Validation and Prospective Testing of a High-Sensitivity, Quantitative Analytic Assay for HER2 on Histopathology...

Area of Science:

• Oncology
• Biomarker Assay Development
• Molecular Diagnostics

Background:

• Recent approvals of HER2-targeted antibody drug conjugates (ADCs), such as Trastuzumab Deruxtecan (T-DXd), necessitate improved companion diagnostic tests.
• Current immunohistochemical (IHC) tests for HER2 are optimized for gene-amplified levels and face challenges in accurately assessing low-level HER2 expression, potentially impacting patient selection for T-DXd therapy.

Purpose of the Study:

• To develop and validate a highly sensitive and objective assay for quantifying low-level HER2 expression.
• To improve the accuracy of patient selection for HER2-targeted ADC therapies, including T-DXd.

Main Methods:

• A novel high-sensitivity HER2 assay was developed, integrating requirements of both IHC and ligand-binding assays.
• The assay was validated using a 40-case breast cancer tissue set, demonstrating high accuracy and precision (coefficient of variation <10%).
• Prospective testing was conducted on 316 core biopsy specimens, evaluating the dynamic range of HER2 expression and comparing results with pathologist scores.

Main Results:

• The validated assay provides a defined reportable range in amol/mm² with high accuracy and precision.
• Prospective analysis revealed discordance between pathologist scores and quantitative measurements, particularly in low HER2 expression ranges.
• A significant portion of cases (6%) fell below the assay's limit of detection, and 71% of IHC 0 cases were above the limit of quantification, highlighting assay sensitivity.

Conclusions:

• This validated, objective HER2 assay offers a method for accurate measurement, crucial for patient selection in T-DXd therapy.
• The assay has the potential to enhance the selection of patients for T-DXd and similar ADC therapies by overcoming limitations of existing IHC tests.
• Further research is ongoing to establish a definitive HER2 expression threshold for predicting T-DXd response.