Expression and Prognostic Significance of Human Epidermal Growth Factor Receptors 1, 2 and 3 in Periampullary Adenocarcinoma.

Jacob Elebro,Björn Nodin,Jakob Eberhard,Margareta Heby,Carl Fredrik Warfvinge,Karin Jirström,Yves St-Pierre

doi:10.1371/journal.pone.0153533

Jacob Elebro, Björn Nodin + Show 5 more

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https://doi.org/10.1371/journal.pone.0153533

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Journal: PloS one	Publication Date: Apr 12, 2016
Citations: 25	License type: CC BY 4.0

Affiliation: Skåne University Hospital, Lund University

Abstract

Periampullary adenocarcinoma, including pancreatic cancer, is a heterogeneous group of tumours with dismal prognosis, for which there is an urgent need to identify novel treatment strategies. The human epithelial growth factor receptors EGFR, HER2 and HER3 have been studied in several tumour types, and HER-targeting drugs have a beneficial effect on survival in selected types of cancer. However, these effects have not been evident in pancreatic cancer, and remain unexplored in other types of periampullary cancer. The prognostic impact of HER-expression in these cancers also remains unclear. The aim of this study was therefore to examine the expression and prognostic value of EGFR, HER2 and HER3 in periampullary cancer, with particular reference to histological subtype. To this end, protein expression of EGFR, HER2 and HER3, and HER2 gene amplification was assessed by immunohistochemistry and silver in situ hybridization, respectively, on tissue microarrays with tumours from 175 periampullary adenocarcinomas, with follow-up data on recurrence-free survival (RFS) and overall survival (OS) for up to 5 years. EGFR expression was similar in pancreatobiliary (PB) and intestinal (I) type tumours, but high HER2 and HER3 expression was significantly more common in I-type tumours. In PB-type cases receiving adjuvant gemcitabine, but not in untreated cases, high EGFR expression was significantly associated with a shorter OS and RFS, with a significant treatment interaction in relation to OS (pinteraction = 0.042). In I-type cases, high EGFR expression was associated with a shorter OS and RFS in univariable, but not in multivariable, analysis. High HER3 expression was associated with a prolonged RFS in univariable, but not in multivariable, analysis. Neither HER2 protein expression nor gene amplification was prognostic. The finding of a potential interaction between the expression of EGFR and response to adjuvant chemotherapy in PB-type tumours needs validation, and merits further study.

Highlights

Adenocarcinomas originating in the head of the pancreas, the distal bile duct, the ampulla of Vater and the duodenum are often grouped together as periampullary tumours, since they can be difficult to distinguish from each other clinically
We have evaluated the prognostic impact of EGFR, HER2 and HER3 in periampullary adenocarcinoma, by morphological type and adjuvant treatment
In intestinal-type adenocarcinoma, we found that high HER3 expression was a favourable prognostic factor and that high EGFR expression was an adverse prognostic factor, none of these associations were independent of other prognostic factors

Summary

Introduction

Adenocarcinomas originating in the head of the pancreas, the distal bile duct, the ampulla of Vater and the duodenum are often grouped together as periampullary tumours, since they can be difficult to distinguish from each other clinically. Pancreatobiliary (PB) type morphology dominates in periampullary tumours of pancreatic and distal bile duct origin, but is seen in the ampulla of Vater [4, 5]. They have a significantly worse prognosis than tumours with an intestinal (I) type morphology, which are mainly found in the ampulla of Vater and in the duodenum [4,5,6]. Combinations of HERs give dimers that vary in stability, affinity for their ligands and activation of different signalling-cascades [7]

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