晚期結(jié)直腸癌整體策略下個(gè)體化治療的思考

1、結(jié)直腸癌規(guī)范化診療,,,,mCRC整體策略下個(gè)體化治療的思考,整體策略,可切除,潛在可切除,不可切除,切除,,,轉(zhuǎn)化,,內(nèi)科,,,整體策略,FOLFOX,CapeOX,bevacizumab,FOLFIRI,Cetuximab orPanitumumab(RAS WT only),OX,IRI,bevacizumab,bevacizumab,Cetuximab orPanitumumab(RAS WT only),IRI,O

2、X,FOLFIRI,FOLFOX,bevacizumab,Ziv-aflibercept,Cetuximab orPanitumumab(RAS WT only),bevacizumab,bevacizumab,Ziv-aflibercept,Irinotecan,CapeOX,Irinotecan,Cetuximab orPanitumumab(RAS WT only),bevacizumab,FOLFOX,CapeOX,

3、bevacizumab,Regorafenib,Clinical trial,ramucirumab,Best supportive care,TAS-102,整體策略,bevacizumab,5-FU,FOLFIRI,FOLFOX,bevacizumab,Ziv-aflibercept,Cetuximab orPanitumumab(RAS WT only),Irinotecan,Irinotecan,Cetuximab or

4、Panitumumab(RAS WT only),FOLFOXIRI,CapeOX,Capecitabine,bevacizumab,Regorafenib,Regorafenib,Regorafenib,ramucirumab,TAS-102,TAS-102,TAS-102,創(chuàng)建龐大遺傳學(xué)數(shù)據(jù)信息庫(kù),精準(zhǔn)診斷,患者個(gè)體化遺傳信息,精準(zhǔn)治療,堿基突變,拷貝擴(kuò)增,片段缺失,基因重組,表觀遺傳學(xué),,,個(gè)體化治療,Mutation fre

5、quencies in human CRC,TCGA . Nature. 2013,487(7407): 330–337.,個(gè)體化治療,Integrative analysis of genomic changes in 195 CRC tumors,TCGA . Nature. 2013,487(7407): 330–337.,個(gè)體化治療,Copy number changes and structural aberrations i

6、n CRC,個(gè)體化治療,Diversity and frequency of genetic changes leading to deregulation of signaling pathways in CRC,個(gè)體化治療,Integrative analyses of multiple data sets,個(gè)體化治療,創(chuàng)建龐大遺傳學(xué)數(shù)據(jù)信息庫(kù),精準(zhǔn)診斷,對(duì)比患者個(gè)體化信息,精準(zhǔn)治療,,,用什么藥？,得什么??？,,預(yù)后因子,,預(yù)

7、測(cè)因子,注定的結(jié)局,人為的干預(yù),個(gè)體化治療,個(gè)體化治療,APC=7-乙基-10-[4-N-(5-氨基戊酸)-1-哌啶基]-羰基氧喜樹堿NPC=7-乙基-10-(4-氨基-1-哌啶基)-羰基氧喜樹堿SN-38=7-乙基-10-羥基喜樹堿SN-38G=葡萄糖醛酸化SN-38M4=伊立替康第四種未明確代謝產(chǎn)物CES=羧酸酯酶CYP3A=細(xì)胞色素P450 3A亞型(3A4/3A5)UGT1A=尿苷二磷酸葡醛酰轉(zhuǎn)移酶,伊立替康,SN

8、-38,SN-38G,CES,UGT1A1,CES,CYP3A,,,個(gè)體化治療,Chan J, et al. 2011 ASCO GI Abstract 412.,,,,1.0,0.8,,0.6,,0.4,,0.2,,0,,0,,100,,200,,300,,400,,500,,600,,700,,800,,900,,1000,,,,無(wú)中性粒細(xì)胞減少的生存率,時(shí)間 (天),,,,野生型雜合子型*28純合子型*28,Kaplan-Me

