Prostate Cancer Antigen 3 Score Research Articles

Age-Adapted Prostate Cancer Gene 3 Score Interpretation - Suggestions for Clinical Use.

The prostate cancer antigen 3 (PCA3) gene urine assay is established for biopsy decision in case of prostate cancer (PC) suspicion. Recent findings pointed to an age dependence of PCA3, with putative impact on test interpretation. However, to date no experience has been reported with regard to the extent age might modify the score in certain age ranges. Therefore, the aim of the present study was to re-evaluate the age dependency and, moreover, give suggestions for interpretation of the PCA3 score in dependence of patient's age in daily routine. The study comprised 684 patients before prostate biopsy or prostatectomy. Post-massage voided urine samples were assessed by PCA3 measurement. PCA3 scores were correlated to patient's age. The collective was divided into four subcollectives by quartiles of age distribution. For every subcollective the cutoff value at specificity of ≥ 60 was determined. Results were classified by age-class specific cutoff values and test qualities were compared at different cutoffs. In the collective, 59.1% of patients had a positive biopsy. PCA3 correlated to patient's age in univariate and multivariate analysis (p < 0.001 each). The division into age subcollectives revealed groups < 60, 60 - 65, 66 - 69 and > 69 years. Median PCA3 values of patients without/with PC were 17/32, 27/42, 34/55 and 52/68 in the four age classes. Cutoff values for which specificity was determined with ≥ 60 were 23, 39, 42, and 65. Constant cutoff values showed lower sensitivities in younger and lower specificities in older patients. Only the age adjusted values revealed an improved performance with PPV 68.7, accuracy 59.5 and sensitivity 57.7 at specificity of 62.1% in the whole cohort. The study confirms that the PCA3 score increases with age. The recommended cutoff score of 35 is suitable especially for patients aged in their sixties. Lower reference values between 20 and 30 have to be taken into account in patients aged < 60 years and higher values around 40 to 50 may point to suspicion for PC in patients > 69 years. These results may further improve the diagnostic performance of the PCA3 test and keep the PCA3 test as a significant test in PC diagnostics along with new upcoming urine markers.

Combination of Prostate Cancer Antigen 3 and Prostate-Specific Antigen Improves Diagnostic Accuracy in Men at Risk of Prostate Cancer.

- Prostate cancer antigen 3 (PCA3) is a noncoding RNA that is highly overexpressed in prostate cancer (PCa) tissue and excreted in urine in patients with PCa. - To assess the clinical utility of urinary PCA3 in men at risk of PCa. - We retrospectively reviewed a cohort of 271 men (median age, 63 years) with elevated prostate-specific antigen (PSA), and/or strong family history, and/or abnormal digital rectal examination findings. Diagnostic sensitivity, specificity, positive and negative predictive values (PPV, NPV), positive and negative likelihood ratios (LR+, LR-), and diagnostic odds ratio (DOR), and area under the receiver-operating characteristic curves (AUC) were evaluated. - PCA3 score was a significant predictor of prostate biopsy outcome ( P < .001). A PCA3 score of 30 was the optimal cutoff for our study cohort, with a diagnostic sensitivity of 72.7%, specificity of 67.5%, PPV of 47.1%, NPV of 86.2%, LR+ of 2.24, LR- of 0.40, and DOR of 5.55. At this cutoff score, the PCA3 assay could avoid 57.4% of unnecessary invasive biopsies in the overall study cohort and 70.3% in the subgroup with PSA level in the "gray zone" (4-10 ng/mL). A logistic regression algorithm combining PCA3 with PSA increased the AUC from 0.571 for PSA-only to 0.729 ( P < .001). The logistic combined marker gained the ability to discriminate low-grade from high-grade cancers. - Our data suggest that PCA3 improves the diagnostic sensitivity and specificity of PSA and that the combination of PCA3 with PSA gives better overall performance in identification of PCa than serum PSA alone in the high-risk population.

Defining a Cohort that May Not Require Repeat Prostate Biopsy Based on PCA3 Score and Magnetic Resonance Imaging: The Dual Negative Effect

Prostate cancer over diagnosis and overtreatment are concerns for clinicians and policy makers. Multiparametric magnetic resonance imaging and the PCA3 (prostate cancer antigen 3) urine test select for clinically significant cases. We explored how well the tests performed together with previous biopsies. In accordance with ethics committee approval we collected clinicopathological data on all patients in whom a PCA3 test was done from January 2011 to June 2016. This included patients on active surveillance for low risk prostate cancer and those without prostate cancer who had previous negative biopsies and suspicion of occult disease. We explored whether age, prostate specific antigen, PCA3 score, multiparametric magnetic resonance imaging, digital rectal examination, family history and prostate size would predict clinically significant prostate cancer on repeat biopsy. The negative predictive value of multiparametric magnetic resonance imaging and PCA3 score was calculated. A total of 470 patients were included in study. The PCA3 score was abnormal at 35 or greater in 32.5% of cases. In the multivariate model including 154 men only age (OR 1.08, 95% CI 1.01-1.16), multiparametric magnetic resonance imaging PI-RADS™ (Prostate Imaging-Reporting and Data System) score 4 (OR 16.6, 95% CI 3.9-70.0) or 5 (OR 28.3, 95% CI 5.7-138) and PCA3 score (OR 2.9, 95% CI 1.0-8.8) predicted clinically significant cancer on biopsy. No patient with negative multiparametric magnetic resonance imaging and a normal PCA3 score had clinically significant prostate cancer on biopsy for a negative predictive value of 100% (p <0.0001). In patients with dual negative tests (multiparametric magnetic resonance imaging and PCA3 score) clinically significant prostate cancer was never found on biopsy, which may be unnecessary in this group. This study was limited by its retrospective design, selection bias and lack of cost-effectiveness data.

