Independent Validation of a Diagnostic Noninvasive 3-MicroRNA Ratio Model (uCaP) for Prostate Cancer in Cell-Free Urine

Abstract BACKGROUND Detection of prostate cancer (PC) based on serum prostate-specific antigen (PSA) testing leads to many unnecessary prostate biopsies, overdiagnosis, and overtreatment of clinically insignificant tumors. Thus, novel and more accurate molecular biomarkers are required. METHODS Using reverse transcription quantitative PCR, we measured the concentrations of 45 preselected microRNAs (miRNAs) in extracellular vesicle-enriched cell-free urine samples from 4 independent patient cohorts from Spain and Denmark, including 758 patients with clinically localized PC, 289 noncancer controls with benign prostatic hyperplasia (BPH), and 233 patients undergoing initial transrectal ultrasound (TRUS)-guided prostate biopsy owing to PC suspicion (101 with benign and 132 with malignant outcome). Diagnostic potential was assessed by ROC and decision curve analysis. RESULTS We identified and successfully validated 8 upregulated and 21 downregulated miRNAs in urine from PC patients. Furthermore, we validated a previously identified 3-miRNA diagnostic ratio model, uCaP (miR-222–3p*miR-24–3p/miR-30c-5p). High uCaP scores were distinctive of PC in urine samples from BPH vs PC patients in 3 independent cohorts [area under the curve (AUC) = 0.84, 0.71, 0.72]. Additionally, uCaP predicted TRUS biopsy results with greater accuracy than PSA (AUC uCaP = 0.644; AUC PSA = 0.527) for patients within the diagnostic gray zone (PSA ≤ 10 ng/mL). CONCLUSIONS We successfully validated a urine-based diagnostic 3-miRNA signature for PC (uCaP) in 3 independent patient cohorts from 2 countries. In the future, the simple and noninvasive uCaP test may be used to help more accurately select patients for prostate biopsy. Prospective clinical validation is warranted.

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Accuracy of Tumour-Associated Circulating Endothelial Cells as a Screening Biomarker for Clinically Significant Prostate Cancer

Cancers ◽

10.3390/cancers11081064 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1064 ◽

Cited By ~ 2

Author(s):

Sebastian Chakrit Bhakdi ◽

Prapat Suriyaphol ◽

Ponpan Thaicharoen ◽

Sebastian Tobias Karl Grote ◽

Chulaluk Komoltri ◽

...

Keyword(s):

Prostate Cancer ◽

Endothelial Cells ◽

Predictive Value ◽

Specific Antigen ◽

Transrectal Ultrasound ◽

Circulating Endothelial Cells ◽

Index Test ◽

Psa Testing ◽

Diagnostic Potential ◽

Clinically Significant

Even though more than 350,000 men die from prostate cancer every year, broad-based screening for the disease remains a controversial topic. Guidelines demand that the only commonly accepted screening tool, prostate-specific antigen (PSA) testing, must be followed by prostate biopsy if results are elevated. Due to the procedure’s low positive predictive value (PPV), however, over 80% of biopsies are performed on healthy men or men with clinically insignificant cancer—prompting calls for new ways of vetting equivocal PSA readings prior to the procedure. Responding to the challenge, the present study investigated the diagnostic potential of tumour-associated circulating endothelial cells (tCECs), which have previously been described as a novel, blood-based biomarker for clinically significant cancers. Specifically, the objective was to determine the diagnostic accuracy of a tCEC-based blood test to detect clinically significant prostate cancer (defined as Gleason score ≥ 3 + 4) in high-risk patients. Performed in a blinded, prospective, single-centre set-up, it compared a novel tCEC index test with transrectal ultrasound-guided biopsy biopsy as a reference on a total of 170 patients and found that a tCEC add-on test will almost double the PPV of a standalone PSA test (32% vs. 17%; p = 0.0012), while retaining a negative predictive value above 90%.

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Racial variation in the reliability of prostate cancer indicators in men undergoing subsequent prostate biopsy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.115 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 115-115

Author(s):

Robert Scott Libby ◽

Hoang MT Nguyen ◽

Jordan J. Kramer ◽

Allison H. Feibus ◽

Raju Thomas ◽

...

Keyword(s):

