转移性结肠癌靶向治疗的未来治疗策略研究课件.pptx

1、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 Clin Oncol 2005;23:20202027;3.MartnezLpez E,et al.Gastroe

2、nterology 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FluoropyrimidinesTS,DPD*,TP,MSI,MTHFR expression/polymorphismsIrinotecanUGT polymorphisms*,MSI,transporter polymorphismsOxaliplatinERCC1,GST P1,XPD expression,transporter

3、 polymorphismsEGFR antibodiesGene amplification/polymorphism,RAS mutation,BRAF mutation,ligand expression,PTEN expression,VEGF levelsVEGF inhibitorsVEGF polymorphisms,ICAM polymorphisms/levels,E-selectin levels,HIF1,Glut-1,VEGFR gene expressionGeneralCirculating tumor cells*FDA recognized潜在的潜在的EGFR

4、抑制剂的疗效预测标记物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 VEGF61.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;6:2

5、79286;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（结直肠癌（CRC）少见）少见EGFR基因突变基因突变 结直肠癌（结直肠癌（CRC）肿瘤标本中很少见）肿瘤标本中很少见EGFR基基因突变因突变 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

6、1.Khambata-Ford S,et al.J Clin Oncol 2007;25:32303237FISH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301020p=0.05EGFR FISH+EGFR FISH-TTP(months)Cumulative distribution functionCumulative survival function0102030p=0.7EGFR FISH-EGFR FISH+Survival time(months)爱

7、必妥治疗爱必妥治疗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.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 双微染色体双微染色体 染色体区域扩增染色体区域扩增 在基因组内广泛分布在基因组内

8、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a02468EGFR mRNA levels7.3 months2.2 monthsMedian survival(months)95%CI:4.413.5 months95%CI:1.74.5 monthsp=0.09a39例伊诺替康和奥沙利铂耐药的mCRC接受 爱必妥单药治疗LowHigh1.Vallbhmer D,et al.J Clin Oncol 2005;23:35363544EGFR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）1EGF 受体信号传导通路：个性化治疗的合理性受体信号

9、传导通路：个性化治疗的合理性Survival(anti-apoptosis)Gene transcriptionCell-cycle progressionMYCMYCCyclin D1FOSJUNPPCyclin D1AngiogenesisInvasion andmetastasisChemotherapy/radiotherapy resistanceProliferation/maturationMAPKMEKRASRAFSOSGRB2PTENAKTSTATP13KpYpYLigand:AREG/EREGTarget for EGFR-ERBITUXEGFR-TKTarget for

10、EGFT-TK inhibitorpYYarden 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;60:490498V

11、EGFTSP-1GAPDHIEC-18RAS-3RAS-4IEC-18SRC-3SRC-4Tumor volume(mm3)25002000150010005000Time(days)0510152025IEC-18IEC-18/4AIEC-184BRAS-3RAS-4SRC-3SRC-4VEGF: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预后的作用有待证实Livre A,et al.J Clin Onc

12、ol 2008;26:374379MAPK=丝裂原激活的蛋白激酶Fodde R,et al.Nature Rev Cancer 2001;1:556740%的的CRC具有具有KRAS基因突变基因突变KRAS基因突变是基因突变是CRC发生的早期事件发生的早期事件KRAS基因突变并非基因突变并非CRC的孤立事件的孤立事件 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

13、;38:787793;3.Livre A,et al.Cancer Res 2006;66:39923995 KRAS基因突变者基因突变者EGFR抑制剂的疗效差抑制剂的疗效差对化疗耐药对化疗耐药mCRC进行的回顾性分析进行的回顾性分析 Reference Treatment No.of patients(wild-type:mutant)Objective response,n(%)Wild-typeMutant Livre A,et al.1 ERBITUX CT89(65:24)26(40)0(0)Benvenuti S,et al.2 Panitumumab or ERBITUX or

14、ERBITUX+CT48(32:16)10(31)1(6)De Roock W,et al.3ERBITUX or ERBITUX+irinotecan113(67:46)27(41)0(0)Finocchiaro G,et al.4 ERBITUX CT81(49:32)13(27)2(6)Di Fiore F,et al.5 ERBITUX+CT59(37:22)12(32)0(0)Khambata-Ford S,et al.6 ERBITUX80(50:30)5(10)0(0)Amado RG,et al.7 Panitumumab208(124:84)21(17)0(0)1.Livre

15、 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

16、Clin Oncol 2008;26:16261634Estimated PFS probabilityChemotherapy/radiotherapy resistance18号染色体长臂（18q）缺失COX-2 765GC 多态性与接受爱必妥治疗mCRC患者的PFS相关回顾性研究：FISH法检测的EGFR表达水平有可能预测爱必妥疗效1,2(unpublished data)Finocchiaro G,et al.PanitumumabaIn the combination therapy group(mutant vs wild-type):PFS=12 vs 34 weeks(p=0.

