1、基因分型在肝胆肿瘤的探索与实践 肿瘤精准治疗：肿瘤的分子水平理解和分类 针对driver mutation进行治疗在肝胆肿瘤中的应用肝胆肿瘤精准治疗的探索篇 肿瘤精准治疗：肿瘤的分子水平理解和分类 针对driver mutation进行治疗在肝胆肿瘤中的应用检测方法推动肿瘤治疗的发展组织学检测集中在对于形态学的研究病理检测人群中发生频率较高的驱动变异被作为作为研究重点基因变异热点检测高通量二代测序NGS多基因、全部位点、多种变异形式同时检测放疗结合化疗不同组织类型肿瘤选择差异性化疗药物，毒副作用高，疗效趋于极限靶向个性治疗适应症内biomarker筛选阳性人群大部分获益，生存大大提高精准医学深
2、入阐明癌症基因组的异质性特征，精确找到每个患者疾病的原因和治疗的靶点精准医学建立在肿瘤异质性的理论基础上 肝癌中的基因变异涉及多条不同信号通路的基因 约30个基因在243例肝癌样本的WES检测中突变频率超过4%Nat Genet. 2015 May;47(5):505-11.肝内，肝外胆管癌和胆囊癌分子水平的异同大样本量NGS检测揭示胆道肿瘤变异图谱Cancer. 2016 Sep 13. doi: 10.1002/cncr.30254.Intrahepatic cholangiocarcinoma (n=412)extrahepatic cholangiocarcinoma(n=57)gal
3、lbladder carcinoma(n=85)肝内胆管癌不同分子亚型的临床意义TP53 mutationOS: 226vs140 wksKRAS mutationOS: 214vs166 wksFGFR2 mutationOS: NA vs 187 wksCancer. 2016 Sep 13. doi: 10.1002/cncr.30254.驱动基因变异的个体化差异明显Gastroenterology. 2016 Apr;150(4):998-1008. 同一病人多病灶之间基因变异共享率从0-97%不等驱动基因变异的个体化差异明显Gastroenterology. 2016 Apr;150
4、(4):998-1008.“Variability is the law of lifeno two individuals react alike and behave alike under the abnormal conditions which we know as disease”- Sir William Osler, address to the New Haven Medical Association in 1903 肿瘤精准治疗：肿瘤的分子水平理解和分类 针对driver mutation进行治疗在肝胆肿瘤中的应用肝胆肿瘤精准治疗的探索篇Meta分析提示不同瘤种的个体化治
5、疗疗效均优于常规抗肿瘤治疗 570个筛选biomarker的单药物靶向治疗的phase II临床研究（32,149病人） 2010.1.1至2012.12.31期间发表的结果 研究终点：有效率(RR)，无疾病进展期(PFS)和总生存(OS)J Clin Oncol. 2015 Nov 10;33(32):3817-25. 肝内，肝外胆管癌和胆囊癌分子水平的异同胆道肿瘤中的抗HER2靶向治疗J Hematol Oncol. 2015 May 29;8:58.FGFR通路变异患者从FGFR靶向治疗获益Cancer. 2016 Sep 13. doi: 10.1002/cncr.30254.Ecan
6、cermedicalscience. 2014 Nov 6;8:479.PET scan before (upper panel A) and two months after dabrafenib and trametinib combination (lower panel B), showing improvement in liver metastasis (blue arrow), resolution of malignant left pleural effusion and lung nodules (red arrow) and improvement of bone met
7、astasis (blue circle).免疫微环境对肿瘤的调控与杀伤Liver Cancer. 2015 Dec; 4(4): 201207.肿瘤突变负荷（TMB）可能作为抗PD-1治疗的biomarkerJ Clin Oncol 34, 2016 (suppl; abstr 9017)MMR缺陷提示可能从抗PD-1治疗获益N Engl J Med. 2015 Jun 25;372(26):2509-20.精准治疗在技术上以二代测序（NGS）为主凸显优势NGS检测突变插入/缺失TMB基因重排扩增/缺失ARMsddPCR一代测序FISH转录水平变化蛋白表达异常IHCproteinRNADNA
8、基因融合 NGS identifies actionable genomic alterations in “driver-negative” lung adenocarcinomas：no mutations in EGFR, ERBB2, KRAS, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1 and fusions involving ALK, ROS1, and RET) A genomic alteration with a corresponding targeted therapeutic based on the NCCN guidelines f
9、or NSCLC was identified in 26% of patients (8/31)EGFR G719A, BRAF V600E, SOCS5-ALK, CLIP4-ALK, CD74-ROS1, KIF5B-RET (n=2) and CCDC6-RET Of these 8 patients, 75% (n=6) went on to receive their targeted therapy, and all six of these patients derived clinical benefit from targeted therapy.Alexander Dri
10、lon, et al, CCR, 2015; Balko JM, et al, Cancer Dis, 2015; Siraj M, et al, ASCO, 2014二代测序 vs 传统检测方法NGS identified 7/81 (8.6%) TNBC patients with ERBB2 gene amplification which was confirmed by FISH in both the pre- and post-treatment tissue. 32% of ALK rearranged cases as identified by NGS previously
11、 tested negative by FISH (9/28). 70% of the FISH negative patients from this study treated with crizotinib responded demonstrating the ALK rearrangements detected by NGS are acting as a oncogenic driver 全美前十癌症医院的NGS检测平台排名中心名称床位NGS基因检测基因数量开始时间1University of Texas MD Anderson Cancer Center654-200 gene
12、s20132Memorial Sloan Kettering Cancer Center478MSK-IMPACT341 genes20143Mayo Clinic1243CANCP50 genes20144Dana-Farber/Brigham and Womens Cancer Center757OncoPanel300 genes20135Seattle Cancer Care Alliance/University of Washington Medical Center428UW-OncoPlex263 genes20136Johns Hopkins Hospital998NGS 5
13、0 gene panel50 genes20157UCLA Medical Center466clinical exome sequencing20,000 genes20158Massachusetts General Hospital999SNaPshot39 genes20139UCSF Medical Center650UCSF500429 genes201510Stanford Health Care-Stanford Hospital481-NGS检测关键步骤生信后分析确认测序质量及生信分析变异calling真伪，鉴定明确的体细胞基因变异（包括SNV/Indel，CNV，重排/融合
14、和大片段Indel）QC分析变异造成的功能影响：临床数据(药物响应)，临床前实验数据，计算生物学预测的driver或者passenger变异Knowledge Database全面的信息来源及时更新，与时俱进统一的数据格式数据结论明确数据库根据证据等级选择相关靶向药物(直接相关或者间接相关)Take home messagesNGS技术的发展帮助我们更好的了解肝胆肿瘤的生物学特性，并细分病人群体在肝胆肿瘤中已有初步研究及实践提示针对driver变异使用靶向治疗是潜在的临床治疗机会免疫治疗作为新兴的肿瘤治疗手段，急需找到明确的biomarker来筛选人群，少量临床证据提示TMB或者MSI可能作为潜在biomarkerNGS在检测肿瘤基因变异中具有同时检测多种变异形式和高通量的技术优势NGS临床检测技术的关键步骤在于生信后的进一步数据分析Thank YouThank You领航分子诊断技术提升医学检测服务Thank YouThank You
