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Loss of human epidermal growth factor receptor 2 (HER2) expression in HER2-overexpressing esophagogastric (EG) tumors treated with trastuzumab

Janjigian YY, Riches JC, Ku GY, Imtiaz T, Capanu M, Chou JF, et al.

Journal of Clinical Oncology 2015;33(3 suppl):63



Trastuzumab-based therapy is the standard therapeutic approach for patients with metastatic HER2+ esophagogastric (EG) tumors. While trastuzumab prolongs survival in this population, responses are rarely complete and resistance invariably develops. Loss of HER2 and presence of co-occurring molecular alterations may impact the efficacy of HER2 targeted agents in second line setting.


We reviewed clinical and pathologic data of patients (pts) with metastatic HER2+ (IHC 3+ or FISH >2.0) EG adenocarcinoma undergoing trastuzumab/chemotherapy treatment at MSKCC. Samples with ample tissue were analyzed using an on-site 341 cancer-associated gene bait capture, next generation sequencing (NGS) assay. When available, biopsy at the time of disease progression on trastuzumab was tested for HER2 by IHC and FISH.


Eighty four pts with Stage IV HER2+ EG adenocarcinoma (57 IHC 3+, 27 IHC2+/FISH+) treated with trastuzumab with chemotherapy. Median progression free survival on 1stline trastuzumab therapy 9.4 months (mos) [95%CI: 6.9-13.3 mos]. Median overall survival 20.3 mos [95%CI: 14.7-22.4 mos]. Post-trastuzumab biopsy available in 23 of 84 (27%) pts, of those 35% (8 of 23) lost HER2 positivity (4-IHC 0, 4 FISH negative). NGS performed on 24 of 84 (28%) samples. Alterations were observed in EGFR (13%), TP53 mut (92%), cell cycle mediators such as cyclin dependent kinases (42%) and the phosphoinositide 3-kinase/AKT/mTOR axis (21%).


Loss of HER2 expression occurs in patients with HER2+ EG cancer treated with trastuzumab and presents a possible mechanism for trastuzumab resistance. Our data suggest the need for repeat biopsies to accurately determine appropriate use of second-line HER2 directed therapy.

Copyright 2015 American Society of Clinical Oncology

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