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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Androgen receptor expression in circulating tumour cells from castration-resistant prostate cancer patients treated
M Crespo1, G van Dalum2, R Ferraldeschi3
1Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
Background:
Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated nuclear AR expression in CTCs in patients treated with enzalutamide and abiraterone.
Methods:
CTCs were captured and characterised using the CellSearch system. An automated algorithm to identify CTCs and quantify AR expression was employed. The primary aim was to evaluate the association between CTC AR expression and prior treatment with abiraterone or enzalutamide.
Results:
AR expression in CTCs was evaluated in 94 samples from 48 metastatic CRPC patients. We observed large intra-patient heterogeneity of AR expression in CTCs. Prior exposure to abiraterone or enzalutamide was not associated with a change in CTCs AR expression (median intensity and distribution of AR-positive classes). In support of this, we also confirmed maintained nuclear AR expression in tissue samples collected after progression on abiraterone. AR staining also identified additional AR-positive CD45-negative circulating cells that were CK-negative/weak and therefore missed using standard protocols. The number of these events correlated with traditional CTCs and was associated with worse outcome on univariate analysis.
Conclusions:
We developed a non-invasive method to monitor AR nuclear expression in CTCs. Our studies confirm nuclear AR expression in CRPC patients progressing on novel endocrine treatments. Owing to the significant heterogeneity of AR expression in CTCs, studies in larger cohorts of patients are required to identify associations with outcome.
Insights
This study developed a new assay to measure androgen receptor (AR) in circulating tumor cells (CTCs) of prostate cancer patients. The assay found AR expression in CTCs did not change after treatment with abiraterone or enzalutamide.
Area of Science:
- Oncology
- Molecular Biology
- Urology
Background:
- Abiraterone and enzalutamide are novel endocrine therapies targeting androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC).
- Monitoring AR expression in CRPC is crucial for understanding treatment response and resistance.
- Circulating tumor cells (CTCs) offer a non-invasive window into tumor biology.
Purpose of the Study:
- To develop and validate a CTC-based assay for real-time AR expression analysis in CRPC patients.
- To investigate the association between CTC AR expression and prior treatment with abiraterone or enzalutamide.
- To assess nuclear AR expression in CTCs from patients undergoing novel endocrine therapy.
Main Methods:
- CTCs were captured and characterized using the CellSearch system.
- An automated algorithm quantified AR expression in identified CTCs.
- AR expression in CTCs was evaluated in 94 samples from 48 metastatic CRPC patients.
Main Results:
- No significant association was observed between prior abiraterone/enzalutamide treatment and CTC AR expression levels.
- Intra-patient heterogeneity in AR expression within CTCs was substantial.
- Maintained nuclear AR expression was confirmed in tissue samples post-abiraterone progression.
- Additional AR-positive, CK-negative/weak circulating cells were identified, correlating with CTCs and worse outcomes.
Conclusions:
- A non-invasive method for monitoring AR nuclear expression in CTCs was successfully developed.
- Nuclear AR expression persists in CRPC patients progressing on novel endocrine treatments.
- Significant heterogeneity of AR expression in CTCs necessitates larger cohort studies to establish outcome associations.