Prostate Cancer Antigen 3 Score Does Not Predict for Adverse Pathologic Features at Radical Prostatectomy or for Progression-Free Survival in Intermediate- and High-Risk Prostate Cancer

Pre-operative urinary prostate cancer antigen 3 (PCA3) gene scores predict for adverse pathologic features (APF) at radical prostatectomy (RP) in men with low- and intermediate-risk prostate cancer (PCa). However, whether these predict for APF in men with higher-risk disease, or for progression-free survival (PFS) in general, is unknown. We retrospectively investigated whether PCA3 scores were predictive for APF or PFS in men with higher-risk PCa. One hundred nine men with cT1-T2 National Comprehensive Care Network (NCCN) intermediate- and high-risk PCa were treated with RP from 2010-2015. Logistic regression analysis was performed to evaluate the association of PCA3 score with selected APFs—seminal vesicle invasion [SVI], lymph node positivity (pLN+), upgrading to Gleason score (pGS) 8-10 or tertiary pattern 5, and upstaging to pT3 disease—after adjusting for age, initial PSA (iPSA), clinical T-stage, biopsy GS, percent positive biopsies (PPB), and MRI T-stage. Biochemical recurrence was defined as confirmatory PSA ≥ 0.2 ng/mL or initiation of salvage therapy. Among 78 men with ≥ 1 year follow-up, the association between PCA3 score and PFS was assessed using Cox regression analysis after adjusting for age, pre-operative risk group, maximal tumor diameter (MTD), pGS, extracapsular extension (ECE), SVI, and pLN+. Kaplan-Meier analysis was performed to estimate 3-year PFS. Median follow-up was 2.3 years. Forty-eight percent had intermediate-risk and 52% had high-risk PCa. At RP, 42% had ECE, 10% had SVI, and 10% had pLN+. Twenty-one percent experienced GS upgrading and 41% were upstaged to pT3. On multivariate analysis (MVA), multiple significant predictors for individual APFs were elucidated, including increasing bGS predicting for SVI (OR 6.80, p=0.040), increasing iPSA and PPB predicting for pLN+ (ORs 1.12 and 1.06; p<0.05 for both), and increasing bGS, iPSA, and PPB predicting for upstaging to pT3 (ORs of 3.64, 1.08, and 1.03; p<0.05 for all). Overall, 3-year PFS was 70%. No significant predictors for PFS were found on MVA, but NCCN risk group (hazard ratio [HR] 4.17), MTD (HR 1.83), ECE (HR 2.69), SVI (HR 3.04), pLN+ (HR 3.70), and pGS (HR 4.79) were all significant on univariate analysis (UVA, p<0.05 for all). PCA3 score was not associated with any APF or with PFS on UVA or MVA. Unlike in lower-risk cohorts, PCA3 score was not associated with any APF in this higher-risk cohort, despite enrichment for APFs. Similarly, despite a relatively high number of biochemical recurrences, PCA3 score was not associated with PFS. Notably, multiple known pre-operative predictors for APFs were significant on MVA, and multiple predictors were associated with PFS on UVA. These results suggest that PCA3 may not be a useful adjunct predictive marker in men with higher-risk PCa.

Abstract 732: Potentials of some serum proteins and urinary molecular biomarkers for early diagnosis of prostate cancer in Nigeria patients

Abstract Background: Prostate cancer (PCa) an adenocarcinoma is the most common cancer diagnosed in African men today. At present, the only widely accepted screening tools for prostate cancer are prostate specific antigen (PSA) and digital rectal examination. There is controversy regarding the appropriate level of serum PSA that should trigger a biopsy. This study is aimed at finding a better marker/panel of markers for prostate cancer. Methods: 150 consented patients requiring a prostate biopsy and 100 age matched controls were recruited for this study. Genetic materials were found in 132 (88%) of the samples. Serum Total PSA (TPSA) , and free PSA were assayed using ELISA method, % free/total PSA(%f/tpsa) was obtained statistically, prostatic volume was determined using TRUS. In addition, selected urinary RNA’s were assayed; transmembrane serine protease (TMPRSS2:ERG and TMPRSS2:ETS) fusion genes, PSA gene and PCA3 (prostate cancer antigen 3) , using standard polymerase chain reaction (PCR) protocols. Results: TMPRSS2:ERG was detected in 9 (7 %) of the samples and limited to biopsy positive for PCa. Similarly, TMPRSS2:ETS was found in only 4 (3%) of the samples and also restricted to biopsy positive for PCa. PCA3 score had the best discriminatory accuracy in diagnosing PCa amongst patients with serum Total PSA in the range of 4 - 10 ng/ml with AUC of 0.705 compared to Total PSA, f/t PSA ratio, and PSA Density which were 0.365, 0.695, and 0.541 respectively. At the cut off value of 24.6, PCA3 score yielded its best sensitivity of 0.615 and specificity of 0.630. At the cutoff of 18, free/total PSA ratio (0.615, 0.77), at the cutoff of 0.14 PSAD yielded its best (0.538, 0.704.) respectively. Direct logistic regression was performed to access the predictability of PCa using different models comprising of three (3) covariates, the model comprising PCA3 Score, f/t PSA ratio and PSAD had the best discriminating accuracy in the subgroup with TPSA range of 4 - 10ng/ml, with the sensitivity, specificity, positive predictive value, and negative predictive values of 0.59, 0.93, 71.4% and 75.8% respectively, over models comprising PCA3 Score ,TPSA and %f/t PSA, and PCA3 Score, TPSA and PSAD with these values (0.23, 0.85, 42.9 % and 70.1%), (0.39, 0.89, 62.5%, and 75 %) and ( 0.15, 0.85,66.7% and 67.6%) respectively. Conclusions: In predicting PCa amongst patients with serum total PSA in the grey area of 4 - 10 ng/ml, the model comprising PCA3 Score, f/t PSA ratio and PSAD had the best discriminating accuracy. Note: This abstract was not presented at the meeting. Citation Format: Oluyemi Akinloye, Aniebietabasi S. Obot, Taiwo A. Adewole. Potentials of some serum proteins and urinary molecular biomarkers for early diagnosis of prostate cancer in Nigeria patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 732. doi:10.1158/1538-7445.AM2017-732

