Urinary PCA3 Research Articles

Diagnostic Accuracy of Urinary PCA3 for Prostate Cancer in Thai Patients With PSA Levels of 3 to 10 ng/ml Undergoing an Initial Prostate Biopsy

Purpose: To examine the diagnostic accuracy of the urinary prostate cancer gene 3 score for prostate cancer in Thai patients with prostate-specific antigen levels of 3 to 10 ng/ml undergoing an initial prostate biopsy. Materials and methods: In this prospective, single-center study, urine samples were collected after prostate massage. Urinary prostate cancer gene 3 mRNA levels were measured by real-time quantitative polymerase chain reaction. Data, including age, biopsy results, preoperative prostate-specific antigen levels, prostate-specific antigen density, prostate-specific antigen velocity, prostate volume, and prostate imaging findings, were collected between June 1, 2020, and May 15, 2021. Results: The median prostate-specific antigen level of the 70 included patients was 6.31 ng/ml. Sixteen patients had positive biopsy results (22.9%). The prostate cancer gene 3 score (695.09 vs 268.79, P < .01), prostate-specific antigen density (0.19 vs 0.13, P < .01), and prostate-specific antigen velocity (2.68 vs 0.44, P < .01) significantly differed between the positive and negative biopsy groups. The predictive power of the prostate cancer gene 3 score was evaluated using receiver operating characteristic curves. At a prostate cancer gene 3 score threshold of 366.02, the sensitivity and specificity were 78.57% and 79.25%, respectively. Meanwhile, the areas under the curve of the prostate cancer gene 3 score, prostate-specific antigen velocity, and prostate-specific antigen density were better than that of prostate-specific antigen for predicting a positive biopsy. Conclusion: Our study confirmed the diagnostic accuracy of prostate cancer gene 3 for predicting a positive biopsy in Thai men with prostate-specific antigen levels of 3 to 10 ng/mL. Combining the prostate cancer gene 3 score and prostate-specific antigen derivatives might be helpful for identifying patients who can avoid unnecessary biopsies and subsequent complications.

Abstract 6507: E3 ubiquitin-protein ligase, tetratricopeptide repeat domain 3 (TTC3), H4 clustered histone 5 (H4C5), and epithelial cell adhesion molecule (EpCAM) are novel urine-enriched liquid biopsy biomarkers to detect prostate cancer in men

Abstract Background: Prostate Cancer (PCa) is one of the leading causes of cancer deaths among American men; however, the estimated number of diagnoses represents a small fraction of disease-related biopsies performed yearly. Although the Prostate-Specific Antigen (PSA) test is widely used for screening, several advisory groups recommend against using PSA because of its suboptimal performance. Thus, there is an urgent unmet need for novel and more accurate diagnostic biomarkers for PCa detection and to differentiate aggressive cancer from its indolent form. Methods: In our study, we used voided urine (50ml) from pre and post-prostatectomy men with PCa and urine from normal healthy men as control. We isolated RNA from exfoliated cells and debris shed into urine and performed RNA-sequencing using the Illumina Next-seq 550 platform. Advanced computational and machine-learning approaches were employed to identify candidate biomarkers in men with PCa. We examined the TCGA database to validate the PCa-specific expression of the identified RNA in tumor tissues. Two RNA markers were further tested by qPCR, and one urinary soluble protein marker was measured by immunoassays. Results: Our study included 106 men with PCa and 88 control men. We identified and validated the presence of ≥1 RNA markers (TTC3, H4C5) and a protein marker (EpCAM) in urine as potential candidate biomarkers for PCa detection. We tested and developed these markers using qPCR for TTC3, H4C5, and ELISA assay for EpCAM with higher specificity and sensitivity (Table 1). Our results outperformed known urinary markers, PCA3 and SPDEF (Figure 1). TTC3, H4C5, and EpCAM markers diminished to low or undetectable levels in post-prostatectomy compared to pre-prostatectomy men with PCa. shRNA knockdown of TTC3 and EpCAM in androgen-sensitive and insensitive cells induced biological changes, suggesting their relevance to Prostate Cancer. Conclusions: We report a highly accurate panel of 3 urine-based biomarkers that detect PCa consisting of EpCAM (protein) and TTC3 and H4C5 (RNA). To identify the advantage of using individual or combinatorial markers is an ongoing study in our laboratory. Citation Format: Ranjan Joseph Perera, Marcio Moschovas, Roshane Perera, Bongyong Lee, Alexandra Miller, Ernest K. Amankwah, Rudramani Pokhrel, Christian Pavlovich, Guru Sonpavde, Vipul Patel. E3 ubiquitin-protein ligase, tetratricopeptide repeat domain 3 (TTC3), H4 clustered histone 5 (H4C5), and epithelial cell adhesion molecule (EpCAM) are novel urine-enriched liquid biopsy biomarkers to detect prostate cancer in men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6507.

