HER2 as a Prognostic Marker in Gastric Cancer - A Systematic Analysis of Data from the Literature

Abstract

Through the recent conduct of the ToGA trial, HER2 has shown to be predictive for the treatment with trastuzumab in advanced gastric and gastro-oesophageal cancer. When it comes to the prognostic properties the situation is different. Despite the fact that it is more than 20 years ago since the first studies demonstrating an association between a positive HER2 status and poor prognosis were published the issue is still controversial. In this current systematic review a large number of studies on HER2 and gastric cancer have been reviewed. The studies included in this review should fulfill the following two criteria. First criterion: The number of patients in each study should be ≥ 100, and the HER2 status should have been determined either by immunohistochemistry (IHC) or in situ hybridization (ISH). Second criterion: The selected articles should include an analysis of the association between the HER2 status and survival or relevant clinicopathological characteristics. Forty-two publications with a total of 12,749 patients fulfilled the two criteria and were reviewed in detail. The majority of the publications (71%) showed that a HER2-postive status measured either by IHC or ISH was associated with poor survival and/or clinicopathological characteristics, such as serosal invasion, lymph node metastases, disease stage, or distant metastases. Based on the current analysis a clear trend towards a potential role for HER2 as a negative prognostics factor in gastric cancer was shown, suggesting that HER2 overexpression and/or amplification is a molecular abnormality that might be linked to the development of gastric cancer.

Keywords: CISH.; FISH; HER2; IHC; gastric cancer; prognostic marker.

Figure 1

Examples of positive HER2 status in gastric adenocarcinoma of the stomach with overexpression of the HER2 protein (IHC3+) or amplification of the HER2 gene (HER2/CEN-17 ≥ 2.0). A. Immunohistochemistry (HercepTest^™, Dako (20×)). B. Fluorescence in situ hybridization (HER2 FISH pharmDx^™ Kit, Dako (40×)). C. Chromogenic in situ hybridization (HER2 CISH pharmDx^™ Kit, Dako (40×)).

Figure 2

The number of IHC and ISH studies and patients (N) in each of the three scoring categories. Symbols: Two pluses (++) indicate the strongest association with the HER2+ status, one plus (+) indicates a somewhat weaker association with the HER2+ status, and minus (-) indicates that no associations with the HER2+ was found.