title: Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer.
abstract: BACKGROUND
  Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC).
  
  
  OBJECTIVE
  To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations.
  
  
  METHODS
  In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment.
  
  
  METHODS
  Androgen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography-tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied.
  
  
  CONCLUSIONS
  Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9-29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ≥ 50% and ≥ 90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (> 75%) and CYP17 (> 10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation.
  
  
  CONCLUSIONS
  The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance.
  
  
  RESULTS
  We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier NCT01091103.
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA; Department of Clinical Therapeutics, University of Athens, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Titus
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA.
authors.forename: Sijin
authors.initials: S
authors.lastname: Wen
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA.
authors.forename: Anh
authors.initials: A
authors.lastname: Hoang
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Karlou
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA.
authors.forename: Robynne
authors.initials: R
authors.lastname: Ashe
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA.
authors.forename: Shi Ming
authors.initials: SM
authors.lastname: Tu
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Aparicio
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.affiliation: Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: James
authors.initials: J
authors.lastname: Mohler
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA. Electronic address: clogothe@mdanderson.org.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001853:Bone Marrow / Q000378:metabolism; D019046:Bone Marrow Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000556:secondary; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000556:secondary; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D018628:Gene Dosage; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013739:Testosterone / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D019394:Ki-67 Antigen; D009570:Nitriles; D020033:Protein Isoforms; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D015682:Retroviridae Proteins, Oncogenic; C050379:oncogene proteins v-ets; D010669:Phenylthiohydantoin; D013739:Testosterone; C540278:enzalutamide; D013254:Steroid 17-alpha-Hydroxylase; D017430:Prostate-Specific Antigen
keywords: Adaptive feedback mechanism; Androgen receptor; Androgen signaling inhibition; Bone metastasis; Bone tumor microenvironment; Castration-resistant prostate cancer; Enzalutamide; Predictors of outcome; Primary resistance to enzalutamide; Tissue-based research