MP44-18 E3 UBIQUITIN-PROTEIN LIGASE, TETRATRICOPEPTIDE REPEAT DOMAIN 3 (TTC3), H4 CLUSTERED HISTONE 5 (H4C5), AND EPITHELIAL CELL ADHESION MOLECULE (EPCAM) ARE NOVEL URINE-ENRICHED LIQUID BIOPSY BIOMARKERS TO DETECT PROSTATE CANCER IN MEN

You have accessJournal of UrologyCME1 Apr 2023MP44-18 E3 UBIQUITIN-PROTEIN LIGASE, TETRATRICOPEPTIDE REPEAT DOMAIN 3 (TTC3), H4 CLUSTERED HISTONE 5 (H4C5), AND EPITHELIAL CELL ADHESION MOLECULE (EPCAM) ARE NOVEL URINE-ENRICHED LIQUID BIOPSY BIOMARKERS TO DETECT PROSTATE CANCER IN MEN Menglang Yuan, Marcio Moschovas, Roshane Perera, Bongyong Lee, Alexandra Miller, Ernest Amankwah, Rudramani Pokhrel, Christian Pavlovich, Guru Sonpavde, Vipul Patel, and Ranjan Perera Menglang YuanMenglang Yuan More articles by this author , Marcio MoschovasMarcio Moschovas More articles by this author , Roshane PereraRoshane Perera More articles by this author , Bongyong LeeBongyong Lee More articles by this author , Alexandra MillerAlexandra Miller More articles by this author , Ernest AmankwahErnest Amankwah More articles by this author , Rudramani PokhrelRudramani Pokhrel More articles by this author , Christian PavlovichChristian Pavlovich More articles by this author , Guru SonpavdeGuru Sonpavde More articles by this author , Vipul PatelVipul Patel More articles by this author , and Ranjan PereraRanjan Perera More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003290.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate Cancer (PCa) is one of the leading causes of cancer deaths among American men; however, the estimated number of diagnoses represents a small fraction of disease-related biopsies performed yearly. Although the Prostate-Specific Antigen (PSA) test is widely used for screening, several advisory groups recommend against using PSA because of its suboptimal performance. Thus, there is an urgent unmet need for novel and more accurate diagnostic biomarkers for PCa detection and to differentiate aggressive cancer from its indolent form. METHODS: In our study, we used voided urine (50ml) from pre and post-prostatectomy men with PCa and urine from normal healthy men as control. We isolated RNA from exfoliated cells and debris shed into urine and performed RNA-sequencing using the Illumina Next-seq 550 platform. Advanced computational and machine-learning approaches were employed to identify candidate biomarkers in men with PCa. We examined the TCGA database to validate the PCa-specific expression of the identified RNA in tumor tissues. Two RNA markers were further tested by qPCR, and one urinary soluble protein marker was measured by immunoassays. RESULTS: Our study included 106 men with PCa and 88 control men. We identified and validated the presence of ≥1 RNA markers (TTC3, H4C5) and a protein marker (EpCAM) in urine as potential candidate biomarkers for PCa detection. We tested and developed these markers using qPCR for TTC3, H4C5, and ELISA assay for EpCAM with higher specificity and sensitivity (Table 1). Our results outperformed known urinary markers, PCA3 and SPDEF (Figure 1). TTC3, H4C5, and EpCAM markers diminished to low or undetectable levels in post-prostatectomy compared to pre-prostatectomy men with PCa. shRNA knockdown of TTC3 and EpCAM in androgen-sensitive and insensitive cells induced biological changes, suggesting their relevance to Prostate Cancer. CONCLUSIONS: We report a highly accurate panel of 3 urine-based biomarkers that detect PCa consisting of EpCAM (protein) and TTC3 and H4C5 (RNA). To identify the advantage of using individual or combinatorial markers is an ongoing study in our laboratory. Source of Funding: Florida Department of Health, Bankhead-Coley Cancer Research Program 5BC08 to RJP. International Prostate Cancer Foundation (IPCF) to R.J.P and VP. National Institutes of Health grant NCI 5P30CA030199 to RJP © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e619 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Menglang Yuan More articles by this author Marcio Moschovas More articles by this author Roshane Perera More articles by this author Bongyong Lee More articles by this author Alexandra Miller More articles by this author Ernest Amankwah More articles by this author Rudramani Pokhrel More articles by this author Christian Pavlovich More articles by this author Guru Sonpavde More articles by this author Vipul Patel More articles by this author Ranjan Perera More articles by this author Expand All Advertisement PDF downloadLoading ...

