1、结直肠癌规范化诊疗,mCRC整体策略下个体化治疗的思考,整体策略,可切除,潜在可切除,不可切除,切除,转化,内科,整体策略,FOLFOX,CapeOX,bevacizumab,FOLFIRI,Cetuximab orPanitumumab(RAS WT only),OX,IRI,bevacizumab,bevacizumab,Cetuximab orPanitumumab(RAS WT only),IRI,OX,FOLFIRI,FOLFOX,bevacizumab,Ziv-aflibercept,Cetuximab orPanitumumab(RAS WT only),bevacizumab,
2、bevacizumab,Ziv-aflibercept,Irinotecan,CapeOX,Irinotecan,Cetuximab orPanitumumab(RAS WT only),bevacizumab,FOLFOX,CapeOX,bevacizumab,Regorafenib,Clinical trial,ramucirumab,Best supportive care,TAS-102,整体策略,bevacizumab,5-FU,FOLFIRI,FOLFOX,bevacizumab,Ziv-aflibercept,Cetuximab orPanitumumab(RAS WT only
3、),Irinotecan,Irinotecan,Cetuximab orPanitumumab(RAS WT only),FOLFOXIRI,CapeOX,Capecitabine,bevacizumab,Regorafenib,Regorafenib,Regorafenib,ramucirumab,TAS-102,TAS-102,TAS-102,创建庞大遗传学数据信息库,精准诊断,患者个体化遗传信息,精准治疗,碱基突变,拷贝扩增,片段缺失,基因重组,表观遗传学,个体化治疗,Mutation frequencies in human CRC,TCGA . Nature. 2013,487(74
4、07): 330337.,个体化治疗,Integrative analysis of genomic changes in 195 CRC tumors,TCGA . Nature. 2013,487(7407): 330337.,个体化治疗,Copy number changes and structural aberrations in CRC,个体化治疗,Diversity and frequency of genetic changes leading to deregulation of signaling pathways in CRC,个体化治疗,Integrative anal
5、yses of multiple data sets,个体化治疗,创建庞大遗传学数据信息库,精准诊断,对比患者个体化信息,精准治疗,用什么药？,得什么病？,预后因子,预测因子,注定的结局,人为的干预,个体化治疗,个体化治疗,APC=7-乙基-10-4-N-(5-氨基戊酸)-1-哌啶基-羰基氧喜树碱NPC=7-乙基-10-(4-氨基-1-哌啶基)-羰基氧喜树碱SN-38=7-乙基-10-羟基喜树碱SN-38G=葡萄糖醛酸化SN-38M4=伊立替康第四种未明确代谢产物CES=羧酸酯酶CYP3A=细胞色素P450 3A亚型(3A4/3A5)UGT1A=尿苷二磷酸葡醛酰转移酶,伊立替康,SN-38,S
6、N-38G,CES,UGT1A1,CES,CYP3A,个体化治疗,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,无中性粒细胞减少的生存率,时间 (天),野生型杂合子型*28纯合子型*28,Kaplan-Meier Log Rank检验 P=0.002,杂合型*28+野生型 vs. 纯合子型*28Cox比例HR=3.05 (95% CI 1.55-5.99) P=0.001,UGT1A1 是伊立替康治疗的预测因素,63例患者检测U
7、GT1A1*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/m2,6/6型野生型患者最大耐受剂量为420mg/m26/7型患者的最大耐受剂量为370mg/m2,个体化治疗,Src,PIP2,PI3K,PIP3,RAS,RAF,MEK,ERK,PTEN,AKT,p70s6k,MTOR,Rictor,MTOR,Raptor,EGFTGF-HB-EGFEpiregulin,VEGFPDGF,VEGFR,EGFR (HER1),Adapted from Sie
8、na, et al. JNCI 2009,生长因子的转录,个体化治疗,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 (%),个体化治疗,VEGFR 受体单抗：Cyramza,抑制VEGF单抗：安维汀,可溶性VEGF受体(VEGF-TRAP)， Aflibercept,抑制VEGF受体的小分子TKIs, 如Regorafenib,个体化治疗,个体化治疗,RAS,个体化
9、治疗,RAS MT 53%,RAS WT 47%,随机研究中5,000患者的荟萃分析,KRAS WT 58%,KRAS MT 42%,Sorich, et al. Ann Oncol 2015,个体化治疗,FOLFIRI,化疗 + 贝伐珠,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 + 贝伐珠,25.8 34.4,29.0 31.2,29.9 32.0,FOLFIRI,化疗 + 西妥昔
