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

2、用胸腺嘧啶合成酶（Thymidylate synthase）表達 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潛在的結腸癌療效預測標志物Meropol NJ, et al. ASCO 2008藥物標記物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 抑制劑的療效預測標記物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結直腸癌（CRC）少見EGFR基因突變結直腸癌（CRC）腫瘤標本中很少見EGFR基因突變對愛必妥單藥治療轉移性結直腸癌（mCRC）臨床試驗中110例活檢標本進行的研究未發現 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基因表達回顧性研究：FISH法檢測的EGFR表達水平有可能預測愛必妥療效1,2但近期的一項研究并未發現EGFR表達水平與療效之間的具有相關性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) 擴增基因的表現形式Albertson DG. Trends Genet 2006;22:447455雙微染色體染色體區域擴增在基因組內廣泛分布 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: 潛在的生物標記物?KRAS基因突變的理論假設KRAS基因突變能夠激活下游RAS/MAPK信號傳導通路，這種激活無需配體誘導的EGFR激活導致愛必妥耐藥KRAS基因突變預測愛必妥療效和判斷mCRC預后的作用有待證實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發生的早期事件靶病灶縮小百分比可評價KRAS基因狀態患者的資料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突變狀態和愛必妥皮膚毒性與總生存期（OS）的關系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配體高表達可預測愛必妥治療能夠獲得更長的無進展生存期（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配體高表達患者的DCR和中位PFS 具有明顯優勢(EREG p=0.0002; AREG p=0.0001)1Epiregulin表達水平對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 多態性COX-2基因多態性與愛必妥療效的關系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 多態性與接受愛必妥治療mCRC患者的PFS相關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多態性與接受愛必妥治療mCRC

20、患者的PFS相關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抗體依賴性細胞毒作用（ADCC）Courtesy of Dr ArteagaFC受體2a和3a的多態性與PFS相關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多態性與愛必妥和bevacizumab的療效相關（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對多個分子生物學標記物的分析檢測多個指標有可能提高預測療效的效力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基因突變狀態的四個理由避免不必要的不良反應控制不必要的費用確認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