晚期结直肠癌整体策略下个体化治疗的思考课件

结直肠癌规范化诊疗mCRC整体策略下个体化治疗的思考1结直肠癌规范化诊疗mCRC整体策略下个体化治疗的思考1整体策略可切除潜在可切除不可切除切除转化内科2整体策略可切除潜在可切除不可切除切除转化内科2整体策略FOLFOXCapeOXbevacizumabFOLFIRICetuximaborPanitumumab(RASWTonly)OXIRIbevacizumabbevacizumabCetuximaborPanitumumab(RASWTonly)IRIOXFOLFIRIFOLFOXbevacizumabZiv-afliberceptCetuximaborPanitumumab(RASWTonly)bevacizumabbevacizumabZiv-afliberceptIrinotecanCapeOXIrinotecanCetuximaborPanitumumab(RASWTonly)bevacizumabFOLFOXCapeOXbevacizumabRegorafenibClinicaltrialramucirumabBestsupportivecareTAS-1023整体策略FOLFOXCapeOXbevacizumabFOL整体策略bevacizumab5-FUFOLFIRIFOLFOXbevacizumabZiv-afliberceptCetuximaborPanitumumab(RASWTonly)IrinotecanIrinotecanCetuximaborPanitumumab(RASWTonly)FOLFOXIRICapeOXCapecitabinebevacizumabRegorafenibRegorafenibRegorafenibramucirumabTAS-102TAS-102TAS-1024整体策略bevacizumab5-FUFOLFIRIFOLF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5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MutationfrequenciesinhumanCRCTCGA.Nature.2013,487(7407):330–337.个体化治疗6MutationfrequenciesinhumanIntegrativeanalysisofgenomicchangesin195CRCtumorsTCGA.Nature.2013,487(7407):330–337.个体化治疗7IntegrativeanalysisofgenomiCopynumberchangesandstructuralaberrationsinCRC个体化治疗8CopynumberchangesandstructDiversityandfrequencyofgeneticchangesleadingtoderegulationofsignalingpathwaysinCRC个体化治疗9DiversityandfrequencyofgenIntegrativeanalysesofmultipledatasets个体化治疗10Integrativeanalysesofmultip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11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P4503A亚型(3A4/3A5)UGT1A=尿苷二磷酸葡醛酰转移酶伊立替康SN-38SN-38GCESUGT1A1CESCYP3A12个体化治疗APC=7-乙基-10-[4-N-(5-氨基戊酸)个体化治疗ChanJ,etal.2011ASCOGIAbstract412.1.00.80.60.40.2001002003004005006007008009001000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-MeierLogRank检验

P=0.002杂合型*28+野生型vs.纯合子型*28Cox比例HR△=3.05(95%CI1.55-5.99)P=0.001UGT1A1是伊立替康治疗的预测因素13个体化治疗ChanJ,etal.2011ASCO63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/m2

6/7型患者的最大耐受剂量为370mg/m2个体化治疗1463例患者检测UGT1A1*2835例*1/*1(6/6)2SrcPIP2PI3KPIP3RASRAFMEKERKPTENAKTp70s6kMTORRictorMTORRaptorEGF

TGF-

HB-EGF

EpiregulinVEGF

PDGFVEGFREGFR(HER1)AdaptedfromSiena,etal.JNCI2009生长因子的转录个体化治疗15SrcPIP2PI3KPIP3RASRAFMEKERKPTE1992年vs.2015年VenookA,etal.2014ASCOAbstractLBA3.100806040200012243648月CALGB/SWOG804055FU+LV(n=803)5FU(n=578)OS(%)个体化治疗161992年vs.2015年VenookA,etaVEGFR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17VEGFR受体单抗：

抑制VEGF单抗：可溶性VEGF受体个体化治疗18个体化治疗18RAS个体化治疗19RAS个体化治疗19RASMT53%RASWT47%随机研究中>5,000患者的荟萃分析KRASWT58%KRASMT42%Sorich,etal.AnnOncol2015个体化治疗20RASMT53%RASWT47%随机研究中>5,FOLFIRI化疗+贝伐珠FOLFIRIFOLFIRIFOLFIRICRYSTALCALGBKRASRAS20.020.223.528.4FIRE-3FOLFIRI+西妥昔28.733.1FOLFIRI+西妥昔FOLFIRIFOLFIRI+贝伐珠25.834.429.031.229.932.0FOLFIRI化疗+西妥昔1.Bokemeyer.2011;2.Bokemeyer.2014;3.VanCutsem.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mCRCOS更长个体化治疗21FOLFIRI化疗+贝伐珠FOLFIRIFOLFIR2016ASCOCIMP-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+20qGain18qLossHer-2Gain发生率：

