PERCENT FREE PROSTATE-SPECIFIC ANTIGEN: THE NEXT FRONTIER IN PROSTATE-SPECIFIC ANTIGEN TESTING

P cancer (PCa) has become a major concern for men and health organizations worldwide. In the United States, approximately 317,000 new cases and 40,000 deaths from this disease are expected for 1996.1 This makes PCa the most frequently detected malignancy in men and the second leading cause of cancer death in the adult male population. In recent years, major efforts have been put forth to reduce the mortality rate from this entity. In short, this means early detection and local definitive therapy, since there is no curative systemic treatment for prostate cancer. Since its isolation and description in seminal fluid and prostatic tissue and ultimately in human serum nearly two decades ago, prostate-specific antigen (PSA) has been under intensive basic science and clinical investigation by the urologic community.2–4 As a result of such efforts and due to its unique characteristics, PSA has established itself as the most clinically useful tumor marker for the early detection and staging of PCa as well as for monitoring response to therapy.5,6 Though unique, PSA has important limitations that prevent it from being the ideal tumor marker for early detection of prostate cancer.7–12 This comes from the fact that PSA is not cancer-specific; as a result, serum PSA levels above normal are not pathognomonic for PCa and values within the reference range are not always indicative of the absence of cancer. Nevertheless, several studies have demonstrated that PSA alone detects a greater number of malignancies than digital rectal examination (DRE) or any other isolated parameter.13–15 Most importantly, the majority of such tumors have histopathologic features of clinically-important, lifethreatening cancer.16–18 In order to reliably detect PCa at an early stage, a low serum PSA cutoff level is used in screening programs (4.0 ng/mL). Use of this cutoff level is associated with a considerable number of falsepositive findings and false-negative findings (65% false-positive and a 20% false-negative rate), demonstrating PSA’s lack of power in discriminating PCa from other benign prostate pathologies (benign prostatic hyperplasia, BPH).5,19,20 On the other hand, at least 20% of men with biopsyproven PCa at the time of diagnosis have a serum PSA concentration within the reference range of 0.0 to 4.0 ng/mL.21 Had the total serum PSA concentration been the sole diagnostic criterion used, those patients would not have had their cancer detected. The obvious conclusion is that the immunotechniques currently employed in the determination of serum PSA concentration have limited ability in distinguishing early PCa from BPH. This lack of sensitivity and specificity have led researchers to investigate various methods for improving the reliability of the total serum PSA test with respect to diagnosing PCa. Several concepts have been developed and investigated recently, with the purpose of optimizing the clinical use of PSA by improving its specificity and yet preserving its sensitivity. These new techniques include PSA density, PSA velocity, and age/ race-specific PSA reference ranges.22–26 Moreover, investigations have shown that PSA is present in the human serum in several molecular forms and that the concentration of these forms may vary according to specific pathologic states present in the prostate gland.26a The objective of this presentation is to review our current understanding of the so-called molecular forms of PSA and assess their clinical utility in 1997.