Lauren分型对胃癌治疗的价值和意义

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,Lauren分型对胃癌治疗的价值和意义,胃癌Lauren分型和预后意义及流行病学变化,弥漫型胃癌个性化治疗的研究与探索,S-1,铂类,伊立替康,紫杉醇,等药物在弥漫型胃癌中的应用,在弥漫型胃癌中的探索,新的胃癌分子病理分型展望,小结,主要内容,胃癌病理组织学分型,胃癌病理分型,大体形态：息肉型、溃疡型、溃疡浸润型、弥漫浸润型；,组织学分型：管状腺癌、乳头状腺癌、低分化腺癌、粘液腺癌、印戒细胞癌。少见类型：鳞癌、腺鳞癌、类癌、未分化癌,Lauren分型,也是胃癌常用的组织学分型方法之一，分为肠型、弥漫型和混合型，该分型操作简便、可重复性高，对胃癌预后预测分析具有一定的指导价值,胃癌,Lauren,分型,2024/9/20,肠型,具有明显的腺管结构,肿瘤细胞分泌黏液,细胞呈极性排列,弥漫型,无腺管样结构,缺乏细胞连接,癌细胞散在并呈浸润性生长,混合型,兼有肠型和弥漫型成分,Emily S. Turner,Jerrold R. Turner,department of pathology,the university of Chicago,我国约一半的胃癌患者为弥漫型,Miao-zhen Q, et al. Journal of Translational Medicine. 2013,11:58.,肠型呈减少趋势，弥漫型呈增长趋势,自,1973-2000,年，美国流病性调研显示肠型胃癌不断减少，弥漫型胃癌逐渐增多。,Henson DE, et al. Arch Pathol Lab Med. 2004; 128(7): 765-770,P,女性,相似,好发部位,胃窦,胃体,转移部位,淋巴结，肝脏,淋巴结，内脏,生物学特征,雌激素保护？,神经内分泌分化？,幽门杆菌感染,血清学常见（,8090%,）,常见（,90%,）,Lauren,分型与预后：弥漫型胃癌预后较差,胃癌总生存率的多因素分析,因素,特征,风险比,95%CL,P,年龄,59,59,1.111,0.899-1.374,0.328,性别,女,男,1.057,0.843-1.324,0.631,Lauren,分型,肠型,弥漫型,0.736,0.595-0.910,0.005,组织学分级,好,/,适度,差,1.025,0.899-1.167,0.714,大小,5 cm,5 cm,1.605,1.307-1.972,0.001,部位,远端,近,端,0.852,0.697-1.042,0.120,肿瘤深度,(T),2/3/4,1,1.890,1.230-2.746,0.001,淋巴结分期,(N),1/2/3,0,1.368,1.048-1.894,0.001,淋巴管血管浸润,(-),(+),1.209,0.831-1.759,0.321,胃切除术的类型,不完全,完全,1.135,0.859-1.468,0.582,Qiu MZ, et al. J Transl Med. 2013; 11:58,弥漫型患者的,5,年生存率显著低于肠型患者,Liu et al. Anticancer Aqents Med Chem. 2013 Feb;13(2):227-34.,Qiu et al. J Transl Med.2013;11:58.,P,0.001,1,2,61.7%,41.1%,52.7%,44.1%,ToGA,研究提示：,HER2+,胃癌多为肠型,Yung-Jue Bang, et al. Lancet 2010; 376: 68797,沈琳等。中华肿瘤杂志，2013,ToGA,研究提示：,Lauren,分型与疗效有一定相关性,Bang YJ, et al. Lancet 2010; 376: 68797,Her-2,过表达的,晚期弥漫型胃癌,接受化疗联合曲妥珠单抗靶向治疗较单纯化疗没有显著的生存获益,弥漫型胃癌个性化治疗的,研究,与探索,弥漫型胃癌自身特性：,DPD,高表达,Y. Yamada, et al. Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings. 27(15S): 4535,Y. Yamada, et al. Journal of Clinical Oncology. 2011 ASCO Annual Meeting Abstracts. 