10、,1. Bokemeyer. 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. Lenz. 2014.,FOLFIRI,RAS 野生型mCRC OS更长,个体化治疗,2016ASCO,CIMP-H,MSI,BRAF-MT,PI3KCA,
11、EGFR +,20q Gain,18q Loss,Her-2 Gain,个体化治疗,Presented By Dung Le at 2016 ASCO Annual Meeting,80405 研究,2016ASCO,KRAS wt N=1137,KRAS mt N=252,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*,个体化治疗,左、右半之争,1,RAS野生型mCRC的一线靶向治疗，EGFR单抗仅限于左侧结肠癌患者,RAS,BRAF
12、,个体化治疗,Bokemeyer C, et al. Eur J Cancer 2012;48:14661475,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,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 西妥昔单抗+FOLFIRI/FO
13、LFOX,BRAF 突变 ORR PFS OS 更差,个体化治疗,Seligmann, et al. ASCO 2015,1L 治疗,1L治疗BRAF MT 患者中位OS明显缩短；接受2L治疗的BRAF MT 仅有39%，而BRAF WT患者为60%,0,3,6,9,12,15,18,24,0,0.25,0.50,0.75,1.00,BRAF WTBRAF MTHR=1.48P0.001,BRAF WTBRAF MTHR=1.17P=0.33,21,6.9,10.2,10.8,16.4,(月),2L 治疗,个体化治疗,三药化疗 (FOLFOXIRI) + 贝伐珠单抗双药化疗 (FOLFOX,
14、XELOX or FOLFIRI) + 贝伐珠单抗双药化疗 (FOLFOX or FOLFIRI) + 抗EGFR抗体氟尿嘧啶类药物 + 贝伐珠单抗,高强度,低强度,BRAF突变患者在一线应给予最强的治疗方案 ？,个体化治疗,初治mCRC(N=508),贝伐珠单抗 + FOLFIRI*(n=256),贝伐珠单抗 +FOLFOXIRI*(n=252),贝伐珠单抗 + 5-FU/LV(n=114),贝伐珠单抗+ 5-FU/LV(n=130),诱导,维持,*Up to 12 cycles,TRIBE研究,PD,个体化治疗,TRIBE研究,个体化治疗,TRIBE研究,BRAF突变患者在一线应给予最强的
15、治疗方案！,个体化治疗,RAS,BRAF,MMR,个体化治疗,15% MSI-H,12% 启动子甲基化- 散发性,3% Lynch,根据患者MMR状态，未经治疗的DFS,Daniel J. et al. JCO. 2010;28:20: 32193226,HR=0.51P=0.002,DSF%,dMMR(n=79)pMMR(n=436),0,100,1,3,5 年,MMR状态是II/III期肠癌的预后因素,个体化治疗,过度突变免疫细胞浸润表达PD-L1,PD-L1,CD8,dMMR,pMMR,个体化治疗,研究设计,Presented By Dung Le at 2015 ASCO Annual
16、 Meeting,A dMMR,B pMMR,C dMMR,肠癌,非肠癌,Pembrolizumab 10mg/kg q2w,主要研究终点： 20w PFS率及有效率,个体化治疗,研究结果,Presented By Dung Le at 2015 ASCO Annual Meeting,A dMMR,B pMMR,C dMMR,肠癌,非肠癌,ORR,62%,0%,60%,DCR,92%,16%,70%,个体化治疗,研究结果,Presented By Dung Le at 2015 ASCO Annual Meeting,PFS,A dMMR,B pMMR,C dMMR,HR:0.103 P0.
17、001,个体化治疗,HR:0.103 P0.001,研究结果,Presented By Dung Le at 2015 ASCO Annual Meeting,OS,A dMMR,B pMMR,C dMMR,HR:0.216P=0.02,个体化治疗,研究结果,Presented By Dung Le at 2016 ASCO Annual Meeting,A dMMR N=28,B pMMRN=25,2016ASCO,肠癌,Pembrolizumab 10mg/kg q2w,主要研究终点： 20w PFS率及有效率,个体化治疗,研究结果,Presented By Dung Le at 2016 ASCO Annual Meeting,A dMMR N=28,B pMMRN=25,2016ASCO,随访8.7m,RR,50%,0%,89%,DCR,16%,NR,PFS,2.4m,NR,OS,6.0m,个体化治疗,NCCN,PD-1单抗免疫治疗,首次推荐PD-1单抗免疫治疗用于dMMR/MSI-H的mCRC之末线治疗,RAS,BRAF,MMR,个体化治疗,基因信息,肿瘤负荷,体力状态,支付能力,个体化治疗,谢 谢 大 家,
