进展期胃癌个体化药物治疗 ppt课件

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, ,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！ 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,Factors that affect Xeloda Efficacy,The efficacy of Capecitabine correlated with the ratio of TP/DPD.,DPD exists in various types of human cancers,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 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 Capecitabine 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,Cape1000mg/m2 bid d1-14 PTX 80mg/m2 d1,8, Q3w,Cape1000mg/m2 bid d1-14,Primary results-PTX+Cape sequenced with Cape,192 patiens，158 evaluated CR 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,个体化？,-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,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 more 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? tubulin III ？ SNP？ 预测疗效、预后标志物？,分子标志物,18,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,胃癌靶向药物治疗 个体化治疗的体现,Protocol design of ToGA,HER2-positive advanced GC (n=584),5-FU or capecitabinea + cisplatin (n=290),R,aChosen at investigators discretion GEJ, gastroesophageal junction,5-FU or capecitabinea + cisplatin + trastuzumab (n=294),Stratification factors advanced vs metastatic GC vs GEJ measurable vs non-measurable ECOG PS 0-1 vs 2 capecitabine vs 5-FU,Phase III, randomized, open-label, international, multicenter study,1Bang et al; Abstract 4556, ASCO 2009,3807 patients screened1 810 HER2-positive (22.1%),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,patients of our center enrolled in ToGA study,104 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+H Response 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 ）,11 3,OS in IHC2+/FISH+ or IHC3+ (exploratory analysis),1.0,0.8,0.6,0.4,0.2,0.0,36,34,32,30,28,26,24,22,20,18,16,14,12,10,8,6,4,2,0,Time (months),11.8,16.0,FC + T,FC,Events 120 136,HR 0.65,95% CI 0.51, 0.83,Median OS 16.0 11.8,Event,0.1,0.3,0.5,0.7,0.9,218 198,4 0,5 3,12 4,20 11,228 218,196 170,170 141,142 112,122 96,100 75,84 53,65 39,51 28,1 0,0 0,No. at risk,39 20,28 13,2019/4/18,Investigator initiated studies in AGC,EXTRA study A phase II study of cetuximab (Erbitux) with cisplatin and capecitabine (Xeloda) as 1st line treatment in the advanced gastric cancer,Waterfall plot of single center,Predictive markers to cetuximab in EXTRA study,Multiple variant analysis,How to resol