EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer
Abstract
The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of EGFR and ERBB2. Heterogeneous 89Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplification or with acquisition of MET amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2-amplified EG cancer.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2019
- Source ID
- 10.1158/2159-8290.cd-18-0598
Entities
People
- Barry S. Taylor
- Besnik Qeriqi
- Christine A Iacobuzio-Donahue
- Christopher J. Fong
- David B Solit
- David H. Ilson
- David P Kelsen
- Efsevia Vakiani
- Elisa De Stanchina
- Fabiola Cecchi
- Francisco Sanchez-vega
- Geoffrey Ku
- Gouri J. Nanjangud
- Heiko Schöder
- Helen Won
- Jaclyn F. Hechtman
- Jason S. Lewis
- Joanne Soong
- Jorge A. Carrasquillo
- Karen T. Brown
- Marinela Capanu
- Mario E. Lacouture
- Marissa Mattar
- Mark Schattner
- Maurizio Scaltriti
- Michael F. Berger
- Nancy Bouvier
- Neeta Pandit-taskar
- Nikolaus Schultz
- Pau Castel
- Rebecca J. Nagy
- Richard B. Lanman
- Robert A. Lefkowitz
- Steven M. Larson
- Todd Hembrough
- Wolfgang A. Weber
- Yaelle Tuvy
- Yelena Y. Janjigian
- Yuan Tian
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Department of Defense
- Weill Cornell Medicine