Evaluating a 4-marker signature of aggressive prostate cancer using time-dependent AUC.

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.

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.

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.

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. Prostate 75:1926-1933, 2015. © 2015 Wiley Periodicals, Inc.

The Prostate. 2015 Sep 07 [Epub]

Travis A Gerke, Neil E Martin, Zhihu Ding, Elizabeth J Nuttall, Edward C Stack, Edward Giovannucci, Rosina T Lis, Meir J Stampfer, Phillip W Kantoff, Giovanni Parmigiani, Massimo Loda, Lorelei A Mucci

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. , Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts. , Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. , Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. , Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. , Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. , Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. , Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. , Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. , Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. , Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. , Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

PubMed

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