17、Khambata-Ford S,et al.Patients(%)Di Fiore F,et al.KRAS基因检测是mCRC个体化治疗的第一步95%CI:1.Livre A,et al.靶病灶缩小百分比靶病灶缩小百分比可评价可评价KRAS基因状态患者的资料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-typePatientPatientBSCaloneC

18、hange(%)Change(%)PatientPatientPR(0%)SD(12%)PD(70%)PR(0%)SD(8%)PD(60%)16012080400-40-8016012080400-40-80Change(%)PR(0%)SD(12%)PD(75%)16012080400-40-8016012080400-40-80KRAS基因突变可预测基因突变可预测爱必妥治疗患者的生存期和有效率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

19、(KRAS-evaluable population)All patients KRAS mutantPFS(weeks)OS(months)Livre A,et al.1304337016.3 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

20、 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

21、的影响基因突变状态对生存期的影响1.000.750.500.250.00020406080100Time(weeks)p=0.0001Progression-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)

22、10.1(816)10.1(5.113)Wild-typemutantan=88an=88 Livre A,et al.J Clin Oncol 2008;26:374379KRAS突变状态和爱必妥皮肤毒性与总生存期（突变状态和爱必妥皮肤毒性与总生存期（OS）的关系）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 fa

23、ctors(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1a)EGFR配体在配

24、体在CRC中的作用中的作用1.Khambata-Ford S,et al.J Clin Oncol 2007;25:32303237b)ERBITUXb)依赖EGFR信号传导通路的肿瘤对爱必妥治疗更加敏感1EGFR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）HighLowEGFR ligand expression020406080100120140Median PFS(days)103.5 days115.5 days57days57daysn=110,ERBITUX monotherapy;DCR=疾病控制率（dise

25、ase 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表达水平对表达水平对KRAS突变型和野生型患者突变型和野生型患者PFS和和OS的影响的影响 Tejpar S,et al.ASCO GI 2008(Abstract No.411)KRAS statusEpiregulin expressionMedian PFS(months)Median OS(mont

26、hs)All0.52333045.9Overall1836Wild-type0.52333665.4Overall2444.3Mutant0.52331229.1Overall1224.3p0.001p0.001Lenz H-J,et al.(unpublished data)COX-2 多态性多态性EGF 受体信号传导通路：个性化治疗的合理性Chung KY,et al.but only for patients with wild-type KRAS tumors1Cancer Res 2006;66:39923995;2.Zhang W,et al.Tejpar S,et al.KRAS

27、 mutantLenz H-J,et al.Lancet 2005;6:279286;3.J Clin Oncol 2007;25:32303237KRAS mutantEGFR ligands(EGF,heregulin,epiregulin,amphiregulin)5an=88 Livre A,et al.aIn the combination therapy group(mutant vs wild-type):PFS=12 vs 34 weeks(p=0.EMEA/CHMP/280402/2008COX-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PRPRPRSDSDS

28、DPDPD0102030405060708090100G/G(n=78)G/C(n=30)C/C(n=4)p=0.097Patients(%)Nagashima F,et al.ASCO 2007(Abstract No.4129)COX-2 765GC 多态性与接受爱必妥治疗多态性与接受爱必妥治疗mCRC患者的患者的PFS相关相关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.

29、70.80.91.0036912Log-rank p-value=0.031 G/G(n=87)G/C(n=34)C/C(n=4)113(67:46)1Di Fiore F,et al.Ann Oncol 2008;19:717723KRAS wild-typePFS(weeks)Tejpar S,et al.Lenz H-J,et al.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1,20002;AREG p=0.Ann Oncol 2008;19:717723;2.Livre A,et al.Lancet 2005;6:279286;3.某些分子标记物具有上述两种作用F

30、luoropyrimidinesCOX-2 T+8473C多态性与接受爱必妥治疗多态性与接受爱必妥治疗mCRC患者的患者的PFS相关相关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（抗体依赖性细胞毒作用（ADCC）Courtesy of Dr ArteagaFC受体受体2a和和3a的多态性与的多态性与PFS相关相关Zh

31、ang W,et al.J Clin Oncol 2007;25:37123718Estimated PFS probability1.00.90.80.70.60.0Months 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受体受体3a多态性与爱必妥和多态性与爱必妥和bevacizumab的的疗效相关（疗效相关（BOND 2）Lenz H,et al.

