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.

The HER3 pathway as a potential target for inhibition in patients with biliary tract cancers

“…The current results have identified HER3 as a potential target which warrants further investigation in BTC, as it was expressed in a significant subset of patients diagnosed with BTC. Previously, HER3 expression has been examined in several studies including BTC patients, and are summarised in Table 3 [ 36 , 37 , 20 , 38 , 26 ]. HER3 expression varies between studies, due to the use of different scoring systems and differing definitions of “expression” [ 36 , 20 ].…”

“…HER3 expression varies between studies, due to the use of different scoring systems and differing definitions of “expression” [ 36 , 20 ]. In addition, in some studies the cytoplasmic expression is not separately reported [ 38 ], thus, confounding the results and making comparisons difficult. When the current series is compared with studies with similar methodology, results on HER3 expression are similar [ 37 ].…”

“… NR: not reported: ICC: intra-hepatic cholangiocarcinoma, ECC: extra-hepatic cholangiocarcinoma; AMP ampullary cancer; GBC: gallbladder cancer; 95% CI: 95% confidence interval; N: number of patients; %: percentage; IHC: immunohistochemistry; FISH: Fluorescent in situ hybridisation; HER: Human epidermal growth factor receptor; TMA: tissue micro-array; CC: cholangiocarcinoma; NR: not reported; n/a: not applicable. * all percentages are calculated using the total number of samples included in the series as a denominator (the number of samples tested for FISH has not been used as a denominator due to discrepancy between studies (some studies performed FISH for every sample regardless of IHC results[ 37 ] [ 20 ], some studies performed FISH only if IHC2+/3+ [ 38 ] or 2+ (Lamarca et al, this series). & there was variability regarding patients tested with FISH (selected based on IHC/non-selected), data for “un-selected” population as defined by authors are provided in the table [ 26 ].…”

“… * all percentages are calculated using the total number of samples included in the series as a denominator (the number of samples tested for FISH has not been used as a denominator due to discrepancy between studies (some studies performed FISH for every sample regardless of IHC results[ 37 ] [ 20 ], some studies performed FISH only if IHC2+/3+ [ 38 ] or 2+ (Lamarca et al, this series). …”

“…It is notable that similar HER2 expression (<10%) to our study was identified in one of the largest pan-cancer HER2 studies to date using high quality and internationally agreed IHC/FISH criteria [ 35 ]. Thirdly, tumour pathological and morphological characteristics may play a role, as suggested by Elebro and colleagues, who reported a significant variation in HER2 and HER3 expression according to AMP subtype (intestinal type (HER2 6%, HER3 51%) vs pancreato-biliary (HER2 0%, HER3 17%) type) [ 38 ].…”