Cancer Discovery
Cancer Discovery
5 years ago

Genetic predictors of response to systemic therapy in esophagogastric cancer.

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

Publisher URL: http://doi.org/10.1158/2159-8290.CD-17-0787

DOI: 10.1158/2159-8290.CD-17-0787

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