青海大学附属医院结直肠癌PPT课件

基因检测在结直肠癌治疗中的意义,青海大学附属医院胃肠外科,1,.,恶性肿瘤发病率与死亡率呈上升趋势,摘自：卫生部网站,2,.,结直肠癌病理分型,3,.,结直肠癌发生发展遗传模型,4,.,结直肠癌不同阶段生存期,5,.,EGFR分子信号通路对肿瘤细胞影响,6,.,EGFR信号通路与EGFR靶向治疗,7,.,EGFR信号通路与相关靶向药物,8,.,KRAS突变与爱必妥总生存率,metastaticcolorectalcancer,MichelDucreux,etal.CancerRes,2006,E.VanCutsem,etal.ECCO15-ESMO34,2009,9,.,KRAS突变与爱必妥无病情发展生存率和总生存率,Progression-freesurvivalOverallsurvivalofthe113pooledpatientsaccordingtothepresenceorabsenceofKRASmutation(P=1.4*10-7andP=0.0017,respectively).,colorectalcancer,AstridLievre,etal.JOURNALOFCLINICALONCOLOGY.2008(26),374,10,.,KRAS突变与爱必妥药效,V.Heinemannetal.CancerTreatmentReviews,2009,colorectalcancer,11,.,KRASBRAF突变与爱必妥响应率,metastaticcolorectalcancer,FLoupakis,etal.BritishJournalofCancer,2009,12,.,BRAF突变与爱必妥无病情发展生存率和总生存率,Fig1.(A)Progression-freesurvivaland(B)overallsurvivalinwild-typeKRASpatientsaccordingtoBRAFstatus.M,mutated;NM,nonmutated.,PierreLaurent-Puig,etal.JClinOncol,2009,13,.,PIK3CA突变与EGFR单抗疗效,panitumumab/cetuximab,metastaticcolorectalcancer,AndreaSartore-Bianchi,etal.CancerRes,2009,14,.,PIK3CA突变与结肠癌手术患者预后关系,resectablecoloncancer(stageItoIII),Ogino,etal.JClinOncol,2009,15,.,PTEN表达与EGFR单抗疗效,panitumumab/cetuximab,metastaticcolorectalcancer,AndreaSartore-Bianchi,etal.CancerRes,2009,16,.,PIK3CA突变、PTEN表达与EGFR单抗疗效,panitumumab/cetuximab,metastaticcolorectalcancer,AndreaSartore-Bianchi,etal.CancerRes,2009,17,.,EGFR扩增，KRAS、BRAF突变，PTEN表达与爱必妥疗效,PierreLaurent-Puig,etal.JClinOncol,2009,18,.,小结：相关标记物与爱必妥疗效,Russoetal;Oncology2009,Russoetal;Oncology2009,19,.,血管生成是恶性肿瘤快速增长所必须的,Stagesatwhichangiogenesisplaysaroleintumorprogression,Premalignantstage,Malignanttumor,Tumorgrowth,Vascularinvasion,Dormantmicrometastasis,Overtmetastasis,(Avasculartumor),(Angiogenicswitch),(Vascularizedtumor),(Tumorcellintravasation),(Seedingindistantorgans),(Secondaryangiogenesis),AdaptedfromPoonRT,etal.JClinOncol.2001;19:120725,20,.,血管生成相关因子,TumourCells,PDGF,VEGF,PDGFReceptor,VEGFReceptor,FGFReceptor,FGF,Hostcells,CO2,HypoxiaCOX-2,NOsrc,HER2/neu,rasP53,VHLOxidativeStress,MitoticSpindle,SignalTransductionCascade,ProliferationInvasionMigrationDegradationofbasementmembranePermeabilityCapillarytubeformation,21,.,VEGF信号通路与血管生成,22,.,针对VEGF基因家族的靶向药物,23,.,针对VEGF基因家族靶向治疗临床试验,LeeM.Ellis,etal.NATUREREVIEWScancer,2008,24,.,NishanH.F.,etal.TheOncologist.2004(9suppl1),11.,靶向VEGF基因治疗药物贝伐单抗,colorectalcancer,25,.,KRAS突变与贝伐单抗药效,randomizedphaseIII：AVF2107,metastaticcolorectalcancer,ROSEN,etal.TheOncologist,2009,26,.,EGFR、ERCC1表达与伊立替康疗效,PFS,OS,EGFR、ERCC1高表达（mRNA水平）的患者采用对应治疗方案具有更长的生存期，其中PFS差异显著。,Daniel,etal.Int.J.Cancer,2006,27,.,ERCC1密码子118CT多态性与铂类药物疗效,Chang,etal.CancerSci,2009,metastaticcolorectalcancer,28,.,ERCC1密码子118CT多态性影响蛋白表达水平,Chang,etal.CancerSci,2009,29,.,TYMS表达与氟类药物疗效相关性,PatrickG.Johnston,etal.CANCERRESEARCH.1995(55),1407,colorectalcancergastriccancer,30,.,ERCC1/TS基因表达联合检测,YoshinoriShirota,etal.JournalofClinicalOncology.2001(19),4298.,5-FU/oxaliplatin,metastaticcolorectalcancer,31,.,结直肠癌潜在治疗靶点,32,.,个性化治疗及分子检测导致的变革,过去标准化的治疗方案未来个性化的治疗方案,分子检测,有响应患者,无响应患者,存活率受益,毒性反应而存活率没有受益延误有效治疗,有响应患者,无响应患者,存活率受益,毒性反应而存活率没有受益延误有效治疗,给适合的患者正确的治疗方案,化疗药,敏感度（+）,敏感度（-）,敏感度（+）,敏感度（-）,33,.,更合理的癌症个性化治疗和临床试验方案,34,.,分子检测在癌症个性化治疗中的应用,风险评估,早筛,诊断,分期,预后评估,治疗选择,疗效监测,复发监控,第一代分子诊断,更高价值的第二代应用,35,.,靶向治疗所需的(组织活检)基本生物分析,36,.,中国抗癌协会推荐的标准方法优化的定量寡核苷酸探针法,主要基因突变检测方法比较,37,.,优化的定量寡核苷酸探针法,优化后将灵敏度提高到1%的水平,高灵敏度,目前国内外唯一的定量方法,精确定量,新鲜组织样本组织切片（蜡块）血液、胸腔积液,多种样本,突变+表达检测定性+定量检测预后指标检测疗效监测、复发监测,多种应用,专利技术,38,.,K-ras野生型DNA标准曲线的确定,39,.,K-ras突变型DNA标准曲线的确定,40,.,突变检测定性与定量的对比,定量突变检测的意义,OkamiJ,TaniguchiK,HigashiyamaM,etal,Oncology,2007;72:234