29(15): 4021,二氢嘧啶脱氢酶（,DPD,）,Yamada,等学者的研究显示：弥漫型胃癌的,DPD,表达水平显著高于肠型,0,0.5,1,1.5,2.5,3,2,DPD-value,弥漫型,n = 82,肠 型,n = 86,秩和检验,IP,5-FU,S-1,*,S-1,构成及作用原理,Patrick Schoffskia. Anti-Cancer Drugs 2004, 15:85106,骨髓毒性,神经毒性,手足综合症,心脏毒性,胃肠道毒性,(,腹泻,口腔炎,),抗肿瘤活性,F-,-,丙氨酸,5-FU,肿瘤,胃肠道,骨髓,FdUMP,OPRT,FdUMP,FdUMP,S-1:,DPD,-,吉美嘧啶,Gimeracil,奥替拉西钾,Oteracil,替加氟,Tegafur,体内代谢,-,S-1,对肠型和弥漫型均有效：,JCOG9912,DPD,高表达,-,弥漫型,生存率,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,5,10,15,PFS (mo),5-FU,S-1,DPD,低表达,-,肠型,生存率,0,5,10,15,PFS (mo),5-FU,S-1,Arm,N,mPFS (months),5-FU,20,2.1,S-1,31,4.2,HR 2.05 95% Cl (1.13-3.71),Arm,N,mPFS (months),5-FU,29,3.1,S-1,33,4.2,HR 1.01 95% Cl (0.60-1.70),Y. Yamada, et al. Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings. 27(15S): 4535,传统,5-FU,在弥漫型,胃癌效果不佳,292,270,226,198,161,122,99,69,51,39,29,24,16,10,5,3,0,298,258,218,182,137,110,85,60,43,30,20,15,10,5,4,2,0,Months From Randomization,% Survival,N at Risk,S-1:,5-FU:,0,10,20,30,40,50,60,70,80,90,100,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,S,1联合顺铂（SP）显著改善弥漫型胃癌生存：,FLAGS,SP=S-1 +,顺铂,FP=5FU+,顺铂,p,中位OS,(,月,),HR,95%CI,SP,9.0,0.83,0.70-0.99,FP,7.1,Jaffer A. Ajani,et al.,J Clin Oncol. 2010 Mar 20;28(9):1547-53.,弥漫型胃癌中的,III,期试验,DIGEST,研究：ongoing,主要终点,: OS,次要终点,: PFS, TTF, RR,安全性,病例数,: 500,例,弥漫型,转移性胃癌、无化疗史,S-1+CDDP,S-1 : 25mg/m,2,bid,for 21 days, q4wks,CDDP : 75 mg/m,2,iv on day 1,(,最多,6 cycles ),FU,+CDDP,5-FU,:,8,00 mg/m,2,24 hr civ day1-5, q,3,wks,CDDP :,80,mg/m,2,iv,on,day 1,(,最多,8 cycles ),R,17,G-SOX,方案不劣于SP方案：日本的注册临床研究,S-1+ L-OHP(SOX) n=340,S-1: 40 mg/m,2,bid,，,治疗,14,天,L-OHP:100 mg/m,2,iv,，第,1,天，每隔,3,周,S-1+ CDDP(SP) n=340,S-1: 40 mg/m,2,bid,，治疗,21,天,CDDP: 60 mg/m,2,iv,第,8,天，每隔,5,周,无法切除,/,复发胃癌,初治病例,随机分组,结论：,主要终点,PFS,获得非劣效性统计结果。,SOX,方案无需静脉水化和住院，临床使用更方便。,SOX,方案可以考虑替代,SP,方案，作为晚期胃癌化疗的一线方案。,【,试验设计,】,【,试验结果,】,【,缓解率,】,SOX,（,n=318,）,SP,（,n=324,）,亚组分析：相对于SP，,SOX,对弥漫型胃癌更有效,?,类别,亚组,n,性别,男性,477,女性,165,年龄,65,305,65,337,70,443,70,199,PS,0,452,1,183,2,7,疾病状态,不可切除,533,辅助,(+),54,辅助,(-),55,病理类型,肠型,289,弥漫型,353,主要病灶,无,146,有,496,转移部位,肝,253,腹膜,125,腹部淋巴结,568,腹水,271,转移数目,1,203,2,277,3,162,合计,642,HR,95% CI,0.954,0.779-1.169,0.904,0.640-1.278,1.058,0.821-1.364,0.868,0