HER2 alterations across solid tumors: implications for comprehensive testing.

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.