RT Journal Article SR Electronic T1 Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer JF Cancer Discovery JO Cancer Discov FD American Association for Cancer Research SP 49 OP 58 DO 10.1158/2159-8290.CD-17-0787 VO 8 IS 1 A1 Janjigian, Yelena Y. A1 Sanchez-Vega, Francisco A1 Jonsson, Philip A1 Chatila, Walid K. A1 Hechtman, Jaclyn F. A1 Ku, Geoffrey Y. A1 Riches, Jamie C. A1 Tuvy, Yaelle A1 Kundra, Ritika A1 Bouvier, Nancy A1 Vakiani, Efsevia A1 Gao, Jianjiong A1 Heins, Zachary J. A1 Gross, Benjamin E. A1 Kelsen, David P. A1 Zhang, Liying A1 Strong, Vivian E. A1 Schattner, Mark A1 Gerdes, Hans A1 Coit, Daniel G. A1 Bains, Manjit A1 Stadler, Zsofia K. A1 Rusch, Valerie W. A1 Jones, David R. A1 Molena, Daniela A1 Shia, Jinru A1 Robson, Mark E. A1 Capanu, Marinela A1 Middha, Sumit A1 Zehir, Ahmet A1 Hyman, David M. A1 Scaltriti, Maurizio A1 Ladanyi, Marc A1 Rosen, Neal A1 Ilson, David H. A1 Berger, Michael F. A1 Tang, Laura A1 Taylor, Barry S. A1 Solit, David B. A1 Schultz, Nikolaus YR 2018 UL http://cancerdiscovery.aacrjournals.org/content/8/1/49.abstract AB 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. 14.See related article by Pectasides et al., p. 37.This article is highlighted in the In This Issue feature, p. 1