~60%年纪较小的患者WT为主预后较好左侧肿瘤个体化治疗222016CIMP-HMSIBRAF-MTPI3KCA右侧肿瘤PresentedByDungLeat2016ASCOAnnualMeeting80405研究2016ASCOKRASwtN=1137KRASmtN=252左右N280(25%)689(61%)OS19.4m34.2m*KRASwtCet16.4m37.5mBev23.1m32.1mKRASmtOS23.1m30.3m*个体化治疗23PresentedByDungLeat2016A左、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24左、右半之争1RAS野生型mCRC的一线靶向治疗，EGFR单RASBRAF个体化治疗25RASBRAF个体化治疗25BokemeyerC,etal.EurJCancer2012;48:1466–1475ORR,%CET+CTCTalonen=349n=381n=32n=38n=349n=381n=32n=38BRAFwtBRAFmt60.721.940.913.2CET+CTCTalone10.97.17.73.7PFS,月0S,月n=349n=381n=32n=38CET+CTCTalone24.814.121.19.9CRYSTAL+OPUS西妥昔单抗+FOLFIRI/FOLFOXBRAF突变ORRPFSOS更差个体化治疗26BokemeyerC,etal.EurJCancSeligmann,etal.ASCO20151L治疗1L治疗BRAFMT患者中位OS明显缩短；接受2L治疗的BRAFMT仅有39%，而BRAFWT患者为60%(月)06121824303642OS预估00.250.500.751.0003691215182400.250.500.751.00BRAFWT

BRAFMTHR=1.48

P<0.001BRAFWT

BRAFMTHR=1.17

P=0.33216.910.210.816.4(月)2L治疗个体化治疗27Seligmann,etal.ASCO20151L三药化疗(FOLFOXIRI)+贝伐珠单抗双药化疗(FOLFOX,XELOXorFOLFIRI)+贝伐珠单抗双药化疗(FOLFOXorFOLFIRI)+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？个体化治疗三药化疗(FOLFOXIRI)+贝伐珠单抗高强度低强度初治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*Upto12cyclesTRIBE研究PD个体化治疗初治贝伐珠单抗+FOLFIRI*

(n=256)贝伐珠单TRIBE研究中位OS,月n贝伐珠单抗+FOLFIRI贝伐珠单抗+FOLFOXIRIHR(95%CI)ITT50825.829.80.80(0.65–0.98)RAS及BRAFWT9333.541.70.77(0.46–1.27)RASMT23623.927.30.88(0.65–1.18)BRAFMT2810.719.00.54(0.24–1.20)RASWT12126.837.10.78(0.51–1.20)RASMT23623.927.30.88(0.65–1.18)个体化治疗TRIBE研究中位OS,月n贝伐珠单抗+FOLFIRITRIBE研究BRAF突变患者在一线应给予最强的治疗方案！个体化治疗TRIBE研究BRAF突变患者在一线应给予最强的治疗方案！个RASBRAFMMR个体化治疗15%MSI-H12%启动子甲基化---散发性

3%Lynch32RASBRAFMMR个体化治疗15%MSI-H12根据患者MMR状态，未经治疗的DFSDanielJ.etal.JCO.2010;28:20:3219–3226HR=0.51P=0.002DSF%dMMR(n=79)pMMR(n=436)0100135年MMR状态是II/III期肠癌的预后因素个体化治疗33根据患者MMR状态，未经治疗的DFSDanielJ.et过度突变免疫细胞浸润表达PD-L1PD-L1CD8dMMRpMMR个体化治疗34过度突变PD-L1CD8dMMRpMMR个体化治疗34研究设计PresentedByDungLeat2015ASCOAnnualMeetingAdMMRBpMMRCdMMR肠癌非肠癌Pembrolizumab10mg/kgq2w主要研究终点：20wPFS率及有效率个体化治疗35研究设计PresentedByDungLeat20研究结果PresentedByDungLeat2015ASCOAnnualMeetingAdMMRBpMMRCdMMR肠癌非肠癌ORR62%0%60%DCR92%16%70%个体化治疗36研究结果PresentedByDungLeat20研究结果PresentedByDungLeat2015ASCOAnnualMeetingPFSAdMMRBpMMRCdMMRHR:0.103

P<0.001个体化治疗37研究结果PresentedByDu