title: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.
abstract: BACKGROUND
  The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone.
  
  
  METHODS
  We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival.
  
  
  RESULTS
  A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA.
  
  
  CONCLUSIONS
  Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).
authors.affiliation: From the Departments of Oncology (E.S.A., H.W., B.L., J.T.I., R.N., C.J.P., S.R.D., M.A.C., M.A.E.), Pathology (H.L.F., T.L.L., Q.Z., A.M.D.M.), and Urology (C.L., M.N., J.C.R., Yan Chen, W.B.I., J.L.), Johns Hopkins University School of Medicine, Baltimore; and Greehey Children's Cancer Research Institute (T.A.M., Yidong Chen) and the Department of Epidemiology and Biostatistics (Yidong Chen), University of Texas Health Science Center at San Antonio, San Antonio.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Antonarakis
authors.forename: Changxue
authors.initials: C
authors.lastname: Lu
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Brandon
authors.initials: B
authors.lastname: Luber
authors.forename: Mary
authors.initials: M
authors.lastname: Nakazawa
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Roeser
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Tabrez A
authors.initials: TA
authors.lastname: Mohammad
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.forename: Helen L
authors.initials: HL
authors.lastname: Fedor
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lotan
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Zheng
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: Rosa
authors.initials: R
authors.lastname: Nadal
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Paller
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
mesh_terms: D000736:Androstenes; D000737:Androstenols / Q000627:therapeutic use*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008297:Male; D009019:Morphinans / Q000032:analysis; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D012334:RNA, Neoplasm / Q000032:analysis*; D011944:Receptors, Androgen / Q000032:analysis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D000736:Androstenes; D000737:Androstenols; D001549:Benzamides; D009019:Morphinans; D009570:Nitriles; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C013757:Mr 1257 MS; C540278:enzalutamide; C089740:abiraterone