Current biomarkers of prostate cancer

Prostate cancer is one of the most common malignancies in men. Early detection of prostate cancer is largely determined by the widely used prostate specific antigen (PSA) blood test. However, as a diagnostic and prognostic test of prostate cancer, PSA has limited specificity, sensitivity and leads to hyper or underdiagnosis, which, in turn, can lead to excessive treatment. There fore, it is very important to develop diagnostic markers that can be used to determine prostate cancer at an early stage of development, assess the possible progression of the disease and prescribe optimal therapy. Significant progress has been made in the discovery of biomarkers for prostate cancer. For example, biomarkers such as %-free PSA, Prostate Health Index (PHI) or 4K score can be used to increase specificity and reduce the number of unnecessary biopsies, while the PCA3 test can be used to reduce the number of repeated biopsies in men with previously negative biopsy. To determine aggressiveness and predict the outcome of the disease, tissue multigenic tests can be used, such as: T2-ERG, ExoDx, SelectMDx and ConfirmMDx, Prolaris, Oncoytype DX, Decipher. The development of such diagnostic tests opens up new opportunities for improving the diagnosis of prostate cancer, prognosis and decision-making on the appointment of therapy. And with the increase in their availability, finally, the possibility of an individual approach to the appointment of treatment for men with prostate cancer appears on the horizon. This review paper presents the data on the most advanced diagnostic biomarkers of prostate cancer.

SIGNIFICANCE OF DETECTION OF FREE/TOTAL PSA RATIO AND OTHER BIOCHEMICAL PARAMETERS IN PATIENTS WITH BPH, CARCINOMA PROSTATE AND ITS CLINICOPATHOLOGIC CORRELATION

Background. Benign prostatic hyperplasia (BPH) can raise prostate-specific antigen (PSA) levels two to three times higher than the normal level. An increased PSA level does not indicate Prostate Cancer (PCa), but the higher the PSA level, the higher the chance of having PCa. Detection and treatment have been profoundly affected by the advent of Free/Total PSA ratio testing. Objectives. The aim of the study was to estimate free, total PSA levels and its ratio for serum levels of calcium, acid phosphatase and alkaline phosphatase in patients with BPH and PCa; to correlate clinical, biochemical and histopathological findings in the above patients. Methods. PSA levels were detected by Chemiluminescent assay; serum calcium – by Modified Arsenazo method; serum acid phosphatase – by Doumas et al method; and Alkaline phosphatase – by Lowry et al method. Results. Present study found high levels of total PSA in BPH and PCa. Levels of free PSA were high in BPH as compared to PCa rate. Free/Total PSA ratio is reduced considerably in PCa as compared to BPH. Serum acid phosphatase and alkaline phosphatase were considerably higher in PCa as compared to BPH. Serum calcium levels did not show significant difference in control and study groups. Conclusions. It was established that patients with PCa have a greater fraction of bound PSA and a lower percentage of free PSA than in those without PCa. Therefore, in clinical practice Free/Total PSA ratio helps clinicians to decide if a biopsy is necessary. Objectives: The study was carried out with the following objectives: to estimate free, total PSA levels and calculate Free/Total PSA ratio in patients with BPH and Carcinoma Prostate, to study the serum levels of calcium, acid phosphates, and alkaline phosphatase in patients with BPH and PCa. and to correlate clinical, biochemical and histopathological findings in the above patients. Methods. Free and total PSA levels were detected by Chemiluminescent assay; Serum Calcium was detected by Modified Arsenazo method. Serum acid phosphatase was detected by Doumas et al method and Alkaline phosphatase were detected by Lowry et al method Results: Present study found high levels of Total PSA in BPH and PCa. Levels of free PSA were high in BPH as compared to PCa ate. Free /Total PSA ratio is reduced considerably in PCa as compared to BPH. Serum acid phosphatase and alkaline phosphatase were slightly raised in PCa as compared to BPH. Serum calcium levels did not show a significant difference in control and study groups. Conclusion: We concluded that patients with PCa have a greater fraction of bound PSA and a lower percentage of free PSA than in men without PCa. There was a negative correlation found between the free/total PSA ratio and the histopathologic findings. The lower the ratio higher is the grade of malignancy. Therefore in clinical practice Free/Total PSA ratio helps clinicians to decide if a biopsy is necessary

The Clinical Significance Of Circulating Mir-21, Mir-142, Mir-143, And Mir-146a In Patients With Prostate Cancer

