title: Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone.
abstract: OBJECTIVE
  Persistent androgen signaling is implicated in castrate-resistant prostate cancer (CRPC) progression. This study aimed to evaluate androgen signaling in bone marrow-infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations.
  
  
  METHODS
  This was an open-label, observational study of 57 patients with bone-metastatic CRPC who underwent transiliac bone marrow biopsy between October 2007 and March 2010. Patients received oral abiraterone acetate (1 g) once daily and prednisone (5 mg) twice daily. Androgen receptor (AR) and CYP17 expression were assessed by immunohistochemistry, testosterone concentration by mass spectrometry, AR copy number by polymerase chain reaction, and TMPRSS2-ERG status by fluorescent in situ hybridization in available tissues.
  
  
  RESULTS
  Median overall survival was 555 days (95% CI, 440 to 965+ days). Maximal prostate-specific antigen decline ≥ 50% occurred in 28 (50%) of 56 patients. Homogeneous, intense nuclear expression of AR, combined with ≥ 10% CYP17 tumor expression, was correlated with longer time to treatment discontinuation (> 4 months) in 25 patients with tumor-infiltrated bone marrow samples. Pretreatment CYP17 tumor expression ≥ 10% was correlated with increased bone marrow aspirate testosterone. Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression.
  
  
  CONCLUSIONS
  The observed pretreatment androgen-signaling signature is consistent with persistent androgen signaling in CRPC bone metastases. This is the first evidence that abiraterone acetate achieves sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels. Potential admixture of blood with bone marrow aspirate limits our ability to determine the origin of measured testosterone.
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Unit 1374, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.forename: Mark
authors.initials: M
authors.lastname: Titus
authors.forename: Dimitra
authors.initials: D
authors.lastname: Tsavachidou
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Tzelepi
authors.forename: Sijin
authors.initials: S
authors.lastname: Wen
authors.forename: Anh
authors.initials: A
authors.lastname: Hoang
authors.forename: Arturo
authors.initials: A
authors.lastname: Molina
authors.forename: Nicole
authors.initials: N
authors.lastname: Chieffo
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Smith
authors.forename: Maria
authors.initials: M
authors.lastname: Karlou
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes; D000737:Androstenols / Q000009:adverse effects / Q000627:therapeutic use*; D001853:Bone Marrow / Q000378:metabolism; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D002369:Castration; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007239:Infections / Q000139:chemically induced; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000601:surgery; D011944:Receptors, Androgen / Q000378:metabolism*; D012074:Remission Induction; D013739:Testosterone / Q000097:blood / Q000378:metabolism; D014652:Vascular Diseases / Q000139:chemically induced; D055815:Young Adult
chemical_list: D000736:Androstenes; D000737:Androstenols; D056572:Histone Deacetylase Inhibitors; D011944:Receptors, Androgen; D013739:Testosterone; C089740:abiraterone