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Epitope Expression Persists in Circulating Tumor Cells as Breast Cancers Acquire Resistance to Antibody Drug
Abstract:
Antibody-drug conjugates (ADCs) targeting cell surface proteins TROP2 or HER2 are effective in metastatic breast cancer, but the precise clinical contribution of epitope expression is uncertain. We prospectively monitored circulating tumor cells (CTCs) in 33 patients receiving ADC therapies using quantitative imaging. The expression of TROP2 and HER2 are heterogeneous across single CTCs from untreated patients, comparable to matched tumor biopsies, and display poor association with clinical response. Within three weeks of treatment initiation, declining CTC numbers correlate with a durable response (TROP2: median time to progression 391 versus 97 days, HR 4.15, P=0.0046; HER2: 322 versus 66 days, HR 9.12, P=0.0002). Neither TROP2 nor HER2 expression is reduced at progression, compared to matched pretreatment CTCs, and switching ADC epitope while maintaining a similar payload shows poor efficacy. Thus, epitope downregulation is not a common driver of acquired resistance to TROP2 or HER2 ADCs, and second-line ADC therapies may benefit from distinct payloads.
Significance:
ADCs target tumor-associated antigens, followed by internalization and release of drug payloads. However, clinical studies of epithelial-targeting ADCs show efficacy despite low tumor epitope expression. Our finding that epitope downregulation does not commonly accompany acquired resistance suggests alternative drivers of clinical efficacy and the need for testing non-cross-resistant payloads to overcome resistance.
Insights
Antibody-drug conjugates (ADCs) show efficacy in metastatic breast cancer. Declining circulating tumor cells (CTCs) predict response, and epitope downregulation is not a common resistance mechanism for TROP2 or HER2 ADCs.
Area of Science:
- Oncology
- Translational Research
- Biomarkers
Background:
- Antibody-drug conjugates (ADCs) targeting TROP2 or HER2 are used for metastatic breast cancer.
- The role of epitope expression in ADC efficacy is not fully understood.
Purpose of the Study:
- To investigate the clinical contribution of TROP2 and HER2 epitope expression in patients receiving ADC therapy.
- To evaluate the association between circulating tumor cell (CTC) dynamics and clinical response.
- To determine if epitope downregulation drives acquired resistance to ADCs.
Main Methods:
- Prospective monitoring of CTCs using quantitative imaging in 33 patients undergoing ADC therapy.
- Analysis of TROP2 and HER2 expression heterogeneity in single CTCs and matched tumor biopsies.
- Correlation of CTC number changes with clinical response and time to progression.
Main Results:
- TROP2 and HER2 expression on CTCs is heterogeneous and does not strongly correlate with initial clinical response.
- A decrease in CTC numbers within three weeks of treatment initiation strongly correlates with durable response for both TROP2 and HER2 ADCs.
- Epitope expression (TROP2/HER2) is not reduced at progression, and switching ADC targets with the same payload shows limited efficacy.
Conclusions:
- Epitope downregulation is not a primary mechanism of acquired resistance to TROP2 or HER2 ADCs.
- Alternative resistance mechanisms may be involved, necessitating further investigation.
- Future second-line ADC therapies might benefit from employing distinct payloads rather than targeting different epitopes of the same antigen.
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