Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro-esophageal junctional carcinoma.

Åsa Dahle-Smith,Caroline Clark,David Ferry,Susan J Dutton,Russell D Petty,Doreen Massie,Corran Roberts,David Stevenson,Graeme I Murray,Aileen Osborne,Zosia Miedzybrodzka

doi:10.1186/s13039-015-0181-0

Abstract

BackgroundClinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies. Other investigations suggest increases in EGFR copy number are associated with poor prognosis in EC, but have used a variety of different techniques and tested numbers remain small. A validated assay for EGFR copy number in EC is needed, to allow investigation of EGFR copy number gain as a predictive biomarker for the anti-EGFR responsive subgroup of patients. We developed a scoring system in EC based upon established systems for EGFR fluorescence in-situ hybridisation (FISH) in lung cancer, and applied this in a series of 160 UK patients with advanced EC.ResultsDual colour FISH on formalin fixed paraffin embedded (FFPE) biopsies were scored independently by two operators as: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3), low polysomy (score = 4), high polysomy (score = 5) and amplification (score = 6). EGFR FISH positive cases (scores 5 and 6) were found in 32/160 (20 %) tumours, with high polysomy in 22 (13.8 %) and amplification in 10 (6.3 %). Two independent operator scores for FISH positivity were 100 % concordant. EGFR FISH positive status was not associated with clinic-pathological features. EGFR amplification was associated with worse survival (HR = 2.64, 95 % CI 1.04 to 6.71, p = 0.03).ConclusionOur FISH scoring system for EGFR in advanced EC identifies a significant subgroup (20.0 %) of FISH positive patients. EGFR amplification, which is found in 6.3 %, is associated with poor survival. It is not known if there is a role for EGFR targeted treatment in this subgroup of patients, however we are now utilising this EGFR FISH assay and scoring system in biopsies from clinical trials utilising anti-EGFR targeted therapies.

Highlights

Clinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies
The primary end point of overall survival was met with median OS of 13.8 months in the trastuzumab arm compared to 11.1 months in the chemotherapy alone arm, p = 0.046
Patients whose tumours had either very high Human epidermal growth factor receptor 2 (HER-2) over expression (IHC3+) or HER-2 amplification confirmed by fluorescence in-situ hybridisation (FISH), achieved a median survival of 17.9 months when treated with trastuzumab plus chemotherapy, compared to median survival of 12.3 months when treated with chemotherapy alone, HR 0.57 [11]

Summary

Introduction

Clinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies. We developed a scoring system in EC based upon established systems for EGFR fluorescence in-situ hybridisation (FISH) in lung cancer, and applied this in a series of 160 UK patients with advanced EC. Dahle-Smith et al Molecular Cytogenetics (2015) 8:78 with advanced gastro-esophageal junction or gastric adenocarcinomas overexpressing HER-2 by immunohistochemistry or HER-2 gene amplification by FISH [11]. Patients whose tumours had either very high HER-2 over expression (IHC3+) or HER-2 amplification confirmed by FISH, achieved a median survival of 17.9 months when treated with trastuzumab plus chemotherapy, compared to median survival of 12.3 months when treated with chemotherapy alone, HR 0.57 (95 % CI 0.41-0.81) [11]

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