Prostate cancer (PCa) is the most common type of solid tissue cancer among men in western countries. To enlighten the underlying molecular mechanisms in the pathophysiology of PCa and to help the development of new diagnostics and treatment models, we planned to determine the levels of circulating miR-21, miR-142, miR-143, miR-146a, and RNU 44 levels as controls for the early diagnosis of PCa. The circulating miRNA levels in peripheral blood samples from 43 localized PCa patients, 12 metastatic PCa (MET) patients, and as a control group, 42 benign prostate hyperplasia (BPH) patients with a total of 97 volunteers were determined the by PCR method. No differences in the ΔCT values were found among the groups. In PCa and PCaMet groups the expression of miR21 and miR142 were higher compared to the BHP group. No other differences were observed among the other groups. miR21 expression in the PCa group was 6.29 folds upregulated whereas in the PCaMet group 10.84 folds upregulated. When the total expression of miR142 is evaluated, it showed a positive correlation with mir21 and mir 146 (both p<0.001). Also, the expression of miR146 shows a positive correlation with both miR21 and miR143 (both p<0.001). Expression of miRNAs was found to be an independent diagnostic factor in patients with Gleason score, PSA, and free PSA levels. In conclusion, our study showed that co-expression of miR-21, miR-142, miR-143, and miR-146a and the upregulation of miR-21 resulted in increased prostate carcinoma cell growth. In the PCaMet group, miR21 is the most upregulated of all miRNAs. These miRNA markers that are expressed in different levels may provide a novel diagnostic tool to help diagnose PCa with aggressive behavior.

Usefulness of the prostate health index in predicting the presence and aggressiveness of prostate cancer among Korean men: a prospective observational study

Background We aimed to evaluate the usefulness of the Beckman Coulter prostate health index (PHI) and to compare it with total prostate-specific antigen (PSA) levels and related derivatives in predicting the presence and aggressiveness of prostate cancer (PCa) in the Korean population. Methods A total of 140 men who underwent their first prostate biopsy for suspected PCa were included in this prospective observational study. The diagnostic performance of total PSA, free PSA, %free PSA, [–2] proPSA (p2PSA), %p2PSA, and PHI in detecting and predicting the aggressiveness of PCa was estimated using the receiver operating characteristic curve (ROC) and logistic multivariate regression analyses. Results Of 140 patients, PCa was detected in 63 (45%) of participants, and 48 (76.2%) of them had significant cancer with a Gleason score (GS) ≥ 7. In the whole group, the area under the curve (AUC) for ROC analysis of tPSA, free PSA, %fPSA, p2PSA, %p2PSA, and PHI were 0.63, 0.57, 0.69, 0.69, 0.72, and 0.76, respectively, and the AUC was significantly greater in the PHI group than in the tPSA group (p = 0.005). For PCa with GS ≥ 7, the AUCs for tPSA, free PSA, %fPSA, p2PSA, %p2PSA, and PHI were 0.62, 0.58, 0.41, 0.79, 0.86, and 0.87, respectively, and the AUC was significantly greater in the PHI group than in the tPSA group (p < 0.001). In the subgroup with tPSA 4–10 ng/mL, both %p2PSA and PHI were strong independent predictors for PCa (p = 0.007, p = 0.006) and significantly improved the predictive accuracy of a base multivariable model, including age, tPSA, fPSA and %fPSA, using multivariate logistic regression analysis. (p = 0.054, p = 0.048). Additionally, at a cutoff PHI value > 33.4, 22.9% (32/140) of biopsies could be avoided without missing any cases of aggressive cancer. Conclusions This study shows that %p2PSA and PHI are superior to total PSA and %fPSA in predicting the presence and aggressiveness (GS ≥ 7) of PCa among Korean men. Using PHI, a significant proportion of unnecessary biopsies can be avoided.

Machine Learning Techniques in Prostate Cancer Diagnosis According to Prostate-Specific Antigen Levels and Prostate Cancer Gene 3 Score

Purpose: To explore the role of artificial intelligence and machine learning (ML) techniques in oncological urology. In recent years, our group investigated the prostate cancer gene 3 (PCA3) score, prostate-specific antigen (PSA), and free-PSA predictive role for prostate cancer (PCa), using the classical binary logistic regression (LR) modeling. In this research, we approached the same clinical problem by several different ML algorithms, to evaluate their performances and feasibility in a real-world evidence PCa detection trial.Materials and Methods: The occurrence of a positive biopsy has been studied in a large cohort of 1,246 Italian men undergoing first or repeat biopsy. Seven supervised ML algorithms were selected to build biomarkers-based predictive models: generalized linear model, gradient boosting machine, eXtreme gradient boosting machine (XGBoost), distributed random forest/ extremely randomized forest, multilayer artificial Deep Neural Network, naïve Bayes classifier, and an automatic ML ensemble function.Results: All the ML models showed better performances in terms of area under curve (AUC) and accuracy, when compared to LR model. Among them, an XGBoost model tuned by the autoML function reached the best metrics (AUC, 0.830), well overtaking LR results (AUC, 0.738). In the variable importance ranking coming from this XGBoost model (accuracy, 0.824), the PCA3 score importance was 3-fold and 4-fold larger, when compared to that of free-PSA and PSA, respectively.Conclusions: The ML approach proved to be feasible and able to achieve good predictive performances with reproducible results: it may thus be recommended, when applied to PCa prediction based on biomarkers fluctuations.