Prostate Cancer ◽

Prostate Biopsy ◽

Health Care Services ◽

African American Men ◽

Medical Center ◽

Specific Antigen ◽

Transrectal Ultrasound ◽

Veterans Health ◽

Psa Testing ◽

Incidence And Mortality

115 Background: Many men with an initial negative prostate biopsy have a persistently elevated prostate specific antigen (PSA) prompting physicians to perform repeat biopsies. African American men (AA) are at particular risk as they have a greater prostate cancer (PCa) incidence and mortality, yet traditional PSA testing may be less reliable in this cohort. We sought to determine the predictors of PCa and PCa severity in a racially diverse population on subsequent biopsy following an initial benign biopsy. Methods: Upon receiving Institutional Review Board approval, a retrospective analysis was performed on men with repeat prostate biopsies at Tulane Medical Center and Southeast Louisiana Veterans Health Care Services in New Orleans, Louisiana from 2003-2015. Inclusion criteria included patients with a benign initial prostate biopsy and underwent subsequent repeat prostate biopsy within 5 years. Race, age, serum PSA, PSA density (PSAD), and prostate volume by transrectal ultrasound (TRUS) were evaluated to determine if they correlate with the presence and severity of PCa. Aggressive PCa was defined as Gleason score >6. Results: A total of 209 men were included; 127 (61%) were AA, and 82 (39%) were Caucasian American men (CA). The two groups were similar with respect to PSA, PSAD, and TRUS. More AA (25.2% vs. 17.1%) had a repeat biopsy showing any PCa. Of those with PCa, 28.1% of AA and 28.6% of CA had aggressive PCa. PSAD positively correlated with any PCa (p=.015). TRUS negatively correlated with any PCa (p=.008). PSA levels (p<.001) and PSAD (p<.001) positively correlated with aggressive PCa in CA but not in AA. Conclusions: The goal of prostate biopsy particularly for those with a prior negative biopsy is to detect aggressive PCa. PSA and PSAD positively correlated with finding any PCa in both AA and CA but not with aggressive PCa in AA. PSA and PSAD are less accurate predictors of aggressive PCa in AA, and novel biomarkers are needed. [Table: see text]

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A review of optimal prostate biopsy: indications and techniques

Therapeutic Advances in Urology ◽

10.1177/1756287219870074 ◽

2019 ◽

Vol 11 ◽

pp. 175628721987007 ◽

Cited By ~ 2

Author(s):

Justin Streicher ◽

Brian Lee Meyerson ◽

Vidhya Karivedu ◽

Abhinav Sidana

Keyword(s):

Prostate Cancer ◽

Patient Selection ◽

Prostate Biopsy ◽

Specific Antigen ◽

Transrectal Ultrasound ◽

Diagnostic Technique ◽

Fusion Biopsy ◽

Advantages And Disadvantages ◽

Software Platforms ◽

Selection For

Prostate biopsy is the gold standard diagnostic technique for the detection of prostate cancer. Patient selection for prostate biopsy is complex and is influenced by emerging use of prebiopsy imaging. The introduction of the magnetic resonance imaging (MRI)–transrectal ultrasound (TRUS) fusion prostate biopsy has clear advantages over the historical standard of care. There are several biopsy techniques currently utilized with unique advantages and disadvantages. We review and summarize the current body of literature pertaining to when and how a prostate biopsy should be performed. We discuss current recommendations regarding patient selection for biopsy and discuss future directions regarding prebiopsy imaging. We offer a description of the MRI–TRUS fusion biopsy technique and a comparison of many of the currently available fusion software platforms. Articles pertaining to the title were obtained via PubMed index search with relevant keywords supplemented with personal collection of related publications. Prostate biopsy should be considered for patients with gross digital rectal exam (DRE) abnormality, patients with a prostate-specific antigen (PSA) greater than 4 ng/ml, and concomitant risk factors for prostate cancer or patients with lesions identified on multiparametric MRI (mpMRI) with Prostate Imaging Reporting and Data System 2 (PI-RADS2) score of 4 or 5. MRI–TRUS fusion biopsy has demonstrated advantages in cancer detection when compared with TRUS-guided biopsy. There are currently several fusion software platforms available with a variety of biopsy approaches. Future efforts should detail the role of prebiopsy imaging as a triage tool for prostate biopsy. Consensus should be sought regarding the preferred modality of fusion biopsy. Additional data describing each fusion software platform would enable a more rigorous comparison of platform sensitivities.

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APTIMA PCA3 Molecular Urine Test: Development of a Method to Aid in the Diagnosis of Prostate Cancer

Clinical Chemistry ◽

10.1373/clinchem.2005.063289 ◽

2006 ◽

Vol 52 (6) ◽

pp. 1089-1095 ◽

Cited By ~ 340

Author(s):

Jack Groskopf ◽

Sheila MJ Aubin ◽

Ina Lim Deras ◽

Amy Blase ◽

Sharon Bodrug ◽

...

Keyword(s):

