American Association for Cancer Research
21598290cd170787-sup-186054_2_supp_4362146_lynf2l.pdf (243.87 kB)

Figure S1 from Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer

Download (243.87 kB)
journal contribution
posted on 2023-04-03, 22:01 authored by Yelena Y. Janjigian, Francisco Sanchez-Vega, Philip Jonsson, Walid K. Chatila, Jaclyn F. Hechtman, Geoffrey Y. Ku, Jamie C. Riches, Yaelle Tuvy, Ritika Kundra, Nancy Bouvier, Efsevia Vakiani, Jianjiong Gao, Zachary J. Heins, Benjamin E. Gross, David P. Kelsen, Liying Zhang, Vivian E. Strong, Mark Schattner, Hans Gerdes, Daniel G. Coit, Manjit Bains, Zsofia K. Stadler, Valerie W. Rusch, David R. Jones, Daniela Molena, Jinru Shia, Mark E. Robson, Marinela Capanu, Sumit Middha, Ahmet Zehir, David M. Hyman, Maurizio Scaltriti, Marc Ladanyi, Neal Rosen, David H. Ilson, Michael F. Berger, Laura Tang, Barry S. Taylor, David B. Solit, Nikolaus Schultz

Comparison of mutation frequencies in non-MSI-H tumors in the MSK cohort vs. TCGA and comparison of mutation frequencies in primary vs. metastatic samples in the MSK cohort.



Department of Defense Congressionally Directed Medical Research Program

National Cancer Institute

Metastasis Research of the Sloan Kettering Institute



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