A Prospective, Multicenter, National Cancer Institute Early Detection Research Network Study of [−2]proPSA: Improving Prostate Cancer Detection and Correlating with Cancer Aggressiveness

Background: The free prostate-specific antigen (PSA) isoform, [−2]proPSA, has been shown to be associated with prostate cancer. The study objective was to characterize the clinical utility of serum [−2]proPSA for prostate cancer detection and assess its association with aggressive disease. Methods: From among 669 subjects in a prospective prostate cancer detection study at four National Cancer Institute Early Detection Research Network clinical validation centers, 566 were eligible. Serum PSA, free PSA, and [−2]proPSA were measured (Beckman Coulter Access 2 Analyzer). Results: Two hundred and forty-five (43%) of the 566 participants had prostate cancer on biopsy. At 70% specificity, the sensitivity of %[−2]proPSA ([−2]proPSA/fPSA) was 54% [95% confidence interval (CI), 48-61%; null hypothesis, 40%]. Including %[−2]proPSA in a multivariate prediction model incorporating PSA and %fPSA improved the performance (P < 0.01). In the 2 to 4 ng/mL PSA range, %[−2]proPSA outperformed %fPSA (receiver operator characteristic-areas under the curve, 0.73 versus 0.61; P = 0.01). At 80% sensitivity, %[−2]proPSA had significantly higher specificity (51.6%; 95% CI, 41.2-61.8%) than PSA (29.9%; 95% CI, 21.0-40.0%) and %fPSA (28.9%; 95% CI, 20.1-39.0%). In the 2 to 10 ng/mL PSA range, a multivariate model had significant improvement (area under the curve, 0.76) over individual PSA forms (P < 0.01 to <0.0001). At 80% sensitivity, the specificity of %[−2]proPSA (44.9%; 95% CI, 38.4-51.5%) was significantly higher than PSA (30.8%; 95% CI, 24.9-37.1%) and relatively higher than %fPSA (34.6%; 95% CI, 28.5-41.4%). %[−2]proPSA increased with increasing Gleason score (P < 0.001) and was higher in aggressive cancers (P = 0.03). Conclusions: In this prospective study, %[−2]proPSA showed potential clinical utility for improving prostate cancer detection and was related to the risk of aggressive disease. Impact: The addition of %[−2]proPSA could affect the early detection of prostate cancer. Cancer Epidemiol Biomarkers Prev; 19(5); 1193–200. ©2010 AACR.

[1]  D. Chan,et al.  Clinical utility of proPSA and "benign" PSA when percent free PSA is less than 15%. , 2004, Urology.

[2]  J. Crowley,et al.  Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. , 2004, The New England journal of medicine.

[3]  William E Grizzle,et al.  Standard operating procedures for serum and plasma collection: early detection research network consensus statement standard operating procedure integration working group. , 2009, Journal of proteome research.

[4]  R. Getzenberg,et al.  Biomarkers for prostate cancer , 2009, Journal of cellular biochemistry.

[5]  P. Walsh,et al.  Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. , 1994, JAMA.

[6]  A. Partin,et al.  Pro–Prostate-Specific Antigen Measurements in Serum and Tissue Are Associated with Treatment Necessity among Men Enrolled in Expectant Management for Prostate Cancer , 2009, Clinical Cancer Research.

[7]  B. G. Blijenberg,et al.  The value of (−7, −5)pro‐prostate‐specific antigen and human kallikrein‐2 as serum markers for grading prostate cancer , 2004, BJU international.

[8]  R. Babaian,et al.  Evaluation of precursor prostate-specific antigen isoform ratios in the detection of prostate cancer. , 2005, Urologic oncology.

[9]  D. Chan,et al.  [-2]proenzyme prostate specific antigen for prostate cancer detection: a national cancer institute early detection research network validation study. , 2007, The Journal of urology.

[10]  H. Cammann,et al.  PSA and new biomarkers within multivariate models to improve early detection of prostate cancer. , 2007, Cancer letters.

