Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents

M. Crespo, Guus van Dalum, R. Ferraldeschi, Z. Zafeiriou, S. Sideris, D. Lorente, D. Bianchini, D.N. Rodrigues, R. Rijsnaes, S. Miranda, I. Figueiredo, P. Flohr, K. Nowakowska, J.S. de Bono, Leonardus Wendelinus Mathias Marie Terstappen, G. Attard

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Abstract

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
Original languageEnglish
Pages (from-to)1166-1174
JournalBritish journal of cancer
Volume112
DOIs
Publication statusPublished - 2015

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Circulating Neoplastic Cells
Castration
Androgen Receptors
Prostatic Neoplasms
Cytoplasmic and Nuclear Receptors

Keywords

  • METIS-312075
  • IR-98164

Cite this

Crespo, M. ; van Dalum, Guus ; Ferraldeschi, R. ; Zafeiriou, Z. ; Sideris, S. ; Lorente, D. ; Bianchini, D. ; Rodrigues, D.N. ; Rijsnaes, R. ; Miranda, S. ; Figueiredo, I. ; Flohr, P. ; Nowakowska, K. ; de Bono, J.S. ; Terstappen, Leonardus Wendelinus Mathias Marie ; Attard, G. / Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents. In: British journal of cancer. 2015 ; Vol. 112. pp. 1166-1174.
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title = "Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents",
abstract = "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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author = "M. Crespo and {van Dalum}, Guus and R. Ferraldeschi and Z. Zafeiriou and S. Sideris and D. Lorente and D. Bianchini and D.N. Rodrigues and R. Rijsnaes and S. Miranda and I. Figueiredo and P. Flohr and K. Nowakowska and {de Bono}, J.S. and Terstappen, {Leonardus Wendelinus Mathias Marie} and G. Attard",
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doi = "10.1038/bjc.2015.63",
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volume = "112",
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Crespo, M, van Dalum, G, Ferraldeschi, R, Zafeiriou, Z, Sideris, S, Lorente, D, Bianchini, D, Rodrigues, DN, Rijsnaes, R, Miranda, S, Figueiredo, I, Flohr, P, Nowakowska, K, de Bono, JS, Terstappen, LWMM & Attard, G 2015, 'Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents' British journal of cancer, vol. 112, pp. 1166-1174. https://doi.org/10.1038/bjc.2015.63

Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents. / Crespo, M.; van Dalum, Guus; Ferraldeschi, R.; Zafeiriou, Z.; Sideris, S.; Lorente, D.; Bianchini, D.; Rodrigues, D.N.; Rijsnaes, R.; Miranda, S.; Figueiredo, I.; Flohr, P.; Nowakowska, K.; de Bono, J.S.; Terstappen, Leonardus Wendelinus Mathias Marie; Attard, G.

In: British journal of cancer, Vol. 112, 2015, p. 1166-1174.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents

AU - Crespo, M.

AU - van Dalum, Guus

AU - Ferraldeschi, R.

AU - Zafeiriou, Z.

AU - Sideris, S.

AU - Lorente, D.

AU - Bianchini, D.

AU - Rodrigues, D.N.

AU - Rijsnaes, R.

AU - Miranda, S.

AU - Figueiredo, I.

AU - Flohr, P.

AU - Nowakowska, K.

AU - de Bono, J.S.

AU - Terstappen, Leonardus Wendelinus Mathias Marie

AU - Attard, G.

PY - 2015

Y1 - 2015

N2 - 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

AB - 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

KW - METIS-312075

KW - IR-98164

U2 - 10.1038/bjc.2015.63

DO - 10.1038/bjc.2015.63

M3 - Article

VL - 112

SP - 1166

EP - 1174

JO - British journal of cancer

JF - British journal of cancer

SN - 0007-0920

ER -