Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer.
Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer.
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DOI：
10.1158/2159-8290.cd-17-0787
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发表时间：
2018-01
期刊：
影响因子：
28.2
通讯作者：
Schultz N
中科院分区：
文献类型：
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作者：
Janjigian YY;Sanchez-Vega F;Jonsson P;Chatila WK;Hechtman JF;Ku GY;Riches JC;Tuvy Y;Kundra R;Bouvier N;Vakiani E;Gao J;Heins ZJ;Gross BE;Kelsen DP;Zhang L;Strong VE;Schattner M;Gerdes H;Coit DG;Bains M;Stadler ZK;Rusch VW;Jones DR;Molena D;Shia J;Robson ME;Capanu M;Middha S;Zehir A;Hyman DM;Scaltriti M;Ladanyi M;Rosen N;Ilson DH;Berger MF;Tang L;Taylor BS;Solit DB;Schultz N
食管胃癌的发病率正在迅速上升，但只有少数患者从目前的治疗中获得持久的益处。化疗以及抗her2和PD-1抗体是标准的治疗方法。为了确定药物敏感性和耐药机制的预测性生物标志物，我们对转移性食管胃癌患者进行了前瞻性肿瘤测序。HRD缺陷和对铂基化疗的反应之间没有关联。MSI-H肿瘤患者本质上对化疗有耐药性，但更有可能对免疫治疗产生持久的反应。单个EBV阳性患者对免疫治疗产生了持久的完全反应。通过测序确定的ERBB2扩增水平可预测曲妥珠单抗的获益。缺乏ERBB2扩增的肿瘤亚克隆的选择、ERBB2外显子16的缺失以及受体酪氨酸激酶、RAS、PI3K途径的共突变与固有和/或获得性曲妥珠单抗耐药相关。前瞻性基因组分析可以确定最有可能从免疫治疗和曲妥珠单抗中获得持久益处的患者，并指导克服耐药性的策略。
The incidence of esophagogastric cancer is rapidly rising but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of metastatic esophagogastric cancer patients. There was no association between HRD defects and response to platinum-based chemotherapy. Patients with MSI-H tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single EBV+ patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and co-mutations in the receptor tyrosine kinase, RAS, PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab, and guide strategies to overcome drug resistance.