ASCO2015结直肠癌治疗进展 -个体化医学探索篇,应杰儿 浙江省肿瘤医院腹部肿瘤内科,讲课内容,LBA100：PD-1信号通路阻断用于错配修复缺陷肿瘤 3508:mCRC中HER2通路的双抑制3505：结直肠癌综合分子分析显示免疫细胞浸润的基因组预测因子 3506：分析DNA MMR在接受 FOLFOX /-cetuximab （PETACC8 and NCCTG N0147） III期结肠癌中临床结局的作用 3507：分析BRAF V600E 和 KRAS exon 2 mutations in MSS在接受 FOLFOX+/- cetuximab3期结肠癌辅助化疗 （PETACC8 and NCCTG N0147）中的预后价值,PD-1 Blockade in Tumors with Mismatch Repair Deficiency,Presented By Dung Le at 2015 ASCO Annual Meeting,LBA100：PD-1信号通路,Mutations per tumor,Presented By Dung Le at 2015 ASCO Annual Meeting,肿瘤的突变数目,PD-1 Pathway and Pembrolizumab,Presented By Dung Le at 2015 ASCO Annual Meeting,LBA100：PD-1信号通路,Slide 8,Presented By Dung Le at 2015 ASCO Annual Meeting,LBA100：研究设计,Baseline Demographics ,Presented By Dung Le at 2015 ASCO Annual Meeting,LBA100：基线特征,Presented By Dung Le at 2015 ASCO Annual Meeting,LBA100：研究结果ORR,生化学反应,靶病灶变化,Presented By Dung Le at 2015 ASCO Annual Meeting,LBA100：研究结果 PFS及OS,PFS,OS,HR:0.103P0.001,HR:0.216 P=0.02,Slide 20,LBA100：Biomarker探索,P=0.04,P=0.04,P=0.07,dMMR,dMMR,dMMR,pMMR,pMMR,pMMR,浸润性CD8+ T细胞,浸润性PD-L1表达细胞,PD-L1表达的肿瘤细胞,单个肿瘤细胞的 体细胞突变数,LBA100：dMMR与肿瘤免疫？,dMMR肿瘤具备如下特征 IV期肠癌发生率低，约5%（既往抗PD-1治疗mCRC的有效率不足5%） 具MSI-H表型 肿瘤内体细胞过度突变 肿瘤周围免疫细胞浸润 肿瘤细胞及基质表达PD-L1,dMMR与肿瘤免疫之间 可能存在内在联系,dMMR,pMMR,PD-L1,CD8,小结,dMMR肿瘤对抗PD-1免疫监测点阻断治疗高度有效 临床获益可见于错配修复缺陷的肿瘤中包括结肠、子宫、胃、前列腺、十二指肠、胆管 生化反应与影像学反应、DFS,OS相关 错配修复缺陷肿瘤突变率高且CD8+T细胞和PD-1表达高,结 论,这是第一个研究用肿瘤基因组学指导免疫治疗 错配修复缺陷在结肠、子宫、胃、前列腺、十二指肠、胆管中的概率大概4-5% 错配修复缺陷临床检测容易,Presented By Dung Le at 2015 ASCO Annual Meeting,LBA100：后续研究设计,入组MSI-H mCRC 首要终点：ORR,Therapeutic Dual Inhibition of HER2 Pathwayin Metastatic Colorectal Cancer The HERACLES Trial *,Presented By Salvatore Siena at 2015 ASCO Annual Meeting,转移性结直肠癌HER2联合抑制治疗,HER2+ mCRC xenopatients are sensitive to dual HER2 blockade with lapatinib and trastuzumabbut not to either drug alone,Presented By Salvatore Siena at 2015 ASCO Annual Meeting,HERACLES CONSORT diagram,Presented By Salvatore Siena at 2015 ASCO Annual Meeting,入住标准：结直肠癌组织学诊断明确 不能R0切除的转移性病变 KRAS 外显子2 WT HER-2+根据HERACLES诊断标准 氟尿嘧啶类药物，伊立替康，奥沙利铂，西妥昔单抗后帕托木单抗治疗失败； ECOG评分 0-1 无症状性脑转移 正常血、肝、肾及心血管功能,HERACLES treatment and assessments,Presented By Salvatore Siena at 2015 ASCO Annual Meeting,主要终点：RR；次要终点：TTP，安全性,Patients characteristics,Presented By Salvatore Siena at 2015 ASCO Annual Meeting,Safety and tolerability,Presented By Salvatore Siena at 2015 ASCO Annual Meeting,Response,Presented By Salvatore Siena at 2015 ASCO Annual Meeting,TTP,不同HER评分TTP,Presented By Salvatore Siena at 2015 ASCO Annual