The Prognostic Impact of HER2 Genetic and Protein Expression in Pancreatic Carcinoma-HER2 Protein and Gene in Pancreatic Cancer.

Song-Hee Han,Ah-Young Kwon,Ki Hyun Ryu

doi:10.3390/diagnostics11040653

Song-Hee Han, Ah-Young Kwon + Show 1 more

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https://doi.org/10.3390/diagnostics11040653

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal and clinically heterogeneous disease with a limited benefit from human epidermal growth factor receptor 2 (HER2)-targeted therapy. Recently, some studies have addressed the antitumoral effect of novel anti-HER2 drugs in HER2 low-expressing tumors. However, there have been few studies on the significance of low HER2 expression and genetic heterogeneity in PDAC. Using immunohistochemistry and dual-color silver-enhanced in situ hybridization based on the Trastuzumab for a gastric cancer scoring scheme, we evaluated HER2 protein expression, gene amplification, and genetic heterogeneity in three groups (HER2-neg, HER2-low, HER2-pos) of 55 patients. Among the 55 cases, 41.8% (23/55) showed HER2 expression of any intensity. HER2 amplification independent of HER2 expression was 25.5% (14/55). Patients in both these groups had a shorter overall survival than did patients in the HER2-neg group. HER2 genetic heterogeneity was identified in 37 (70.9%) of the 55 cases, mainly in HER2-neg and HER2-low groups. HER2 genetic heterogeneity significantly correlated with worse survival in the HER2-low and HER2-neg groups of PDAC. These findings support the hypothesis that low-level HER2 expression and heterogeneity have significant clinical implications in PDAC. HER2 heterogeneity might indicate the best strategies of combination therapies to prevent the development of subdominant clones with resistance potential.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the fifth most common cause of cancerrelated death in Korea [1]
human epidermal growth factor receptor 2 (HER2)-positive cases defined by HER2 overexpression and HER2 amplification can be treated with anti-HER2 agents
Despite low HER2 expression, tumor cells with weak staining (1+) are considered negative for HER2 overexpression because such tumors are unlikely to respond to anti-HER2 therapy

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the fifth most common cause of cancerrelated death in Korea [1]. An understanding of the molecular characteristics of PDAC is urgently needed to select appropriate patients for the current treatment options available as well as the development of novel therapeutic targets. Amplification of HER2 on chromosome 17q21 and overexpression of the HER2 protein at the cell membrane have been associated with malignant transformation and poor survival rates in patients with breast cancer [7]. Numerous studies have shown that amplification of the gene and protein overexpression drive oncogenesis in different types of cancers, such as stomach, esophagogastric, ovary, and lung cancers [6,8,9]. Differential expression of HER2 at the gene and protein levels between normal and cancer cells and the prognostic significance of high HER2 levels support defining HER2 as an ideal selective target for patients with HER2-overexpressing cancer

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