[11]  B. G. Blijenberg,et al.  Additional use of [-2] precursor prostate-specific antigen and "benign" PSA at diagnosis in screen-detected prostate cancer. , 2005, Urology.

[12]  D. Chan,et al.  Evaluation of proprostate specific antigen for early detection of prostate cancer in men with a total prostate specific antigen range of 4.0 to 10.0 ng/ml. , 2003, The Journal of urology.

[13]  T. Stamey,et al.  Complexed prostate specific antigen improves specificity for prostate cancer detection: results of a prospective multicenter clinical trial. , 2003, The Journal of urology.

[14]  E. Schiffer.  Biomarkers for prostate cancer , 2007, World Journal of Urology.

[15]  A W Partin,et al.  Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. , 1998, JAMA.

[16]  A W Partin,et al.  Analysis of percent free prostate-specific antigen (PSA) for prostate cancer detection: influence of total PSA, prostate volume, and age. , 1996, Urology.

[17]  Donna P. Ankerst,et al.  Prostate-specific antigen in the early detection of prostate cancer , 2007, Canadian Medical Association Journal.

[18]  U. Stenman,et al.  A complex between prostate-specific antigen and alpha 1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. , 1991, Cancer research.

[19]  H. Klocker,et al.  Proenzyme psa for the early detection of prostate cancer in the 2.5-4.0 ng/ml total psa range: preliminary analysis. , 2003, Urology.

[20]  R. Babaian,et al.  Volume-based evaluation of serum assays for new prostate-specific antigen isoforms in the detection of prostate cancer. , 2004, Urology.

[21]  Klaus Jung,et al.  A (-5, -7) proPSA based artificial neural network to detect prostate cancer. , 2006, European urology.

[22]  Georg Bartsch,et al.  Serum pro-prostate specific antigen preferentially detects aggressive prostate cancers in men with 2 to 4 ng/ml prostate specific antigen. , 2004, The Journal of urology.

[23]  W. Catalona,et al.  Proenzyme forms of prostate-specific antigen in serum improve the detection of prostate cancer. , 2004, Clinical chemistry.

[24]  Antoinette M Stroup,et al.  Prostate cancer early detection , 2010 .

[25]  P. Carpenter,et al.  A truncated precursor form of prostate-specific antigen is a more specific serum marker of prostate cancer. , 2001, Cancer research.

[26]  O. Nilsson,et al.  Prostate-specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin. , 1991, Clinical chemistry.

[27]  T. Wheeler,et al.  A precursor form of prostate-specific antigen is more highly elevated in prostate cancer compared with benign transition zone prostate tissue. , 2000, Cancer research.

[28]  Kazuto Ito,et al.  Proprostate‐specific antigen: Its usefulness in the era of multiple‐core prostate biopsy , 2009, International journal of urology : official journal of the Japanese Urological Association.

[29]  H. Klocker,et al.  Serum pro prostate specific antigen improves cancer detection compared to free and complexed prostate specific antigen in men with prostate specific antigen 2 to 4 ng/ml. , 2003, The Journal of urology.

[30]  S. Loening,et al.  Serum (-5, -7) proPSA for distinguishing stage and grade of prostate cancer. , 2007, Anticancer research.

[31]  H. Cammann,et al.  A [‐2]proPSA‐based artificial neural network significantly improves differentiation between prostate cancer and benign prostatic diseases , 2009, The Prostate.

[32]  S. Loening,et al.  A multicenter clinical trial on the use of (-5, -7) pro prostate specific antigen. , 2005, The Journal of urology.

[33]  A. Partin,et al.  Free prostate-specific antigen in serum is becoming more complex. , 2002, Urology.

[34]  K. Pettersson,et al.  Prostate-Specific Antigen in Serum Occurs Predominantly in Complex with a . 1-Antichymotrypsin , 2004 .

[35]  D. Johnston,et al.  The incidence of prostate cancer in a screening population with a serum prostate specific antigen between 2.5 and 4.0 ng/ml: relation to biopsy strategy. , 2001, The Journal of urology.