.682-1.105,1.016,0.824-1.253,0.825,0.601-1.133,0.883,0.714-1.093,1.173,0.858-1.605,1.414,0.196-10.192,1.035,0.857-1.249,0.458,0.243-0.898,1.028,0.526-2.006,1.075,0.830-1.392,0.839,0.661-1.064,0.716,0.486-1.056,1.045,0.860-1.271,1.007,0.769-1.320,0.858,0.580-1.268,0.921,0.766-1.108,0.922,0.710-1.198,1.048,0.756-1.454,0.930,0.715-1.211,0.822,0.588-1.149,1.004,0.840-1.199,K Higuchi, et al. ASCO-GI 2013.,SOX,更好,SP,更好,弥漫型胃癌中的,III,期试验-,SOX-DGCA,：ongoing,随机、开放、平行对照、多中心,期临床研究,计划入组共,446,例,SP,S-1,：,80-120mg/d d1-14,顺铂：,75mg/m,2,d1-3 iv,每,3,周为一个周期,SOX,S-1,：,80-120mg/d d1-14,奥沙利铂：,130mg/m,2,d1 iv,每,3,周为一个周期,经组织学证实的不能手术的晚期或复发性弥漫型胃腺癌,18,岁,75,岁,有客观可测量肿瘤病灶,ECOG,全身状态评分为,0,2,R,Xu Ruihua,，,et al.,NCT01824459,紫杉醇对弥漫型胃癌更有效？,Yamaguchi,、,Emi,等人单药紫杉醇的小样本,期临床研究中显示，弥漫型胃癌较肠型胃癌患者具有更高的有效率,Yamaguchi,K, et al.Gastric cancer 2002;5(2):90-5,Emi Y.et al. Surg Today. 2008;38(11):1013-20.,%,单药紫杉醇的反应率,弥漫型,弥漫型胃癌中的,III,期试验-,PS vs SOX,：ongoing,多中心、随机、对照,期临床研究,计划入组共,240,例,紫杉醇,+,替吉奥（,PS,）,S-1,：,80-120mg/d d1-14,紫杉醇：,135mg/m,2,d1 iv,每,3,周为一个周期,奥沙利铂,+,替吉奥（,SOX,）,S-1,：,80-120mg/d d1-14,奥沙利铂：,130mg/m,2,d1 iv,每,3,周为一个周期,初治进展期弥漫型胃癌,18,岁,ECOG,全身状态评分为,0,2,R,Bifeng,，,et al.,含伊立替康的方案对,弥漫型胃癌更有效？,Hiroyukl N, et al. Gastric Cancer.,2011;14:72-80.,Narikazu B, et al. Lancet Oncol 2009;10:1063-1069.,GC0301/TOP-002,研究,1,JCOG9912,研究,2,新的胃癌分子病理分型展望,Lauren,分型的扩展,Emily S. Turner,Jerrold R. Turner,department of pathology,the university of Chicago,Gastroenterology 2013;145:554565,胃癌新的分子病理亚型,最近发表于,Nature,的研究报告：,295,个胃癌样本，应用,6,种分子分析技术分析它们的特征和分子改变，明确地将胃癌分为,4,个亚型,（一）,PI3-K,信号通路突变、,DNA,极度超甲基化、,PD-1,和,PD-L1,基因额外拷贝。占胃癌的,10%,（二）,DNA,修复机制失常导致的一些高频突变，激活了癌症相关的信号蛋白。约占胃癌的,20%,（三）染色体不稳定型，具有许多额外或缺失的基因和染色体片段，一些重要的促癌基因发生大量扩增，约占胃癌的,50%,（四）基因组稳定型胃癌，缺少其它三种类型胃癌的一些分子特征，主要为弥漫型胃癌，特点为迅速发生转移，缺乏有效的疗法。占胃癌的,20%,以上研究为癌症基因组图谱（,TCGA,）计划的一个组成部分,Nature, 23 July 2014,小,结,弥漫型胃癌发病率逐年升高，患者比例接近,50%,，且预后较差,个性化治疗的探索发现，弥漫型胃癌,DPD,高表达，多项研究提示,S-1,、伊立替康和紫杉醇对弥漫型胃癌可能更有效,S-1,为基础的治疗方案成为弥漫型胃癌个体化治疗研究的热点，,SOX,方案、SP方案、,PS,方案孰优孰劣，我们拭目以待,随着癌症基因组图谱计划的开展和最终完成，,未来胃癌的治疗必定是基于分子病理特征分型的个体化治疗,谢 谢！,谢谢大家！,结 语,