进展期胃癌个体化药物治疗

进展期胃癌个体化药物治疗——药物优化与个体化探索北京大学肿瘤医院消化肿瘤内科沈琳2010年5月CACA目前胃癌化疗药物氟脲嘧啶类包括口服药：5-FU,capecitabine,S-1紫杉醇类：紫杉醇、多稀紫杉醇。铂类：DDP、OXA（oxaliplatin）蒽环类：EPI拓扑异构酶I抑制剂：Irinotecan(CPT-11),HCPT靶向治疗药物:Herceptin，AVASTIN,C225,…..RandomizedPhaseIIIStudyInFirstLineForAGCStudyRegimenNRR(%)pOSpV3252006DCFCF10310538.723.2.01210.2m8.5m.0064KangY2006XPFP16015641290.0310.5m9.3m0.27S.Al-Batran2006FLOFP9810234270.0125.7(TTP)3.80.081Wasaburo2008S-1+PDDS-11451505431.00213.0m11.0m.04JAjani5FU+PDDS-1+PDD50852124.222.5NS7.9m8.6mNSCunningham2008ECFECXEOFEOX24924123523940.746.442.447.9NS9.9m9.9m9.3m11.2mNS胃癌化疗存在的临床问题•三药同时联合高效、高毒！•氟尿嘧啶类药物为基础的两药联合成为共识方案，是靶向药物联合基础以及对照方案•疗效提升空间仍然很大，一线方案仍待优化•但个体化进程较慢方案的改良•减少药物组合——三药变两药•改变给药方法——三周变两周或一周•更换药物——新药换老药目的：保证疗效，减低毒性！如何优化方案•1+1=2•1+12从临床到基础•序贯•一线选择NNHNFOOOHOOHOHNNFOOHOOHOHNNHFOOTPDPDAnabolicpathwayTumor5’-DFUR5-FUTP:ThymidinephosphorylaseDPD:DihydropyrimidinedehydrogenaseFUPAFBALFUH2(inactive)XelodaGrowthinhibitionFHHHHNNHOOFactorsthataffectXelodaEfficacyTheefficacyofCapecitabinecorrelatedwiththeratioofTP/DPD.DPDexistsinvarioustypesofhumancancers05101520050100150200*(mg/kg)Exp.1ControlTaxolTaxotereVincristineVinblastineVindesineMitomycinCDoxorubicinCDDPExp.2ControlMethotrexateCPA100151.53557.51050200DPD(pmol/mgprotein/min)*P0.05vs.ControlbytheStudent’st-test********InductionofTPbyantitumoragents(HumanWiDrcoloncancerxenograft)CombinationwithTPup-regulatorsExp.3oxaliplatin*Taxol:TPInductionandEnhancementofantitumoractivityofXeloda024681020151050Daysaftertaxoladministration(iv)Taxoli.v.(U/mgprotein)TPactivityintumorControl100mg/kg15mg/kgTaxol+5-FU0.80.60.40.20-0.21520253035404515202530354045ControlTaxol(qw)Taxol+XelodaControlTaxol5-FUXeloda5-FUTumorvolumechangeDaysaftertumorinnoculation(cm3)Xeloda(qd)Humancolorectaltumor,WiDr(refractorytocapecitabine:duetolowTP/DPDratio)SawadaN.,IshitsukaH.etal,Clin.CancerRes.,4,1013CombinationwithTaxol如何优化方案•1+12从基础到临床多个小样本临床研究显示了紫杉醇与卡培他滨联合应用在胃癌一二线中都显示出很好的前景AphaseIIstudyofCapecitabineincombinationwithpaclitaxelsequencedwithcapecitabinemaintenanceas1stlinetherapyinadvancedorrecurrentgastriccancerML20312(ongoing)PTX＋CAPECAPE•Pathologicallyconfirmed，unrectable，measurablelesions•Firstline•KPS704-6cysRR+SDUntillthepatientsintoleranceorPDCape1000mg/m2bidd1-14PTX80mg/m2d1,8,Q3wCape1000mg/m2bidd1-14Primaryresults---PTX+CapesequencedwithCape•192patiens，158evaluatedCR2cases，PR61cases(RR39.9%)SD74cases（46.8%）PD21cases（13.3％）DCR86.7%•同样是病理明确的胃腺癌，同样的分期，接受同样的药物、同样的剂量化疗，取得的疗效不同。•临床特点相同的个体，肿瘤分子生物学特性大不相同，导致治疗效果的差异个体化？