The widespread application of PSA assays to CaP screening and detection has revolutionized the diagnosis and management of this disease1
. While the issues of ‘overdiagnosis’ and ‘overtreatment’ remain controversial, the use of tPSA has resulted in a significant downward migration of diagnostic stage2
The clinical utility of tPSA assays is limited, however, by relatively poor specificity and predictive value. The tendency of benign conditions including inflammation, BPH, infection, instrumentation and trauma to confound the diagnostic process by causing false elevations of tPSA is well documented3
. As a result, current diagnostic paradigms that utilize tPSA thresholds to determine the need for confirmatory biopsy demonstrate false positive rates of 55–75%4
. In addition, false negative rates of at least 15% have been reported5
using the traditional threshold of 4.0 ng/ml. Suboptimal performance of tPSA contributes substantially to patient anxiety, morbidity, and the aggregate cost of CaP screening and surveillance protocols. This lack of accuracy is directly related to the failure of standard tPSA assays to reliably differentiate malignant from benign disease.
The need to improve the operating characteristics of tPSA has led to much research aimed at improving the diagnostic accuracy and clinical utility of CaP testing. Concepts to improve specificity include use of age-adjusted tPSA, tPSA velocity, volume-adjusted tPSA, and %free PSA6
. However, diagnostic accuracy and predictive value remain problematic. Contemporary research has generally focused on identifying genetic and protein markers that reflect malignant phenotypes which are detectable by straightforward assays.7,8
In this study, we instead refocus attention to the evaluation of PSA and its structural isoforms to attempt to improve the diagnostic accuracy of the test.
The benefits afforded by the specificity of PSA to prostate tissue have led other researchers to explore the diagnostic potential of its structural variants. Several isoforms of PSA have been identified, including the inactive precursor pro-PSA. Pro-PSA includes a leading peptide sequence which is normally cleaved to form the active mature PSA protein. Incomplete cellular processing of pro-PSA may result in its accumulation in malignant cells. When this leading peptide is incompletely removed by proteolysis, various truncated forms result. These truncated forms of pro-PSA have been found to be specific to malignant prostate cells in some studies9
. In addition, PSA is known to be a glycoprotein with a single N-oligosaccharide chain attached to Asparagine-45. Glycosylation patterns of PSA have been demonstrated to be distinct between malignant cells and benign tissue. Specifically, PSA from malignant prostatic tissue and transformed prostate cell line contains complex-type oligosaccharides with more antennas than from benign tissue10–12
. Current research suggests identifying changes in PSA glycosylation show promise for improved diagnostic performance of PSA testing13–17
, but the use of lectin-based assays is complicated in serum due to the formation of extensive glycosylated ACT ligand complexes with the majority of PSA in serum.
In this study we report preliminary findings from a trial designed to investigate the diagnostic performance of a new urine based test, in which the heterogeneous mixture of structural isoforms of PSA is partitioned in a unique aqueous two-phase system. The partitioning behavior of the overall isoform population is different depending on its origin - cancer versus benign epithelium. This differential partitioning is evaluated in a novel quantitative assay called PSA/SIA (AnalizaDx, Cleveland, Ohio, USA). We report preliminary outcomes and operating characteristics of the PSA/SIA assay and compare its performance against serum tPSA.