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 patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus-positive 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 comutations in the receptor tyrosine kinase, RAS, and 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.Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49-58. ©2017 AACR.See related commentary by Sundar and Tan, p. 14See related article by Pectasides et al., p. 37This article is highlighted in the In This Issue feature, p. 1.

中文翻译：

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食管胃癌对全身治疗反应的遗传预测因素。

食管胃癌的发病率正在迅速上升，但是只有少数患者从目前的治疗中获得持久的收益。化学疗法以及抗HER2和PD-1抗体是标准治疗方法。为了确定药物敏感性和耐药机制的预测性生物标志物，我们实施了转移性食管胃癌患者的前瞻性肿瘤测序。同源重组缺陷缺陷与对铂类化学疗法的反应之间没有关联。微卫星不稳定性高肿瘤患者对化学疗法具有内在抵抗力，但更可能获得对免疫疗法的持久反应。单个爱泼斯坦-巴尔病毒阳性的患者对免疫疗法获得了持久，完全的反应。通过测序确定的ERBB2扩增水平预示了曲妥珠单抗的益处。缺乏ERBB2扩增，ERBB2外显子16缺失和受体酪氨酸激酶，RAS和PI3K通路突变的肿瘤亚克隆的选择与内在和/或获得性曲妥珠单抗相关。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。意义：多重测序的临床应用可以确定转移性食管胃癌对当代全身疗法的治疗反应生物标志物。这项广泛的前瞻性分析揭示了转移性食管胃癌的生物学复杂性和治疗耐药性的动态性质。巨蟹座Discov; 8（1）；49-58。©2017 AACR，请参阅Sundar和Tan的相关评论，第1页。14参见Pectasides等人的相关文章，第1页。37本文在本期功能中突出显示。1。