β-tubulinⅢ、TP、TS表达与XPa有效率的相关性36例XPa方案化疗患者临床疗效有效无效有效率P值TSmRNA低表达10758.8%高表达71236.8%0.187TPmRNA低表达51529.4%高表达12763.2%0.043β-tubulinⅢ低表达11761.1%高表达61233.3%0.095TP和β-tubulinⅢ表达TP高/β-tubulinⅢ低表达7187.5%TP高/β-tubulinⅢ高表达5645.5%0.147*TP低/β-tubulinⅢ高表达4640%0.066*TP低/β-tubulinⅢ高表达1614.3%0.01*实验结果注：*为与第一组比较结果实验结果33例接受卡培他滨+紫杉醇化疗患者中β-tubulinIII表达与疗效及预后的关系：β-tubulinIII表达分组+-+++++negativepositiveCR+PRSD+PDTotalRRP值TTP(d)P值OS(d)P值β-tubulinIII组化Positive8132238.1%86201Negative831172.7%0.0632370.0243880.064结论：β-tubulinIII低表达患者接受紫杉醇治疗的疗效及预后较好。Analysistherelationshipofβ－tubulinIIIexpressionandPFS、OSinAGCpatientswithCAPE+PTXβ-tubulinIII-++negativepositiveCR+PRSD+PDTotalRRPTTP(d)POS(d)Pβ-tubulinIII组化Positive8132238.1%86201Negative831172.7%0.0632370.0243880.064Patientscangotmorebenefitinβ-tubulinIIIlowexpresionsgroupOSTTPTS、DPYD、MTHFR基因分型与疗效、TTP及OS的相关性：结论：在所检测病例中未检测到DPYD基因IVS14+1GA突变；TS基因5’端UTR区3R/3R基因型的疗效、TTP及OS均较2R/3R基因型高；3’端+6/+6基因型的疗效及总生存期最高。MTHFR不同基因型中，TT型的有效率及OS＞CC型＞CT型实验结果GenotypeCR+PRSD+PDPValueTTP(d)PValueOS(d)PValueTS-VNTR+G/CSNP*GroupAGroupB124120430.2741291490.9512052610.372TS-VNTR(28bprepeat)2/33/3233036270.1401291780.2572472500.869TS-1494del6+6/+6+6/-6-6/-672422732240.8311491221520.2792611702050.076MTHFR-C677TCCCTTT1419201334160.143179158970.2352502072730.947注：GroupA:2R/2R+2R/3C+3C/3C；GroupB:2R/3G+3G/3C+3G/3G胃癌药物治疗的个体化选择•TS、TP、DPD?•β－tubulinIII？•SNP？•预测疗效、预后标志物？分子标志物18ML22697---III期多中心、随机、对照研究随机1:1紫杉醇＋卡培他滨顺铂＋卡培他滨4周期直到进展或至少6周期卡培他滨直到进展A组B组•晚期/复发胃或胃食管结合部腺癌•未接受过化疗，或经新辅助、辅助化疗结束超过6个月出现进展N=320胃癌靶向药物治疗——个体化治疗的体现ProtocoldesignofToGAHER2-positiveadvancedGC(n=584)5-FUorcapecitabinea+cisplatin(n=290)RaChosenatinvestigator’sdiscretionGEJ,gastroesophagealjunction5-FUorcapecitabinea+cisplatin+trastuzumab(n=294)Stratificationfactors−advancedvsmetastatic−GCvsGEJ−measurablevsnon-measurable−ECOGPS0-1vs2−capecitabinevs5-FUPhaseIII,randomized,open-label,international,multicenterstudy1Bangetal;Abstract4556,ASCO20093807patientsscreened1810HER2-positive(22.1%)HER2-positivityrateEurope(23.6%)Asia(23.5%)Taiwan5.9%(n=34)Australia32.8%(n=61)China22.6%±（n=590）PositiveratioofHER2issimilarinEurope/Asiaarea,butdifferentamongcountriespatientsofourcenterenrolledinToGAstudy104AGCptswithoutpreviouschemotherapyscreened–HER2positivein33pts(31.7%)19ptsbyFISH,2byIHC(3+),11ptsbybothmethods,1ptsunknown,–25ptsrandomized：20ptsofXP，5ptsofXP+H–Responserate：PR11/2544%in5ptsofXP+H:2PR,1perforation，2SD，2PD,oneptscontinuedtreatmentof36cyc（SDafter6cycofXP----30cycofmaintainedherceptinwithSD,thelastadministrationwas2weeksago）113OSinI