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.

Bhardwaj S, Morris E, Halthore A, +7 more, Baraban E.

Journal ArticleAbstract only — full text under license

AI summary — for doctors, generated from the abstract only

In a series of 139 urothelial carcinoma specimens, HER2 IHC scoring using upper gastrointestinal (GI) criteria classified more cases as HER2 3+ (41%) than breast cancer criteria (34%), with HER2 3+ positivity enriched in micropapillary and plasmacytoid subtypes and brain metastases.

What was studied

A study of 139 urothelial carcinoma specimens from 129 patients comparing ASCO/CAP HER2 IHC scoring criteria developed for breast versus upper GI cancers, correlating HER2 expression with histologic subtype, metastatic site, temporal heterogeneity (in 11 paired primary/metastatic specimens), and next-generation sequencing (NGS) findings.

Key findings

Using upper GI criteria, 43 of 105 cases (41%) were HER2 3+, versus 35 of 105 (34%) using breast criteria; 12 of 139 cases (9%) scored higher with upper GI criteria.
ERBB2 mutations were found in 15 of 96 sequenced cases (16%) and amplification in 4 of 96 (4%).
HER2 3+ staining was enriched in micropapillary (11/14, 79%) and plasmacytoid (3/5, 60%) histologic subtypes.
Brain metastases had the highest proportion of HER2 3+ cases (6/15, 40%); in paired primary/metastatic samples, HER2 scores in metastases were the same (9/12, 75%) or higher (3/12, 25%) than in primaries.

Clinical relevance

These findings suggest that the choice of HER2 scoring criteria (breast versus upper GI) can meaningfully affect eligibility for HER2-targeted therapy in urothelial carcinoma, and that histologic subtype and metastatic site may be relevant to disease-specific testing strategies.

Who should care

Pathology

Limitations

This was a single-institution study with a moderate sample size (139 specimens, 129 patients) and a small subset of paired primary/metastatic samples (n=11); the abstract does not report a standardized reference scoring system against which to validate either criteria set.

HER2 scoring criteria choice (breast vs upper GI) can substantially change HER2 3+ classification rates in urothelial carcinoma, with implications for targeted therapy eligibility.

This is an AI-generated summary of the published abstract, not a clinical recommendation. It may not reflect the full text or subsequent updates — verify against the original source before acting on it.

Abstract

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.

DOI

10.5858/arpa.2025-0386-oa

PMID

42386186

Research metadata (titles, abstracts, authors, publication dates) is sourced from Europe PMC, which aggregates content from PubMed/MEDLINE, PubMed Central, and other providers under the U.S. National Library of Medicine (NLM/NCBI). NLM does not claim copyright on abstracts; the original journal publishers or authors may hold rights to the full articles. AI-generated summaries are derived only from the abstract, never the full text, and are always labeled as AI-generated.

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