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Updated: Apr 18, 2026
Validated Immunochemical Assay for Comprehensive Determination of the Human Epidermal Growth Factor Receptor 2 Released from and Bound to Cells
Published on: May 9, 2025
Pathologic diagnostics of HER2 positivity in gastroesophageal adenocarcinoma
Timco Koopman1, Maarten Louwen2, Mariska Hage2
1From the Departments of Medical Oncology and.
Objectives:
The human epidermal growth factor receptor 2 (HER2) oncogene shows overexpression in 15% to 30% of gastroesophageal adenocarcinomas. Targeted anti-HER2 therapy with trastuzumab has been recently validated in advanced gastric and gastroesophageal junction cancer treatment. A standardized modified scoring system was recently introduced for gastroesophageal HER2 scoring. We aimed to validate this scoring system, including an analysis of interobserver variability of immunohistochemistry (IHC) scoring.
Methods:
In total, 323 patients with histologically confirmed invasive gastric or esophageal adenocarcinoma were examined for HER2 by IHC and chromogenic in situ hybridization (CISH). IHC 3 + or IHC 2 +/CISH positive tumors were considered HER2 positive. Interobserver variability on IHC scoring using the currently standard modified HER2 scoring system was determined among three clinical pathologists. Clinicopathologic characteristics were retrospectively retrieved from the patient records.
Results:
HER2 positivity was found in 50 (15.5%) of 323 patients. Interobserver agreement on IHC scoring was high (κ = 0.78). Most disagreement was found in diffuse or mixed tumor types and in weak to moderate stained samples (IHC 2 +). The HER2 IHC scoring system is sensitive in differentiating HER2 status before ISH.
Conclusions:
The currently used standardized HER2 scoring system is an excellent, clinically applicable method to establish HER2 status in appropriately educated and trained pathologists.
Insights
The standardized HER2 scoring system accurately determines HER2 status in gastroesophageal cancer, showing high interobserver agreement among pathologists for targeted therapy selection.
Area of Science:
- Oncology
- Gastroenterology
- Pathology
Background:
- HER2 oncogene overexpression occurs in 15-30% of gastroesophageal adenocarcinomas.
- Trastuzumab, an anti-HER2 therapy, is validated for advanced gastric and gastroesophageal junction cancer.
- A modified scoring system for gastroesophageal HER2 assessment was recently introduced.
Purpose of the Study:
- To validate the standardized modified HER2 scoring system for gastroesophageal adenocarcinomas.
- To analyze the interobserver variability of immunohistochemistry (IHC) scoring using this system.
Main Methods:
- 323 patients with gastric or esophageal adenocarcinoma underwent HER2 testing via IHC and CISH.
- HER2 positivity was defined as IHC 3+ or IHC 2+/CISH positive.
- Interobserver variability was assessed among three pathologists using the modified HER2 scoring system.
Main Results:
- HER2 positivity was identified in 15.5% (50/323) of patients.
- High interobserver agreement (κ = 0.78) was observed for IHC scoring.
- Disagreements primarily occurred in diffuse/mixed tumors and weak-to-moderate staining (IHC 2+).
Conclusions:
- The standardized HER2 scoring system is clinically applicable and effective for establishing HER2 status.
- The system demonstrates high reliability among trained pathologists.
- It aids in differentiating HER2 status prior to in situ hybridization (ISH).
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