Prostate Cancer Antigen 3 Score Does Not Predict for Adverse Pathologic Features at Radical Prostatectomy or for Progression-free Survival in Clinically Localized, Intermediate- and High-risk Prostate Cancer

To evaluate whether preoperative urinary prostate cancer antigen 3 (PCA3) scores predict for adverse pathologic features (APFs) or progression-free survival (PFS) in men with intermediate- or high-risk prostate cancer (PCa) undergoing radical prostatectomy (RP). One hundred nine men with intermediate- (n = 52) or high-risk (n = 57) PCa who underwent RP were retrospectively identified. Logistic regression analysis was performed to evaluate the association of PCA3 score with various APFs (eg, extracapsular extension, seminal vesicle invasion, etc.). Among 78 men with ≥1 year of follow-up, the association between PCA3 score and PFS was assessed using Cox regression analysis. At RP, 52% of patients had at least 1 APF, and with median follow-up of 2.3 years, overall 3-year PFS was 70%. PCA3 was not a significant predictor of any APF on multivariate analysis (MVA), whereas canonical predictors (eg, biopsy Gleason score and initial prostate-specific antigen) remained predictive of various APFs. No significant predictors for PFS were found on MVA, although certain canonical predictors (eg, National Comprehensive Cancer Network risk group) were significant predictors of PFS on univariate analysis (UVA). PCA3 score was not a significant predictor of PFS on either UVA or MVA. Unlike in lower risk cohorts, increasing PCA3 score was not associated with any APF in this higher risk cohort, despite enrichment for APFs, nor was it associated with PFS. Notably, multiple known preoperative predictors for APFs were significant on MVA, and multiple predictors were associated with PFS on UVA. Therefore, PCA3 may not be a useful adjunct predictive marker in men with intermediate- or high-risk PCa.

Longitudinal assessment of urinary PCA3 for predicting prostate cancer grade reclassification in favorable-risk men during active surveillance.

BackgroundTo assess the utility of urinary prostate cancer antigen 3 (PCA3) as both a one-time and longitudinal measure in men on active surveillance (AS).MethodsThe Johns Hopkins AS program monitors men with favorable-risk prostate cancer with serial PSA, digital rectal examination (DRE), prostate MRI, and prostate biopsy. Since 2007, post-DRE urinary specimens have also been routinely obtained. Men with multiple PCA3 measures obtained over ≥3 years of monitoring were included. Utility of first PCA3 score (fPCA3), subsequent PCA3 (sPCA3), and change in PCA3 were assessed for prediction of Gleason grade reclassification (GR, Gleason score>6) during follow-up.ResultsIn total, 260 men met study criteria. Median time from enrollment to fPCA3 was 2 years (IQR 1–3) and from fPCA3 to sPCA3 was 5 years (IQR 4–6). During median follow-up of 6 years (IQR 5–8), 28 men (11%) underwent GR. Men with GR had higher median fPCA3 (48.0vs.24.5, p=0.007) and sPCA3 (63.5vs.36.0, p=0.002) than those without GR, while longitudinal change in PCA3 did not differ by GR status (log-normalized rate 0.07vs.0.06, p=0.53). In a multivariable model including age, risk-classification, and PSA density, fPCA3 remained significantly associated with GR (log[fPCA3] odds ratio=1.77, p=0.04).ConclusionsPCA3 scores obtained during AS were higher in men who underwent GR, but the rate of change in PCA3 over time did not differ by GR status. PCA3 was a significant predictor of GR in a multivariable model including conventional risk factors, suggesting that PCA3 provides incremental prognostic information in the AS setting.

Intérêt du test PCA3 avant une première série de biopsies prostatiques négatives : 5 ans de suivi

We report a 5-year follow-up of a cohort of patients who underwent a first prostate biopsy following a prostate cancer antigen 3 (PCA3) test. We reviewed consecutive patients who had in 2008 a single urinary PCA3 test using the Gen-Probe® assay before a first prostate biopsy for a prostate-specific antigen (PSA) between 3 and 20ng/mL and/or a suspicious digital rectal examination. PCA3 performances were analyzed in 2008 and then in 2013 after taking into account the results of repeat biopsies. At initial biopsy in 2008, among the 125 patients study cohort, prostate cancer was diagnosed in 47 patients (37.6%). Abnormal digital rectal exam, PSA density, prostate volume and PCA3 score were significantly associated with prostate cancer diagnosis. PCA3 area under the curve of the receiver operating curve was 0.67 [95%CI: 0.57-0.76] with an optimal threshold of PCA3 in this sample of 24 units. During the 5-year follow-up, among the 78 patients with a negative prostate biopsy in 2008, 23 (29.5%) had a repeat prostate biopsy of whom 14 were diagnosed with prostate cancer. PCA3 score measured in 2008 was associated with prostate cancer diagnosis (P=0.002). All 9 patients with a negative repeat prostate biopsy had a PCA3 score below the cut-off while this was the case in only 2 patients among the 14 with a positive repeat prostate biopsy. The results of a single PCA3 test before a first prostate biopsy seems to be a useful aid in deciding whether to perform a repeat biopsy. 4.