MyProstateScore in men considering repeat biopsy: validation of a simple testing approach

BackgroundMen with persistent risk of Grade Group (GG) ≥ 2 cancer after a negative biopsy present a unique clinical challenge. The validated MyProstateScore test is clinically-available for pre-biopsy risk stratification. In biopsy-naïve patients, we recently validated a straightforward testing approach to rule-out GG ≥ 2 cancer with 98% negative predictive value (NPV) and 97% sensitivity. In the current study, we established a practical MPS-based testing approach in men with a previous negative biopsy being considered for repeat biopsy.MethodsPatients provided post-digital rectal examination urine prior to repeat biopsy. MyProstateScore was calculated using the validated, locked model including urinary PCA3 and TMPRSS2:ERG scores with serum PSA. In a clinically-appropriate primary (i.e., training) cohort, we identified a lower (rule-out) threshold approximating 90% sensitivity and an upper (rule-in) threshold approximating 80% specificity for GG ≥ 2 cancer. These thresholds were applied to an external validation cohort, and performance measures and clinical outcomes associated with their use were calculated.ResultsMyProstateScore thresholds of 15 and 40 met pre-defined performance criteria in the primary cohort (422 patients; median PSA 6.4, IQR 4.3–9.1). In the 268-patient validation cohort, 25 men (9.3%) had GG ≥ 2 cancer on repeat biopsy. The rule-out threshold of 15 provided 100% NPV and sensitivity for GG ≥ 2 cancer and would have prevented 23% of unnecessary biopsies. Use of MyProstateScore >40 to rule-in biopsy would have prevented 67% of biopsies while maintaining 95% NPV. In the validation cohort, the prevalence of GG ≥ 2 cancer was 0% for MyProstateScore 0–15, 6.5% for MyProstateScore 15–40, and 19% for MyProstateScore >40.ConclusionsIn patients who previously underwent a negative prostate biopsy, the MyProstateScore values of 15 and 40 yielded clinically-actionable rule-in and rule-out risk groups. Using this straightforward testing approach, MyProstateScore can meaningfully inform patients and physicians weighing the need for repeat biopsy.

Urinary PCA3 a Superior Diagnostic Biomarker for Prostate Cancer among Ghanaian Men

Introduction Prostate cancer is one of the most commonly diagnosed cancers in men. Prostate-specific antigen (PSA) has been the biomarker of choice for screening and diagnosis of prostate cancer. However, inefficiencies exist with its diagnostic capabilities. This study thus evaluated the diagnostic and prognostic potential of urinary PCA3 as an alternative biomarker for prostate cancer in the Ghanaian population. Methods A hospital-based cross-sectional study was conducted at the Urology Department of the 37 Military Hospital, Accra, Ghana. A total of 237 participants aged 40 years and above with any form of suspected prostate disorder were recruited into the study after written informed consent was obtained. Total serum PSA levels was measured using the electrochemiluminescence method and transrectal ultrasound-guided systematic core needle biopsies were obtained from each study participant. Receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic accuracies of serum PSA, DRE, and PCA3 as diagnostic tools for prostate cancer. These three diagnostic tools were also evaluated in various combinations to ascertain the combinations with the best diagnostic accuracy. Results Prostate cancer was diagnosed in 26.6% of the participants. Benign prostate hyperplasia and prostatitis were diagnosed in 48.5% and 24.9% participants, respectively. DRE had a sensitivity of 93.7% and a specificity of 12.1%. PSA had a sensitivity of 92.1% and a specificity of 16.1%. PCA3 had a sensitivity of 57.1% and a specificity of 85.6% and showed a better accuracy (AUC = 83.0) compared to PSA (AUC = 60.0) and DRE (AUC = 65.0) as individual diagnostic tools. The combination of DRE+PCA3 score had the best diagnostic accuracy (AUC = 0.80) with a sensitivity and specificity of 60.3% and 80.5%, respectively. Conclusion The urinary PCA3 assay showed a better diagnostic performance compared to serum PSA and DRE. PCA3 as a stand-alone and in combination with DRE could be a suitable complimentary marker in diagnosis and management of prostate cancer.

Effective Diagnosis of Prostate Cancer Based on mRNAs From Urinary Exosomes.