32、ASCO GI 2007(Abstract No.401)Response rate(%)60504030200FC receptor 3a F/F(n=9)V/F(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 number41.Loupakis

33、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抗抗EGFR治疗前检测治疗前检测KRAS基因突变状态的基因突变状态的四个理由四个理由1.避免不必要的不良反应避免不必要的不良反应2.控制不必要的费用控制不必要的费用3.确认能够从治疗中获益的野生型患者确认能够从治疗中获益的野生型患者4.避免治疗对突变型患者的潜

34、在毒性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 tumors11.Committee for Medicinal Products for Human Use post-authorisation summary of positive opinion for ERBITUX 2008.Doc.Ref.EMEA/CHMP/28

35、0402/2008KRAS基因状态的应用基因状态的应用 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-Ford S,et al.J Clin Oncol 2007;25:32303237;3.Yuen ST,et al.Cancer Res

36、 2002;62:64516455展展 望望 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;17:450456FISH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

37、表达水平与疗效之间的具有相关性301020p=0.05EGFR FISH+EGFR FISH-TTP(months)Cumulative distribution functionCumulative survival function0102030p=0.7EGFR FISH-EGFR FISH+Survival time(months)爱必妥治疗爱必妥治疗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;

38、6:279286;3.Personeni N,et al.J Clin Oncol 2007;25(18S)(Abstract No.10569)Fodde R,et al.Nature Rev Cancer 2001;1:556740%的的CRC具有具有KRAS基因突变基因突变KRAS基因突变是基因突变是CRC发生的早期事件发生的早期事件Log-rank p-value=0.KRAS mutantMonths since start of ERBITUX therapyJ Clin Oncol 2005;23:18031810;0002;AREG p=0.靶病灶缩小百分比可评价KRAS基因状

39、态患者的资料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）J Clin Oncol 2007;25:37123718某些分子标记物具有上述两种作用重要的是，爱必妥治疗有效率的提高能够增加R0切除2DCR=疾病控制率（disease control rate）Livre A,et al.Di Fiore F,et al.(unpublished data)抗EGFR治疗前检测KRAS基因突变状态的四个理由靶病灶缩小百分比靶病灶缩小百分比可评价可评价KRAS基因状态患者的资料基因状态患者的资料BSC=Best supportive care;Pmab=panitumumab

40、 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%)16012080400-40-8016012080400-40-80Change(%)PR(0%)SD(12%)PD(75%)16012080400-40-8016012080400-40-80Overall surv

41、ival(OS)aFISH法检测的EGFR基因表达Estimated PFS probabilityJ Clin Oncol 2007;25(18S)(Abstract No.潜在的EGFR 抑制剂的疗效预测标记物MartnezLpez E,et al.重要的是，爱必妥治疗有效率的提高能够增加R0切除2KRAS mutantEur J Cancer 2001;37(Suppl.2000 American Association for Cancer Research Rak J,et al.KRAS基因突变可预测爱必妥治疗患者的生存期和有效率Estimated PFS probabilityF

42、odde R,et al.0002;AREG p=0.FISH detection3EGFR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）HighLowEGFR ligand expression020406080100120140Median PFS(days)103.5 days115.5 days57days57daysn=110,ERBITUX monotherapy;DCR=疾病控制率（disease control rate）EREGAREG1.Khambata-Ford S,et al.J Clin Oncol

43、 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)1COX-2 T+8473C多态性与接受爱必妥治疗多态性与接受爱必妥治疗mCRC患者的患者的PFS相关相关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=0.003113(67:46)95%CI:1.PI3

44、K mutations3Gastroenterology 1998;114:11801187;4.Fodde R,et al.Estimated PFS probability1 good prognostic factor(wild-type or grade 2/3 skin toxicity)EGFR ligand expressionCumulative survival functionFodde R,et al.J Clin Oncol 2007;25:32303237Vallbhmer D,et al.Median OS(95%CI),monthsAngiogenesisWild-type vs mutant (KRAS-evaluable population)展展 望望 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