Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2018
- Source ID
- 10.1158/2159-8290.cd-17-0787
Entities
People
- Ahmet Zehir
- Barry S. Taylor
- Benjamin E. Gross
- Daniel G. Coit
- Daniela Molena
- David B Solit
- David H. Ilson
- David M Hyman
- David P Kelsen
- David R Jones
- Efsevia Vakiani
- Francisco Sanchez-vega
- Geoffrey Ku
- Hans Gerdes
- Jaclyn F. Hechtman
- Jamie C. Riches
- Jianjiong Gao
- Jinru Shia
- Laura Tang
- Liying Zhang
- Manjit Bains
- Marc Ladanyi
- Marinela Capanu
- Mark E. Robson
- Mark Schattner
- Maurizio Scaltriti
- Michael F. Berger
- Nancy Bouvier
- Neal Rosen
- Nikolaus Schultz
- Philip Jonsson
- Ritika Kundra
- Sumit Middha
- Valerie W. Rusch
- Vivian E. Strong
- Walid K. Chatila
- Yaelle Tuvy
- Yelena Y. Janjigian
- Zachary Heins
- Zsofia K. Stadler
Organizations
- Memorial Sloan Kettering Cancer Center
- National Cancer Institute
- Robertson Foundation
- United States Department of Defense
- Weill Cornell Medicine