Related Experiment Video
Updated: Aug 11, 2026
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
HER2 alterations across solid tumors: implications for comprehensive testing
Ahmed Ismail1,2, Chimay Jani3, Nusrat Jahan1
1Section of Hematology & Oncology, Department of Medicine, The University of Alabama at Birmingham and O'Neal Comprehensive Cancer Center, Birmingham, AL 35233, United States.
Purpose:
ERBB2 (HER2) alterations (eg, 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 3 had CN amplifications (1-positive, 2-intermediate). Somers'-D analysis revealed a strong association between CNV and IHC expression (D = 0.73, P < .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.
Insights
Understanding ERBB2 (HER2) alterations in diverse cancers is crucial for targeted therapies. Comprehensive genomic and protein analysis is essential for accurate patient identification and treatment.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- ERBB2 (HER2) alterations are key drivers of tumor progression, especially in non-breast and gastric cancers.
- HER2-targeted therapies, such as Trastuzumab deruxetecan (T-DXd), have gained pan-tumor approval.
- Characterizing ERBB2 alterations across various cancer types is critical for expanding patient eligibility for these therapies.
Purpose of the Study:
- To investigate the spectrum and clinical significance of ERBB2 alterations in a diverse cohort of solid tumors.
- To evaluate the correlation between ERBB2 gene copy number variations (CNV) and HER2 protein expression (IHC).
- To assess the prevalence of ERBB2 mutations and their relationship with HER2 protein levels and CN amplification.
Main Methods:
- Analysis of 653 solid tumor specimens using immunohistochemistry (IHC), copy number variation (CNV) assessment, and mutational profiling.
- Evaluation of the association between CN amplification and IHC expression using Somers' D ordinal association.
- Correlation of pathogenic ERBB2 mutations with IHC scores and CN amplification status.
Main Results:
- HER2 IHC scores showed 3+ in 3.1%, 2+ in 13.2%, and 1+ in 19.8% of cases; 63.9% were IHC-negative.
- ERBB2 CN amplification occurred in 3.1% of tumors, with 75% showing IHC3+. Pathogenic mutations were found in 3.1%, with low IHC3+ rates (5%).
- A strong positive association was observed between ERBB2 CNV and IHC expression (Somers' D = 0.73, p < 0.001).
Conclusions:
- ERBB2 alterations are heterogeneous across diverse cancers, underscoring their clinical significance.
- Tumors with ERBB2 mutations often exhibit lower HER2 protein expression or CN amplification, necessitating comprehensive genomic testing.
- Integrating genomic and phenotypic data is crucial for precise diagnosis and optimal therapeutic decision-making for HER2-targeted therapies.
More Related Videos
11:12Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
08:28Validated Immunochemical Assay for Comprehensive Determination of the Human Epidermal Growth Factor Receptor 2 Released from and Bound to Cells
Published on: May 9, 2025
