精准治疗时代下的临床研究与临床机会与挑战---2016-浙江会议-0510--培训课件.ppt

mTOR抑制剂靶向信号通路 60岁女性，尿路上皮癌晚期 一线化疗：顺铂+吉西他滨，2个月进展 二线化疗：多西他赛单药治疗+盆腔放疗，2个月进展 二代测序：NF2基因突变 mTOR抑制剂在尿路上皮癌中的精准治疗 A:依维莫司治疗前 B：依维莫司治疗10个月后 1.Eur Urol .2015 Jan 2.MCB.2009 Aug 29(15) :4250-61. mTOR信号通路TSC1基因变异肿瘤对依维莫司敏感 Science. 2012; Oct 1. Dacic S. Adv Anat Pathol 2008; 15(4):241-247. 2. Sequist LV, et al. Clin Cancer Res 2006; 12(14S):4403s-4406s. 3. Bai H, et al. J Clin Oncol 2009; 27(16):2653-2659. 问题2：选择何种组织？ 新鲜或者冻存组织 外科手术标本：最好标本，可得高质量肿瘤DNA 支气管镜、穿刺活检测标本：量少，但肿瘤DNA质量仍好 固定包埋组织 外科手术标本：可得足量肿瘤DNA，但DNA片段化 支气管镜、穿刺活检测标本：可得肿瘤DNA量少且片段化 细胞学标本 胸水、肺泡冲洗液和痰液标本：肿瘤细胞含量不确定，通常很少 血液标本 血液标本：含肿瘤DNA，但受治疗影响含量不稳定，DNA片段化 问题3：二代测序样本质控的重要性 NCI-MATCH：基于高频分布的actionable mutation The study was paused in November so that the trial leaders could assess how it was progressing. Dr. Keith Flaherty, the oncologist who is leading the trial, didn’t expect the interim analysis to reveal such stark and frequent?quality concerns in the biopsy samples. The issues include low volume of sample (the trial protocol calls for four biopsy cores, but routinely only two cores are being received by the central laboratory) as well as the quality of the biopsy specimens (cores containing very few cancer cells). Overall, 10 to 20 percent of the samples did not yield enough cancer tissue for DNA testing, Flaherty said. More often than not, he found, these subpar biopsies came from smaller, more rural treatment centers, though many did come from major academic research hospitals. The slipshod?biopsies had real implications for the patients. Biopsy质量决定NCI-MATCH进展 * 肿瘤组织是EGFR突变检测的最适标本。肿瘤组织标本包括冰冻组织和固定包埋组织。冰冻组织中，外科手术标本是最好标本，可得高质量肿瘤DNA；支气管镜、穿刺活检检测标本的量少，但肿瘤DNA质量仍好。固定包埋组织方面，外科手术标本可得足量肿瘤DNA，但DNA片段化；支气管镜、穿刺活检测标本可得肿瘤DNA量少且片段化。细胞学标本中，胸水、肺泡冲洗液和痰液标本的肿瘤细胞含量不确定，通常很少。血液标本中，血清、血浆标本含肿瘤DNA，但含量不稳定，DNA片段化；循环血肿瘤细胞可得较高质量肿瘤DNA，但量很少。 3D Medicines Diagnostics and Drug Development 精准治疗时代下的临床研究与治疗 ------机会与挑战 思路迪精准医药 熊磊 什么是精准医疗？ ISEL Trial 0709 Lancet 2005; 366: 1527–37 Median survival 5·6m for gefitinib and 5·1m for placebo 6·3 months vs 5·4 mo