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. 2019 Jan 8;19(1):38.
doi: 10.1186/s12885-018-5242-4.

HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma

Patrick Sven Plum  1   2 , Florian Gebauer  1   2 , Max Krämer  3 , Hakan Alakus  1   2 , Felix Berlth  1 , Seung-Hun Chon  1 , Lars Schiffmann  1 , Thomas Zander  4   2 , Reinhard Büttner  3 , Arnulf Heinrich Hölscher  5 , Christiane Josephine Bruns  1 , Alexander Quaas  1   2 , Heike Loeser  6   7
Affiliations

HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma

Patrick Sven Plum et al. BMC Cancer. .

Abstract

Background: HER2 (ERBB2 or HER2/neu) is a tyrosine-kinase increasing cell proliferation. Overexpression/amplification of HER2 is correlated with worse prognosis in solid malignancies. Consequently, HER2 targeting is established in breast and upper gastrointestinal tract cancer. There are conflicting data concerning the impact of HER2 overexpression on esophageal adenocarcinoma (EAC), as most studies do not differ between cancers of the esophagus/gastroesophageal junction and the stomach. The aim of this study was to analyze the expression/amplification of HER2 in EAC in correlation to clinicopathological data to verify its prognostic impact.

Methods: We analyzed 428 EAC patients that underwent transthoracic thoraco-abdominal esophagectomy between 1997 and 2014. We performed HER2 immunohistochemistry (IHC) according to the guidelines and fluorescence-in-situ-hybridization (FISH) for IHC score2+, using tissue micro arrays (TMA) with up to eight biopsies from the surface and infiltration area of a single tumor for evaluating HER2-heterogeneity and single-spot TMA. The HER2-status was correlated with clinicopathological data.

Results: HER2-positivity was found in up to 14.9% in our cohort (IHC score 3+ or IHC score 2+ with gene amplification) and demonstrated a significantly better overall survival (OS) in correlation to HER2-negative tumors (median OS 70.1 vs. 24.6 months, p = 0.006). HER2-overexpression was more frequently seen in lower tumor stages (pT1/pT2, p = 0.038), in the absence of lymphatic metastases (pN0/pN+, p = 0.020), and was significantly associated with better histological grading (G1/G2) (p = 0.041).

Conclusion: We demonstrated a positive prognostic impact of HER2 overexpression in a large cohort of EAC, contrary to other solid malignancies including gastric cancer and breast cancer, but consistent to the results of a large study on EAC from 2012.

Keywords: Esophageal adenocarcinoma (EAC); Fluorescence-in-situ-hybridization (FISH); HER2/neu (ERBB2); Immunohistochemistry; Prognosis; Tissue microarray (TMA).

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Conflict of interest statement

Ethics approval and consent to participate

All procedures performed in the current study involving human tumor specimens were in accordance with the ethical standards of the local research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This was performed according to the criteria of the ethics committee of the University Hospital of Cologne.

Informed consent was not obtained because this secondary analysis of single protein staining is also regularly performed during pathological diagnostics.

Consent for publication

Not applicable.

Competing interests

Dr. Zander reports grants from the NRW Government during the conduct of the study; personal fees from Roche, personal fees from Novartis, personal fees from Lilly, personal fees from MSD, personal fees from BMS, personal fees from AstraZeneca, personal fees from Sanofi, outside the submitted work.

All other authors declare that they have no conflicts of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Representative images of histopathological slides to illustrate the immunohistochemistrical scoring system a-d) as well as FISH-analyses (e, f): a) Negative or staining in < 5 cells (score 0); b) very weak staining in cell groups ≥5 (score 1+); c) weak to moderate complete/basolateral/lateral staining in cell groups ≥5 (score 2+); d) strong complete/basolateral/lateral staining in cell groups ≥5 (score 3+). Representative FISH-specimens e) without and f) with HER2 amplification
Fig. 2
Fig. 2
Heatmap showing heterogeneity of HER2 expression between the luminal and the infiltration area of the primary tumor. Blue area represents absence of HER2 expression (IHC score 0); light red immunohistochemistry (IHC) score 2+, FISH confirmation negative; medium red IHC score 2+, FISH positive; dark red IHC score 3 +
Fig. 3
Fig. 3
Kaplan-Meier survival analysis (log-rank test) for the entire patient cohort on the single-spot TMA. Significant survival difference between patients with HER2 expression (median OS 70.1 months (95% confidence interval 44.0–95.6 months) compared to patients without HER2 expression (median OS 24.6 months (95% confidence interval 20.7–28.5 months), p < 0.006))
See this image and copyright information in PMC

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