9、ier Log Rank檢驗(yàn) P=0.002,雜合型*28+野生型 vs. 純合子型*28Cox比例HR△=3.05 (95% CI 1.55-5.99) P=0.001,UGT1A1 是伊立替康治療的預(yù)測(cè)因素,63例患者檢測(cè)UGT1A1*28,35例*1/*1(6/6),24例*1/*28(6/7),4例*28/*28(7/7),FOLFIRI215mg/m2,260mg/m2,310mg/m2,370mg/m2,420mg/m

10、2,,,,,,,,,,6/6型野生型患者最大耐受劑量為420mg/m26/7型患者的最大耐受劑量為370mg/m2,個(gè)體化治療,,,,Src,PIP2,PI3K,PIP3,RAS,RAF,MEK,ERK,PTEN,AKT,p70s6k,MTOR,Rictor,MTOR,Raptor,EGFTGF-?HB-EGFEpiregulin,VEGFPDGF,VEGFR,EGFR (HER1),Adapted from Siena, e

11、t al. JNCI 2009,生長(zhǎng)因子的轉(zhuǎn)錄,個(gè)體化治療,1992年 vs. 2015年,Venook A, et al. 2014 ASCO Abstract LBA3.,,,,,,,,100,80,60,40,20,0,,0,12,,,24,,36,,48月,,,,,CALGB/SWOG80405,5FU + LV (n=803),5FU (n=578),OS (%),,個(gè)體化治療,VEGFR 受體單抗：Cyramza,

12、抑制VEGF單抗：安維汀,可溶性VEGF受體(VEGF-TRAP)， Aflibercept,抑制VEGF受體的小分子TKIs, 如Regorafenib,,,,,個(gè)體化治療,個(gè)體化治療,RAS,個(gè)體化治療,RAS MT 53%,RAS WT 47%,隨機(jī)研究中>5,000患者的薈萃分析,KRAS WT 58%,KRAS MT 42%,Sorich, et al. Ann Oncol 2015,個(gè)體化治療,FOLFIRI

13、,化療 + 貝伐珠,FOLFIRI,FOLFIRI,FOLFIRI,,CRYSTAL,CALGB,KRAS ? RAS,20.0 ? 20.2,23.5 ? 28.4,FIRE-3,FOLFIRI + 西妥昔,28.7 ? 33.1,FOLFIRI + 西妥昔,FOLFIRI,FOLFIRI + 貝伐珠,25.8 ? 34.4,29.0 ? 31.2,29.9 ? 32.0,FOLFIRI,化療 + 西妥昔,1. Bo

14、kemeyer. 2011; 2. Bokemeyer. 2014; 3. Van Cutsem. 2011; 4. Ciardiello. 2014; 5. Douillard. 2011; 6. Douillard. 2013;7. Heinemann. 2013; 8. Stintzing. 2014; 9. Falcone. 2013; 10. Loupakis. 2014; 11. Venook. 2014; 12. Le

15、nz. 2014.,FOLFIRI,RAS 野生型mCRC OS更長(zhǎng),個(gè)體化治療,2016ASCO,CIMP-H,MSI,BRAF-MT,PI3KCA,EGFR +,20q Gain,18q Loss,Her-2 Gain,個(gè)體化治療,Presented By Dung Le at 2016 ASCO Annual Meeting,80405 研究,2016ASCO,KRAS wt N=1137,KRAS mt N=2

16、52,左,右,N 280(25%) 689(61%),OS 19.4m 34.2m*,KRAS wt,Cet 16.4m 37.5m,Bev 23.1m 32.1m,KRAS mt,OS 23.1m 30.3m*,個(gè)體化治療,,左、右半之爭(zhēng),1,RAS野生

17、型mCRC的一線靶向治療，EGFR單抗僅限于左側(cè)結(jié)腸癌患者,RAS,BRAF,個(gè)體化治療,Bokemeyer C, et al. Eur J Cancer 2012;48:1466–1475,ORR, %,CET + CT,CT alone,n=349,n=381,n=32,n=38,n=349,n=381,n=32,n=38,BRAF wt,BRAF mt,,60.7,21.9,,40.9,13.2,CET + CT,CT alone

