沈琳晚期胃癌治疗瓶颈及未来发展方向

晚期胃癌治疗瓶颈及未来中国发展方向,北京大学肿瘤医院 消化内科 沈琳,胃癌治疗发展历程,1960s,2010s,腹腔镜手术标准化疗方案ECF、CF,新的化疗药物及联合方案围手术期化疗、放化疗,氟尿嘧啶用于临床,1970s,联合化疗出现氟尿嘧啶+DDP,1990s,1881,1980s,胃大部切除术,内镜手术EMR、ESD,2000s,靶向药物联合化疗一线治疗HER2阳性转移性胃腺癌,OS 6M,OS 16M,Murad AM, et al. Cancer. 1993;72:37-41. 2. Vanhoefer U, et al. J Clin Oncol. 2000;18:2648-2657.3Koizumi et al. Lancet Oncol 2008;9:215-21. 4. Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.5. Dank M, et al. Ann Oncol. 2008;19:1450-1457. 6. Cunningham D, et al. N Engl J Med. 2008;358:36-46. 7. Kang YK, et al. Ann Oncol. 2009;20:666-673. 8. Bang YJ, et al. Lancet. 2010;376:687-697.,目前晚期胃癌治疗临床问题,术后患者的复发转移监测，腹腔播散转移？综合治疗化放疗结合，手术治疗？药物治疗，特别是个体化治疗？多种药物包括靶点药物胃癌临床病理特征的影响.,有限临床研究证据使可选择的药物很少,胃癌一线化疗氟尿嘧啶类 + 铂类: 5FU/CAPE/S-1 + 顺铂 或 + 奥沙利铂（ FOLFOX/XELOX)氟尿嘧啶类 紫杉类/蒽环类DDP胃癌二线化疗的选择DOC vs IRI 或 PAC vs IRI靶向药物在胃癌治疗中的起步与挑战Her-2阳性胃癌（ToGA研究）; c-MET？,治疗疗效不满意,RR 20-60%PFS 4-7月, OS 9-16月毒性较大, 长期用药难以耐受腹膜转移疗效差评价难肠梗阻、营养状况差等生活质量差的问题难以解决,新的治疗手段明显滞后,靶点：beyond Her-2？化疗联合分子靶向药物？胃癌异质性？,内 容,胃癌治疗临床和研究难点胃癌靶向治疗胃癌转化研究新手段,胃癌治疗临床和研究难点弥漫性胃癌,胃癌个体差异弥漫型胃癌,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,替吉奥：,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,FLAGS: 组织学分型弥漫型的患者OS,Log-rank Test: p = 0.0413Hazard Ratio: 0.83 (95% CI: 0.70, 0.99)Median Overall Survival: CS: 9.0 months CF: 7.1 months,START:不可评估疾病亚组的OS,PFS(144例）,OS,PFS,Yoshida K,et al. 2012 ESMO Abstract LBA19.,腹腔给予PTX： Overall survival,Joji Kitayama, Hironori Ishigami, Hironori Yamaguchi,et al. Gastrointestinal Cancer Research.2012,Joji Kitayama, Hironori Ishigami, Hironori Yamaguchi,et al. Gastrointestinal Cancer Research.2012,腹腔镜在胃癌腹膜转移和疗效判定中起重要作用,In some cases, the peritoneal nodules were significantly reduced in size and appearance by second-look laparoscopy. Gastrectomy was considered and performed in 52 patients.,HER2阳性率很低，且获益率也低,胃食管结合部腺癌HER2阳性率高,肠型胃癌阳性率高，混合型次之，弥漫型最低,弥漫型胃癌MET蛋白表达？,HE Lee, et al. British Journal of Cancer 2012, 107(2), 325333,MET镜下图片 免疫组化IHC (AC)银染SISH (DF).,不同Lauren胃癌分型中MET表达不同不同分期胃癌患者MET表达情况也不同,15,晚期胃癌患者转移特征与CTCs的关系,CTCs阳性在肝转移，腹膜转移及骨转移患者中明显增多,Uenosona Y et al., Cancer, 2013, doi: 10.1002/cncr.28309,2013年CSCO年会厦门,需要解决的问题研究方向,腹膜播撒的原因：原发灶分子分型特征腹膜易感性CTCs早期发现：特异PET？腹腔镜？干预：临床研究！腹腔化疗或靶向药物热灌注,113,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,Events120136,HR0.65,95% CI0.51, 0.83,MedianOS16.011.8,Event,0.1,0.3,0.5,0.7,0.9,218 198,40,53,124,2011,228 218,196 170,170 141,142 112,12296,10075,8453,6539,5128,10,00,No. at risk,3920,2813,胃癌靶向治疗,胃癌靶向治疗多遭遇失败,EXPAND10 西妥昔单抗,REAL39帕尼单抗,TYTAN11拉帕替尼,AVAGAST安维汀2,CLASSIC7XELOX,REGARD8ramucirumab,V325多西他赛4,ML17032/REAL2卡培他滨3,SPIRIT、SC101FLAGS S-15,ToGA6曲妥珠单抗,GRANITE-112依维莫司,IF