BackgroundNovel non-invasive biomarkers are urgently required to improve the diagnostic sensitivity and specificity of prostate cancer (PCa). Therefore, the diagnostic value of following candidate genes (ERG, PCA3, ARV7, PSMA, CK19, and EpCAM) were estimated by testing mRNAs from urinary exosomes of patients with primary PCa.MethodsExosomes were obtained using size-exclusion chromatography (SEC), out of which RNAs were extracted, then analyzed by quantitative reverse transcription-polymerase chain reaction according to manufacturer’s protocol.ResultsThe expression of urinary exosomal ERG, PCA3, PSMA, CK19, and EpCAM were significantly increased in patients with PCa compared with healthy males. In addition, the levels of urinary exosomal ERG, ARV7, and PSMA were intimately correlated with the Gleason score in PCa patients (P < 0.05). The receiver operating characteristic curves (ROCs) showed that urinary exosomal ERG, PCA3, PSMA, CK19, and EpCAM were able to distinguish patients with PCa from healthy individuals with the area under the curve (AUC) of 0.782, 0.783, 0.772, 0.731, and 0.739, respectively. Urinary exosomal PCA3 and PSMA distinguished PCa patients from healthy individuals with an AUC of 0.870. Combination of urinary exosomal PCA3, PSMA with serum PSA and PI-RADS achieved higher AUC compared with PSA alone (0.914 and 0.846, respectively). Kaplan-Meier curves demonstrated that PCA3, ARV7, and EpCAM were associated in androgen-deprivation therapy (ADT) failure time which is defined as from the initiation of ADT in hormone-sensitive stage to the development of castration-resistant prostate cancer.ConclusionThese findings suggested that mRNAs from urinary exosomes have the potential in serving as novel and non-invasive indicators for PCa diagnosis and prediction.

Urinary MyProstateScore (MPS) to Rule out Clinically-Significant Cancer in Men with Equivocal (PI-RADS 3) Multiparametric MRI: Addressing an Unmet Clinical Need

ObjectiveTo evaluate the complementary value of urinary MyProstateScore (MPS) testing and multiparametric MRI (mpMRI) and assess outcomes in patients with equivocal mpMRI. Materials and MethodsIncluded patients underwent mpMRI followed by urine collection and prostate biopsy at the University of Michigan between 2015 –2019. MPS values were calculated from urine specimens using the validated model based on serum PSA, urinary PCA3, and urinary TMPRSS2:ERG. In the PI-RADS 3 population, the discriminative accuracy of PSA, PSAD, and MPS for GG≥2 cancer was quantified by the AUC curve. Decision curve analysis was used to assess net benefit of MPS relative to PSAD. ResultsThere were 540 patients that underwent mpMRI and biopsy with MPS available. The prevalence of GG≥2 cancer was 13% for PI-RADS 3, 56% for PI-RADS 4, and 87% for PI-RADS 5. MPS was significantly higher in men with GG≥2 cancer [median 44.9, IQR (29.4 –57.5)] than those with negative or GG1 biopsy [median 29.2, IQR (14.8 –44.2); P <.001] in the overall population and when stratified by PI-RADS score. In the PI-RADS 3 population (n = 121), the AUC for predicting GG≥2 cancer was 0.55 for PSA, 0.62 for PSAD, and 0.73 for MPS. MPS provided the highest net clinical benefit across all pertinent threshold probabilities. ConclusionIn patients that underwent mpMRI and biopsy, MPS was significantly associated with GG≥2 cancer across all PI-RADS scores. In the PI-RADS 3 population, MPS significantly outperformed PSAD in ruling out GG≥2 cancer. These findings suggest a complementary role of MPS testing in patients that have undergone mpMRI.

Association of Urinary MyProstateScore, Age, and Prostate Volume in a Longitudinal Cohort of Healthy Men: Long-term Findings from the Olmsted County Study

BackgroundSerum prostate-specific antigen (PSA), used in prostate cancer screening, is nonspecific for cancer and is affected by age and prostate volume. More specific biomarkers could be more accurate for early detection of prostate cancer and reduce unnecessary prostate biopsies. ObjectiveTo evaluate the association of age and prostate volume with urinary MyProstateScore (MPS) in a screened, longitudinal cohort without evidence of prostate cancer. Design, setting, and participantsThe Olmsted County Study included men aged 40–79 yr who underwent biennial prostate cancer screening. PSA ≥4.0 ng/ml or abnormal rectal examination triggered prostate biopsy, and patients with cancer were excluded. The remaining men submitted urinary specimens for PCA3 and TMPRSS2:ERG testing. Outcome measurements and statistical analysisMPS was calculated using the validated, locked model for grade group ≥2 cancer that includes serum PSA, urinary PCA3, and urinary TMPRSS2:ERG. The associations of age and volume with biomarkers were assessed in multivariable regression models. The t statistic was used to quantify the strength of associations independent of the unit of measurement, and R2 values were used to estimate the proportion of biomarker variance explained by each factor. Results and limitationsThe study included 314 screened men without evidence of cancer. In multivariable models including age and volume, PCA3 score was significantly associated with age (t = 7.51; p < 0.001), while T2:ERG score was not associated with age or volume. MPS was significantly associated with both age (t = 7.45; p < 0.001) and volume (t = 3.56; p < 0.001), but accounting for age alone explained the variability observed (R2 = 0.29) in a similar way to the model including age and volume (R2 = 0.31). The variability of PCA3, T2:ERG, and MPS was less dependent on age and volume than the variability for PSA (R2 = 0.45). ConclusionsIn a cohort of longitudinally screened men without evidence of cancer, we found that MPS demonstrated less variability with noncancer factors (age, prostate volume) than PSA did. These findings support the biology of these markers as more cancer-specific than PSA and highlight their promise in reducing the morbidity associated with PSA-based screening. Patient summaryIn a group of men with no evidence of prostate cancer, we found that each of three urine-based markers of cancer—PCA3, T2:ERG, and the commercially available MyProstateScore test—showed less variability with noncancer factors (age and prostate volume) than serum PSA (prostate-specific antigen) did. These findings support their proposed use as noninvasive markers of prostate cancer that could improve the accuracy of early detection.

