Document Type

Article

Publication Date

2025

DOI

10.1093/oncolo/oyaf258

Publication Title

Oncologist

Volume

30

Issue

9

Pages

oyaf258 (1-8)

Abstract

Purpose

ERBB2 (HER2) alterations (e.g., overexpression, amplification, and mutations) are known to drive tumor progression. These changes, particularly in non-breast and gastric/gastroesophageal cancers, remain poorly characterized. With pan-tumor approval of HER2-targeted therapies like Trastuzumab deruxetecan (T-DXd), understanding ERBB2 alterations across diverse cancers is crucial.

Methods

HER2 analysis was conducted on 653 solid tumor specimens at the University of Alabama, using immunohistochemistry (IHC), copy number (CN) variation (CNV) assessment, and mutational profiling. The correlation between CN amplification and IHC expression was evaluated using Somers' D ordinal association.

Results

Of the 653 cases, HER2 IHC scores were distributed as 3 + (3.1%), 2 + (13.2%), and 1 + (19.8%), with 63.9% being IHC-negative. ERBB2 CN amplification was observed in 3.1%, with 75% exhibiting IHC3+. Pathogenic mutations were found in 3.1%, with low IHC3+ rates (5%). Among samples with ERBB2 mutations, only three had CN amplifications (one-positive, two-intermediate). Somers'-D analysis revealed a strong association between CNV and IHC expression (D = 0.73, p <  0.001).

Conclusion

This study highlights ERBB2 alterations across diverse cancers, demonstrating their heterogeneity and clinical significance. ERBB2 mutation-carrying tumors are less likely to have HER2 protein 3+ expression or CN amplification, indicating the need for comprehensive genomic analysis to identify those patients. In the context of pan-tumor approval of T-DXd for HER2, findings support integrating genomic and phenotypic data to enhance diagnostic precision and inform therapeutic decision-making. Comprehensive ERBB2 (HER2) testing across tumor types is essential to expand access to HER2-targeted therapies.

Rights

© The Authors 2025.

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Data Availability

Article states: "All information is included in Table 1 in the manuscript."

Original Publication Citation

Ismail, A., Jani, C., Jahan, N., Midhun, M., Basu, A., Gupta, G., El-Rayes, B., Bae, S., Mattox, T., Hawkins, C., Arend, R. C., Akce, M., Boumber, Y., & Desai, A. (2025). HER2 alterations across solid tumors: Implications for comprehensive testing. Oncologist, 30(9), 1-8, Article oyaf258. https://doi.org/10.1093/oncolo/oyaf258

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