title: Evaluating a 4-marker signature of aggressive prostate cancer using time-dependent AUC.
abstract: BACKGROUND
  We previously identified a protein tumor signature of PTEN, SMAD4, SPP1, and CCND1 that, together with clinical features, was associated with lethal outcomes among prostate cancer patients. In the current study, we sought to validate the molecular model using time-dependent measures of AUC and predictive values for discriminating lethal from non-lethal prostate cancer.
  
  
  METHODS
  Using data from the initial study, we fit survival models for men with prostate cancer who were participants in the Physicians' Health Study (PHS; n = 276). Based on these models, we generated prognostic risk scores in an independent population, the Health Professionals Follow-up Study (HPFS; n = 347) to evaluate external validity. In each cohort, men were followed prospectively from cancer diagnosis through 2011 for development of distant metastasis or cancer mortality. We measured protein tumor expression of PTEN, SMAD4, SPP1, and CCND1 on tissue microarrays.
  
  
  RESULTS
  During a median of 11.9 and 14.3 years follow-up in the PHS and HPFS cohorts, 24 and 32 men (9%) developed lethal disease. When used as a prognostic factor in a new population, addition of the four markers to clinical variables did not improve discriminatory accuracy through 15 years of follow-up.
  
  
  CONCLUSIONS
  Although the four markers have been identified as key biological mediators in metastatic progression, they do not provide independent, long-term prognostic information beyond clinical factors when measured at diagnosis. This finding may underscore the broad heterogeneity in aggressive prostate tumors and highlight the challenges that may result from overfitting in discovery-based research.
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.|Department of Epidemiology, University of Florida, Gainesville, Florida.
authors.forename: Travis A
authors.initials: TA
authors.lastname: Gerke
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Martin
authors.affiliation: Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Zhihu
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Nuttall
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.|Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Rosina T
authors.initials: RT
authors.lastname: Lis
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.|Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.|Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Kantoff
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D018450:Disease Progression; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D053495:Osteopontin / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011379:Prognosis; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D051901:Smad4 Protein / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; C506895:SPP1 protein, human; D051901:Smad4 Protein; D053495:Osteopontin; D019938:Cyclin D1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: biomarker validation; prognostic biomarkers; prostate cancer