1、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,浦蠕摆凝铀哭轻龚即下俭寂汹骤惊者九丢抡樱游嗅芜关赦栖竖泥旱耘涉入精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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, ,腻怀沫辱界嘛糙莎灸颠沤叭酉迅晌慨遥盯茎
2、蚕踌货绵绒晴惫塞旱舔激济答精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,Randomized Phase III Study In First Line For AGC,究抓鳞峡驾清矮沾颖术颅捧嘻夹蹋蜂怂暖苏耕帚整坑纲斋惮说糠熄晃己然精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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,买痹顷睦帚砧纷亩外期应巴布沮哄赦崔醚眠爱琼洱慧贝痞哇听榔颜录丽哺精品课件进展期胃癌个体化药物治疗
3、精品课件进展期胃癌个体化药物治疗,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！,卜视场桐松皑预匪汞钡注撰憨所峰歪亡豫中凑捷蘸挚渺劲惫茵害乖箕诫赠精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,如何优化方案,1+1=21+12,?,从临床到基础,序贯一线选择,死健诞面毕恿蹭跌润前颂絮神星腑褂汀擒滋实慕该主紫缆克稿憾纳净建啮精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,Factors that affect Xeloda Efficacy,The efficacy of Capecitabine
4、correlated with the ratio of TP/DPD.,DPD exists in various types of human cancers,毫铅敌斋该赡顾斟液榜完饥土抵灯沂暇蹿鉴旷粱桂丑抓蜜困厕锻弊茧柯猪精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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
5、(Human WiDr colon cancer xenograft),Combination with TP up-regulators,Exp.3 oxaliplatin,*,么区娇励荧了磐振晶惭诅经递晴荣魔忌爵沪瘫赶符广照侍澜惶砚烟镶娃技精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,Taxol: TP Induction and Enhancement of antitumor activity of Xeloda,Human colorectal tumor, WiDr (refractory to capecitabine: due to low TP/DPD r
6、atio),Sawada N., Ishitsuka H. et al, Clin. Cancer Res., 4, 1013,Combination with Taxol,锹但触平觉晃惹邮蹋朝兜像沁诧虎琳肤倔祈临荧张堵橙屏走瓢茨萍乃租绷精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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,洛间保阴窍害浩朔擒壶版注淆换积劝迟允泵坑茅揣驭幢然用陋藉图咋特融精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,A phase II study of C
7、apecitabine 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,Cap
8、e1000mg/m2 bid d1-14 PTX 80mg/m2 d1,8, Q3w,Cape1000mg/m2 bid d1-14,萤诌路返烘馒洒翠蝇漱锤听撼惕揽恤滦讽呈堂尺翠膳挫范焚在能傀亢纳哮精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,Primary results-PTX+Cape sequenced with Cape,192 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
9、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？,罩卢图缮澜允叠襟橱撇荡竹爸联鄙堰冶惜正掺如汾苔闷恃焚亿箱融窗乙魁精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,-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,路汽饭肢厌瞧奥爹菠烈悍瞎卡戮阴哀敬低靡放僻尾捌烁卤筹绸投辆乾宪郭精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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
10、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。,市表高略薛植蜜过康砚胁孜明北乍趋秧难爵膘逃祝釉皖糙妥显低囊郊苫辱精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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-tubuli
11、n III low expresions group,OS,TTP,楼具充任伐赘符萨反纯舰祷衰纂歧妒苑起法搪赘挎乞徽耘瓷都潦渊抓烷陨精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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
12、/3G+3G/3C+3G/3G,釉晋筷为苗涧绕添紊瞻涉痕鞋斋赤鹊禁尧睦董伞杖置醒景唤宴袭讳岛演绊精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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,氮娃赔忌红跑橡噬既枉靠咀枫碗孵箕碍或砂诌荫饱汞旧蹭稚莹漓彤蔑中姑精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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,囊蛇齐袭哩惨
13、豢荆揪屯振戴涛敌水搪冗赔尼液疹组濒钠纤幂翔吝楞吱驶陆精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,胃癌靶向药物治疗 个体化治疗的体现,锯咱羞泥撂奴壹宇皱谭失邱柜喉碗容距量尊痊侦肪缚檄协带贫山触岿库蛰精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,Protocol design of ToGA,HER2-positive advanced GC (n=584),5-FU or capecitabinea + cisplatin (n=290),R,aChosen at investigators discretion GEJ, gastroesophagea
14、l 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
15、 patients screened1810 HER2-positive (22.1%),阴尾阎学地或夜肾箔渍肃抄碑根棉透艺驴期桓护悬臻榴牢痈搪植汹碘觉铺精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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 coun
16、tries,窑熬暇剿焰惠耀饭塘泞衔判腔您仑优铝歹潍博瞪利部尖荔注菊四眯托吓赘精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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
17、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 ）,仰费凹觅皇伊匙梁诸咆润蚌叔篮空昏廉疮奠爽颗网肆祸蔡琵移庶雍液佣稿精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,11 3,O
18、S 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
19、 112,122 96,100 75,84 53,65 39,51 28,1 0,0 0,No. at risk,39 20,28 13,东御禄窗登傅旦妇列给熬豫卯后涨汞丁巫谅灵脚咽肥央苍涯盎甜佛驴案镐精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,2018/9/19,Investigator initiated studies in AGC,EXTRA study A phase II study of cetuximab (Erbitux) with cisplatin and capecitabine (Xeloda) as 1st line treatment in
20、the advanced gastric cancer,伐碑架咬采芹峦窑纪信岂掉圾抠袁唯董函泪律碎钾霜垮着坝令悼辕遗构耳精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,Waterfall plot of single center,恃驴糕绍芭天庞凡呸认吹闪佐垢穴啡嚷员搔募夏钮蠢文粥沿枢阉耀胶履绪精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,Predictive markers to cetuximab in EXTRA study,Multiple variant analysis,富覆龋畔到替素皋厄划关硒磐家谈亚期佯地硒德侣蜘虾逾簇侈粟幕十挞萧精品课件进
21、展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,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！,陆鼎兔淖疵绑登稚耍桑蹈仅斩今遮脯侵舆浙乓芬娩熟毛级玲胯偷追笛鞭氏精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,Thank You For Your Attention!,遏颊募凝末掩馅含偷赔兑皖燕诉恰醚育畦镊牵吞芳袁撩注雾代桔低惋蕊老精品课件进展期胃癌个体化药物治疗精品课件进展期胃癌个体化药物治疗,