MP15-09 BASELINE AND LONGITUDINAL PCA3 PREDICT MORE EXTENSIVE CANCER IN AN ACTIVE SURVEILLANCE POPULATION

You have accessJournal of UrologyProstate Cancer: Localized: Active Surveillance II1 Apr 2016MP15-09 BASELINE AND LONGITUDINAL PCA3 PREDICT MORE EXTENSIVE CANCER IN AN ACTIVE SURVEILLANCE POPULATION Jeffrey Tosoian, Mufaddal Mamawala, Patricia Landis, Sacha Wolf, Jonathan Epstein, Lori Sokoll, and Christian Pavlovich Jeffrey TosoianJeffrey Tosoian More articles by this author , Mufaddal MamawalaMufaddal Mamawala More articles by this author , Patricia LandisPatricia Landis More articles by this author , Sacha WolfSacha Wolf More articles by this author , Jonathan EpsteinJonathan Epstein More articles by this author , Lori SokollLori Sokoll More articles by this author , and Christian PavlovichChristian Pavlovich More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2533AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES One drawback of active surveillance (AS) is the use of serial prostate biopsy, which is costly and associated with various risks. As such, alternative methods of monitoring AS patients are needed. Prostate cancer antigen 3 (PCA3) is a urinary biomarker that may improve diagnostic ability in some populations. Whether PCA3 has a role in AS remains unclear, and its utility as a longitudinal measure has not been evaluated. We sought to evaluate the role of baseline and longitudinal PCA3 values in predicting higher-risk cancer among men in AS. METHODS A total of 1511 men with favorable-risk (i.e. VLR or LR) cancer have enrolled in the Johns Hopkins AS program. Monitoring includes semiannual PSA and DRE, and annual prostate biopsy for most men; post-DRE urine specimens have been obtained since 2007. To assess the value of repeated PCA3 (Progensa PCA3, Hologic, Inc.) measurements, we identified patients with two urine samples obtained over an interval of three or more years. Initial (iPCA3) and subsequent (sPCA3) PCA3 scores were compared based on grade reclassification (GR, defined as any Gleason score >6) and high-volume (defined as >2 cores or >50% involvement of any core) or bilateral cancer during follow-up. A multivariate model was used to evaluate PCA3 score in conjunction with other pathologic parameters. RESULTS In total, 294 men met study criteria; median time between PCA3 measures was 5 years (IQR 4-6). Thirty-five (12%) men underwent GR at a median of 7 years (IQR 5-9) after enrollment. Men who underwent GR had a higher median iPCA3 (49.6 vs. 25.5, p=0.003) and sPCA3 (62.0 vs. 39.0, p=0.004) than those who did not. While PCA3 score increased over time in the cohort (median iPCA3 vs. sPCA3, 27.1 vs. 41.0, p<0.0001), the rate of increase did not differ by GR status (log-normalized rate 0.07 vs. 0.08, p=0.88). In a multivariate model, high-volume (OR=3.09, p=0.006) and bilateral (OR=9.83, p<0.0001) disease significantly predicted GR while PCA3 score was not statistically significant (OR=1.00, p=0.13). Nonetheless, on univariate analysis PCA3 values predicted high-volume cancer (OR=1.30, p=0.006) and the presence of bilateral cancer (OR= 1.61, p<0.0001). CONCLUSIONS In men with favorable-risk cancer on AS, PCA3 scores were associated with higher-risk cancer, while time-related changes in PCA3 score were not. PCA3 score did not independently predict GR, but did demonstrate a robust association with more extensive disease on biopsy. These findings suggest PCA3 may provide a non-invasive alternative to biopsy for identifying men at higher risk of reclassification during AS. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e155 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Jeffrey Tosoian More articles by this author Mufaddal Mamawala More articles by this author Patricia Landis More articles by this author Sacha Wolf More articles by this author Jonathan Epstein More articles by this author Lori Sokoll More articles by this author Christian Pavlovich More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Factors predicting progression to castrate-resistant prostate cancer in patients with advanced prostate cancer receiving long-term androgen-deprivation therapy.

To assess time to progression to castrate-resistant prostate cancer (CRPC) and factors influencing longer-term outcomes in patients receiving androgen-deprivation therapy (ADT) in an extension to the Triptocare study (NCT01020448). This is pertinent as the Triptocare study did not show that urinary prostate cancer antigen-3 (PCA3) score was a reliable marker of cancer stage in advanced prostate cancer and was not useful for assessing response 6 months after initiation of ADT with triptorelin 22.5 mg. An international, multicentre, non-interventional, observational, longitudinal, prospective study involving patients from the Triptocare study. CRPC status of patients was collected for up to 3 years from ADT initiation. Patient treatment and assessments were at the investigator's discretion. Co-primary endpoints were rate of CRPC at 3 years after initiating ADT and the median time to CRPC. An exploratory endpoint was the association of Triptocare baseline variables (including TMPRSS2-ERG and PCA3 scores) and PCA3 score at Triptocare last value available with CRPC onset. Of the 325 patients in the Triptocare study safety population, 180 patients were enrolled in the Triptocare LT study (102 received continuous and 78 received intermittent ADT). CRPC rates at 3 years were 24/102 (23.5%) and 6/78 (7.7%) patients in the continuous and intermittent ADT groups, respectively. The median time to CRPC was not reached for either group. PCA3 score status at baseline was the only variable associated with a higher risk of progression to CRPC in both the intermittent and continuous ADT groups; compared with a baseline PCA3 score of ≥35, a PCA3 score below the level of quantification had a hazard ratio (HR) of 20.04 ([95% confidence interval (CI) 2.71-148.34] and a HR of 9.44 [95% CI 2.39-37.27], respectively). Baseline metastatic disease and testosterone level were additionally associated with progression to CRPC in the continuous ADT population (HR 5.20, 95% CI 1.68-16.06 and HR 0.995, 95% CI 0.991-0.999, respectively). In men with locally advanced or metastatic prostate cancer, a PCA3 score of ≥35 at the time of initiating ADT may predict a lower risk of developing CRPC in the following 3 years.

