转移性结肠癌靶向治疗的未来治疗策略研究ppt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别的标志物作为疗效预测和预后判别的标志物 疗效预测标志物：可以预测某种特定治疗方式疗效的标志物 KRAS基因突变导致肿瘤对EGFR抑制剂抵抗 预后判别标志物：在不思索治疗要素的情况下可以判别患者结局的标志物 18号染色体长臂18q

2、缺失 某些分子标志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, et

3、al. ASCO 2021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 expre

4、ssion, 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志物抑制剂的疗效预测标志物 EGFR1 IHC detection2 FISH detection3 Mutations3 Gene levels/polymorphi

5、sms1,4 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. Khambata-Fo

6、rd 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对爱必妥单药治疗转移性结直肠癌mCRC临床实验中临床实验中110例活检标本进展的研讨未发现例活检标本进展的研讨未发现 EGFR基因突变外显子基因突变外显子182111. Khambata-Ford S, et al. J Clin Oncol

7、 2007;25:32303237FISH法检测的法检测的EGFR基因表达基因表达回想性研讨：FISH法检测的EGFR表达程度有能够预测爱必妥疗效1,2但近期的一项研讨并未发现EGFR表达程度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=850.00.20.40.60.81

8、.00.00.20.40.60.81.01. Cappuzzo F, et al. Ann Oncol 2021;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) 扩增基因的表现方式扩增基因的表现方式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mR

9、NA程度与生存期无关程度与生存期无关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基因表达程度与爱必妥治疗后患者的生存期无明显相关性小样本研讨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Sur

10、vival (anti-apoptosis)Gene transcriptionCell-cycle progressionMYCMYCCyclin D1FOSJUNPPCyclin D1AngiogenesisInvasion andmetastasisChemotherapy/radiotherapy resistanceProliferation/maturationMAPKMEKRASRAFSOSGRB2PTENAKTSTATP13KpYpYLigand: AREG/EREGTarget for EGFR-ERBITUXEGFR-TKTarget for EGFT-TK inhibit

11、orpYYarden Y, Sliwkowski MX. Nat Rev Mol Cell Biol 2001;2:127; 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;60:490498VEGFTS

12、P-1GAPDHIEC-18RAS-3RAS-4IEC-18SRC-3SRC-4Tumor volume (mm3)25002000150010005000Time (days)0510152025IEC-18IEC-18/4AIEC-184BRAS-3RAS-4SRC-3SRC-4VEGF: 潜在的生物标志物潜在的生物标志物?KRAS基因突变的实际假设基因突变的实际假设 KRAS基因突变可以激活下游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别mCRC预后的作用有待证明Livre A, et al. J Clin Onc

13、ol 2021;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突变相联络，后者与CpG岛甲基化表型CIMP1，2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 G

14、enet 2006;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进展的回想性分析进展的回想性分析 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 Pani

15、tumumab or 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

16、 RG, et al.7 Panitumumab208 (124:84)21 (17)0 (0)1. Livre A, et al. J Clin Oncol 2021;26:374379; 2. Benvenuti S, et al. Cancer Res 2007;67:26432648; 3. De Roock W, et al. Ann Oncol 2021;19:508515;4. Finocchiaro G, et al. ASCO 2007 (Abstract No. 4021); 5. Di Fiore F, et al. Br J Cancer 2007;96:1166116

17、9; 6. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237; 7. Amado RG, et al. J Clin Oncol 2021;26:16261634靶病灶减少百分比靶病灶减少百分比可评价可评价KRAS基因形状患者的资料基因形状患者的资料BSC = Best supportive care; Pmab = panitumumab Amado RG, et al. J Clin Oncol 2021;26:16261634Change (%)MutantPmab+ BSCPR (17%)SD (34%)PD (36%)Wild

18、-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%)16012080400-40-8016012080400-40-80KRAS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 (%)Obje

19、ctive responserate (%) 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. 8

20、92729031.4 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 2021;19:508515; 4. Livre A, et al. J Clin Oncol 2021;26:374379 aIn the combination therapy group (mutant vs wild-type)

21、: PFS=12 vs 34 weeks (p=0.016); OS=6.3 vs 10.3 months (p=0.003)KRAS基因突变形状对生存期的影响基因突变形状对生存期的影响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-type

22、KRAS 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 al. J Clin Oncol 2021;26:374379KRAS突变形状和爱必妥皮肤毒性与总生存期突变形状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: 10.92

23、2) 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 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 Annu

24、al Meeting 2007 (Abstract 5671)epiregulin (EREG)和/或amphiregulin (AREG)表达上调可经过与EGFR构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可以获配体高表达可预测爱必妥治疗可以获得更长的无进展生存期得更长的无进展生存期PFSHighLowEGFR ligand expressio

25、n020406080100120140Median PFS (days)103.5 days115.5 days57days57daysn=110, ERBITUX monotherapy; DCR=疾病控制率disease control rateEREGAREG1. 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表达程度对表达程度对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

26、的影响 Tejpar S, et al. ASCO GI 2021 (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的

27、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 probabilit

28、y 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=0.003

29、抗体依赖性细胞毒作用抗体依赖性细胞毒作用ADCCCourtesy 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/R or

30、FC 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 2Lenz 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志物的分析对多个分子生物学标志物的分析 检测多个目的有能够提高预测疗效的效能 PTEN loss1 EGFR ligands2 PI3K mutations3 EGFR gene copy number41. Loupakis F, et al ASCO 2021 (Abstract No. 4003); 2. Tejpar S, et al. ASCO GI 2021 (Abstract No. 411) 3. Jhawer M, et al. Cancer Res 2021;68:195