title: Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer.
abstract: OBJECTIVE
  Circulating tumor cell (CTC) enumeration has not been prospectively validated in standard first-line docetaxel treatment for metastatic castration-resistant prostate cancer. We assessed the prognostic value of CTCs for overall survival (OS) and disease response in S0421, a phase III trial of docetaxel plus prednisone with or without atrasentan.
  
  
  METHODS
  CTCs were enumerated at baseline (day 0) and before cycle two (day 21) using CellSearch. Baseline counts and changes in counts from day 0 to 21 were evaluated for association with OS, prostate-specific antigen (PSA), and RECIST response using Cox regression as well as receiver operator characteristic (ROC) curves, integrated discrimination improvement (IDI) analysis, and regression trees.
  
  
  RESULTS
  Median day-0 CTC count was five cells per 7.5 mL, and CTCs < versus ≥ five per 7.5 mL were significantly associated with baseline PSA, bone pain, liver disease, hemoglobin, alkaline phosphatase, and subsequent PSA and RECIST response. Median OS was 26 months for < five versus 13 months for ≥ five CTCs per 7.5 mL at day 0 (hazard ratio [HR], 2.74 [adjusting for covariates]). ROC curves had higher areas under the curve for day-0 CTCs than for PSA, and IDI analysis showed that adding day-0 CTCs to baseline PSA and other covariates increased predictive accuracy for survival by 8% to 10%. Regression trees yielded new prognostic subgroups, and rising CTC count from day 0 to 21 was associated with shorter OS (HR, 2.55).
  
  
  CONCLUSIONS
  These data validate the prognostic utility of CTC enumeration in a large docetaxel-based prospective cohort. Baseline CTC counts were prognostic, and rising CTCs at 3 weeks heralded significantly worse OS, potentially serving as an early metric to help redirect and optimize therapy in this clinical setting.
authors.affiliation: Amir Goldkorn, David I. Quinn, and Tong Xu, University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles; Przemyslaw Twardowski, City of Hope, Duarte; Philip C. Mack and Primo Lara Jr, University of California, Davis, Sacramento, CA; Benjamin Ely and Catherine M. Tangen, Southwest Oncology Group Statistical Center; Celestia S. Higano, Puget Sound Oncology Consortium, Seattle Cancer Care Alliance, and University of Washington, Seattle, WA; Louis M. Fink, Nevada Cancer Institute; Nicholas J. Vogelzang, Comprehensive Cancer Centers of Nevada and US Oncology Research, Las Vegas, NV; Peter J. Van Veldhuizen, University of Kansas Cancer Center, Westwood, KS; Neeraj Agarwal, University of Utah Huntsman Cancer Institute, Salt Lake City, UT; Michael A. Carducci, Johns Hopkins Kimmel Cancer Center and Eastern Cooperative Oncology Group, Baltimore, MD; J. Paul Monk III, Ohio State University and Cancer and Leukemia Group B, Columbus, OH; Ram H. Datar and Richard J. Cote, University of Miami Miller School of Medicine, Miami, FL; Mark Garzotto, Portland Veterans Affairs Medical Center, Portland, OR; Maha Hussain, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; and Ian Murchie Thompson Jr, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Amir
authors.initials: A
authors.lastname: Goldkorn
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ely
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Tangen
authors.forename: Louis M
authors.initials: LM
authors.lastname: Fink
authors.forename: Tong
authors.initials: T
authors.lastname: Xu
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Twardowski
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Van Veldhuizen
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: J Paul
authors.initials: JP
authors.lastname: Monk
authors.forename: Ram H
authors.initials: RH
authors.lastname: Datar
authors.forename: Mark
authors.initials: M
authors.lastname: Garzotto
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
authors.forename: Primo
authors.initials: P
authors.lastname: Lara
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
authors.forename: Ian Murchie
authors.initials: IM
authors.lastname: Thompson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cote
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077868:Atrasentan; D014408:Biomarkers, Tumor / Q000097:blood; D002369:Castration; D002452:Cell Count; D018450:Disease Progression; D000077143:Docetaxel; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009360:Neoplastic Cells, Circulating; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011759:Pyrrolidines / Q000627:therapeutic use*; D043823:Taxoids / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011759:Pyrrolidines; D043823:Taxoids; D000077143:Docetaxel; D000077868:Atrasentan