Prostate cancer antigen 3 moderately improves diagnostic accuracy in Chinese patients undergoing first prostate biopsy.

Prostate cancer antigen 3 (PCA3) is a biomarker for diagnosing prostate cancer (PCa) identified in the Caucasian population. We evaluated the effectiveness of urinary PCA3 in predicting the biopsy result in 500 men undergoing initial prostate biopsy. The predictive power of the PCA3 score was evaluated by the area under receiver operating characteristic (ROC) curve (AUC) and by decision curve analysis. PCA3 score sufficed to discriminate positive from negative prostate biopsy results but was not correlated with the aggressiveness of PCa. The ROC analysis showed a higher AUC for the PCA3 score than %fPSA (0.750 vs 0.622, P = 0.046) in patients with a PSA of 4.0–10.0 ng ml−1, but the PCA3-based model is not significantly better than the base model. Decision curve analysis indicates the PCA3-based model was superior to the base model with a higher net benefit for almost all threshold probabilities, especially the threshold probabilities of 25%–40% in patients with a PSA of 4.0–10.0 ng ml−1. However, the AUC of the PCA3 score (0.712) is not superior to %fPSA (0.698) or PSAD (0.773) in patients with a PSA >10.0 ng ml−1. Our results confirmed that the RT-PCR-based PCA3 test moderately improved diagnostic accuracy in Chinese patients undergoing first prostate biopsy with a PSA of 4.0–10.0 ng ml−1.

The clinical effectiveness and cost-effectiveness of the PROGENSA® prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.

There is no single definitive test to identify prostate cancer in men. Biopsies are commonly used to obtain samples of prostate tissue for histopathological examination. However, this approach frequently misses cases of cancer, meaning that repeat biopsies may be necessary to obtain a diagnosis. The PROGENSA(®) prostate cancer antigen 3 (PCA3) assay (Hologic Gen-Probe, Marlborough, MA, USA) and the Prostate Health Index (phi; Beckman Coulter Inc., Brea, CA, USA) are two new tests (a urine test and a blood test, respectively) that are designed to be used to help clinicians decide whether or not to recommend a repeat biopsy. To evaluate the clinical effectiveness and cost-effectiveness of the PCA3 assay and the phi in the diagnosis of prostate cancer. Multiple publication databases and trial registers were searched in May 2014 (from 2000 to May 2014), including MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science, Medion, Aggressive Research Intelligence Facility database, ClinicalTrials.gov, International Standard Randomised Controlled Trial Number Register and World Health Organization International Clinical Trials Registry Platform. The assessment of clinical effectiveness involved three separate systematic reviews, namely reviews of the analytical validity, the clinical validity of these tests and the clinical utility of these tests. The assessment of cost-effectiveness comprised a systematic review of full economic evaluations and the development of a de novo economic model. The perspective of the evaluation was the NHS in England and Wales. Men suspected of having prostate cancer for whom the results of an initial prostate biopsy were negative or equivocal. The use of the PCA3 score or phi in combination with existing tests (including histopathology results, prostate-specific antigen level and digital rectal examination), multiparametric magnetic resonance imaging and clinical judgement. In addition to documents published by the manufacturers, six studies were identified for inclusion in the analytical validity review. The review identified issues concerning the precision of the PCA3 assay measurements. It also highlighted issues relating to the storage requirements and stability of samples intended for analysis using the phi assay. Fifteen studies met the inclusion criteria for the clinical validity review. These studies reported results for 10 different clinical comparisons. There was insufficient evidence to enable the identification of appropriate test threshold values for use in a clinical setting. In addition, the implications of adding either the PCA3 assay or the phi to clinical assessment were not clear. Furthermore, the addition of the PCA3 assay or the phi to clinical assessment plus magnetic resonance imaging was not found to improve discrimination. No published papers met the inclusion criteria for either the clinical utility review or the cost-effectiveness review. The results from the cost-effectiveness analyses indicated that using either the PCA3 assay or the phi in the NHS was not cost-effective. The main limitations of the systematic review of clinical validity are that the review conclusions are over-reliant on findings from one study, the descriptions of clinical assessment vary widely within reviewed studies and many of the reported results for the clinical validity outcomes do not include either standard errors or confidence intervals. The clinical benefit of using the PCA3 assay or the phi in combination with existing tests, scans and clinical judgement has not yet been confirmed. The results from the cost-effectiveness analyses indicate that the use of these tests in the NHS would not be cost-effective. This study is registered as PROSPERO CRD42014009595. The National Institute for Health Research Health Technology Assessment programme.

Improved sensitivity and specificity for prostate cancer diagnosis based on the urine PCA3/PSA ratio acquired by sequence‑specific RNA capture.

