title: Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration-resistant Prostate Cancer Reveals Novel Intra-AR Structural Variation and Splice Variant Expression Patterns.
abstract: Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative.
  
  
  
  To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy.
  
  
  
  Peripheral blood was collected from patients with CRPC (n=30) before initiation of a new line of systemic therapy. We performed profiling of circulating tumour DNA via low-pass whole-genome sequencing and targeted sequencing of the entire AR gene, including introns. Targeted RNA sequencing was performed on enriched circulating tumour cell fractions to assess the expression levels of seven AR splice variants (ARVs).
  
  
  
  Somatic AR variations, including copy-number alterations, structural variations, and point mutations, were combined with ARV expression patterns and correlated to clinicopathologic parameters.
  
  
  
  Collectively, any AR perturbation, including ARV, was detected in 25/30 patients. Surprisingly, intra-AR structural variation was present in 15/30 patients, of whom 14 expressed ARVs. The majority of ARV-positive patients expressed multiple ARVs, with AR-V3 the most abundantly expressed. The presence of any ARV was associated with progression-free survival after second-line endocrine treatment (hazard ratio 4.53, 95% confidence interval 1.424-14.41; p=0.0105). Six out of 17 poor responders were AR-V7-negative, but four carried other AR perturbations.
  
  
  
  Comprehensive AR profiling, which is feasible using liquid biopsies, is necessary to increase our understanding of the mechanisms underpinning resistance to endocrine treatment.
  
  
  
  Alterations in the androgen receptor are associated with endocrine treatment outcomes. This study demonstrates that it is possible to identify different types of alterations via simple blood draws. Follow-up studies are needed to determine the effect of such alterations on hormonal therapy.
authors.affiliation: Centre for Oncological Research, University of Antwerp, Antwerp, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: De Laere
authors.affiliation: Centre for Oncological Research, University of Antwerp, Antwerp, Belgium.
authors.forename: Pieter-Jan
authors.initials: PJ
authors.lastname: van Dam
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tom
authors.initials: T
authors.lastname: Whitington
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Mayrhofer
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Emanuela Henao
authors.initials: EH
authors.lastname: Diaz
authors.affiliation: Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Van den Eynden
authors.affiliation: Department of Oncology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium.
authors.forename: Jean
authors.initials: J
authors.lastname: Vandebroek
authors.affiliation: Multiplicom N.V., Niel, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
authors.affiliation: Centre for Oncological Research, University of Antwerp, Antwerp, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Van Laere
authors.affiliation: Centre for Oncological Research, University of Antwerp, Antwerp, Belgium; Department of Oncology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Grönberg
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden. Electronic address: johan.lindberg@ki.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005240:Feasibility Studies; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D053208:Kaplan-Meier Estimate; D000073890:Liquid Biopsy; D008297:Male; D010641:Phenotype; D010865:Pilot Projects; D017354:Point Mutation; D011237:Predictive Value of Tests; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011487:Protein Conformation; D020033:Protein Isoforms; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics*; D013997:Time Factors; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: C410798:AR protein, human; D018931:Antineoplastic Agents, Hormonal; D020033:Protein Isoforms; D011944:Receptors, Androgen
keywords: AR splice variants; AR-V7; Androgen receptor; Castration-resistant prostate cancer; Circulating tumour DNA; Endocrine treatment; Structural variation