Since the discovery a decade ago that free PSA is comprised of an isoform (10
) that may be specific for cancer, several assays of differing formats recognizing full-length and truncated forms of proPSA have been developed and evaluated for the improved detection of prostate cancer. There is less consensus on the utility of an automated assay measuring [-5, -7]proPSA (14
) compared to the automated assay measuring [-2]proPSA used in this study, or to manual assays measuring [-2]-, [-4]-, and [-7]proPSA evaluated individually or summed to form total proPSA (12
). Potential roles for [-2]proPSA and proPSA improving the diagnostic ability of %fPSA when %fPSA is >25% (21
) or <15% (19
), identifying aggressive prostate cancer (16
), and aiding in treatment decisions for men on expectant management (31
) have also been investigated.
In the overall study population, %[-2]proPSA was equivalent to PSA and %fPSA using ROC analysis. Moreover, it was complementary and provided independent value to PSA and %fPSA when the three PSA markers were combined with demographic and clinical parameters in a logistic regression model. This model had improved performance over the individual markers. It should be noted that since PSA concentration is the most common indication for prostate biopsy, many of the men in this study were pre-selected by total PSA. It should also be noted that there was higher than usual representation of biopsy Gleason score ≥ 7 in this multicenter cohort. However, patients were consecutively enrolled in a prospective fashion at four geographically distributed sites and thus we do not believe any biases were introduced that would affect the observed results.
In previous studies, %[-2]proPSA has shown utility in clinically important PSA ranges from 2–20 ng/mL where PSA loses specificity (12
). In this study, %[-2]proPSA had the best diagnostic utility in the 2–4 ng/mL range where it is now recognized that 25% of men may have cancer (32
) and where cutoffs lower than 4 ng/mL for PSA have been suggested (34
). We found that %[-2]proPSA was significantly better than %fPSA in overall diagnostic efficacy (AUC 0.73 vs. 0.61) and has higher specificity at a fixed sensitivity of 80%, a trend reported in two previous studies for %[-2]proPSA and %proPSA which showed the potential to spare unnecessary biopsies (16
). The better performance of %[-2]proPSA compared to the other PSA derivatives was also evidenced by the logistic regression model (AUC=0.76) whereby only %[-2]proPSA remained in the model using a backwards elimination approach.
In the 4–10 ng/mL and 2–10 ng/mL PSA ranges, logistic regression models incorporating clinical and demographic factors and PSA derivatives had the highest discriminatory value for prostate cancer detection (ROC AUC = 0.76). In this study, the AUCs for %[-2]proPSA were slightly larger than for %fPSA, although statistical significance was not achieved. In a previous, EDRN study using samples from 89 men collected pre-biopsy (13
), %[-2]proPSA (AUC=0.73) performed significantly better than %fPSA (AUC=0.53) in the 2–10 ng/mL PSA range. Differences between studies include retrospective versus prospective collection, as well as slightly more stringent eligibility criteria and consistent specimen collection and processing procedures in the current study. As we have shown, and others have reported (12
), [-2]proPSA as part of multivariate models, algorithms, or combinations of markers, may be an ideal approach to improve differentiation of prostate cancer from benign disease compared to individual PSA molecular forms. Successful approaches have included a multivariate logistic regression model with total PSA, %fPSA, and sum-proPSA (18
), the ratio [-2]proPSA/(fPSA-sum proPSA) (24
), and artificial neural networks and logistic regression models with age, total PSA, %fPSA, and %[-2]proPSA (12
In addition to the need for biomarkers to identify prostate cancer at an early, curative stage, it is also important to identify aggressive cancers for which treatment may be most beneficial. [-2]proPSA may be helpful since both [-2]proPSA and %[-2]proPSA correlated with Gleason score. Higher [-2]proPSA and %[-2]proPSA values were also highly associated with significant disease using the Epstein criteria (30
). A recent study (12
) incorporating the same assay for [-2]proPSA used in this study showed %[-2]proPSA and [-2]proPSA/%fPSA could distinguish between Gleason sum <7 and ≥ 7 as well as organ-confined versus non-organ confined disease. Makarov et al (31
) found that [-2]proPSA/%fPSA at diagnosis was able to predict which men in an expectant management program for prostate cancer would require treatment based on development of an unfavorable biopsy. [-2]proPSA and proPSA (sum -2, -4/-5, -7) analyzed with microtiter-plate based assays have also been associated with aggressive prostate cancer characteristics (16
) while screening studies (14
) evaluating the automated [-5, -7]proPSA assay failed to find an association with stage or grade.
In summary, we have further validated the utility of %[-2]proPSA for the early detection of prostate cancer showing potential utility in the 2–10 ng/mL total PSA range and demonstrated the utility of combining %[-2]proPSA with other PSA forms in logistic regression models. Our observation that [-2]proPSA and %[-2]proPSA may be associated with aggressive and significant prostate cancer is worthy of further investigation. The EDRN-NCI standardized prostate cancer reference set is available for the validation of other prostate cancer markers, allowing both comparisons of marker performance as well as the creation of multiple-marker panels.