAREG1. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237EGFR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)1Epiregulin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 statusEpiregulin expressionMedi

18、an PFS(months)Median OS(months)All0.52333045.9Overall1836Wild-type0.52333665.4Overall2444.3Mutant0.52331229.1Overall1224.3p0.001p0.001Lenz 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PRPRPRSDSDSDPDPD0102030405060708090100G/G(n=78)G/C(n=30)C/C(n=4) p=0.097Patients (%)Nagashima F, et al.

19、 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 treatmentEstimated PFS probability 0.00.10.20.30.40.50.60.70.80.91.0036912Log-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

20、患者的PFS相关12Estimated PFS probabilityMonths since start of ERBITUX treatment1.00.90.80.70.60.003690.50.40.30.20.1C/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 ArteagaFC受体2a和3a的多态性与PFS相关Zhang W, et al. J Clin Oncol 2007;25:37123718Estimated PFS probability1.00.90.80

21、.70.60.0Months since start of ERBITUX therapy0369120.50.40.30.20.1FC 2A: H/H pr H/R andFC 3A F/F or F/V (n=22)Log-rank p-value=0.004FC 2A: R/R orFC 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 (%)60504030200FC receptor 3a F/F (n=9)V/F

22、 (n=12)V/V (n=12)10Fishers exact test p=0.054Response 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 loss1EGFR ligands2PI3K mutations3EGFR gene copy number41. 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