Comparison of PHI and PHI Density for Prostate Cancer Detection in a Large Retrospective Caucasian Cohort

<b><i>Background:</i></b> Beyond prostate-specific antigen (PSA), other biomarkers for prostate cancer (PCa) detection are available and need to be evaluated for clinical routine. <b><i>Objective:</i></b> The aim of the study was to evaluate the Prostate Health Index (PHI) density (PHID) in comparison with PHI in a large Caucasian group &#x3e;1,000 men. <b><i>Methods:</i></b> PHID values were used from available patient data with PSA, free PSA, and [−2]pro­PSA and prostate volume from 3 former surveys from 2002 to 2014. Those 1,446 patients from a single-center cohort included 701 men with PCa and 745 with no PCa. All patients received initial or repeat biopsies. The diagnostic accuracy was evaluated by receiver operating characteristic (ROC) curves comparing area under the ROC curves (AUCs), precision-recall approach, and decision curve analysis (DCA). <b><i>Results:</i></b> PHID medians differed almost 2-fold between PCa (1.12) and no PCa (0.62) in comparison to PHI (48.6 vs. 33; <i>p</i> always &#x3c;0.0001). However, PHID and PHI were equal regarding the AUC (0.737 vs. 0.749; <i>p</i> = 0.226), and the curves of the precision-recall analysis also overlapped in the sensitivity range between 70 and 100%. DCA had a maximum net benefit of only ∼5% for PHID versus PHI between 45 and 55% threshold probability. Contrary, in the 689 men with a prostate volume ≤40 cm³, PHI (AUC 0.732) showed a significant larger AUC than PHID (AUC 0.69, <i>p</i> = 0.014). <b><i>Conclusions:</i></b> Based on DCA, PHID had only a small advantage in comparison with PHI alone, while ROC analysis and precision-recall analysis showed similar results. In smaller prostates, PHI even outperformed PHID. The increment for PHID in this large Caucasian cohort is too small to justify a routine clinical use.

The prostate health index and the percentage of [-2]proPSA maintain their diagnostic performance when calculated with total and free PSA from different manufacturers

Objectives To evaluate the diagnostic performance of the prostate health index (PHI) and of the percentage of [-2]proPSA (%[-2]proPSA) calculated with total and free PSA from non-Beckman Coulter manufacturers (Roche and Abbott), and compare it with the fully Beckman Coulter [-2]proPSA derivatives. Methods In this study, 237 men (PSA: 2–10 μg/L) scheduled for prostate biopsy were enrolled. %[-2]proPSA and PHI were calculated with total and free PSA from three manufacturers. Beckman Coulter PSA and [-2]proPSA were performed on the Access 2 analyzer (Hybritech calibration). Roche PSA was performed on the cobas e411 and the Abbott PSA on the Architect i2000sr. Statistical analysis was performed, considering prostate cancer (PCa) as the outcome. Results Univariate analysis showed that all indices were predictors of cancer, irrespective of the manufacturer (p<0.001). The AUC was similar for all manufacturers, both for %[-2]proPSA (Beckman Coulter: 0.756; Roche: 0.770; Abbott: 0.756) and PHI (Beckman Coulter: 0.776; Roche: 0.785; Abbott: 0.778). When considering the cutoffs that allowed 90% sensitivity, [-2]proPSA derivatives calculated with Roche and Abbott PSA had similar specificities and predictive values when compared to Beckman Coulter. The percentage of missed cancers (8–9%) was the same between manufacturers. The percentage of spared biopsies was significantly higher with Roche’s PHI (21.0%) and Abbott’s PHI (20.6%) than with Beckman Coulter’s PHI (17.2%). Conclusions In the PSA range between 2 and 10 μg/L, [-2]proPSA derivatives maintain their diagnostic performance in PCa detection when calculated with PSA from Roche and Abbott. This can lead to a broader implementation of these indices in clinical laboratories worldwide.

Predictive value of standard serum markers for bone metastases in prostate cancer

Background The early detection of bone metastases is very important in prostate cancer follow-up. This study aimed to compare conventional tumor markers, namely free prostate-specific antigen (free PSA), total prostate-specific antigen (total PSA), free PSA/total PSA ratio, alkaline phosphatase (ALP) values, Gleason scores and 99 m Tc-MDP bone scintigraphy findings in the prediction of bone metastases in prostate cancer. Methods In total, 175 patients with prostate cancer who underwent whole-body bone scintigraphy were included in the study. All selected scintigraphic studies were reprocessed. Free PSA, total PSA, free PSA/total PSA ratio, alkaline phosphatase (ALP) values and Gleason scores of patients were recorded. Results The results of our study show that the presence of bone metastasis correlates very weakly with free PSA/total PSA ratio (rho = 0.179), weakly with total PSA (rho = 0.318) and Gleason score (rho = 0.382), moderately with ALP (rho = 0.539), free PSA (0.416). Only ALP variable had a diagnostic value and ALP cutoff value was 76.50 IU/L, with 80% sensitivity and 82.1% specificity. Conclusion According to the results of our study; the free PSA, total PSA, free PSA/total PSA ratio and Gleason score values were not considered as a reliable parameter in the prostate cancer cases follow-up for bone metastasis development. Only ALP had a diagnostic value and ALP cutoff value was 76.50 IU / L with 80% sensitivity and 82.1% specificity in predicting bone metastases in prostate cancer.