Urinary PCA3 detection in prostate cancer by magnetic nanoparticles coupled with colorimetric enzyme-linked oligonucleotide assay.

PCA3 is one of the most prostate cancer-specific genes described to date. Of note, PCA3 expression is detectable at high level in the urine of prostate cancer (PCa) patients. Accordingly, PCA3 is an ideal biomarker for PCa diagnosis. Several techniques for the measurement of this biomarker in urine have been developed but there are still some drawbacks. In this study, magnetic nanoparticle-based PCR coupled with streptavidin-horseradish peroxidase and a substrate for colorimetric detection was established as a potential assay for urinary PCA3 detection. The method provided a high specificity for PCA3 gene in LNCaP prostate cancer cell line. Additionally, this technique could detect PCA3 at femtogram level which was approximately 1,000-fold more sensitive than the conventional RT-PCR followed by agarose gel electrophoresis. The effectiveness of the method was assessed by PCA3 detection in clinical specimens. The relative PCA3 expression of PCa patients determined by this assay was significantly greater than that of benign prostatic hyperplasia (BPH) patients and healthy controls. The results of our test were comparable with the results of qRT-PCR. The proposed method is promising to distinguish between cancerous and non-cancerous groups. Altogether, this simple assay is practicable and useful for prostate cancer diagnosis.

Performance of PCA3 and TMPRSS2:ERG urinary biomarkers in prediction of biopsy outcome in the Canary Prostate Active Surveillance Study (PASS).

Background:For men on active surveillance for prostate cancer, biomarkers may improve prediction of reclassification to higher grade or volume cancer. This study examined the association of urinary PCA3 and TMPRSS2:ERG (T2:ERG) with biopsy-based reclassification.Methods:Urine was collected at baseline, 6, 12, and 24 months in the multi-institutional Canary Prostate Active Surveillance Study (PASS), and PCA3 and T2:ERG levels were quantitated. Reclassification was an increase in Gleason score or ratio of biopsy cores with cancer to ≥34%. The association of biomarker scores, adjusted for common clinical variables, with short-term and long-term reclassification was evaluated. Discriminatory capacity of models with clinical variables alone or with biomarkers was assessed using receiver operating characteristic (ROC) curves and decision curve analysis (DCA).Results:782 men contributed 2,069 urine specimens. After adjusting for PSA, prostate size and ratio of biopsy cores with cancer, PCA3 but not T2:ERG was associated with short-term reclassification at the first surveillance biopsy (OR=1.3; 95% CI 1.0–1.7, p=0.02). The addition of PCA3 to a model with clinical variables improved area under the curve from 0.743 to 0.753 and increased net benefit minimally. After adjusting for clinical variables, neither marker, nor marker kinetics, was associated with time to reclassification in subsequent biopsies.Conclusions:PCA3 but not T2:ERG was associated with cancer reclassification in the first surveillance biopsy, but has negligible improvement over clinical variables alone in ROC or DCA analyses. Neither marker was associated with reclassification in subsequent biopsies.

Colorimetric detection of PCA3 in urine for prostate cancer diagnosis using thiol-labeled PCR primer and unmodified gold nanoparticles

BackgroundPCA3, a non-coding RNA, has been approved as a potential urinary biomarker for prostate cancer. However, PCA3 urine tests have some limitations. Therefore, we developed a colorimetric method for PCA3 detection in urine. MethodsThe assay was based on interactions between unmodified gold nanoparticles (AuNPs) and thiolated PCR products. Thiolated PCR products were amplified by RT-PCR using a thiol-labeled primer at the 5′ end. Thiolated products of PCA3 bound to the surface of AuNPs and led to the prevention of salt-induced aggregation (red color). In the absence of the PCR products, AuNPs changed their color from red to blue due to the salt-induced aggregation. These changes were detected by the naked eye and spectrophotometer. ResultsOur assay was specific for PCA3 in prostate cancer cell lines with a visual detection limit of 31.25 ng/reaction. The absorption ratio 520/640 nm was linear against PCR product concentration (R2 = 0.9798) in the reaction. This method is promising for discrimination of prostate cancer patients from both healthy controls and benign prostatic hyperplasia patients according to their urinary PCA3 expression levels. ConclusionsThis study established a simple, rapid, sensitive and specific assay for PCA3 detection which may be applicable for prostate cancer diagnosis.

