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

Jacob Elebro, Margareta Heby, Carl Fredrik Warfvinge, Björn Nodin, Jakob Eberhard, Karin Jirström, Jacob Elebro, Margareta Heby, Carl Fredrik Warfvinge, Björn Nodin, Jakob Eberhard, Karin Jirström

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Sample immunohistochemical images.
Fig 1. Sample immunohistochemical images.
Photomicrographs representing different categories of immunohistochemical staining for EGFR, HER2 and HER3, respectively. An image visualizing HER2 gene amplification by silver in situ hybridization is shown together with the HER2 3+ case.
Fig 2. Recurrence-free and overall survival according…
Fig 2. Recurrence-free and overall survival according to EGFR and HER3 expression in PB-type adenocarcinoma.
Kaplan Meier analysis of five-year recurrence-free survival in strata according to high and low expression of (A) EGFR and (C) HER3 and overall survival according to high and low expression of (B) EGFR and (D) HER3.
Fig 3. Recurrence-free and overall survival in…
Fig 3. Recurrence-free and overall survival in strata according to EGFR expression and adjuvant gemcitabine in PB-type adenocarcinoma.
Kaplan Meier analysis of (A) five-year recurrence-free survival and (B) overall survival in combined strata according to EGFR expression (high/low) and adjuvant gemcitabine (yes/no).
Fig 4. Recurrence-free and overall survival according…
Fig 4. Recurrence-free and overall survival according to EGFR, HER2 and HER3 expression in I-type adenocarcinoma.
Kaplan Meier analysis of five-year recurrence-free survival in strata according to high and low expression of (A) EGFR, (C) HER2, (E) HER3 and overall survival according to high and low expression of (B) EGFR, (D) HER2, and (F) HER3.

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