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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

Abstract:

Background:

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.

Methods:

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.

Results:

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%).

Conclusions:

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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