轉(zhuǎn)移性結(jié)腸癌靶向治療的未來治療策略研究課件

1、Investigating future treatment strategies with targeted therapy in mCRCHeinz-Josef LenzUniversity of Southern CaliforniaUSC/Norris Comprehensive Cancer Center Los Angeles, USA作為療效預(yù)測和預(yù)后判斷的標(biāo)記物療效預(yù)測標(biāo)記物：能夠預(yù)測某種特定治療方式療效的標(biāo)記物KRAS基因突變導(dǎo)致腫瘤對EGFR抑制劑抵抗預(yù)后判斷標(biāo)記物：在不考慮治療因素的情況下能夠判斷患者結(jié)局的標(biāo)記物18號染色體長臂（18q）缺失 某些分子標(biāo)記物具有上述兩種作

2、用胸腺嘧啶合成酶（Thymidylate synthase）表達(dá) 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潛在的結(jié)腸癌療效預(yù)測標(biāo)志物Meropol NJ, et al. ASCO 2008藥物標(biāo)記物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潛在的EGFR 抑制劑的療效預(yù)測標(biāo)記物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結(jié)直腸癌（CRC）少見EGFR基因突變結(jié)直腸癌（CRC）腫瘤標(biāo)本中很少見EGFR基因突變對愛必妥單藥治療轉(zhuǎn)移性結(jié)直腸癌（mCRC）臨床試驗(yàn)中110例活檢標(biāo)本進(jìn)行的研究未發(fā)現(xiàn) EGFR基因突變（外顯子1821）11. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237FISH法檢測的EGFR基因表達(dá)回顧性研究：FISH法檢測的EGFR表達(dá)水平有可能預(yù)測愛必妥療效1,2但近期的一項(xiàng)研究并未發(fā)現(xiàn)EGFR表達(dá)水平與療效之間的具有相關(guān)性301020p=0.0

7、5EGFR FISH+EGFR FISH-TTP (months)Cumulative distribution functionCumulative survival function0102030p=0.7EGFR FISH-EGFR FISH+Survival time (months)愛必妥治療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) 擴(kuò)增基因的表現(xiàn)形式Albertson DG. Trends Genet 2006;22:447455雙微染色體染色體區(qū)域擴(kuò)增在基因組內(nèi)廣泛分布 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: 潛在的生物標(biāo)記物?KRAS基因突變的理論假設(shè)KRAS基因突變能夠激活下游RAS/MAPK信號傳導(dǎo)通路，這種激活無需配體誘導(dǎo)的EGFR激活導(dǎo)致愛必妥耐藥KRAS基因突變預(yù)測愛必妥療效和判斷mCRC預(yù)后的作用有待證實(shí)Livre A, et al. J Clin Oncol 2008;26:374379MAPK = 絲裂原激活的蛋白激酶Fodde R, et al. Nature Rev Cancer 2001;1:556740%的CRC具有KRAS基因突變K

10、RAS基因突變是CRC發(fā)生的早期事件靶病灶縮小百分比可評價KRAS基因狀態(tài)患者的資料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基因突變可預(yù)測愛必妥治療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基因突變狀態(tài)對生存期的影響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突變狀態(tài)和愛必妥皮膚毒性與總生存期（OS）的關(guān)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配體高表達(dá)可預(yù)測愛必妥治療能夠獲得更長的無進(jìn)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配體高表達(dá)患者的DCR和中位PFS 具有明顯優(yōu)勢(EREG p=0.0002; AREG p=0.0001)1Epiregulin表達(dá)水平對KRAS突變型和野生型患者PFS和OS的影響 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 多態(tài)性COX-2基因多態(tài)性與愛必妥療效的關(guān)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 多態(tài)性與接受愛必妥治療mCRC患者的PFS相關(guān)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多態(tài)性與接受愛必妥治療mCRC

20、患者的PFS相關(guān)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抗體依賴性細(xì)胞毒作用（ADCC）Courtesy of Dr ArteagaFC受體2a和3a的多態(tài)性與PFS相關(guān)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受體3a多態(tài)性與愛必妥和bevacizumab的療效相關(guān)（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對多個分子生物學(xué)標(biāo)記物的分析檢測多個指標(biāo)有可能提高預(yù)測療效的效力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治療前檢測KRAS基因突變狀態(tài)的四個理由避免不必要的不良反應(yīng)控制不必要的費(fèi)用確認(rèn)能夠從治療中獲益的野生型患者避免治療對突變型患者的潛在毒性Committee for Medicinal Products for Human Use (CHMP) gave