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Updated: Jul 3, 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
Assessing Human Epidermal Growth Factor Receptor 2 in Urothelial Carcinoma: Insights From Clinical Practice Into
Context.—:
Human epidermal growth factor receptor 2 (HER2) alterations occur in several solid tumors, including urothelial carcinoma. Although HER2-targeted therapies, such as trastuzumab deruxtecan, have shown promising results in HER2-positive bladder cancer, optimal immunohistochemistry (IHC) scoring criteria for urothelial carcinoma remain unclear.
Objective.—:
To compare American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) HER2 IHC scoring criteria for breast and upper gastrointestinal (GI) cancers in urothelial carcinoma and to correlate HER2 expression with histologic subtypes, metastatic sites, temporal heterogeneity, and next-generation sequencing (NGS) findings.
Design.—:
A total of 139 specimens from 129 patients with urothelial carcinoma were evaluated. HER2 IHC was scored using both breast and upper GI CAP criteria across histologic subtypes and metastatic sites. Temporal heterogeneity was assessed in paired primary and metastatic specimens (n = 11).
Results.—:
Using upper GI criteria, 43 of 105 cases (41%) were HER2 3+ compared with 35 of 105 (34%) HER2 3+ with breast criteria, with 12 of 139 cases (9%) showing higher scores using upper GI criteria. ERBB2 mutations were found in 15 of 96 (16%) and amplification in 4 of 96 (4%) of sequenced cases. HER2 3+ staining was enriched in micropapillary (11 of 14; 79%) and plasmacytoid (3 of 5; 60%) subtypes. Brain metastases had the highest proportion (6 of 15; 40%) of HER2 3+ cases. In paired samples, HER2 scores in metastases were the same (9 of 12; 75%) or higher (3 of 12; 25%) than primaries.
Conclusions.—:
Upper GI and breast scoring criteria yield divergent scores in a significant subset of urothelial carcinomas, potentially affecting eligibility for targeted therapy. Associations with histologic subtype and metastatic site support disease-specific diagnostic and therapeutic strategies.
Insights
Optimal scoring criteria for human epidermal growth factor receptor 2 (HER2) in urothelial carcinoma are unclear. Upper GI criteria identified more HER2-positive cases than breast criteria, impacting targeted therapy eligibility.
Area of Science:
- Oncology
- Pathology
- Genetics
Background:
- Human epidermal growth factor receptor 2 (HER2) alterations are found in urothelial carcinoma.
- HER2-targeted therapies show promise in HER2-positive bladder cancer.
- Optimal immunohistochemistry (IHC) scoring for HER2 in urothelial carcinoma is not established.
Purpose of the Study:
- Compare HER2 IHC scoring criteria from the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) for breast and upper gastrointestinal (GI) cancers in urothelial carcinoma.
- Correlate HER2 expression with histologic subtypes, metastatic sites, temporal heterogeneity, and next-generation sequencing (NGS) findings.
Main Methods:
- Evaluated 139 urothelial carcinoma specimens from 129 patients.
- Scored HER2 IHC using both breast and upper GI CAP criteria.
- Assessed temporal heterogeneity in paired primary and metastatic specimens (n=11).
Main Results:
- Upper GI criteria identified 43% (43/105) of cases as HER2 3+, versus 34% (35/105) with breast criteria.
- ERBB2 mutations were found in 16% (15/96) and amplification in 4% (4/96) of sequenced cases.
- HER2 3+ staining was enriched in micropapillary and plasmacytoid subtypes and brain metastases.
Conclusions:
- Breast and upper GI scoring criteria yield divergent HER2 scores in urothelial carcinoma, potentially affecting targeted therapy eligibility.
- Associations between HER2 expression, histologic subtype, and metastatic site suggest the need for disease-specific diagnostic and therapeutic strategies.