Meeting,对Her-2+mCRC患者的抗Her-2+联合抑制（曲妥珠单抗+拉帕替尼）是有效的（ORR34%,DCR78%,TTP5.5M） 该治疗耐受性良好 HER2+mCRC患者对西妥昔单抗和帕托木单抗原发耐药，支持在没有接受抗EGFR患者中HERACLES治疗 HERACLES，精准医学临床研究，显示HER2双靶点抑制是HER2+mCRC的新的有价值的选择,结 论,讲课内容,LBA100：PD-1信号通路阻断用于错配修复缺陷肿瘤 3508:mCRC中HER2通路的双抑制3505：结直肠癌综合分子分析显示免疫细胞浸润的基因组预测因子 3506：分析DNA MMR在接受 FOLFOX /-cetuximab （PETACC8 and NCCTG N0147） III期结肠癌中临床结局的作用 3507：分析BRAF V600E 和 KRAS exon 2 mutations in MSS在接受 FOLFOX+/- cetuximab3期结肠癌辅助化疗 （PETACC8 and NCCTG N0147）中的预后价值,3505：结直肠癌的综合分子学特征描述揭示:免疫细胞渗透的基因预测因子,免疫构造组成在结直肠癌中具有预后重要性 可预测特定免疫浸润成分的结直肠癌的分子学特征还未完全弄清 大规模的测序通常使得临床和病理标本缺乏 在其他恶性肿瘤中已经发现新抗原可以预测对免疫治疗的反应 体细胞突变可潜在生成新的抗原,目的 结合新增抗原确定结直肠癌的分子亚型 探索新抗原数量(新抗原负荷)与结直肠癌中整体免疫浸润程度之间的相关性 在结直肠癌中检验新抗原负荷与特定淋巴细胞反应成分和T细胞子集之间的相关性 评估新抗原负荷作为结直肠癌特异性死亡的独立预后因子的地位,方法 619个肿瘤标本进行全基因组测序，与正常标本对比，识别肿瘤突变 整合体细胞突变和I类HLA型肿瘤以预测高亲和性新抗原 将全基因组测序和新抗原结果与病理和生存信息进行整合,Giannakis M, et al. 2015 ASCO Abstract 3505.,基线特征,Giannakis M, et al. 2015 ASCO Abstract 3505.,高突变肿瘤有更多新抗原,Giannakis M, et al. 2015 ASCO Abstract 3505.,结直肠癌中免疫浸润的特征描述,Giannakis M, et al. 2015 ASCO Abstract 3505.,新抗原负荷与整体淋巴细胞浸润和特异 淋巴细胞反应成分相关,Giannakis M, et al. 2015 ASCO Abstract 3505.,30,HLA突变在TIL的肿瘤中富集,Giannakis M, et al. 2015 ASCO Abstract 3505.,新抗原负荷与记忆T细胞浸润相关,Giannakis M, et al. 2015 ASCO Abstract 3505.,新抗原负荷对结直肠癌特异生存有预后意义,单独突变负荷不是结直肠癌特异生存的独立预后因子,Giannakis M, et al. 2015 ASCO Abstract 3505.,* 经过肿瘤分期分层、经过年龄、性别、肿瘤部位和肿瘤级别调整,结论,高度微卫星不稳定性(MSI-H)和PoIE突变肿瘤有更多新抗原 新抗原负荷与整体淋巴细胞评分、TILs、克罗恩样免疫浸润以及记忆T细胞相关 HLA突变富集于TILs的肿瘤 新抗原负荷是结直肠癌特异生存的独立预后因子 整合癌症样本的全基因组测序和临床病理信息可行,Giannakis M, et al. 2015 ASCO Abstract 3505.,PETACC8 and NO147study design,Presented By Julien Taieb at 2015 ASCO Annual Meeting,Analysis of DNA mismatch repair and clinical outcome in stage III colon cancers from patients treated with adjuvant FOLFOX +/- cetuximab in the PETACC8 and NCCTG N0147 adjuvant trials.,Presented By Aziz Zaanan at 2015 ASCO Annual Meeting,在PETACC8和NCCTG N0147中接受辅助FOLFOX+/-西妥昔单抗治疗III期结肠癌中DNA错配修复和临床结局的分析,Clinical and Pathological Characteristics,Presented By Aziz Zaanan at 2015 ASCO Annual Meeting,Clinical and Pathological Characteristics,Presented By Aziz Zaanan at 2015 ASCO Annual Meeting,Disease-free survival according to MMR status MV model,Presented By Aziz Zaanan at 2015 ASCO Annual Meeting,Overall survival according to MMR status MV model,Presented By Aziz Zaanan at 2015 ASCO Annual Meeting,DFS according to MMR status Subgroup analyses,Presented By Aziz Zaanan at 2015 ASCO Annual Meeting,OS according to MMR status Subgroup analyses,Presented By Aziz Zaanan at 2015 ASCO Annual Meeting,