Prostate cancer antigen3 (PCA3) is a non-coding RNA fragment that is overexpressed in prostate cancer cells. However, the clinical applications of PCA3 are highly limited due to the instability of RNA and the lack of reliable and efficient RNA extraction and purification methods. Thus, in the present study, we compared three different methods of RNA extraction to further confirm the higher yield of commercial magnetic beads with poly-T functionalization and a capturer strand. The current protocols for RNA extraction of i) the phenol-chloroform method, ii) the affinity column method and iii) magnetic beads with poly-T functionalization and a capturer strand were applied separately for RNA extraction in urine samples. Reverse transcription‑quantitative polymerase chain reaction was performed to evaluate the yield of the three methods of RNA extraction. Furthermore, 52urine samples after prostate massage from patients suspected of a diagnosis of prostate cancer were collected. The Mag-Cap method and RT-PCR were applied to obtain the PCA3 score. The clinical value of the PCA3 score was investigated by comparison with the pathology of the prostate biopsy. The yield of the Mag-Cap method was higher than that of the phenol‑chloroform method and commercial kits. Thirty‑four patients were pathologically diagnosed with prostate cancer and 18with benign prostatic hyperplasia (BPH). It was confirmed that the median PCA3 score was higher among the prostate cancer patients than those with benign disease (53.5vs.17, p=0.000). A sensitivity of 82.4% and a specificity of 77.8% were obtained when the cut-off value for the PCA3 score was 28.5. The Mag-Cap method was found to be more efficient for RNA extraction. The urinary PCA3 score is a promising method for prostate cancer screening, detection and diagnosis, and has the potential to reduce unnecessary prostate biopsies.

Assessment of long-term outcomes associated with urinary prostate cancer antigen 3 and TMPRSS2:ERG gene fusion at repeat biopsy.

In men with clinically localized prostate cancer who have undergone at least 1 previous negative biopsy and have elevated serum prostate-specific antigen (PSA) levels, long-term health outcomes associated with the assessment of urinary prostate cancer antigen 3 (PCA3) and the transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) gene fusion (T2:ERG) have not been investigated previously in relation to the decision to recommend a repeat biopsy. The authors performed a decision analysis using a decision tree for men with elevated PSA levels. The probability of cancer was estimated using the Prostate Cancer Prevention Trial Risk Calculator (version 2.0). The use of PSA alone was compared with the use of PCA3 and T2:ERG scores, with each evaluated independently, in combination with PSA to trigger a repeat biopsy. When PCA3 and T2:ERG score evaluations were used, predefined thresholds were established to determine whether the patient should undergo a repeat biopsy. Biopsy outcomes were defined as either positive (with a Gleason score of <7, 7, or >7) or negative. Probabilities and estimates of 10-year overall survival and 15-year cancer-specific survival were derived from previous studies and a literature review. Outcomes were defined as age-dependent and Gleason score-dependent 10-year overall and 15-year cancer-specific survival rates and the percentage of biopsies avoided. Incorporating the PCA3 score (biopsy threshold, 25; generated based on the urine PCA3 level normalized to the amount of PSA messenger RNA) or the T2:ERG score (biopsy threshold, 10; based on the urine T2:ERG level normalized to the amount of PSA messenger RNA) into the decision to recommend repeat biopsy would have avoided 55.4% or 64.7% of repeat biopsies for the base-case patient, respectively, and changes in the 10-year survival rate were only 0.93% or 1.41%, respectively. Multi-way sensitivity analyses suggested that these results were robust with respect to the model parameters. The use of PCA3 or T2:ERG testing for repeat biopsy decisions can substantially reduce the number of biopsies without significantly affecting 10-year survival.

Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate Cancer Risk Assessment

BackgroundTMPRSS2:ERG (T2:ERG) and prostate cancer antigen 3 (PCA3) are the most advanced urine-based prostate cancer (PCa) early detection biomarkers. ObjectiveValidate logistic regression models, termed Mi-Prostate Score (MiPS), that incorporate serum prostate-specific antigen (PSA; or the multivariate Prostate Cancer Prevention Trial risk calculator version 1.0 [PCPTrc]) and urine T2:ERG and PCA3 scores for predicting PCa and high-grade PCa on biopsy. Design, setting, and participantsT2:ERG and PCA3 scores were generated using clinical-grade transcription-mediated amplification assays. Pretrained MiPS models were applied to a validation cohort of whole urine samples prospectively collected after digital rectal examination from 1244 men presenting for biopsy. Outcome measurements and statistical analysisArea under the curve (AUC) was used to compare the performance of serum PSA (or the PCPTrc) alone and MiPS models. Decision curve analysis (DCA) was used to assess clinical benefit. Results and limitationsAmong informative validation cohort samples (n=1225 [98%], 80% from patients presenting for initial biopsy), models incorporating T2:ERG had significantly greater AUC than PSA (or PCPTrc) for predicting PCa (PSA: 0.693 vs 0.585; PCPTrc: 0.718 vs 0.639; both p<0.001) or high-grade (Gleason score >6) PCa on biopsy (PSA: 0.729 vs 0.651, p<0.001; PCPTrc: 0.754 vs 0.707, p=0.006). MiPS models incorporating T2:ERG score had significantly greater AUC (all p<0.001) than models incorporating only PCA3 plus PSA (or PCPTrc or high-grade cancer PCPTrc [PCPThg]). DCA demonstrated net benefit of the MiPS_PCPTrc (or MiPS_PCPThg) model compared with the PCPTrc (or PCPThg) across relevant threshold probabilities. ConclusionsIncorporating urine T2:ERG and PCA3 scores improves the performance of serum PSA (or PCPTrc) for predicting PCa and high-grade PCa on biopsy. Patient summaryIncorporation of two prostate cancer (PCa)-specific biomarkers (TMPRSS2:ERG and PCA3) measured in the urine improved on serum prostate-specific antigen (or a multivariate risk calculator) for predicting the presence of PCa and high-grade PCa on biopsy. A combined test, Mi-Prostate Score, uses models validated in this study and is clinically available to provide individualized risk estimates.

