轉移性結腸癌靶向治療的未來治療策略研究.ppt

Investigating future treatment strategies with targeted therapy in mCRC,Heinz-Josef Lenz University of Southern California USC/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,*FDA recognized,潛在的EGFR 抑制劑的療效預測標記物,EGFR1 IHC detection2 FISH detection3 Mutations3 Gene levels/polymorphisms1,4 KRAS1 EGFR ligands (EGF, heregulin, epiregulin, amphiregulin)5 COX-26 VEGF6,1. 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. Vallbhmer 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(fā)現 EGFR基因突變（外顯子1821）1,1. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237,FISH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(fā)現EGFR表達水平與療效之間的具有相關性3,愛必妥治療mCRC （n=85）,0.0,0.2,0.4,0.6,0.8,1.0,0.0,0.2,0.4,0.6,0.8,1.0,1. 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),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(qū)域擴增,在基因組內廣泛分布,EGFR 基因轉錄（mRNA）水平與生存期無關a,0,2,4,6,EGFR mRNA levels,7.3 months,2.2 months,Median survival (months),95% CI: 4.413.5 months,95% CI: 1.74.5 months,p=0.09,a39例伊諾替康和奧沙利鉑耐藥的mCRC接受 愛必妥單藥治療,Low,High,1. Vallbhmer D, et al. J Clin Oncol 2005;23:35363544,EGFR基因表達水平與愛必妥治療后患者的生存期無明顯相關性（小樣本研究）1,EGF 受體信號傳導通路：個性化治療的合理性,Yarden 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;60:490498,VEGF,TSP-1,GAPDH,IEC-18,RAS-3,RAS-4,IEC-18,SRC-3,SRC-4,Tumor volume (mm3),2500,2000,1500,1000,500,0,Time (days),0,5,10,15,20,25,IEC-18 IEC-18/4A IEC-184B RAS-3 RAS-4 SRC-3 SRC-4,VEGF: 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;26:374379,MAPK = 絲裂原激活的蛋白激酶,Fodde R, et al. Nature Rev Cancer 2001;1:5567,40%的CRC具有KRAS基因突變 KRAS基因突變是CRC發(fā)生的早期事件,KRAS基因突變并非CRC的孤立事件,KRAS突變與BRAF突變相聯系，后者與CpG島甲基化表型（CIMP）1，2有關 KRAS突變與PI3K突變相關3,1. Yuen ST, et al. Cancer Res 2002;62:64516455; 2. Weisenberger DJ, et al. Nat Genet 2006;38:787793; 3. Livre A, et al. Cancer Res 2006;66:39923995,KRAS基因突變者EGFR抑制劑的療效差 對化療耐藥mCRC進行的回顧性分析,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. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237; 7. Amado RG, et al. J Clin Oncol 2008;26:16261634,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;26:16261634,KRAS基因突變可預測 愛必妥治療患者的生存期和有效率,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 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,1.00,0.75,0.50,0.25,0.00,0,20,40,60,80,100,Time (weeks),p=0.0001,Progression-free survival (PFS)a,Time (months),p=0.026,Overall survival (OS)a,1.00,0.75,0.50,0.25,0.00,0,10,20,30,Survival probability,Survival probability,Wild-type,mutant,an=88,an=88 Livre A, et al. J Clin Oncol 2008;26:374379,KRAS突變狀態(tài)和愛必妥皮膚毒性與總生存期（OS）的關系,Time (months),1.00,0.75,0.50,0.25,0.00,0,10,20,30,p=0.0008,15.6 months (95% CI: 10.922),10.7 months (95% CI: 8.316.3),5.6 months,(95%CI: 2.810.6),Survival probability,2 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 Meeting 2007 (Abstract 5671),epiregulin (EREG)和/或amphiregulin (AREG)表達上調可通過與EGFR形成自分泌環(huán)路促進腫瘤生長1,a),EGFR配體在CRC中的作用,1. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237,b) 依賴EGFR信號傳導通路的腫瘤對愛必妥治療更加敏感1,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）,High,Low,EGFR ligand expression,0,20,40,60,80,100,120,140,Median PFS (days),103.5 days,115.5 days,57 days,57 days,n=110, ERBITUX monotherapy; DCR=疾病控制率（disease control rate）,EREG,AREG,1. Khambata-Ford S, et al. J Clin Oncol 2007;25:32303237,EGFR配體高表達患者的DCR和中位PFS 具有明顯優(yōu)勢(EREG p=0.0002; AREG p=0.0001)1,Epiregulin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),p0.001,p0.001,Lenz 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系,PR,PR,PR,SD,SD,SD,PD,PD,0,10,20,30,40,50,60,70,80,90,100,G/G (n=78),G/C (n=30),C/C (n=4),p=0.097,Patients (%),Nagashima F, et al. 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,Nagashima F, et al. ASCO 2007 (Abstract No. 4129),COX-2 T+8473C多態(tài)性與接受愛必妥治療mCRC患者的PFS相關,12,抗體依賴性細胞毒作用（ADCC）,Courtesy of Dr Arteaga,FC受體2a和3a的多態(tài)性與PFS相關,Zhang W, et al. J Clin Oncol 2007;25:37123718,FC受體3a多態(tài)性與愛必妥和bevacizumab的療效相關（BOND 2）,Lenz H, et al. ASCO GI 2007 (Abstract No. 401),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 loss1 EGFR ligands2 PI3K mutations3 EGFR gene copy number4,1. 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 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 a positive opinion for ERBITUX May 30, 2008 but only for patients with wild-type