title: Evaluating the Four Kallikrein Panel of the 4Kscore for Prediction of High-grade Prostate Cancer in Men in the Canary Prostate Active Surveillance Study.
abstract: Diagnosis of Gleason 6 prostate cancer can leave uncertainty about the presence of undetected aggressive disease.
  
  
  
  To evaluate the utility of a four kallikrein (4K) panel in predicting the presence of high-grade cancer in men on active surveillance.
  
  
  
  Plasma collected before the first and subsequent surveillance biopsies was assessed for 718 men prospectively enrolled in the multi-institutional Canary PASS trial. Biopsy data were split 2:1 into training and test sets. We developed statistical models that included clinical information and either the 4Kpanel or serum prostate-specific antigen (PSA).
  
  
  
  The endpoint was reclassification to Gleason ≥7. We used receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) to assess discriminatory capacity, and decision curve analysis (DCA) to report clinical net benefit.
  
  
  
  Significant predictors for reclassification were 4Kpanel (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31-1.81) or PSA (OR 2.11, 95% CI 1.53-2.91), ≥20% cores positive (OR 2.10, 95% CI 1.33-3.32), two or more prior negative biopsies (OR 0.19, 95% CI 0.04-0.85), prostate volume (OR 0.47, 95% CI 0.31-0.70), and body mass index (OR 1.09, 95% CI 1.04-1.14). ROC curve analysis comparing 4K and base models indicated that the 4Kpanel improved accuracy for predicting reclassification (AUC 0.78 vs 0.74) at the first surveillance biopsy. Both models performed comparably for prediction of reclassification at subsequent biopsies (AUC 0.75 vs 0.76). In DCA, both models showed higher net benefit compared to biopsy-all and biopsy-none strategies. Limitations include the single cohort nature of the study and the small numbers; results should be validated in another cohort before clinical use.
  
  
  
  The 4Kpanel provided incremental value over routine clinical information in predicting high-grade cancer in the first biopsy after diagnosis. The 4Kpanel did not add predictive value to the base model at subsequent surveillance biopsies.
  
  
  
  Active surveillance is a management strategy for many low-grade prostate cancers. Repeat biopsies monitor for previously undetected high-grade cancer. We show that a model with clinical variables, including a panel of four kallikreins, indicates the presence of high-grade cancer before a biopsy is performed.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Washington, Seattle, WA, USA; Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. Electronic address: dlin@uw.edu.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lin
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Washington, Seattle, WA, USA.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Newcomb
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Marshall D
authors.initials: MD
authors.lastname: Brown
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Sjoberg
authors.affiliation: OPKO Labs, Nashville, TN, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Stanford University, Stanford, CA, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Brooks
authors.affiliation: University of California at San Francisco, San Francisco, CA, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Carroll
authors.affiliation: University of California at San Francisco, San Francisco, CA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cooperberg
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Atreya
authors.initials: A
authors.lastname: Dash
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Ellis
authors.affiliation: Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Fabrizio
authors.affiliation: University of British Columbia, Vancouver, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: University of Michigan, Ann Arbor, MI, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Morgan
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Thompson
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wagner
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Yingye
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000368:Aged; D000465:Algorithms; D019540:Area Under Curve; D001706:Biopsy; D003661:Decision Support Techniques; D006801:Humans; D007610:Kallikreins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009656:North America; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood* / Q000473:pathology; D012372:ROC Curve; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D057832:Watchful Waiting
chemical_list: C000595667:KLK2 protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Active surveillance; Biomarker; Kallikrein; Prospective studies; Prostatic neoplasms