MP6-02 LOCATION OF DISEASE DOES NOT IMPACT PCA3'S ABILITY TO PREDICT CANCER ON BIOPSY

You have accessJournal of UrologyProstate Cancer: Markers II1 Apr 2015MP6-02 LOCATION OF DISEASE DOES NOT IMPACT PCA3'S ABILITY TO PREDICT CANCER ON BIOPSY Padraic O'Malley, Bashir Al Hussein Al Awamlh, Daniel P. Nguyen, Martin G. Sanda, Ian M. Thompson, John T. Wei, Richard Lee, Mark A. Rubin, Christopher E. Barbieri, Michael P. Hermann, and Douglas S. Scherr Padraic O'MalleyPadraic O'Malley More articles by this author , Bashir Al Hussein Al AwamlhBashir Al Hussein Al Awamlh More articles by this author , Daniel P. NguyenDaniel P. Nguyen More articles by this author , Martin G. SandaMartin G. Sanda More articles by this author , Ian M. ThompsonIan M. Thompson More articles by this author , John T. WeiJohn T. Wei More articles by this author , Richard LeeRichard Lee More articles by this author , Mark A. RubinMark A. Rubin More articles by this author , Christopher E. BarbieriChristopher E. Barbieri More articles by this author , Michael P. HermannMichael P. Hermann More articles by this author , and Douglas S. ScherrDouglas S. Scherr More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.249AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Urine testing for prostate cancer antigen 3 (PCA3) has been utilized to improve stratification of patients into high or low risk for occult tumors after previous negative biopsy. Many of these tumors are thought to be those under-sampled by traditional biopsy methods, in particular anterior and apical (AnA) lesions. The current study examined the ability of PCA3 to predict prostate cancer in varying locations. METHODS Prospective post-DRE urine was collected at three academic centers from 572 men presenting for traditional, non-targeted, trans-rectal ultrasound biopsy as part of the Early Detection Research Network (EDRN) study. Patients were stratified into three groups: 1) No cancer (NC), 2) AnA, and 3) non-AnA (nAnA). Patients with involvement of both AnA and nAnA were excluded. Outcomes examined included PCA3 score for all, clinically significant (CS; >Gleason 7) lesions, and NC controls. Statistical analyses used included the Shapiro-Wilk, ANOVA, and Mann-Whitney U. Receiver operating characteristics (ROC) curves were generated and the area under the curve (AUC) was obtained for PCA3 as a predictor of positive biopsy RESULTS 572 men had complete demographic and biopsy site information. Amongst all study patients, age and PSA were no different between the three groups (Table 1). Prostate cancer prevention trial (PCPT) risk calculator score, PCPT high risk score, and PCA3 were found to be significantly different for AnA and nAnA groups compared to NC (Table 1). The AUC for ROC curves predicting positive biopsy for the AnA and nAnA groups were 0.69 (95% CI, 0.61-0.76) and 0.72 (95% CI, 0.66-0.77) respectively (p<0.001). Men with CS disease (AnA n=21, nAnA n=68), had significant differences between AnA and nAnA groups compared to NC for PCPT, PCPT HR, and PCA3 scores. The AUC for ROC curves for the AnA and nAnA groups were 0.78 (95% CI, 0.69-0.87) and 0.74 (95% CI, 0.67-0.81), respectively (p<0.001; Table 1). CONCLUSIONS Although PCA3 is approved for use in stratifying the cancer risk in men who may have lesions under-sampled by traditional biopsy methods, its variation with location has not been studied to date. PCA3 can serve as an effective predictor of disease regardless of anatomic location. Its utility only increases for detection of clinically significant disease in these traditionally under-sampled areas. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e54 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Padraic O'Malley More articles by this author Bashir Al Hussein Al Awamlh More articles by this author Daniel P. Nguyen More articles by this author Martin G. Sanda More articles by this author Ian M. Thompson More articles by this author John T. Wei More articles by this author Richard Lee More articles by this author Mark A. Rubin More articles by this author Christopher E. Barbieri More articles by this author Michael P. Hermann More articles by this author Douglas S. Scherr More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Can urinary PCA3 supplement PSA in the early detection of prostate cancer?

Given the limited sensitivity and specificity of prostate-specific antigen (PSA), its widespread use as a screening tool has raised concerns for the overdiagnosis of low-risk and the underdiagnosis of high-grade prostate cancer. To improve early-detection biopsy decisions, the National Cancer Institute conducted a prospective validation trial to assess the diagnostic performance of the prostate cancer antigen 3 (PCA3) urinary assay for the detection of prostate cancer among men screened with PSA. In all, 859 men (mean age, 62 years) from 11 centers scheduled for a diagnostic prostate biopsy between December 2009 and June 2011 were enrolled. The primary outcomes were to assess whether PCA3 could improve the positive predictive value (PPV) for an initial biopsy (at a score > 60) and the negative predictive value (NPV) for a repeat biopsy (at a score < 20). For the detection of any cancer, PPV was 80% (95% CI, 72% to 86%) in the initial biopsy group, and NPV was 88% (95% CI, 81% to 93%) in the repeat biopsy group. The addition of PCA3 to individual risk estimation models (which included age, race/ethnicity, prior biopsy, PSA, and digital rectal examination) improved the stratification of cancer and of high-grade cancer. These data independently support the role of PCA3 in reducing the burden of prostate biopsies among men undergoing a repeat prostate biopsy. For biopsy-naive patients, a high PCA3 score (> 60) significantly increases the probability that an initial prostate biopsy will identify cancer.

Accuracy of the prostate health index versus the urinary prostate cancer antigen 3 score to predict overall and significant prostate cancer at initial biopsy.

