title: Comprehensive validation of published immunohistochemical prognostic biomarkers of prostate cancer -what has gone wrong? A blueprint for the way forward in biomarker studies.
abstract: BACKGROUND
  Treatment planning of localised prostate cancer remains challenging. Besides conventional parameters, a wealth of prognostic biomarkers has been proposed so far. None of which, however, have successfully been implemented in a routine setting so far. The aim of our study was to systematically verify a set of published prognostic markers for prostate cancer.
  
  
  METHODS
  Following an in-depth PubMed search, 28 markers were selected that have been proposed as multivariate prognostic markers for primary prostate cancer. Their prognostic validity was examined in a radical prostatectomy cohort of 238 patients with a median follow-up of 60 months and biochemical progression as endpoint of the analysis. Immunohistochemical evaluation was performed using previously published cut-off values, but allowing for optimisation if necessary. Univariate and multivariate Cox regression were used to determine the prognostic value of biomarkers included in this study.
  
  
  RESULTS
  Despite the application of various cut-offs in the analysis, only four (14%) markers were verified as independently prognostic (AKT1, stromal AR, EZH2, and PSMA) for PSA relapse following radical prostatectomy.
  
  
  CONCLUSIONS
  Apparently, many immunohistochemistry-based studies on prognostic markers seem to be over-optimistic. Codes of best practice, such as the REMARK guidelines, may facilitate the performance of conclusive and transparent future studies.
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Huber
authors.affiliation: Institute of Surgical Pathology, University of Bern, Bern, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Montani
authors.affiliation: Department of Urology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Sulser
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Jaggi
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Wild
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Moch
authors.affiliation: Institute for Medical Biometry, Informatics and Epidemiology, Bonn, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Gevensleben
authors.affiliation: Institute for Medical Biometry, Informatics and Epidemiology, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schmid
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Wyder
authors.affiliation: Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Kristiansen
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D015331:Cohort Studies; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000737:chemistry*
chemical_list: D014408:Biomarkers, Tumor