进展期胃癌个体化药物治疗优秀课件.ppt

进展期胃癌个体化药物治疗第1页，本讲稿共28页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,.第2页，本讲稿共28页Randomized Phase III Study In First Line For AGC StudyRegimenNRR(%)pOSpV3252006DCFCF10310538.723.2.01210.2m 8.5m.0064KangY2006XPFP16015641290.0310.5m 9.3 m0.27S.Al-Batran2006FLOFP9810234270.0125.7(TTP)3.80.081Wasaburo2008S-1+PDDS-11451505431.00213.0m11.0 m.04JAjani5FU+PDDS-1+PDD50852124.222.5NS7.9m8.6m NSCunningham2008ECFECXEOFEOX249241235239 40.746.442.447.9NS9.9 m9.9 m9.3m11.2 m NS 第3页，本讲稿共28页胃癌化疗存在的临床问题胃癌化疗存在的临床问题三药同时联合高效、高毒！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，是靶向药成为共识方案，是靶向药物联合基础以及对照方案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但个体化进程较慢第4页，本讲稿共28页方案的改良方案的改良减少药物组合减少药物组合三药变两药三药变两药改变给药方法改变给药方法三周变两周或一周三周变两周或一周更换药物更换药物新药换老药新药换老药目的：保证疗效，减低毒性！目的：保证疗效，减低毒性！第5页，本讲稿共28页如何优化方案如何优化方案1+1=21+12?从临床到基础从临床到基础序贯序贯一线选择一线选择第6页，本讲稿共28页NNHNFOOOHOOHOHNNFOOHOOHOHNNHFOOTPDPDAnabolicpathwayTumor5-DFUR5-FUTP:Thymidine phosphorylaseDPD:Dihydropyrimidine dehydrogenaseFUPAFBALFUH2(inactive)XelodaGrowthinhibitionFHHHHNNHOOFactors that affect Xeloda Efficacy The efficacy of Capecitabine correlated with the ratio of TP/DPD.DPD exists in various types of human cancers第7页，本讲稿共28页05101520 050100150200*(mg/kg)Exp.1 ControlTaxolTaxotereVincristineVinblastineVindesineMitomycin CDoxorubicinCDDPExp.2 ControlMethotrexateCPA100151.53557.51050200DPD(pmol/mgprotein/min)*P2?从基础到临床从基础到临床多个小样本临床研究显示了多个小样本临床研究显示了紫杉醇与卡培他滨联合应用紫杉醇与卡培他滨联合应用在胃癌一二线中都显示出很在胃癌一二线中都显示出很好的前景好的前景第10页，本讲稿共28页A phase II study of Capecitabine in combination with paclitaxel sequenced with capecitabine maintenance as 1st line therapy in advanced or recurrent gastric cancerML20312(ongoing)PTXCAPECAPEPathologically confirmed，unrectable，measurable lesionsFirst line First line KPS70KPS704-6cys RR+SDUntill the patients intolerance or PD Cape1000mg/m2 bid d1-14PTX 80mg/m2 d1,8,Q3wCape1000mg/m2 bid d1-14第11页，本讲稿共28页Primaryresults-PTX+CapesequencedwithCape192 patiens，158 evaluatedCR 2 cases，PR 61 cases(RR39.9%)SD 74cases（46.8%）PD 21cases（13.3）DCR 86.7%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。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致治疗效果的差异个体化？个体化？第12页，本讲稿共28页-tubulin-tubulin、TPTP、TSTS表达与表达与XPaXPa有效率的相关性有效率的相关性 36例例XPa方案化疗患者临床方案化疗患者临床疗效疗效有效有效无效无效有效率有效率P 值值TS mRNATS mRNA 低表达低表达 10107 758.8%58.8%高表达高表达7 7121236.8%36.8%0.1870.187TP mRNATP mRNA 低表达低表达 5 5151529.4%29.4%高表达高表达 12127 763.2%63.2%0.0430.043-tubulin-tubulin 低表达低表达 11117 761.1%61.1%高表达高表达 6 6121233.3%33.3%0.0950.095TP TP 和和 -tubulin -tubulin 表达表达TPTP高高/-tubulin /-tubulin 低表达低表达 7 71 187.5%87.5%TPTP高高/-tubulin /-tubulin 高表达高表达5 56 645.5%45.5%0.147*0.147*TPTP低低/-tubulin /-tubulin 高表达高表达4 46 640%40%0.066*0.066*TPTP低低/-tubulin /-tubulin 高表达高表达1 16 614.3%14.3%0.01*0.01*实验结果实验结果注：注：*为与第一组比较结果为与第一组比较结果第13页，本讲稿共28页实验结果实验结果33例接受卡培他滨例接受卡培他滨+紫杉醇化疗患者中紫杉醇化疗患者中-tubulin III表达与疗效及预后的关系：表达与疗效及预后的关系：-tubulin III 表达分组表达分组+-+negativepositiveCR+PRSD+PDTotalRR P值值TTP(d)P值值OS(d)P值值-tubulin III组化组化Positive8132238.1%86201Negative831172.7%0.0632370.0243880.064结论：结论：-tubulin III低表达患者接受紫杉醇治疗的疗效及预后较好。低表达患者接受紫杉醇治疗的疗效及预后较好。