轉(zhuǎn)移性結(jié)腸癌靶向治療的未來治療策略研究

1、Investigating future treatment strategies with targeted therapy in mCRC,Heinz-Josef LenzUniversity of Southern CaliforniaUSC/Norris Comprehensive Cancer Center Los Angeles, USA,作為療效預(yù)測和預(yù)后判斷的標記物,療效預(yù)測標記物：能夠預(yù)測某種特定治療方式療效的

2、標記物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. Lièvre A, et al. Cancer Res 2006;66:3992–3995; 2. Sargent DJ, et al. J Clin Oncol 2005

3、;23:2020–2027; 3. Martínez–López E, et al. Gastroenterology 1998;114:1180–1187; 4. Edler D, et al. J Clin Oncol 2002;20:1721–1728,潛在的結(jié)腸癌療效預(yù)測標志物,Meropol NJ, et al. ASCO 2008,*FDA recognized,潛在的EGFR 抑制劑的療效預(yù)測標記物,

4、EGFR1IHC detection2FISH detection3Mutations3Gene levels/polymorphisms1,4 KRAS1EGFR ligands (EGF, heregulin, epiregulin, amphiregulin)5 COX-26VEGF6,1. Lièvre A, et al. Cancer Res 2006;66:3992–3995; 2. Chung

5、 KY, et al. J Clin Oncol 2005;23:1803–1810;3. Moroni M, et al. Lancet Oncol 2005;6:279–286; 4. Zhang W, et al. Pharmacogenet Genomics 2006;16:475–483; 5. Khambata-Ford S, et al. J Clin Oncol 2007;25:3230–3237; 6. Vallb

6、öhmer D, et al. J Clin Oncol 2005;23:3536–3544,結(jié)直腸癌（CRC）少見EGFR基因突變,結(jié)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(zhuǎn)移性結(jié)直腸癌（mCRC）臨床試驗中110例活檢標本進行的研究未發(fā)現(xiàn) EGFR基因突變（外顯子18－21）1,1. Khambata-Ford S, et al. J Clin Oncol 2007;25:3230–3237,F

7、ISH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(yù)測愛必妥療效1,2但近期的一項研究并未發(fā)現(xiàn)EGFR表達水平與療效之間的具有相關(guān)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;19:717–723; 2. Moroni M, et al. L

8、ancet 2005;6:279–286; 3. Personeni N, et al. J Clin Oncol 2007;25 (18S) (Abstract No. 10569),擴增基因的表現(xiàn)形式,Albertson DG. Trends Genet 2006;22:447–455,雙微染色體,染色體區(qū)域擴增,在基因組內(nèi)廣泛分布,EGFR 基因轉(zhuǎn)錄（mRNA）水平與生存期無關(guān)a,,0,2,4,6,8,EGFR mRNA lev

9、els,7.3 months,2.2 months,Median survival (months),95% CI: 4.4–13.5 months,95% CI: 1.7–4.5 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. Vallböhmer D, et al. J Clin Oncol 2005;23:3536–3544,EGFR基因表達水平與

10、愛必妥治療后患者的生存期無明顯相關(guān)性（小樣本研究）1,,,,EGF 受體信號傳導(dǎo)通路：個性化治療的合理性,Yarden Y, Sliwkowski MX. Nat Rev Mol Cell Biol 2001;2:127–137; Chakravarti A, et al. Cancer Res 2002;62:4307–4315; Baselga J. Eur J Cancer 2001;37(Suppl. 4):S16–S22;

11、Kawanaka H, et al. Life Sci 2001;69:3019–3033,© 2000 American Association for Cancer Research Rak J, et al. Cancer Res 2000;60:490–498,,,,,,,,,VEGF,TSP-1,GAPDH,IEC-18,RAS-3,RAS-

12、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-18IEC-18/4AIEC-184BRAS-3RAS-4SRC-3SRC-4,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,VEGF: 潛在的生物標記物?,KRAS基因突變的理論假設(shè),KRAS基因

13、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,Lièvre A, et al. J Clin Oncol 2008;26:374–379,MAPK = 絲裂原激活的蛋白激酶,Fodde R, et al. Nature Rev Cancer 2001;1:55–67,40%的CRC具有KRAS基因突變KRAS基

14、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(lián)系，后者與CpG島甲基化表型（CIMP）1，2有關(guān)KRAS突變與PI3K突變相關(guān)3,1. Yuen ST, et al. Cancer Res 2002;62:6451–6455; 2. Weisenberger DJ, et al. Nat Genet 2006;38:787–793; 3. Lièvre A, et al.

