1、进展期胃癌化疗方案的优化 证据、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 3月于杭州,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, ,Randomized Phase III Study In First Line For AGC,胃癌化疗存在的临床问题,三药同时联合高效、高毒！ 卡培他滨成为口服氟尿
2、嘧啶类药物的代表，以及联合方案的基础，但仍多与顺铂联合 XP成为共识方案，是靶向药物联合基础以及对照方案 与卡被他滨联合应用，疗效提升空间仍然很大，一线方案仍待优化,如何优化方案,1+1=21+12,?,从临床到基础,序贯一线选择,Factors that affect Xeloda Efficacy,The efficacy of Capecitabine correlated with the ratio of TP/DPD.,DPD exists in various types of human cancers,P = 0.0164,N.S.,Drug sensitivity to X
3、eloda vs. TP/DPD expression in human cancer xenograft models (24 tumor lines),S : Sensitive line (50%TGI), R : Insensitive line,100010010,(g 5-FU produced/mg protein/hr),TP,S R,DPD,1000100101,(pmol 5-FUH2 produced/mg protein/min),S R,(dThdPase/DPD),TP/DPD,1001010.1,P = 0.0015,S R,Possibility for pat
4、ient selection based on TP/DPD ratio,0 5 10 15 20,0 50 100 150 200,*,DPD (pmol/mg protein/min),* P 0.05 vs. Control by the Students t-test,*,*,*,*,*,*,*,*,Induction of TP by antitumor agents(Human WiDr colon cancer xenograft),Combination with TP up-regulators,Exp.3 oxaliplatin,*,Taxol: TP Induction
5、and Enhancement of antitumor activity of Xeloda,Human colorectal tumor, WiDr (refractory to capecitabine: due to low TP/DPD ratio),Sawada N., Ishitsuka H. et al, Clin. Cancer Res., 4, 1013,Combination with Taxol,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,A phase II study of Capeci
6、tabine in combination with paclitaxel sequenced with capecitabine maintenance as 1st line therapy in advanced or recurrent gastric cancer ML20312 (ongoing),PTXCAPE,CAPE,Pathologically confirmed，unrectable，measurable lesions First line KPS70,4-6cys RR+SD,Untill the patients intolerance or PD,Cape1000
7、mg/m2 bid d1-14 PTX 80mg/m2 d1,8, Q3w,Cape1000mg/m2 bid d1-14,Primary results-PTX+Cape sequenced with Cape,185 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,Screen,Treatme
8、nt,PTX,Cape,d1,d15,d8,Peripheral blood collection at base line, response evaluation and PD for molecular classification to analyze the relationship between tumor response with differential expression of genes and proteins.,46cycs,Xeloda monotherapy,PD,Statistical Analysis,protocol design,noPD,withdr
9、awl,68cycs,ML20312,Sample collection,分子标志物与化疗疗效的相关性,5-FU类：TS、TP、DPD、MTHFR等 铂类：ERCC1、GSTP1等 紫杉类：-tubulin III ?,留取化疗前患者组织石蜡标本及血液标本，切片行IHC检测，血清行SNP及ELISA检测； IHC表达水平以-、+、+、+表示，以中位置为界分为低表达组（定义为negative）和高表达组（定义为positive）； 统计分析不同表达水平、不同基因型与化疗疗效以及预后的相关性。,TP、TS表达与卡培他滨治疗RR的相关性,实验结果,注：*与第一组比较结果,TP、TS表达与卡培他滨治疗
10、生存期的相关性,实验结果,-tubulin 表达与XPa生存期的相关性,实验结果,-tubulin 、TP、TS表达与XPa有效率的相关性,实验结果,注：*为与第一组比较结果,TP、TS、ERCC1表达与XP疗效相关性,实验结果,实验结果,51例接受卡培他滨联合化疗患者中TS、TP表达与疗效及预后的关系：,TP表达分组,+,-,+,+,TS表达分组,-,+,+,+,negative,negative,positive,positive,以中位值为界分为低表达组（negative）和高表达组（positive）,51例接受卡培他滨联合化疗患者中TS、TP表达与疗效及预后的关系：,实验结果,结论：
11、TP高表达、TS低表达患者的疗效及预后最好。,实验结果,33例接受卡培他滨+紫杉醇化疗患者中-tubulin III表达与疗效及预后的关系：,-tubulin III表达分组,+,-,+,+,negative,positive,结论：-tubulin III低表达患者接受紫杉醇治疗的疗效及预后较好。,Analysis the relationship of tubulin III expression and PFS 、 OS in AGC patients with CAPE+PTX,-tubulin III,-,+,negative,positive,Patients can got mo
12、re benefit in-tubulin III low expresions group,OS,TTP,TS、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OSCC型CT型,实验结果,注：Group A: 2R/2R+2R/3C+3C/3C ；Group B: 2R/3G+3G/3C+3G/3G,胃癌药物治疗的个体化选择,TS? TP？ DPD? tub
13、ulin III ？ ERCC？ SNP？ 其它？,一线：XPa？XP？ 分子标志,26,ML22697-III期多中心、随机、对照研究,随机 1:1,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=320,2018/9/23,Clinical trial for AGC in China,Domestic (As Principal investigotor):ML22697 (ongoing, phase III) TAXGC (ongoing,phase III)BEV+XP (ongoing, Phase III)ENDOCX (ongoi
14、ng, Phase II)ML20312 (ongoing, phase II) SC-101 (completed, Phase III)EXTRA (completed, Phase II)VEGFR2/3 inhibitor (to be initiated, Phase I),New target agents for GC,IGF1R，VEGFR， PI3K/PTEN/AKT/mTOR,How to resolve the Clinical Issues？,Prospective trial：large group patients ，unified agent,detail document data base of FU,Tissue bank,Analyses of gene/protein,Retropective study,Individual treatment,不断的转化研究过程！,Thank You For Your Attention!,