第14页，本讲稿共28页Analysis the relationship of tubulin III expression and PFS、OS in AGC patients with CAPE+PTX-tubulin III-+negativepositiveCR+PRSD+PDTotalRR PTTP(d)POS(d)P-tubulin III组化组化Positive8132238.1%86201Negative831172.7%0.0632370.0243880.064Patients can got more benefit in-tubulin III low expresions groupOSTTP第15页，本讲稿共28页TS、DPYD、MTHFR基因分型与疗效、基因分型与疗效、TTP及及OS的相关性的相关性：结论：结论：在所检测病例中未检测到在所检测病例中未检测到DPYD基因基因IVS14+1GA突变；突变；TS基因基因5端端UTR区区3R/3R基因型的疗效、基因型的疗效、TTP及及OS均较均较2R/3R基因型高；基因型高；3端端+6/+6基因型的疗效及总生存期最高。基因型的疗效及总生存期最高。MTHFR不同基因型中，不同基因型中，TT型的有效率及型的有效率及OSCC型型CT型型实验结果实验结果GenotypeCR+PRSD+PDP ValueTTP(d)P ValueOS(d)P ValueTS-VNTR+G/C SNP*Group A Group B124120430.2741291490.9512052610.372TS-VNTR(28bp repeat)2/3 3/3233036270.1401291780.2572472500.869TS-1494del6 +6/+6 +6/-6 -6/-672422732240.8311491221520.2792611702050.076MTHFR-C677T CC CT TT1419201334160.143179158970.2352502072730.947注：注：Group A:2R/2R+2R/3C+3C/3C；Group B:2R/3G+3G/3C+3G/3G第16页，本讲稿共28页胃癌药物治疗的个体化选择胃癌药物治疗的个体化选择TS、TP、DPD?tubulin III？SNP？预测疗效、预后标志物？预测疗效、预后标志物？分子标志物分子标志物第17页，本讲稿共28页18ML22697-III期多中心、随机、对照研究期多中心、随机、对照研究随机随机1:1紫杉醇卡培他滨紫杉醇卡培他滨 顺铂卡培他滨顺铂卡培他滨4周期周期直到直到进展或展或至少至少6周期周期卡培他滨卡培他滨直到直到进展展A组组B组组晚期晚期/复复发胃或胃食管胃或胃食管结合部腺癌合部腺癌 未接受未接受过化化疗，或，或经新新辅助、助、辅助化助化疗结束超束超过6个月出个月出现进展展N=320第18页，本讲稿共28页胃癌靶向药物治疗胃癌靶向药物治疗个体化治疗的体现个体化治疗的体现第19页，本讲稿共28页ProtocoldesignofToGAHER2-positiveadvancedGC(n=584)5-FUorcapecitabinea+cisplatin(n=290)RaChosenatinvestigatorsdiscretionGEJ,gastroesophagealjunction5-FUorcapecitabinea+cisplatin+trastuzumab(n=294)StratificationfactorsadvancedvsmetastaticGCvsGEJmeasurablevsnon-measurableECOGPS0-1vs2capecitabinevs5-FUPhase III,randomized,open-label,international,multicenter study1Bangetal;Abstract4556,ASCO20093807patientsscreened1810HER2-positive(22.1%)第20页，本讲稿共28页HER2-positivity rate Europe(23.6%)Asia (23.5%)Taiwan 5.9%(n=34)Australia 32.8%(n=61)China 22.6%（n=590）Positive ratio of HER2 is similar in Europe/Asia area,but different among countries第21页，本讲稿共28页patients of our center enrolled in ToGA study104 AGC pts without previous chemotherapy screened HER2 positive in 33 pts(31.7%)19 pts by FISH,2 by IHC(3+),11 pts by both methods,1 pts unknown,25 pts randomized：20 pts of XP，5 pts of XP+HResponse rate：PR 11/25 44%in 5 pts of XP+H:2 PR,1 perforation，2 SD，2 PD,one pts continued treatment of 36cyc（SD after 6cyc of XP-30 cyc of maintained herceptin with SD,the last administration was 2 weeks ago）第22页，本讲稿共28页113OSinIHC2+/FISH+orIHC3+(exploratoryanalysis)1.00.80.60.40.20.0363432302826242220181614121086420Time(months)11.816.0FC+TFCEvents120136HR0.6595%CI0.51,0.83MedianOS16.011.8Event0.10.30.50.70.921819840531242011228218196170170141142112 12296100758453653951281000No.atrisk39202813第23页，本讲稿共28页2022/11/29Investigator initiated studies in AGCEXTRA study A phase II study of cetuximab(Erbitux)with cisplatin and capecitabine(Xeloda)as 1st line treatment in the advanced gastric cancer 第24页，本讲稿共28页Waterfall plot of single center第25页，本讲稿共28页Hazard ratio95%CIP valuerash0.3870.163-0.9220.032TGF1.0400.457-2.3680.925EGF0.6040.277-1.3160.204EGFA61G polymorphism0.4250.202-0.8950.024Predictive markers to cetuximab in EXTRA studySkin rash 2/3:17.57mRash 0/1:7.77mTGF-high 12.867mTGF-low 7.767m EGFA61G GG 13.300mEGFA61G:GA 8.933mMultiple variant analysis第26页，本讲稿共28页HowtoresolvetheClinicalIssues？Prospectivetrial：largegrouppatients，unifiedagentdetail document data base of FUTissue bankAnalyses of gene/proteinRetropective studyIndividualtreatment不断的转化研究过程！不断的转化研究过程！第27页，本讲稿共28页Thank You For Your Attention!第28页，本讲稿共28页