Urine PCA3 mRNA level in diagnostic of prostate cancer.

The objective of this study is to evaluate the diagnostic effects of urine PCA3 mRNA level in patients with prostate cancer (PC). Twenty four patients with pathologically confirmed PC, 40 patients with benign prostatic hyperplasia (BPH), and 13 patients with urolithiasis were recruited in this study. The urine level of PCA3 mRNA was determined with real-time polymerase chain reaction and compared among the three groups. With the reference parameter of urine PCA3 mRNA, the diagnostic sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated. The mRNA level in urine of PC, BPH and urolithiasis were 60.2 ± 32.2, 17.1 ± 12.9, and 6.2 ± 3.1, respectively, indicating that mRNA level in PC was significantly higher than that of in other two groups (P < 0.05). The AUC was 0.90 while the sensitivity and specificity were 87.5% and 79.2% with the cutoff value of 33.86. The urine PCA3 mRNA could be a biomarker for diagnosing patients with PC.

Utility of PCA3 and TMPRSS2: ERG urinary biomarkers to predict pathologic outcomes in African American men undergoing radical prostatectomy.

e547 Background: Tremendous disparity exists between preoperative characteristics and pathologic outcomes in men electing radical prostatectomy (RP) for localized prostate cancer (PCa). We sought to determine the performance characteristics of urinary PCA3 andTMPRSS2:ERG (T2:ERG) to predict pathologic outcomes in a racially diverse group of men undergoing RP. Methods: Following IRB approval, post digital rectal exam (DRE) urine was prospectively collected in consecutive patients with known PCa prior to RP. PCA3 and T2:ERG RNA copies were quantified and normalized to PSA mRNA copies using the Progensa assay (Hologic, San Diego, CA). Nonparametric Mann-Whitney U tests were performed to determine the ability of PCA3 and T2:ERG to predict higher risk PCa and notable disease features. Results: The cohort consisted of 214 men with PCa who underwent RP, and 89 men (42%) were African American (AA). The men in the cohort generally had higher risk disease, with 75% having AUA risk stratification of intermediate/high-risk PCa. PCA3 discriminated between biopsy low- and intermediate/high-grade Gleason Score (p = .005) and pathologic low- and intermediate/high-grade Gleason Score (p = 0.001). For men with low-risk PCa, PCA3 also predicted Gleason Score upgrading from biopsy to prostatectomy specimen (p = 0.003). PCA3 could not predict the presence of perineural invasion, lymph node positivity, seminal vesical invasion, positive surgical margins or extraprostatic extension. When stratified by race, within the AA cohort, T2:ERG did predict upgrading from Gleason 6 disease at the time of biopsy to higher grade pathology at RP (p = 0.016). However, T2:ERG was not predictive for the overall cohort, nor was it predictive for any of the disease features found to be significant with PCA3. Conclusions: In a racially-diverse group of men undergoing RP, PCA3 and T2:ERG urinary assays have limited ability to characterize aggressive pathologic features at the time of RP regardless of race.

Clinical Use of PCA3 and TMPRSS2:ERG Urinary Biomarkers in African-American Men Undergoing Prostate Biopsy

Prostate specific antigen has decreased performance characteristics for the detection of prostate cancer in African-American men. We evaluated urinary PCA3 and TMPRSS2:ERG in a racially diverse group of men. After institutional review board approval, post-examination urine was prospectively collected before prostate biopsy. PCA3 and TMPRSS2:ERG RNA copies were quantified using transcription mediated amplification assays (Hologic, San Diego, California). Prediction models were created using standard of care variables (age, race, family history, prior biopsy, abnormal digital rectal examination) plus prostate specific antigen. Decision curve analysis was performed to compare the net benefit of PCA3 and TMPRSS2:ERG. Of 304 patients 182 (60%) were African-American and 139 (46%) were diagnosed with prostate cancer (69% African-American). PCA3 and TMPRSS2:ERG scores were greater in men with prostate cancer, 3 or more cores, 33.3% or more cores, greater than 50% involvement of greatest biopsy core and Epstein significant prostate cancer (p <0.01). PCA3 added to the standard of care plus prostate specific antigen model for the detection of any prostate cancer in the overall cohort (0.747 vs 0.677, p <0.0001) in African-American men only (0.711 vs 0.638, p=0.0002) and nonAfrican-American men (0.781 vs 0.732, p=0.0016). PCA3 added to the model for the prediction of high grade prostate cancer for the overall cohort (0.804 vs 0.78, p=0.0002) and African-American men only (0.759 vs 0.717, p=0.0003) but not nonAfrican-American men. Decision curve analysis demonstrated improvement with the addition of PCA3. ForAfrican-American men TMPRSS2:ERG did not improve concordance statistics for the detection of prostate cancer. For African-American men urinary PCA3 improves the ability to predict the presence of any and high grade prostate cancer. However, the TMPRSS2:ERG urinary assay does not add significantly to standard tools.