15、 Cancer Res 2006;66:3992–3995,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. Lièvre A, et al. J Clin Oncol 2008;26:374–379; 2. Benvenuti S, et al. Cancer Res 2007;67:2643–2648; 3. De Roock W, et al. Ann Oncol 2008;19:50

16、8–515;4. Finocchiaro G, et al. ASCO 2007 (Abstract No. 4021); 5. Di Fiore F, et al. Br J Cancer 2007;96:1166–1169; 6. Khambata-Ford S, et al. J Clin Oncol 2007;25:3230–3237; 7. Amado RG, et al. J Clin Oncol 2008;26:162

17、6–1634,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;26:1626–1634,,,,,,,,,,,,,,,,,,,,,,,,,,,,,KRAS基因突變可預(yù)測愛必妥治療患者的生存期和有效率,1. Liè

18、;vre A, et al. Cancer Res 2006;66:3992–3995; 2. Di Fiore F, et al. Br J Cancer 2007;96:1166–1169;3. De Roock W, et al. Ann Oncol 2008;19:508–515; 4. Lièvre A, et al. J Clin Oncol 2008;26:374–379,aIn the combination

19、 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 survi

20、val (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

21、 Lièvre A, et al. J Clin Oncol 2008;26:374–379,KRAS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),1.00,0.75,0.50,0.25,0.00,0,10,20,30,,,,,,,,,,,,,,,,,p=0.0008,15.6

22、 months (95% CI: 10.9–22),10.7 months (95% CI: 8.3–16.3),5.6 months,(95%CI: 2.8–10.6),Survival probability,2 good prognostic factors (wild-type and grade 2/3 skin toxicity),,,0 good prognostic factors (KRAS mutant and gr

23、ade 0/1 skin toxicity),1 good prognostic factor (wild-type or grade 2/3 skin toxicity),,Lièvre A, et al. AACR Annual Meeting 2007 (Abstract 5671),epiregulin (EREG)和/或amphiregulin (AREG)表達上調(diào)可通過與EGFR形成自分泌環(huán)路促進腫瘤生長1,a),

24、EGFR配體在CRC中的作用,1. Khambata-Ford S, et al. J Clin Oncol 2007;25:3230–3237,b) 依賴EGFR信號傳導(dǎo)通路的腫瘤對愛必妥治療更加敏感1,EGFR配體高表達可預(yù)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

25、.5 days,115.5 days,57days,57days,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;25:3230–3237,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=&

26、lt;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),,p<0.001,,p<0.001,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(guān)系,,,,,,,,,,,,,,,,,,,,,,PR,PR,PR,S

27、D,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(guān),,Nagashima F, et al. ASCO 2007

28、 (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(guān),12,抗體依賴性細胞毒作用（ADCC）,Courtesy of Dr Arteaga,FCγ受體2a和3a的多態(tài)性與PFS相關(guān),Zhang W, et al. J Clin Oncol 2007;25:3712–3718,FCγ受體3a多態(tài)性與愛必妥和bevacizumab的療效相關(guān)（BOND 2）,Lenz H, et

29、al. ASCO GI 2007 (Abstract No. 401),對多個分子生物學(xué)標記物的分析,檢測多個指標有可能提高預(yù)測療效的效力PTEN loss1EGFR ligands2PI3K mutations3EGFR gene copy number4,1. Loupakis F, et al ASCO 2008 (Abstract No. 4003); 2. Tejpar S, et al. ASCO GI 2008 (

30、Abstract No. 411) 3. Jhawer M, et al. Cancer Res 2008;68:1953–1961; 4. Cappuzzo F, et al. Ann Oncol 2008;19:717–723,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

31、Products for Human Use (CHMP) gave a positive opinion for ERBITUX May 30, 2008 — but only for patients with wild-type KRAS tumors1,1. Committee for Medicinal Products for Human Use post-authorisation summar

32、y of positive opinion for ERBITUX 2008. Doc.Ref. EMEA/CHMP/280402/2008,KRAS基因狀態(tài)的應(yīng)用,前瞻性研究已經(jīng)驗證了KRAS、epiregulin和amphiregulin基因表達的意義1,2EGFR抑制劑能夠提高以下患者的有效率： KRAS野生型 Epiregulin和amphiregulin高表達KRAS野生型和突變型已經(jīng)確定為預(yù)測標記物1,3KRAS突

33、變的腫瘤患者可能適合新藥治療,1. Lièvre A, et al. Cancer Res 2006;66:3992–3995; 2. Khambata-Ford S, et al. J Clin Oncol 2007;25:3230–3237;3. Yuen ST, et al. Cancer Res 2002;62:6451–6455,展 望,愛必妥可以提高KRAS野生型患者的有效率1 重要的是，愛必妥治療有