单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,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,FOLFOX,CapeOX,bevacizumab,FOLFIRI,Cetuximab or,Panitumumab,(RAS WT only),OX,IRI,bevacizumab,bevacizumab,Cetuximab or,Panitumumab,(RAS WT only),IRI,OX,FOLFIRI,FOLFOX,bevacizumab,Ziv-aflibercept,Cetuximab or,Panitumumab,(RAS WT only),bevacizumab,bevacizumab,Ziv-aflibercept,Irinotecan,CapeOX,Irinotecan,Cetuximab or,Panitumumab,(RAS WT only),bevacizumab,FOLFOX,CapeOX,bevacizumab,Regorafenib,Clinical trial,ramucirumab,Best supportive care,TAS-102,3,整体策略FOLFOXCapeOXbevacizumabFOL,整体策略,bevacizumab,5-FU,FOLFIRI,FOLFOX,bevacizumab,Ziv-aflibercept,Cetuximab or,Panitumumab,(RAS WT only),Irinotecan,Irinotecan,Cetuximab or,Panitumumab,(RAS WT only),FOLFOXIRI,CapeOX,Capecitabine,bevacizumab,Regorafenib,Regorafenib,Regorafenib,ramucirumab,TAS-102,TAS-102,TAS-102,4,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,Mutation frequencies in human CRC,TCGA.Nature.2013,487(7407):330337.,个体化治疗,6,Mutation frequencies in human,Integrative analysis of genomic changes in 195 CRC tumors,TCGA.Nature.2013,487(7407):330337.,个体化治疗,7,Integrative analysis of genomi,Copy number changes and structural aberrations in CRC,个体化治疗,8,Copy number changes and struct,Diversity and frequency of genetic changes leading to,deregulation of signaling pathways in CRC,个体化治疗,9,Diversity and frequency of gen,Integrative analyses of multiple data sets,个体化治疗,10,Integrative analyses of multip,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-38,M4=,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,SN-38G,CES,UGT1A1,CES,CYP3A,12,个体化治疗APC=7-乙基-10-4-N-(5-氨基戊酸),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*,28,Cox,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,13,个体化治疗Chan J,et al.2011 ASCO,63,例患者检测,UGT1A1*28,35,例*,1/*1(6/6),24,例*,1/*28(6/7),4,例*,28/*28(7/7),FOLFIRI,215mg/m,2,260mg/m,2,310mg/m,2,370mg/m,2,420mg/m,2,6/6,型野生型患者最大耐受剂量为,420mg/m,2,6/7,型患者的最大耐受剂量为,370mg/m,2,个体化治疗,14,63例患者检测UGT1A1*2835例*1/*1(6/6)2,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,et al.JNCI 2009,生长因子的转录,个体化治疗,15,SrcPIP2PI3KPIP3RASRAFMEKERKPTE,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/SWOG,80405,5FU+LV(n=803),5FU(n=578),O,S,(%),个体化治疗,16,1992年 vs.2015年Venook A,et a,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,17,VEGFR 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18,RAS,个体化治疗,19,RAS个体化治疗19,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,20,RAS MT 53%RAS WT 47%随机研究中5,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,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,21,FOLFIRI化疗 +贝伐珠FOLFIRIFOLFIR,2016,ASCO,CIMP-H,MSI,BRAF-MT,PI3KCA,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 Gain,18q Loss,Her-2 Gain,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,22,2016CIMP-HMSIBRAF-MTPI3KCA右侧肿瘤,Presented By Dung Le at 2016 ASCO Annual Meeting,80405,研究,2016,ASCO,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,23,Presented By Dung Le at 2016 A,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,24,左、右半之争1RAS野生型mCRC的一线靶向治疗，EGFR单,RAS,BRAF,个体化治疗,25,RASBRAF个体化治疗25,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/FOLFOX,BRAF,突变,ORR PFS OS,更差,个体化治疗,26,Bokemeyer C,et al.Eur J Canc,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%,(,月,),0,6,12,18,24,30,36,42,OS,预估,0,0.25,0.50,0.75,1.00,0,3,6,9,12,15,18,24,0,0.25,0.50,0.75,1.00,BRAF WTBRAF MT,HR=1.48,P,0.001,BRAF WTBRAF MT,HR=1.17,P,=0.33,21,6.9,10.2,10.8,16.4,(,月,),2L,治疗,个体化治疗,27,Seligmann,et al.ASCO 20151L,三药化疗,(FOLFOXIRI)+,贝伐珠单抗,双