Unbiased estimation of biomarker panel performance when combining training and testing data in a group sequential design.

Motivated by an ongoing study to develop a screening test able to identify patients with undiagnosed Sjögren's Syndrome in a symptomatic population, we propose methodology to combine multiple biomarkers and evaluate their performance in a two-stage group sequential design that proceeds as follows: biomarker data is collected from first stage samples; the biomarker panel is built and evaluated; if the panel meets pre-specified performance criteria the study continues to the second stage and the remaining samples are assayed. The design allows us to conserve valuable specimens in the case of inadequate biomarker panel performance. We propose a nonparametric conditional resampling algorithm that uses all the study data to provide unbiased estimates of the biomarker combination rule and the sensitivity of the panel corresponding to specificity of 1-t on the receiver operating characteristic curve (ROC). The Copas and Corbett (2002) correction, for bias resulting from using the same data to derive the combination rule and estimate the ROC, was also evaluated and an improved version was incorporated. An extensive simulation study was conducted to evaluate finite sample performance and propose guidelines for designing studies of this type. The methods were implemented in the National Cancer Institutes Early Detection Network Urinary PCA3 Evaluation Trial.

Utility of PCA3 and TMPRSS2:ERG urinary biomarkers in African American men undergoing prostate biopsy.

126 Background: To determine the performance characteristics of urinary PCA3 andTMPRSS2:ERG (T2:ERG) in a racially diverse group of men. Methods: Following IRB approval, from 2013-2015, post digital rectal exam (DRE) urine was prospectively collected in patients without known prostate cancer (PCa), prior to biopsy. PCA3 and T2:ERG RNA copies were quantified and normalized to PSA mRNA copies using Progensa assay (Hologic, San Diego, CA). Prediction models for PCa and high-grade PCa were created using standard of care (SOC) variables (age, race, family history of PCa, prior prostate biopsy and abnormal DRE) plus PSA. Decision Curve Analysis was performed to compare the net benefit of using SOC, plus PSA, with the addition of PCA3 and T2:ERG. Results: Of 304 patients, 182 (60%) were AA; 139(46%) were diagnosed with PCa (69% AA). PCA3 and T2:ERG scores were greater in men with PCa, ≥ 3 cores, ≥ 33.3% cores, &gt; 50% involvement of greatest biopsy core and Epstein significant PCa (p-values &lt; 0.04). PCA3 added to the SOC plus PSA model for the detection of any PCa in the overall cohort (0.747 vs 0.677; p &lt; 0.0001), in AA only (0.711 vs 0.638; p = 0.0002) and non-AA (0.781 vs 0.732; p = 0.0016). PCA3 added to the model for the prediction of high-grade PCa for the overall cohort (0.804 vs 0.78; p = 0.0002) and AA only (0.759 vs 0.717; p = 0.0003) but not non-AA. Decision curve analysis demonstrated significant net benefit with the addition of PCA3 compared with SOC plus PSA. For AA, T2:ERG did not improve concordance statistics for the detection any or high-grade PCa. Conclusions: For AA, urinary PCA3 improves the ability to predict the presence of any and high-grade PCa. However for this population, T2:ERG urinary assay does not add significantly to standard detection and risk stratification tools.

Race, inflammation, and prostate cancer: A comparison of African Americans and Caucasians.

