晚期结直肠癌整体策略下个体化治疗的思考PPT课件.ppt

结直肠癌规范化诊疗12FOLFOXCapeOX bevacizumabFOLFIRICetuximab orPanitumumab(RAS WT only) OXIRIbevacizumabbevacizumabCetuximab orPanitumumab(RAS WT only) IRIOXFOLFIRIFOLFOXbevacizumabZiv-afliberceptCetuximab orPanitumumab(RAS WT only) bevacizumabbevacizumabZiv-afliberceptIrinotecanCapeOXIrinotecanCetuximab orPanitumumab(RAS WT only) bevacizumabFOLFOXCapeOXbevacizumabRegorafenibClinical trialramucirumabBest supportive careTAS-1023bevacizumab5-FUFOLFIRIFOLFOXbevacizumabZiv-afliberceptCetuximab orPanitumumab(RAS WT only) IrinotecanIrinotecanCetuximab orPanitumumab(RAS WT only) FOLFOXIRICapeOXCapecitabinebevacizumabRegorafenibRegorafenibRegorafenibramucirumabTAS-102TAS-102TAS-1024碱基突变拷贝扩增片段缺失基因重组表观遗传学5Mutation frequencies in human CRCTCGA . Nature. 2013,487(7407): 330337.6Integrative analysis of genomic changes in 195 CRC tumorsTCGA . Nature. 2013,487(7407): 330337.7Copy number changes and structural aberrations in CRC8Diversity and frequency of genetic changes leading to deregulation of signaling pathways in CRC9Integrative analyses of multiple data sets10预后因子预测因子注定的结局人为的干预11APC=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-38SN-38GCESUGT1A1CESCYP3A12Chan J, et al. 2011 ASCO GI Abstract 412.1.00.80.60.40.2001002003004005006007008009001000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*28Kaplan-Meier Log Rank检验 P P=0.002=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 P=0.001=0.001UGT1A1 UGT1A1 是伊立替康治疗的预测因素1363例患者检测UGT1A1*2835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/m26/6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/m214SrcPIP2PI3KPIP3RASRAFMEKERKPTENAKTp70s6kMTORRictorMTORRaptorEGFTGF-HB-EGFEpiregulinVEGFPDGFVEGFREGFR (HER1) Adapted from Siena, et al. JNCI 2009生长因子的转录生长因子的转录151992年 vs. 2015年Venook A, et al. 2014 ASCO Abstract LBA3.100806040200012243648月CALGB/SWOG804055FU + LV (n=803)5FU (n=578)OS (%)16VEGFR 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Regorafenib1718RAS19RAS 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 201520FOLFIRI化疗 + 贝伐珠FOLFIRIFOLFIRIFOLFIRICRYSTALCALGBKRAS RAS20.0 20.223.5 28.4FIRE-3FOLFIRI + 西妥昔28.7 33.1FOLFIRI + 西妥昔FOLFIRIFOLFIRI + 贝伐珠25.8 34.429.0 31.229.9 32.0FOLFIRI化疗 + 西妥昔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.FOLFIRIRAS 野生型mCRC OS更长212016ASCOCIMP-HMSIBRAF-MTPI3KCA 发生率： 40% (上升) 年纪较大的患者 微卫星不稳定 更高的突变发生率 预后较差右侧肿瘤EGFR +20q Gain18q LossHer-2 Gain 发生率： 60% 年纪较小的患者 WT为主 预后较好左侧肿瘤22Presented By Dung Le at 2016 ASCO Annual Meeting80405 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 37.5mBev 23.1m 32.1mKRAS mt OS 23.1m 30.3m*23左左、右半之争右半之争1RAS野生型mCRC的一线靶向治疗，EGFR单抗仅限于左侧结肠癌患者24RASBRAF25Bokemeyer C, et al. Eur J Cancer 2012;48:14661475CET + CTCT alonen=349n=381n=32n=38n=349n=381n=32n=38BRAF wtBRAF mt60.721.940.913.2CET + CTCT alone10.9 7.17.73.7n=349n=381n=32n=38CET + CTCT alone24.814.121.19.9CRYSTAL + OPUS 西妥昔单抗+FOLFIRI/FOLFOXBRAF 突变 ORR PFS OS 更差26Seligmann, et al. ASCO 20151L 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%(月)06121824303642OS 预估00.250.500.751.0003691215182400.250.500.751.00BRAF WTBRAF MTHR=1.48P0.001BRAF WTBRAF MTHR=1.17P=0.33216.910.210.816.4(月)2L 治疗27三药化疗 (FOLFOXIRI) + 贝伐珠单抗双药化疗 (FOLFOX, 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 ？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 cyclesTRIBE研究PDTRIBE研究中位 OS,月n贝伐珠单抗 + FOLFIRI贝伐珠单抗 + FOLFOXIRI HR (95% CI)ITT50825.829.80.80 (0.650.98)RAS 及 BRAF WT9333.541.70.77 (0.461.27)RAS MT23623.927.30.88 (0.651.18)BRAF MT2810.719.00.54 (0.241.20)RAS WT12126.837.10.78 (0.511.20)RAS MT23623.927.30.88 (0.651.18)TRIBE研究BRAF突变患者在一线应给予最强的治疗方案！RASBRAFMMR15% MSI-H 12% 启动子甲基化- 散发性 3% Lynch32根据患者MMR状态，未经治疗的DFSDaniel J. et al. JCO. 2010;28:20: 32193226HR=0.51P=0.002DSF%dMMR(n=79)pMMR(n=436)0100135 年MMRMMR状态是II/IIIII/III期肠癌的预后因素33过度突变免疫细胞浸润表达PD-L1PD-L1CD8dMMRpMMR34研究设计Presented By Dung Le at 2015 ASCO Annual MeetingA dMMR B pMMRC dMMR肠癌非肠癌Pembrolizumab 10mg/kg q2w 主要研究终点： 20w PFS率及有效率35研究结果Presented By Dung Le at 2015 ASCO Annual MeetingA A dMMRdMMR B B pMMRpMMRC C dMMRdMMR肠癌非肠癌ORR 62%62%0%0%60%60%DCR 92%92%16%16%70%70%36研究结果Presented By Dung Le at 2015 ASCO Annual MeetingPFSA A dMMRdMMR B B pMMRpMMRC C dMMRdMMRHR:0.103 P0.00137HR:0.103 P0.001研究结果Presented By Dung Le at 2015 ASCO Annual MeetingOSA A dMMRdMMR B B pMMRpMMRC C dMMRdMMRHR:0.216P=0.0238研究结果Presented By Dung Le at 2016 ASCO Annual MeetingA A dMMRdMMR N=28N=28B B pMMRpMMRN=25N=252016ASCO肠癌Pembrolizumab 10mg/kg q2w 主要研究终点： 20w PFS率及有效率39研究结果Presented By Dung Le at 2016 ASCO Annual MeetingA A dMMRdMMR N=28N=28B B pMMRpMMRN=25N=252016ASCO随访8.7mRR50%50%0%0%89%89%DCR16%16%NRNRPFS2.4m2.4mNRNROS6.0m6.0m40NCCNPD-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41RASBRAFMMR4243谢 谢 大 家44