title: Nuclear-specific AR-V7 Protein Localization is Necessary to Guide Treatment Selection in Metastatic Castration-resistant Prostate Cancer.
abstract: Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSi) abiraterone acetate, enzalutamide, and apalutamide.
  
  
  
  To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization ("nuclear-agnostic") identifies more patients who would benefit from a taxane over an ARSi.
  
  
  
  The study used a cross-sectional cohort. Between December 2012 and March 2015, 193 pretherapy blood samples, 191 of which were evaluable, were collected and processed from 161 unique mCRPC patients before starting a new line of systemic therapy for disease progression at the Memorial Sloan Kettering Cancer Center. The association between two AR-V7 scoring criteria, post-therapy prostate-specific antigen (PSA) change (PTPC) and OS following ARSi or taxane treatment, was explored. One criterion required nuclear-specific AR-V7 localization, and the other required an AR-V7 signal but was agnostic to protein localization in CTCs.
  
  
  
  Correlation of AR-V7 status to PTPC and OS was investigated. Relationships with survival were analyzed using multivariable Cox regression and log-rank analyses.
  
  
  
  A total of 34 (18%) samples were AR-V7-positive using nuclear-specific criteria, and 56 (29%) were AR-V7-positive using nuclear-agnostic criteria. Following ARSi treatment, none of the 16 nuclear-specific AR-V7-positive samples and six of the 32 (19%) nuclear-agnostic AR-V7-positive samples had ≥50% PTPC at 12 weeks. The strongest baseline factor influencing OS was the interaction between the presence of nuclear-specific AR-V7-positive CTCs and treatment with a taxane (hazard ratio 0.24, 95% confidence interval 0.078-0.79; p=0.019). This interaction was not significant when nuclear-agnostic criteria were used.
  
  
  
  To reliably inform treatment selection using an AR-V7 protein biomarker in CTCs, nuclear-specific localization is required.
  
  
  
  We analyzed outcomes for patients with metastatic castration-resistant prostate cancer on androgen receptor signaling inhibitors and standard chemotherapy. Patients with circulating tumor cells that had AR-V7 protein in the cellular nuclei were very likely to survive longer on taxane-based chemotherapy, and tests unable to distinguish where the protein is located in the cell are not as predictive of benefit.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Electronic address: scherh@mskcc.org.
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.affiliation: Epic Sciences, La Jolla, CA, USA.
authors.forename: Ryon P
authors.initials: RP
authors.lastname: Graf
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Schreiber
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Brigit
authors.initials: B
authors.lastname: McLaughlin
authors.affiliation: Epic Sciences, La Jolla, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lu
authors.affiliation: Epic Sciences, La Jolla, CA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Louw
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Danila
authors.affiliation: Epic Sciences, La Jolla, CA, USA.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Dugan
authors.affiliation: Epic Sciences, La Jolla, CA, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.affiliation: Clinical Chemistry Service, Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Fleisher
authors.affiliation: Epic Sciences, La Jolla, CA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Dittamore
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D002467:Cell Nucleus / Q000737:chemistry* / Q000473:pathology; D016009:Chi-Square Distribution; D003430:Cross-Sectional Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D000073890:Liquid Biopsy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009360:Neoplastic Cells, Circulating / Q000737:chemistry* / Q000473:pathology; D018579:Patient Selection; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D020033:Protein Isoforms; D011944:Receptors, Androgen / Q000097:blood*; D043823:Taxoids / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D020033:Protein Isoforms; D011944:Receptors, Androgen; D043823:Taxoids
keywords: AR-V7; Circulating tumor cells; Liquid biopsy; Prostate cancer