vs. CF伊立替康1,1. Dank M, et al. Ann Oncol 2008; 19:1450-1457.2. Kang Y, et al. ASCO 2010 Abstract LBA4007.3. Okine AFC, et al. Ann Oncol 2009; 20:1529-1534.4. Van Cutsem E, et al. J Clin Oncol 2006; 24:4991-4997.5. Ajani A, et al. J Clin Oncol 2010; 28:1547-1553.6. Bang YJ, et al. Lancet 2010; 376:687-697.7. Bang YJ, et al. Lancet 2012; 28;379(9813):315-321.8. Fuchs CS, et al. 2013 ASCO GI Abstract LBA5.9. Waddel T, et al. 2012 ESMO Abstract 667PD.10. Lordick F, et al. 2012 ESMO Abstract LBA3.11. Bang YJ, et al. 2013 ASCO GI Abstract 11.12. /ct2/show/NCT00879333.,如何改变现状？,活检组织标本的基因表达差异,Gerlinger M, et al.N Engl J Med. 2012 Mar 8;366(10):883-92.,胃癌是异质性非常高的一类肿瘤,每个瘤种的平均体细胞基因拷贝数变化,Beroukhim R, et al. Nature 2010; 463:899-905.,对来自26个组织，3,131例肿瘤标本的高通量测序分析,胃癌：Beyond HER2,KRAS 突变： 5% to 10%1,2BRAF 突变： 5%1,2EGFR 过表达： 50% to 80%3,4TKIs 无效4西妥昔单抗单药治疗无效5EGFR 突变：极低4,6HER2 过表达： 10% to 25%7HGF/c-Met： 在不同癌症出现过表达或异常表达，包括胃癌8,1.Lee SH, et al. Oncogene. 2003;22:6942-6945. 2. Kim IJ, et al. Hum Genet. 2003;114:118-120. 3. Galizia G, et al. World J Surg. 2007;31:1458-1468. 4. Dragovich T, et al. J Clin Oncol. 2006;24:4922-4927. 5. Chan JA, et al. Ann Oncol. 2011;22:1367-1373. 6. Mammano E, et al. Anticancer Res. 2006;26:3547-3550. 7. Yano T, et al. Oncol Rep. 2006;15:65-71. 8. Birchmeier C, et al. Nat Rev Mol Cell Biol. 2003;4:915-925.,23,FGFR2: 9%,KRAS: 9%,EGFR : 8%,ERBB 2:7%,MET: 4%,Gut:2012;61;673-684,胃癌的分子表达谱,J Clin Oncol. 2011 Dec 20;29(36):4837-8.,细胞增殖细胞存活发生分枝化形态血管生成细胞转移细胞扩散EMT侵袭,MET受体信号通路：细胞增殖、侵袭、转移等,Meta分析：MET基因扩增及过表达预示胃癌预后差,26,OR（95% CI）：2.57（1.97,3.35）,Peters S et al. Nat Rev Clin Oncol 9, 314-326.,在研的MET抑制剂,Volitinib,Rilotumumab能够延长MET高表达G/EGJ肿瘤患者PFS和OS,Davidenko, I et al. ESMO 2012 (Abstract 687P and poster),28,RILOMET-1：Rilotumumab正在进行中用于MET高表达胃癌的全球III期研究,Protocol ID: 20070622; ClinicalT identifier: NCT01697072; EudraCT number: 2011-004923-11.,BID, 每天两次; DCR, 疾病控制率; IV, 静注; ORR, 总有效率; OS, 总生存期; PFS, 无进展生存期; PO, 口服; Q3W, 每3周1次; R, 随机分布; TRR, 达到临床有效时间; TTP, 疾病进展时间,a maximum 12 cycles (6 months) of mFOLFOX6 with MetMAb or placebo to PD.Co-primary objectives: OS in Met 2+/3+ AND OS in Met 1+/2+/3+ ; Secondary Objectives: PFS, ORR, safety, QoL/PROs.,2013 ASCO Annual Meeting,MetGastric：onartuzumab (MetMAb)正在进行中用于HER2阴性MET高表达胃癌的全球III期研究,基于HGF/cMET靶点的酪氨酸激酶抑制剂所处临床阶段总览,Blumenschein GR Jr,et al. J Clin Oncol. 2012 Sep 10;30(26):3287-96.,31,以HGF/c-MET为靶点药物所面临的挑战,患者选择？ 蛋白表达？ 基因扩增？突变？ 治疗前后一致否？下游通路的活化？抗体和小分子抑制剂的优势和劣势？,32,活检组织标本的基因表达差异对靶向药物治疗选择的影响,Gerlinger M, et al.N Engl J Med. 2012 Mar 8;366(10):883-92.,1次活检仅能检测约34-55%的肿瘤基因表达谱 而且转移灶与原发灶的基因表达谱差异明显 重复获得困难 检测结果实时代表性差,血液中肿瘤相关核酸,Schwarzenbach H, et al.Nat R