title: TMPRSS2-ERG status in circulating tumor cells as a predictive biomarker of sensitivity in castration-resistant prostate cancer patients treated with abiraterone acetate.
abstract: BACKGROUND
  Abiraterone acetate (AA) is an androgen biosynthesis inhibitor shown to prolong life in patients with castration-resistant prostate cancer (CRPC) already treated with chemotherapy. AA treatment results in dramatic declines in prostate-specific antigen (PSA) in some patients and no declines in others, suggesting the presence of molecular determinants of sensitivity in tumors.
  
  
  OBJECTIVE
  To study the role of transmembrane protease, serine 2 (TMPRSS2)-v-ets erythroblastosis virus E26 oncogene homolog (ERG) fusion, an androgen-dependent growth factor, in circulating tumor cells (CTCs) as a biomarker of sensitivity to AA.
  
  
  METHODS
  The predictive value of TMPRSS2-ERG status was studied in 41 of 48 men with postchemotherapy-treated CRPC enrolled in sequential phase 2 AA trials.
  
  
  METHODS
  Patients received AA 1000 mg daily and continuously.
  
  
  METHODS
  TMPRSS2-ERG status was characterized by a sensitive, analytically valid reverse transcription polymerase chain reaction assay in CTCs enriched from ethylene-diaminetetraacetic acid anticoagulated blood obtained prior to AA treatment. Outcomes were measured by PSA Working Group 1 criteria.
  
  
  CONCLUSIONS
  Standard procedures for specimen acquisition, processing, and testing using the validated TMPRSS2-ERG assay on a multiplex platform gave intra-assay and interassay coefficients of variation <7%. TMPRSS2-ERG fusion was present in 15 of 41 patients (37%), who had a median baseline CTC count of 17 (interquartile range: 7-103 cells per 7.5 ml). A PSA decline ≥50% was observed in 7 of 15 patients (47%) with the fusion and in 10 of 26 patients (38%) without the fusion. Although limited by the low number of patients, a posttherapy CTC count of less than five per 7.5 ml was prognostic for longer survival relative to a CTC count five or more. TMPRSS2-ERG status did not predict a decline in PSA or other clinical outcomes.
  
  
  CONCLUSIONS
  Molecular profiles of CTCs with an analytically valid assay identified the presence of the prostate cancer-specific TMPRSS2-ERG fusion but did not predict for response to AA treatment. This finding demonstrates the role of CTCs as surrogate tissue that can be obtained in a routine practice setting.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT00474383 (COU-AA-003), NCT00485303 (COU-AA-004).
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Danila
authors.forename: Aseem
authors.initials: A
authors.lastname: Anand
authors.forename: Clifford C
authors.initials: CC
authors.lastname: Sung
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Leversha
authors.forename: Long
authors.initials: L
authors.lastname: Cao
authors.forename: Hans
authors.initials: H
authors.lastname: Lilja
authors.forename: Arturo
authors.initials: A
authors.lastname: Molina
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.forename: Martin
authors.initials: M
authors.lastname: Fleisher
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D000069501:Abiraterone Acetate; D000730:Androstadienes / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005819:Genetic Markers; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D009360:Neoplastic Cells, Circulating / Q000378:metabolism* / Q000473:pathology; D009519:New York City; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D009919:Orchiectomy; D018579:Patient Selection; D011237:Predictive Value of Tests; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D018714:Radiotherapy, Adjuvant; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000730:Androstadienes; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D005819:Genetic Markers; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D000069501:Abiraterone Acetate