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Surface-Available HER2 Levels Alone Are Not Indicative of Cell Response to HER2-Targeted Antibody-Drug Conjugate
Molly Major1, Christine S Nervig2, Annette Gerland1
1Department of Molecular Pharmaceutics, College of Pharmacy, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112, USA.
Abstract:
HER2-targeting therapies have advanced breast cancer treatment over the past decade. Clinically, eligibility for HER2 therapies is determined by assessing HER2 levels on tumor cell surfaces through immunohistochemistry or by gene regulation through fluorescence in situ hybridization. HER2 therapies are not always effective in patients with elevated levels of HER2, questioning whether the amount of HER2 is sufficiently predictive of patient outcomes. Additionally, the HER2-targeting antibody-drug conjugate (ADC) Enhertu® was recently approved for metastasized HER2-low cancers, confirming the benefits of HER2 treatment for patients with low HER2 levels. To evaluate the correlation between HER2 levels and treatment efficacy, we quantified HER2 on eight cell lines using flow cytometry while simultaneously determining the toxicity of two HER2-targeting ADCs. Both HER2-high cell lines and HER2-low cell lines had significant toxicity responses to ADCs. We quantified HER2 internalization and found no correlation between HER2 levels and the percentage of internalization. We found a useful metric suggesting that a minimum number of HER2 receptors trafficked to lysosomes is sufficient to provide effective treatment. Our results indicate that the current standards of determining eligibility for HER2 therapy could limit patients' access to effective treatment. In conclusion, HER2 levels are not wholly adequate to determine the response to ADC treatment.
Insights
Current HER2 testing for breast cancer therapy may limit patient access. A minimum number of HER2 receptors reaching lysosomes, not just HER2 levels, predicts effective treatment with antibody-drug conjugates (ADCs).
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- HER2-targeting therapies have revolutionized breast cancer treatment.
- Current clinical eligibility for HER2 therapies relies on immunohistochemistry or fluorescence in situ hybridization to quantify HER2 levels.
- The effectiveness of HER2 therapies, including antibody-drug conjugates (ADCs), is not always correlated with HER2 expression levels.
Purpose of the Study:
- To evaluate the correlation between HER2 levels and the efficacy of HER2-targeting ADCs.
- To investigate whether current HER2 quantification methods adequately predict patient response to HER2-targeted treatments.
- To identify potential biomarkers for predicting ADC treatment response in breast cancer.
Main Methods:
- Quantification of HER2 receptor levels on eight cancer cell lines using flow cytometry.
- Assessment of the toxicity of two HER2-targeting ADCs on these cell lines.
- Measurement of HER2 receptor internalization and trafficking to lysosomes.
Main Results:
- Significant toxicity responses to ADCs were observed in both HER2-high and HER2-low cell lines.
- No direct correlation was found between HER2 levels and the percentage of HER2 receptor internalization.
- A minimum number of HER2 receptors trafficked to lysosomes was identified as a potential metric for effective ADC treatment.
Conclusions:
- HER2 receptor levels alone are insufficient to determine patient eligibility or predict response to HER2-targeting ADC therapy.
- Current diagnostic standards may restrict patient access to potentially effective treatments.
- Lysosomal trafficking of HER2 receptors may represent a more accurate predictor of ADC efficacy.
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