Free prostate-specific antigen in serum is becoming more complex

Abstract

T measurement of serum prostate-specific antigen (PSA) is used for the screening and early detection of prostate cancer.1–3 These early studies established that serum values greater than 4 ng/mL significantly correlated with an increased risk of prostate cancer, but the PSA assay still suffers from a lack of specificity. It was subsequently discovered by Lilja et al.4 and Stenman et al.5 that serum contained two distinct forms of PSA: one form (complexed PSA) that was covalently attached to the serum protease inhibitor alpha1-antichymotrypsin (ACT) and a second form (free PSA) that was present as the free “non-complexed” form. Antibodies have been identified that can specifically measure the free form of PSA and total PSA (free plus complexed PSA).6 The measurement of free and total PSA has allowed a modest but significant improvement in the discrimination of prostate cancer from benign disease such as benign prostatic hyperplasia (BPH). A higher ratio of free to total PSA in serum correlates with a lower risk of prostate cancer.7,8 Free (uncomplexed) PSA in serum is now known to be composed of at least three distinct forms of inactive PSA. One form has been identified as the proenzyme, or precursor forms of PSA (pPSA), and is associated with cancer.9,10 A second form of PSA, called BPSA, is an internally cleaved or degraded form of PSA that is more highly associated with BPH.11 The third PSA form may contain a number of minor variants, but appears to be composed largely of intact PSA that is similar to native, active PSA, except for structural or conformational changes that have rendered it enzymatically inactive. Figure 1 shows the subtle but distinct differences for each of these free, inactive forms compared with enzymatically active PSA. This update describes each of these inactive forms of free PSA, and reviews their potential clinical application as serum markers.