HER2 Expression in Gastric and Gastroesophageal Junction Adenocarcinoma in a US Population

Abstract

Recent evidence suggests that trastuzumab, a monoclonal antibody which targets HER2, in combination with chemotherapy is a therapeutic option in patients with HER2-positive gastric or gastroesophageal junction cancer. Widely accepted guidelines for HER2 testing in gastric and gastroesophageal junction cancer have not been established. The purpose of this study was to analyze the incidence and patterns of HER2 expression in gastric and gastroesophageal junction cancer using a tissue microarray approach, which closely simulates small biopsies routinely tested for HER2. One hundred sixty-nine patients, including 99 primary gastric adenocarcinomas and 70 primary gastroesophageal junction carcinomas were analyzed for HER2 overexpression by immunohistochemistry and HER2 gene amplification by fluorescence in situ hybridization using scoring schemes proposed by both American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) and the results of the recently published Trastuzumab for Gastric Cancer (ToGA) trial. In our analysis, 19 adenocarcinomas were HER2 positive, defined as either a HER2/CEP17 ratio >2.2 and/or a 3+ HER2 immunohistochemistry score with either the ASCO/CAP or ToGA scoring schemes. Of the 19 HER2-positive adenocarcinomas, 8 (42%) exhibited a characteristic strongly intense basolateral membranous staining pattern which would be interpreted as negative (1+) using the accepted ASCO/CAP scoring scheme for HER2 assessment in breast carcinoma, but were correctly labeled as 3+ positive using the proposed ToGA scoring scheme. Of the 19 HER2-positive adenocarcinomas, 8 (42%) demonstrated heterogeneous HER2 protein expression by immunohistochemistry. Twelve of 99 (12%) gastric carcinomas were positive for HER2. Of these, HER2 was more often identified in intestinal-type adenocarcinomas (10 of 52, 19%) compared with diffuse (2 of 34, 6%) adenocarcinoma. Seven of 70 (10%) gastroesophageal junction carcinomas were positive for HER2 of which all were intestinal type (7 of 58, 12%). HER2 status or primary tumor site did not correlate with patient survival. Gastric and gastroesophageal junction adenocarcinomas typically display a characteristic basolateral membranous pattern of HER2 expression which is often heterogeneous rendering routine evaluation of HER2 status on small tissue samples challenging.

Evaluation of HER2-based biology in 1,006 cases of gastric cancer in a Japanese population

“…Despite the increasing importance of this relationship, the relationship between HER2 overexpression and tumor biology in cases of gastric cancer still remains to be elucidated. Based on the results of the ToGA trial, several studies have evaluated HER2 overexpression in esophagogastric cancer using validated criteria [17][18][19][20][21][22]. The frequency of HER2 overexpression has been reported to be 9-16 %, consistent with the results of two major reviews of previous studies [4,9].…”

“…Actually, recent studies in which the diagnosis of HER2 overexpression was based on immunohistochemical staining using criteria suggested by Hofmann et al [9] reported conflicting results with respect to the prognostic significance of HER2 overexpression in gastric cancer [20][21][22]. The inconsistent results could be attributed to multiple factors.…”

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

“…Previous reports also have shown that only a portion of protein expression cases exhibit gene amplification [24][25][26], so gastric cancers with RTK protein overexpression might be derived not only from RTK gene amplification, but also via other mechanisms. Regarding treatment, since gastric cancers with strong or moderate overexpression of HER2 protein plus gene amplification are associated with the efficacy of trastuzumab, gene amplification does not necessarily surpass protein expression with regard to predicting the effect of targeted therapy with antibodies [5].…”

Expression of human epidermal growth factor receptor 2 in primary and paired parenchymal recurrent and/or metastatic sites of gastric cancer

“…Previous studies have estimated the HER2 positivity ratio to be 8.1-17.1% in gastric cancer (6,15,16). Recent studies reported that the HER2 positivity ratio is lower in patients with curatively resectable gastric cancer compared to that in unresectable patients (15,16).…”