18、,,10.9,7.1,,7.7,3.7,PFS, 月,0S, 月,n=349,n=381,n=32,n=38,CET + CT,CT alone,,24.8,14.1,,21.1,9.9,CRYSTAL + OPUS 西妥昔單抗+FOLFIRI/FOLFOX,,,BRAF 突變 ORR PFS OS 更差,個(gè)體化治療,Seligmann, et al. ASCO 2015,,,1L 治療,1L治療BRAF MT 患者中

19、位OS明顯縮短；接受2L治療的BRAF MT 僅有39%，而BRAF WT患者為60%,,,,0,3,6,9,12,15,18,24,0,0.25,0.50,0.75,1.00,,,BRAF WTBRAF MTHR=1.48P<0.001,BRAF WTBRAF MTHR=1.17P=0.33,21,,6.9,10.2,10.8,16.4,(月),2L 治療,個(gè)體化治療,三藥化療 (FOLFOXIRI) + 貝伐珠單抗

20、雙藥化療 (FOLFOX, XELOX or FOLFIRI) + 貝伐珠單抗雙藥化療 (FOLFOX or FOLFIRI) + 抗EGFR抗體氟尿嘧啶類藥物 + 貝伐珠單抗,高強(qiáng)度,低強(qiáng)度,,BRAF突變患者在一線應(yīng)給予最強(qiáng)的治療方案 ？,個(gè)體化治療,初治mCRC(N=508),貝伐珠單抗 + FOLFIRI*(n=256),貝伐珠單抗 +FOLFOXIRI*(n=252),貝伐珠單抗 + 5-FU/LV(n

21、=114),貝伐珠單抗+ 5-FU/LV(n=130),誘導(dǎo),維持,*Up to 12 cycles,TRIBE研究,,,,PD,個(gè)體化治療,TRIBE研究,,,個(gè)體化治療,TRIBE研究,BRAF突變患者在一線應(yīng)給予最強(qiáng)的治療方案！,個(gè)體化治療,RAS,BRAF,MMR,個(gè)體化治療,15% MSI-H,12% 啟動(dòng)子甲基化--- 散發(fā)性,3% Lynch,根據(jù)患者M(jìn)MR狀態(tài)，未經(jīng)治療的DFS,Daniel J. et al.

22、JCO. 2010;28:20: 3219–3226,HR=0.51P=0.002,DSF%,,,dMMR(n=79)pMMR(n=436),0,100,1,3,5 年,MMR狀態(tài)是II/III期腸癌的預(yù)后因素,個(gè)體化治療,過(guò)度突變免疫細(xì)胞浸潤(rùn)表達(dá)PD-L1,,,,PD-L1,CD8,dMMR,pMMR,,個(gè)體化治療,研究設(shè)計(jì),Presented By Dung Le at 2015 ASCO Annual Meeting,A

23、 dMMR,B pMMR,C dMMR,腸癌,非腸癌,Pembrolizumab 10mg/kg q2w,主要研究終點(diǎn)： 20w PFS率及有效率,個(gè)體化治療,研究結(jié)果,Presented By Dung Le at 2015 ASCO Annual Meeting,A dMMR,B pMMR,C dMMR,腸癌,非腸癌,ORR,62%,0%,60%,DCR,92%,16%,70%,個(gè)體化治療,研究結(jié)果,P

24、resented By Dung Le at 2015 ASCO Annual Meeting,PFS,A dMMR,B pMMR,C dMMR,,HR:0.103 P<0.001,個(gè)體化治療,HR:0.103 P<0.001,研究結(jié)果,Presented By Dung Le at 2015 ASCO Annual Meeting,OS,A dMMR,B pMMR,C dMMR,,HR:0

25、.216P=0.02,個(gè)體化治療,研究結(jié)果,Presented By Dung Le at 2016 ASCO Annual Meeting,A dMMR N=28,B pMMRN=25,2016ASCO,腸癌,Pembrolizumab 10mg/kg q2w,主要研究終點(diǎn)： 20w PFS率及有效率,個(gè)體化治療,研究結(jié)果,Presented By Dung Le at 2016 ASCO Annual Meet