title: Expression and Prognostic Significance of Human Epidermal Growth Factor Receptors 1, 2 and 3 in Periampullary Adenocarcinoma.
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.
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden.
authors.forename: Jacob
authors.identifier: http://orcid.org/0000-0002-9550-8012
authors.initials: J
authors.lastname: Elebro
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden.
authors.forename: Margareta
authors.initials: M
authors.lastname: Heby
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden.
authors.forename: Carl Fredrik
authors.initials: CF
authors.lastname: Warfvinge
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Nodin
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Eberhard
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human