Human Epidermal Growth Factor Receptor 2 [HER-2/neu] Amplification and Microsatellite Stable Status in Gastric and Gastroesophageal Adenocarcinoma: Assessing Frequency and Prognostic Implications at the Cancer Institute of Iran

Abstract

Background: Molecular targeted therapy and immunotherapy have shown promise in managing gastric adenocarcinoma. The amplified expression of Human epidermal growth factor receptor-2 (HER-2) and microsatellite stable (MSI) status serve as indicators of response to targeted therapy and immunotherapy, respectively.

Aims: This study assessed the frequency of MSI status and HER-2 expression in a pretreated sample of Iranian patients with gastric and gastroesophageal (GE) adenocarcinoma.

Methods and results: We conducted HER-2/neu expression and mismatch repair (MMR) system analyses on specimens from patients with gastric and GE adenocarcinoma at the Cancer Institute of Iran. Archival tissues from 135 mainly pre-treated surgical specimens of gastric adenocarcinoma cases were used for HER-2 analysis, and 66 specimens were used for MSI analysis. All specimens were tested for HER-2 amplification, revealing that 11 patients (8.1%) had HER-2 amplification, and three out of 66 examined patients exhibited MSI-H. Patients with HER-2 overexpressed specimens had a shorter median overall survival (OS) compared with HER-2 negative cases (21 months (95% CI: 1.4-40.6) vs. 31 months (95% CI: 22.9-39), p = 0.18). The median disease-free survival (DFS) for HER-2 positive and negative patients was 15 and 28 months, respectively (p = 0.25). The estimated median OS and DFS for patients with negative MSI were 26 and 20 months, respectively. However, none of the patients with MSI-positive status experienced recurrence, metastases, or death within the follow-up period; thus, MSI-H patients had a significantly improved OS and DFS (p = 0.018 and 0.020).

Conclusion: HER-2 expression, while less common in our Iranian population compared with North American or Western European countries, showed a nonsignificant trend toward poor outcomes in patients with gastric adenocarcinoma. MSI-H status was highly infrequent in our population, suggesting that immunotherapy may not be a beneficial treatment for a significant fraction of Iranian patients with gastric adenocarcinoma. However, a minority may still benefit from it. MSI-H was associated with reduced perineural invasion and improved OS and DFS. Therefore, this hypothesis warrants further investigation in clinical trials to underscore the prognostic significance of HER-2 and MSI status and the value of molecular profiling in guiding personalized treatment strategies.

Keywords: Adenocarcinoma; DNA mismatch repair; Gastric neoplasm; HER family receptor.

FIGURE 1

(a) Gastric adenocarcinoma with positive HER‐2 on IHC, Complete membrane intense staining in more than 10% of tumor cells (×100). (b) Gastric adenocarcinoma with negative HER‐2 on IHC, tumoral cells show no staining (×100), tumoral cells.

FIGURE 2

Figure represents a HER‐2 gene amplified specimen (HER‐2/CEN‐17 ratio > 2.0). Green dots: HER‐2 gene, Red dots: CEN‐17 (×400).

FIGURE 3

Flowchart of sample inclusion and exclusion.

FIGURE 4

Overall and disease‐free survival based on MSI status. Hazard ratio (HR) could not be calculated since no events were observed in the MSI‐positive subgroup.