246 Background: African-Americans (AA) have the highest rate of prostate cancer (PCa) incidence and mortality. Studies have shown higher rates of chronic prostate inflammation in AAs compared to Caucasians (CA). In order to better understand racial disparity in PCa and chronic inflammation (CI), this study examined the effects of race and CI on clinical parameters among PCa patients. Methods: This retrospective study sample consisted of 61 AA and 52 CA PCa patients who underwent radical prostatectomies (RP) at Tulane Hospital between 2013 and 2015. Clinical data was extracted from biopsy and RP pathology reports. The study examined the relationship between CI, race, percent of positive cores, extra-prostatic extension, PSA, PSA density, urinary PCA3 and TMPRSS2, and prostate size (g). Pearson’s chi-square, Fisher’s exact, and Kruskal-Wallis tests were used to analyze categorical, non-continuous data; ANOVA tests were used to analyze continuous data. Differences between biopsy and surgical/pathologic Gleason scores and clinical/pathological stages were also assessed. Results: 94 patients (52 AAs and 42 CAs) had CI to some degree and 19 did not (9 AAs and 10 CAs). There was no difference in rate of CI between AA and CA patients (P = 0.526). Among all patients sampled, AAs had higher percentages of positive cores (P = 0.005), PCA3 copy levels (P =0.004), and PCA3 scores (P &lt;0.001), lower TMPRSS2 scores (P =0.039), and were more likely to have “high” or “intermediate” NCCN risk strata (P =0.010). Among patients with CI, AAs were more likely than CAs to have extra-prostatic extension (P =0.026) and less likely to have undergone a prior prostate biopsy (P =0.043). Patients without CI were more likely than patients with CI to have positive tumor margins (P =0.035) and SV invasion (P =0.013). There were no significant relationships between race and CI, and changes in either total Gleason score or stage from biopsy to RP. Conclusions: This study showed that AAs and patients without CI had more advanced forms of PCa (possibly due to PSA detection biases). Findings did not reveal any significant link between race and CI. Larger studies are needed to confirm these results and better understand the relationship between race, CI, and PCa.

Urinary PCA3 to predict prostate cancer in a cohort of 1015 patients

Summary Aim To evaluate the performance of urinary PCA3 test to predict prostate biopsy outcome in a large French cohort. Patients and methods A urine sample was prospectively obtained from 1015 patients undergoing prostate biopsies to determine the PCA3 score. The predictive value of PCA3 was explored using receiver operating characteristic curve analysis (ROC), multivariable logistic regression analysis and decision curve analysis. Results The median PCA3 score was significantly higher in patients with positive biopsies. The PCA3 score AUC was 0.76 (0.73–0.79), significantly higher than that of PSA (0.55; 0.51–0.58). At the cutoff of 35, sensitivity was 68%, specificity 71%, positive and negative predictive values 67% and 71%, and accuracy 69%. Using multivariate analysis, PCA3 score appeared as an independent predictor of biopsy outcome and its addition to a base model including usual clinicobiological parameters resulted in a significant increase in predictive accuracy. At the cutoff of 20, about 1/2 of the ultimately unnecessary biopsies would have been avoided while ignoring 7% of cancers with Gleason score ≥ 7. PCA3 score did not correlate with Gleason score but did correlate with tumor volume (proportion of positive cores). Conclusion Urinary PCA3 is a useful test with high diagnostic performances for early prostate cancer diagnosis. Its correlation with cancer aggressiveness seems rather represented by a link to prostate volume than Gleason score. Level of evidence 5.

Test urinaire PCA3 et diagnostic du cancer prostatique : étude à partir de 1015 patients

To evaluate the performance of urinary PCA3 test to predict prostate biopsy outcome in a large French cohort. A urine sample was prospectively obtained in 1015 patients undergoing prostate biopsies to determine the PCA3 score. The predictive value of PCA3 was explored using receiver operating characteristic curve analysis (ROC), multivariable logistic regression analysis and decision curve analysis. The median PCA3 score was significantly higher in patients with positive biopsies. The PCA3 score AUC was 0.76 (0.73-0.79), significantly higher than that of PSA (0.55; 0.51-0.58). At the cut-off of 35, sensitivity was 68 %, specificity 71 %, positive and negative predictive values 67 % and 71 %, and accuracy 69 %. Using multivariate analysis, PCA3 score appeared as an independent predictor of biopsy outcome and its addition to a base model including usual clinico-biological parameters resulted in a significant increase in predictive accuracy. At the cut-off of 20, about 1/2 of the eventual useless biopsies would have been avoided while ignoring 7 % of cancers with Gleason score ≥ 7. PCA3 score did not correlate to Gleason score but correlated to tumor volume (proportion of invaded cores). Urinary PCA3 is a useful test with high diagnostic performance for early prostate cancer diagnosis. Its correlation with cancer aggressiveness seems rather represented by a link to prostate volume than Gleason score.

Current biomarkers for diagnosing of prostate cancer.

Prostate cancer (PCa) is mostly detected by prostate-specific antigen (PSA) as one of the most widely used tumor markers. But PSA is limited with its low specificity. The prostate health index (phi) can improve specificity over percent free and total PSA and correlates with aggressive cancer. The urinary PCA3 also shows its utility to detect PCa but its correlation with aggressiveness and the low sensitivity at high values are limitations. While the detection of alterations of the androgen-regulated TMPRSS2 and ETS transcription factor genes in tissue of ˜50% of all PCa patients was one research milestone, the urinary assay should only be used in combination with PCA3. Both US FDA-approved markers phi and PCA3 perform equally.