Assessing Human Epidermal Growth Factor Receptor 2 in Urothelial Carcinoma: Insights From Clinical Practice Into Scoring Criteria, Histologic Subtypes, and Genomic Characteristics Across Disease Sites.
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- Also identified by DOI 10.5858/arpa.2025-0386-OA.
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Abstract
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. 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. 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). 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. 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.