Beyond prostate-specific antigen: new serologic biomarkers for improved diagnosis and management of prostate cancer

Abstract

The use of total prostate-specific antigen (tPSA) measurement has dramatically improved the ability to detect prostate cancer at earlier stages. However, as the number of men presenting with advanced disease (and high tPSA levels) has decreased, and given the fact that tPSA is highly reflective of benign prostatic hyperplasia, the need has emerged for novel biomarkers specifically associated with prostate cancer in order to improve predictive models. Several new biomarkers have shown promise, and studies continue to investigate the role of these markers in the detection, staging, and prognosis of prostate cancer. As new useful biomarkers continue to emerge, guidelines for their employment, as well as coordination of further research studies, are needed; a systematic, phased, nomogram-based model is a rational way to manage these efforts.

Figure 1

Baylor College of Medicine strategic approach to testing and validating blood-based biomarkers.

Figure 2

Nomogram software screenshot. TGF ß₁, transforming growth factor ß₁; IL-6 sR, interleukin-6 soluble receptor; PSA, prostate-specific antigen.

Figure 3

Levels of discrimination for some nomograms. LN, lymph node; OC, organ confined; IL-6sR, interleukin-6 soluble receptor; TGF-ß₁, transforming growth factor ß₁.

Figure 4

Survey of the research development of the molecular forms of prostate-specific antigen (PSA): Approximate years of discovery are indicated on the left. Each box represents a different molecular form of PSA. The Bayer cPSA assay measures PSA bound to α₁-antichymotrypsin (PSA-ACT) and PSA bound to α₁-protease inhibitor (PSA-API). BPSA, BPH-associated free PSA; proPSA, precursor form of free PSA; “intact” PSA, other inactive and intact PSA, which also detects proPSA; PSA-A2M, PSA bound to α₂-macroglobulin. Reprinted, with permission, from Stephan C et al. Urology. 2002;59:2–8.

Figure 5

Comparison of the enzymatically active prostate-specific antigen (PSA) in tissues and seminal plasma with the inactive forms of free PSA found in serum: Active PSA contains no internal peptide bond cleavages and forms a complex with α₁-antichymotrypsin (PSA-ACT) in serum. proPSA is a precursor form of PSA that is expressed with a 7-amino acid N-terminus leader peptide but is found in serum containing from 1 to 7 amino acids. “Benign” PSA (BPSA) contains 2 internal peptide bond cleavages. The remainder of the inactive PSA in serum (iPSA) appears to be composed largely of intact, denatured PSA, although it may contain lesser amounts of internal or N-terminus cleavages. BPH, benign prostatic hyperplasia. Adapted, with permission, from Mikolajczyk SD et al. Urology. 2002;59:797–802.

Figure 6

Correlation of prostate-specific antigen (PSA) forms with transition zone volume in 63 men (27 men with and 36 men without prostate cancer) (unpublished data). BPSA, “benign” PSA.

Figure 7

Improved preoperative nomogram including 2 molecular biomarkers-interleukin-6 soluble receptor (IL-6sR) and transforming growth factor ß₁ (TGF-ß₁)-to a core group of clinical variables for predicting prostate-specific antigen (PSA) recurrence after radical prostatectomy based on 713 patients. Bx, biopsy; GG, Gleason grade. Adapted, with permission, from Kattan M et al. J Clin Oncol. 2003;21:3573–3579.