title: Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer.
abstract: OBJECTIVE
  Although novel agents targeting the androgen-androgen receptor (AR) axis have altered the treatment paradigm of metastatic castration-resistant prostate cancer (mCRPC), development of therapeutic resistance is inevitable. In this study, we examined whether AR gene aberrations detectable in circulating cell-free DNA (cfDNA) are associated with resistance to abiraterone acetate and enzalutamide in mCRPC patients.
  
  
  METHODS
  Plasma was collected from 62 mCRPC patients ceasing abiraterone acetate (n = 29), enzalutamide (n = 19), or other agents (n = 14) due to disease progression. DNA was extracted and subjected to array comparative genomic hybridization (aCGH) for chromosome copy number analysis, and Roche 454 targeted next-generation sequencing of exon 8 in the AR.
  
  
  RESULTS
  On aCGH, AR amplification was significantly more common in patients progressing on enzalutamide than on abiraterone or other agents (53% vs. 17% vs. 21%, P = 0.02, χ(2)). Missense AR exon 8 mutations were detected in 11 of 62 patients (18%), including the first reported case of an F876L mutation in an enzalutamide-resistant patient and H874Y and T877A mutations in 7 abiraterone-resistant patients. In patients switched onto enzalutamide after cfDNA collection (n = 39), an AR gene aberration (copy number increase and/or an exon 8 mutation) in pretreatment cfDNA was associated with adverse outcomes, including lower rates of PSA decline ≥ 30% (P = 0.013, χ(2)) and shorter time to radiographic/clinical progression (P = 0.010, Cox proportional hazards regression).
  
  
  CONCLUSIONS
  AR gene aberrations in cfDNA are associated with resistance to enzalutamide and abiraterone in mCRPC. Our data illustrate that genomic analysis of cfDNA is a minimally invasive method for interrogating mechanisms of therapeutic resistance in mCRPC.
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada. Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Arun A
authors.initials: AA
authors.lastname: Azad
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Stanislav V
authors.initials: SV
authors.lastname: Volik
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Haegert
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Stephane
authors.initials: S
authors.lastname: Le Bihan
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bell
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Shawn A
authors.initials: SA
authors.lastname: Anderson
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: McConeghy
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Shukin
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Jenny
authors.initials: J
authors.lastname: Bazov
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
authors.forename: Jack
authors.initials: J
authors.lastname: Youngren
authors.affiliation: Department of Urology, UCSF, UCSF Diller Comprehensive Cancer Center, San Francisco, California.
authors.forename: Pamela
authors.initials: P
authors.lastname: Paris
authors.affiliation: Department of Pathology and Laboratory Medicine, OHSU Knight Cancer Institute, Portland, Oregon.
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada. University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada. University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada. University of British Columbia, Vancouver, British Columbia, Canada. kchi@bccancer.bc.ca ccollins@prostatecentre.com.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Collins
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada. Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. University of British Columbia, Vancouver, British Columbia, Canada. kchi@bccancer.bc.ca ccollins@prostatecentre.com.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000097:blood*; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating; D016016:Proportional Hazards Models; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011944:Receptors, Androgen / Q000235:genetics*; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000736:Androstenes; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel; C089740:abiraterone