转移性结肠癌靶治疗的未来治疗策略研究

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（18

2、q）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潜在的结肠癌疗效预测标志物meropol nj,

3、 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 polymorphismsegfr antibodiesgene amplification/polymorphism, ras mutation, braf mutation, ligand e

4、xpression, 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 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/polymo

5、rphisms1,4 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;6:279286; 4. zhang w, et al. pharmacogenet genomics 2006;16:475483; 5. khambat

6、a-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）11. khambata-ford s, et al. j clin oncol 2007;25:32303237fish法检测

7、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.

8、 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

9、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传导通路：个性化治疗的合理性survival (anti-apop

10、tosis)gene transcriptioncell-cycle progressionmycmyccyclin d1fosjunppcyclin d1angiogenesisinvasion andmetastasischemotherapy/radiotherapy resistanceproliferation/maturationmapkmekrasrafsosgrb2ptenaktstatp13kpypyligand: areg/eregtarget for egfr-erbituxegfr-tktarget for egft-tk inhibitorpyyarden y, sl

11、iwkowski 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;60:490498vegftsp-1gapdhiec-1

12、8ras-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 oncol 2008;26:37

13、4379mapk = 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;3

14、8:787793; 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

15、erbitux or 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.

16、7 panitumumab208 (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. khamb

17、ata-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-typepatien

18、tpatientbscalonechange (%)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 respo

19、nserate (%) wild-type vs mutant (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

20、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

21、 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 mutant

22、median 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 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

23、 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 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 meet

24、ing 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 expression

25、020406080100120140median 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 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

26、响的影响 tejpar s, et al. asco gi 2008 (abstract no. 411)kras statusepiregulin expressionmedian 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

27、的关系prprprsdsdsdpdpd0102030405060708090100g/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 probabili

28、ty 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=0.00

29、3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zhang 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/

30、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. 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 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.