title: Novel prognostic markers in the serum of patients with castration-resistant prostate cancer derived from quantitative analysis of the pten conditional knockout mouse proteome.
abstract: BACKGROUND
  Metastatic castration-resistant prostate cancer (mCRPC) is associated with a poor outcome. Prognostic information is useful and aids treatment decisions. However, current nomograms based on clinical parameters alone have weak prognostic accuracy. Therefore, the identification of new prognostic serum biomarkers could be useful.
  
  
  OBJECTIVE
  To assess if quantitative analysis of the phosphatase and tensin homolog (Pten) conditional knockout mouse proteome reveals significant prognostic biomarkers in mCRPC and to compare the accuracy of these biomarkers with known prognostic factors.
  
  
  METHODS
  Fifty-seven patients with mCRPC were evaluated retrospectively. Prognostic factors used in clinical nomograms were assessed from the records. New candidate biomarkers in patients' sera were derived using a cancer genetics-guided model we recently described, screening the murine Pten-dependent glycoproteome.
  
  
  METHODS
  Quantification in patients' sera was performed by either mass spectrometry-based targeted proteomics or enzyme-linked immunosorbent assays. Prognostic biomarkers for survival were identified based on Kaplan-Meier models. In a second step, random forest analysis was performed to identify a prognostic signature combined from the pooled data of known predictors and newly identified biomarkers.
  
  
  CONCLUSIONS
  With univariate analysis, 13 new significant prognostic factors for survival in the sera of mCRPC patients were found with a Bonferroni-corrected level of significance <5%. Random forest analysis revealed a five-factor predictor (thrombospondin 1; C-reactive protein; poliovirus receptor-related 1; ephrin-A5; and membrane metallo-endopeptidase) with an accuracy of 96% and 94% for 12- and 24-mo survival, respectively. This means that, in our dataset, the error was reduced by 15% compared to using the Halabi et al. nomogram. The retrospective nature of the work and absence of a validating dataset is the major limitation of this work.
  
  
  CONCLUSIONS
  Analysis of the serum proteome in mCRPC patients based on our Pten conditional knockout model, combined with known prognostic factors, potentially improves accuracy of prognostic nomograms. These newly identified markers have to be validated in prospective studies.
authors: Department of Medical Oncology, Kantonsspital St. Gallen, 9007St. Gallen, Switzerland. martin.kaelin@kssg.ch
authors: Martin
authors: M
authors: Kälin
authors: Igor
authors: I
authors: Cima
authors: Ralph
authors: R
authors: Schiess
authors: Niklaus
authors: N
authors: Fankhauser
authors: Tom
authors: T
authors: Powles
authors: Peter
authors: P
authors: Wild
authors: Arnoud
authors: A
authors: Templeton
authors: Thomas
authors: T
authors: Cerny
authors: Ruedi
authors: R
authors: Aebersold
authors: Wilhelm
authors: W
authors: Krek
authors: Silke
authors: S
authors: Gillessen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D002097:C-Reactive Protein / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000097:blood; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D036386:Ephrin-A5 / Q000097:blood; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D000075983:Nectins; D015260:Neprilysin / Q000097:blood; D049451:Nomograms; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D011237:Predictive Value of Tests; D011471:Prostatic Neoplasms / Q000097:blood* / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D040901:Proteomics / Q000379:methods; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013557:Switzerland; D019700:Thrombospondin 1 / Q000097:blood; D013997:Time Factors; D017211:Treatment Failure
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D036386:Ephrin-A5; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins; D019700:Thrombospondin 1; D002097:C-Reactive Protein; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D015260:Neprilysin