Free/total PSA ratio improves differentiation of benign and malignant disease of the prostate: critical analysis of two different test populations.

OBJECTIVES: To evaluate the ability of free PSA (fPSA), total PSA (tPSA), and the free/total PSA (f/t PSA) ratio to differentiate between benign prostate disease (benign prostatic hyperplasia [BPH] and no evidence of malignancy [NEM]) and prostate cancer (CaP) using two different testing populations, and to compare predictive probabilities for the two test populations.
METHODS: One test population consisted of sera from 531 men with clinically well-defined and biopsy-confirmed BPH (n = 255) or CaP (n = 276), with tPSA values ranging from 2 to 20 ng/mL. All of these serum samples were retrospective and obtained from patients evaluated in academic settings before any treatment. A second test population consisted of a prospective analysis of sera obtained from 4870 men, collected by urologists throughout the United States and processed at a single pathology laboratory. All these patients had a systematic biopsy evaluated and diagnosed at the same pathology laboratory, with the diagnosis categorized as either NEM (n = 2961) or CaP (n = 1909). No additional information on concurrent disease or pre- or current treatment status was known for this test population. For both populations, two tPSA reflex range groups, 2 to 10 and 2 to 20 ng/mL, were evaluated.
RESULTS: Both test populations benefited from the application of either fPSA alone or the f/t PSA ratio to differentiate benign from malignant disease (t test P value less than 0.001). The receiver operating characteristic (ROC) curve for the f/t PSA ratio had an area under the curve (AUC) of 72% for n = 531 versus 63% for n = 4870, irrespective of the tPSA reflex range. Average fPSA values demonstrated a linear correlation to a range of tPSA concentrations for both test populations. Predictive probabilities (adjusted for established cancer prevalence rates in the academic population [n = 531]) calculated using f/t PSA ratios also demonstrated their value in contrasting the performance characteristics in the two test populations.
CONCLUSIONS: The fPSA and f/t PSA ratio improved the differentiation of benign disease and CaP in two different patient samples. The f/t PSA ratio demonstrated an increased sensitivity and specificity when applied to differentiate clinically well-defined BPH and CaP (n = 531). The differences in the results between the two test samples are probably attributable to the variability of the patient's disease and treatment status in the larger, less refined, community-based population. The use of predictive probabilities provides the opportunity to provide patient-specific cancer probabilities instead of using population-based specific single cutoffs.