Androgen receptor expression in circulating tumour cells from castration-resistant prostate cancer patients treated with novel endocrine agents.
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Date
2015-03-31Author
Crespo, M
van Dalum, G
Ferraldeschi, R
Zafeiriou, Z
Sideris, S
Lorente, D
Bianchini, D
Rodrigues, DN
Riisnaes, R
Miranda, S
Figueiredo, I
Flohr, P
Nowakowska, K
de Bono, JS
Terstappen, LWMM
Attard, G
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Humans
Neoplasm Metastasis
Disease Progression
Phenylthiohydantoin
Androstenes
Receptors, Androgen
Adult
Aged
Aged, 80 and over
Middle Aged
Male
Neoplastic Cells, Circulating
Prostatic Neoplasms, Castration-Resistant
Research team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Treatment Resistance
Language
eng
Date accepted
2015-01-27
License start date
2015-03-31
Citation
British journal of cancer, 2015, 112 (7), pp. 1166 - 1174
Publisher
NATURE PUBLISHING GROUP