title: Androgen receptor expression in circulating tumour cells from castration-resistant prostate cancer patients treated 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.
authors.affiliation: Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: M
authors.initials: M
authors.lastname: Crespo
authors.affiliation: Department of Medical Cell BioPhysics, MIRA Institute, University of Twente, 7522ND, Enschede, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: van Dalum
authors.affiliation: 1] Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK [2] Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, SM2 5NG, UK.
authors.forename: R
authors.initials: R
authors.lastname: Ferraldeschi
authors.affiliation: 1] Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK [2] Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, SM2 5NG, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Zafeiriou
authors.affiliation: 1] Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK [2] Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, SM2 5NG, UK.
authors.forename: S
authors.initials: S
authors.lastname: Sideris
authors.affiliation: 1] Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK [2] Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, SM2 5NG, UK.
authors.forename: D
authors.initials: D
authors.lastname: Lorente
authors.affiliation: 1] Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK [2] Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, SM2 5NG, UK.
authors.forename: D
authors.initials: D
authors.lastname: Bianchini
authors.affiliation: Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: D N
authors.initials: DN
authors.lastname: Rodrigues
authors.affiliation: Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: R
authors.initials: R
authors.lastname: Riisnaes
authors.affiliation: Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: S
authors.initials: S
authors.lastname: Miranda
authors.affiliation: Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: I
authors.initials: I
authors.lastname: Figueiredo
authors.affiliation: Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: P
authors.initials: P
authors.lastname: Flohr
authors.affiliation: Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: K
authors.initials: K
authors.lastname: Nowakowska
authors.affiliation: 1] Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK [2] Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, SM2 5NG, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: de Bono
authors.affiliation: Department of Medical Cell BioPhysics, MIRA Institute, University of Twente, 7522ND, Enschede, The Netherlands.
authors.forename: L W M M
authors.initials: LW
authors.lastname: Terstappen
authors.affiliation: 1] Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK [2] Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, SM2 5NG, UK.
authors.forename: G
authors.initials: G
authors.lastname: Attard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000187:drug effects* / Q000378:metabolism*; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D011944:Receptors, Androgen / Q000096:biosynthesis*
chemical_list: C410798:AR protein, human; D000736:Androstenes; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; C089740:abiraterone