Predicting prostate cancer biochemical recurrence using a panel of serum proteomic biomarkers.

PURPOSE The pathological state of the prostate may be reflected by serum proteome in a man. We hypothesized that biomarkers are present in preoperative serum, which may be used to predict the probability of biochemical recurrence following radical prostatectomy. MATERIALS AND METHODS Mass spectrometry analysis was used to compare 52 men who experienced biochemical recurrence with 52 who remained biochemical recurrence-free for approximately 5 years after radical retropubic prostatectomy. A total of 30 matched pairs of recurrent and nonrecurrent serum samples were randomly selected as a training set for biomarker discovery and model development. Selected mass spectrometry peaks were combined with pre-radical retropubic prostatectomy prostate specific antigen in a multivariate algorithm to predict recurrence. The algorithm was evaluated using the remaining 22 recurrent and 22 nonrecurrent subjects as test samples. Protein identities of the selected mass spectrometry peaks were investigated. RESULTS Two serum biomarkers for recurrence, P1 and P2, were combined with preoperative prostate specific antigen to predict biochemical recurrence. The ROC AUC for prostate specific antigen and the predicted outcome was 0.606 and 0.691 in the testing data, respectively. Using a single cutoff the samples were divided into 2 groups that were predictive of biochemical recurrence (p = 0.026). In contrast, preoperative prostate specific antigen did not differ between recurrent and nonrecurrent cases (Wilcoxon matched pairs test p = 0.07). The protein identity of P1 was determined to be a truncated form of C4a (C4a des-Arg). Preliminary data indicated that P2 was an N-terminal fragment of protein C inhibitor. CONCLUSIONS In the current study population, which was matched on Gleason score and TNM staging, pre-radical retropubic prostatectomy prostate specific antigen retained no independent power to predict recurrence. However, by adding 2 proteomic biomarkers to preoperative prostate specific antigen the combined model demonstrated statistically significant value for predicting prostate cancer recurrence in men who underwent radical retropubic prostatectomy.

[1]  Graham B. I. Scott,et al.  HUPO Plasma Proteome Project specimen collection and handling: Towards the standardization of parameters for plasma proteome samples , 2005, Proteomics.

[2]  A. Renshaw,et al.  Biochemical Outcome after radical prostatectomy, external beam Radiation Therapy, or interstitial Radiation therapy for clinically localized prostate cancer , 1998 .

[3]  A W Partin,et al.  Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. , 1997, JAMA.

[4]  A. Olshen,et al.  Differential exoprotease activities confer tumor-specific serum peptidome patterns. , 2005, The Journal of clinical investigation.

[5]  C. Lee,et al.  Analysis of specific proteins in prostatic fluid for detecting prostatic malignancy. , 1979, The Journal of urology.

[6]  K. Trinkaus,et al.  Proteins associated with disease and clinical course in pancreas cancer: a proteomic analysis of plasma in surgical patients. , 2006, Journal of proteome research.

[7]  L. Juliano,et al.  Serpin-derived Peptide Substrates for Investigating the Substrate Specificity of Human Tissue Kallikreins hK1 and hK2* , 1997, The Journal of Biological Chemistry.

[8]  M. Moroni,et al.  Eosinophils and C4 predict clinical failure of combination immunotherapy with very low dose subcutaneous interleukin-2 and interferon in renal cell carcinoma patients. , 2000, Haematologica.

[9]  H. Lilja,et al.  Expression of protein C inhibitor (PCI) in benign and malignant prostatic tissues , 2003, The Prostate.

[10]  H. Lilja,et al.  Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen. , 1994, European journal of biochemistry.

[11]  A. D'Amico,et al.  5 year biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer , 1998 .

[12]  H. Lilja,et al.  Protein C inhibitor in human body fluids. Seminal plasma is rich in inhibitor antigen deriving from cells throughout the male reproductive system. , 1992, The Journal of clinical investigation.

[13]  C. Lazure,et al.  Isolation of prostatic kallikrein hK2, also known as hGK-1, in human seminal plasma. , 1995, Biochimica et biophysica acta.

[14]  M. Cooperberg,et al.  The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy. , 2005, The Journal of urology.

[15]  Thomas M. Wheeler,et al.  A Preoperative Nomogram for Disease Recurrence Following Radical Prostatectomy for Prostate Cancer , 1998 .