title: Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide.
abstract: Purpose We reported previously that the detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumor cells (CTCs) correlated with poor outcomes from the use of abiraterone and enzalutamide in patients with castration-resistant prostate cancer (CRPC). Here, we expanded our cohort size to better characterize the prognostic significance of AR-V7 in this setting. Methods We prospectively enrolled 202 patients with CRPC starting abiraterone or enzalutamide and investigated the prognostic value of CTC detection (+ v -) and AR-V7 detection (+ v -) using a CTC-based AR-V7 mRNA assay. We examined ≥ 50% prostate-specific antigen (PSA) responses, PSA progression-free survival, clinical and radiologic progression-free survival, and overall survival. We constructed multivariable models adjusting for PSA, Gleason sum, number of prior hormone therapies, prior abiraterone or enzalutamide use, prior taxane use, presence of visceral metastases, and Eastern Cooperative Oncology Group score. We also separately examined the first-line and second-line novel hormonal therapy (NHT) settings. Results Median follow-up times were 15.0, 21.7, and 14.6 months for CTC-, CTC+/AR-V7- and CTC+/AR-V7+ patients, respectively. CTC+/AR-V7+ patients were more likely to have Gleason scores ≥ 8 ( P = .05), metastatic disease at diagnosis ( P = .01), higher PSA ( P < .01), prior abiraterone or enzalutamide use ( P = .03), prior taxane use ( P = .02), and Eastern Cooperative Oncology Group ≥ 1 ( P = .01). Outcomes for the overall cohort (and separately for the first-line and second-line NHT cohorts) were best for CTC- patients, intermediate for CTC+/AR-V7- patients, and worse for CTC+/AR-V7+ patients. These correlations remained significant in multivariable models. Conclusion This expanded analysis further characterizes the importance of CTC-based AR-V7 mRNA detection in predicting outcomes in patients with CRPC receiving first- and second-line NHT and, to the best of our knowledge, is the first to suggest that this assay be interpreted using three separate prognostic categories: CTC-, CTC+/AR-V7-, and CTC+/AR-V7+.
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Antonarakis
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Changxue
authors.initials: C
authors.lastname: Lu
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Brandon
authors.initials: B
authors.lastname: Luber
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Yezi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: John L
authors.initials: JL
authors.lastname: Silberstein
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Maritza N
authors.initials: MN
authors.lastname: Taylor
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Maughan
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Paller
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
mesh_terms: D000368:Aged; D000736:Androstenes / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D015331:Cohort Studies; D018572:Disease-Free Survival; D006801:Humans; D007610:Kallikreins / Q000097:blood; D008297:Male; D009362:Neoplasm Metastasis; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000097:blood* / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: C410798:AR protein, human; D000736:Androstenes; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D020033:Protein Isoforms; D012333:RNA, Messenger; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; C089740:abiraterone