It remains unclear whether the Prostate Health Index (PHI) or the urinary Prostate-Cancer Antigen 3 (PCA-3) score is more accurate at screening for prostate cancer (PCa). The aim of this study was to prospectively compare the accuracy of PHI and PCA-3 scores to predict overall and significant PCa in men undergoing an initial prostate biopsy. Double-blind assessments of PHI and PCA-3 were conducted by referent physicians in 138 patients who subsequently underwent trans-rectal ultrasound-guided prostate biopsy according to a 12-core scheme. Predictive accuracies of PHI and PCA-3 were assessed using AUC and compared according to the DeLong method. Diagnostic performances with usual cut-off values for positivity (i.e., PHI >40 and PCA-3 >35) were calculated, and odds ratios associated with predicting PCa overall and significant PCa as defined by pathological updated Epstein criteria (i.e., Gleason score ≥7, more than three positive cores, or >50% cancer involvement in any core) were estimated using logistic regression. Prevalences of overall and significant PCa were 44.9% and 28.3%, respectively. PCA-3 (AUC = 0.71) was the most accurate predictor of PCa overall, and significantly outperformed PHI (AUC = 0.65; P = 0.03). However, PHI (AUC = 0.80) remained the most accurate predictor when screening exclusively for significant PCa and significantly outperformed PCA-3 (AUC = 0.55; P = 0.03). Furthermore, PCA-3 >35 had the best accuracy, and positive or negative predictive values when screening for PCa overall whereas these diagnostic performances were greater for PHI >40 when exclusively screening for significant PCa. PHI > 40 combined with PCA-3 > 35 was more specific in both cases. In multivariate analyses, PCA-3 >35 (OR = 5.68; 95%CI = [2.21-14.59]; P < 0.001) was significantly correlated with the presence of PCa overall, but PHI >40 (OR = 9.60; 95%CI = [1.72-91.32]; P = 0.001) was the only independent predictor for detecting significant PCa. Although PCA-3 score is the best predictor for PCa overall at initial biopsy, our findings strongly indicate that PHI should be used for population-based screening to avoid over-diagnosis of indolent tumors that are unlikely to cause death.

The Added Value of Percentage of Free to Total Prostate-specific Antigen, PCA3, and a Kallikrein Panel to the ERSPC Risk Calculator for Prostate Cancer in Prescreened Men

BackgroundProstate-specific antigen (PSA) testing has limited accuracy for the early detection of prostate cancer (PCa). ObjectiveTo assess the value added by percentage of free to total PSA (%fPSA), prostate cancer antigen 3 (PCA3), and a kallikrein panel (4k-panel) to the European Randomised Study of Screening for Prostate Cancer (ERSPC) multivariable prediction models: risk calculator (RC) 4, including transrectal ultrasound, and RC 4 plus digital rectal examination (4+DRE) for prescreened men. Design, setting, and participantsParticipants were invited for rescreening between October 2007 and February 2009 within the Dutch part of the ERSPC study. Biopsies were taken in men with a PSA level ≥3.0 ng/ml or a PCA3 score ≥10. Additional analyses of the 4k-panel were done on serum samples. Outcome measurements and statistical analysisOutcome was defined as PCa detectable by sextant biopsy. Receiver operating characteristic curve and decision curve analyses were performed to compare the predictive capabilities of %fPSA, PCA3, 4k-panel, the ERSPC RCs, and their combinations in logistic regression models. Results and limitationsPCa was detected in 119 of 708 men. The %fPSA did not perform better univariately or added to the RCs compared with the RCs alone. In 202 men with an elevated PSA, the 4k-panel discriminated better than PCA3 when modelled univariately (area under the curve [AUC]: 0.78 vs 0.62; p=0.01). The multivariable models with PCA3 or the 4k-panel were equivalent (AUC: 0.80 for RC 4+DRE). In the total population, PCA3 discriminated better than the 4k-panel (univariate AUC: 0.63 vs 0.56; p=0.05). There was no statistically significant difference between the multivariable model with PCA3 (AUC: 0.73) versus the model with the 4k-panel (AUC: 0.71; p=0.18). The multivariable model with PCA3 performed better than the reference model (0.73 vs 0.70; p=0.02). Decision curves confirmed these patterns, although numbers were small. ConclusionsBoth PCA3 and, to a lesser extent, a 4k-panel have added value to the DRE-based ERSPC RC in detecting PCa in prescreened men. Patient summaryWe studied the added value of novel biomarkers to previously developed risk prediction models for prostate cancer. We found that inclusion of these biomarkers resulted in an increase in predictive ability.

Prostate cancer antigen-3 (PCA3) and PCA3-based nomograms in the diagnosis of prostate cancer: an external validation of Hansen’s nomogram on a Norwegian cohort

Objective. The aim of this study was to test the ability of prostate cancer antigen-3 (PCA3) and Hansen’s PCA3-based nomogram to predict prostate cancer (PCa) probability in a Norwegian cohort, with the goal of reducing unnecessary biopsies. Material and methods. Altogether, 127 consecutive patients were recruited to this study at Haukeland University Hospital, Norway. Prostate-specific antigen (PSA), PCA3 score, digital rectal examination (DRE), prostate volume (Pvol) and age were determined. All patients had an extended 10-core biopsy. The performance of PCA3 score and Hansen’s nomogram was tested. Results. There were 124 evaluable patients. Among these, 59 patients had PCa on the initial biopsies. Mean PSA, PCA3 score and age were significantly higher and Pvol was significantly lower in patients with PCa. PCA3 scores of 35 and 21 led to a sensitivity of 71% and 81% and specificity of 72% and 55%, respectively. Hansen’s nomogram gave an area under the curve (AUC) of 0.806. The intraclass correlation was 0.959 (Cronbach’s alpha). Applied to this material, PCa would be missed in 15.2% of patients when applying the suggested threshold probability of 30%, among whom 66.7% had high-grade PCa. With a threshold probability of 20% only one patient had PCa and this was low grade. Conclusions. Hansen’s PCA3-based nomogram is valid for this cohort. A threshold probability of 20% seems more adequate than 30% for this less screened cohort. PCA3 score only affects the biopsy indication in some patients and is recommended only for this subset. The results need to be confirmed in a larger study.