Prostate Cancer ◽

Prostate Biopsy ◽

Specific Antigen ◽

Digital Rectal Examination ◽

Prostate Cancer Risk ◽

Area Under The Curve ◽

Roc Curve Analysis ◽

Cancer Risk Factors ◽

Specimen Processing ◽

Whole Urine

Abstract Background: Prostate cancer gene 3 (PCA3) encodes a prostate-specific mRNA that has shown promise as a prostate cancer diagnostic tool. This report describes the characterization of a prototype quantitative PCA3-based test for whole urine. Methods: Whole-urine specimens were collected after digital rectal examination from 3 groups: men scheduled for prostate biopsy (n = 70), healthy men (<45 years of age with no known prostate cancer risk factors; n = 52), and men who had undergone radical prostatectomy (n = 21). PCA3 and prostate-specific antigen (PSA) mRNAs were isolated, amplified, and quantified by use of Gen-Probe DTS400® Systems. Prostate biopsy results were correlated with the PCA3/PSA mRNA ratio, and PSA mRNA concentrations were used to normalize PCA3 signals and confirm the yield of prostate-specific RNA. Assay precision, specimen stability, and mRNA yield were also evaluated. Results: The specimen informative rate (fraction of specimens yielding sufficient RNA for analysis) was 98.2%. In this clinical research study, ROC curve analysis of prebiopsy specimens yielded an area under the curve of 0.746; sensitivity was 69% and specificity 79%. Serum PSA assay specificity was 28% for this same group. PCA3 and PSA mRNAs were undetectable in postprostatectomy specimens except for one man with recurrent prostate cancer. Assay interrun CVs were ≤12%. Both mRNAs were stable in processed urine up to 5 days at 4 °C and after 5 freeze–thaw cycles. Conclusion: The APTIMA® PCA3 assay combines simple specimen processing with precise assays and existing instruments and could add specificity to the current algorithm for prostate cancer diagnosis.

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Patterns of Prostate-Specific Antigen Testing and Prostate Biopsies During the COVID-19 Pandemic

JCO Clinical Cancer Informatics ◽

10.1200/cci.21.00074 ◽

2021 ◽

pp. 1028-1033

Author(s):

Harvey W. Kaufman ◽

Zhen Chen ◽

Justin K. Niles ◽

Jeff Radcliff ◽

Yuri Fesko

Keyword(s):

Prostate Cancer ◽

Prostate Biopsy ◽

Diagnostic Testing ◽

Specific Antigen ◽

International Classification Of Diseases ◽

Prostate Biopsies ◽

Psa Testing ◽

Classification Of Diseases ◽

Antigen Testing

PURPOSE This study examined changes in prostate disease screening (prostatic-specific antigen [PSA] testing), prostate biopsy testing, and prostate cancer diagnoses during the COVID-19 pandemic through December 2020. MATERIALS AND METHODS This analysis included test results from men ≥ 40 years, without prior International Classification of Diseases-10 record of prostate cancer since January 2016, who received PSA or prostate biopsy testing at Quest Diagnostics during January 2018-December 2020. Monthly trends were evaluated for three periods: prepandemic (January 2018-February 2020), early-pandemic (March-May 2020), and late-pandemic (June-December 2020). RESULTS Meeting inclusion criteria were 16,365,833 PSA and 48,819 prostate biopsy results. The average monthly number of PSA tests declined from 465,187 prepandemic to 295,786 early-pandemic (36.4% decrease; P = .01) before rebounding to 483,374 (3.9% increase; P = .23) late-pandemic. The monthly average number of PSA results ≥ 50 ng/mL (23,356; 0.14% of all PSA results) dipped from 659 prepandemic to 506 early-pandemic (23.2% decrease; P = .02) and rebounded to 674 late-pandemic (2.3% increase; P = .65). The average monthly number of prostate biopsy results decreased from 1,453 prepandemic to 903 early-pandemic (37.9% decrease; P = .01) before rebounding to 1,190 late-pandemic (18.1% decrease; P = .01). The average monthly number for Gleason score ≥ 8 (6,241; 12.8% of all prostate biopsies) declined from 182 prepandemic to 130 early-pandemic (28.6% decrease; P = .02) and decreased to 161 late-pandemic (11.5% decrease; P = .02). CONCLUSION The findings suggest that a substantial number of prostate screening opportunities and cancer diagnoses have been missed. Efforts are needed to bring such patients back for screening and diagnostic testing and to restore appropriate care for non–COVID-19–related medical conditions.

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Tumor-Associated Release of Prostatic Cells into the Blood after Transrectal Ultrasound-Guided Biopsy in Patients with Histologically Confirmed Prostate Cancer

Clinical Chemistry ◽

10.1373/clinchem.2019.310912 ◽

2019 ◽

Vol 66 (1) ◽

pp. 161-168 ◽

Cited By ~ 5

Author(s):

Simon A Joosse ◽

Burkhard Beyer ◽

Christin Gasch ◽

Paulina Nastały ◽

Andra Kuske ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Cells ◽

Prostate Biopsy ◽

Standard Procedure ◽

Multivariable Analysis ◽

Specific Antigen ◽

Transrectal Ultrasound ◽

Ultrasound Guided ◽

Systemic Spread

Abstract BACKGROUND Transrectal ultrasound-guided prostate biopsy (TRUS) is a standard procedure for prostate cancer diagnosis. Because prostate cancer is a multifocal disease in many patients, multiple sampling (n ≥ 10) is required, which may bear the risk of systemic spread of cancer cells. DESIGN Using the standardized CellSearch® system that allows for the detection of single epithelial cell adhesion molecule-positive circulating tumor cells (CTCs) in blood, we investigated whether prostate biopsy is associated with release of prostatic tumor cells into the circulation. Peripheral blood was obtained before and within 30 min after performing prostate biopsy from 115 men with increased serum prostate-specific antigen. RESULTS The number of CTCs significantly increased after biopsy in men with histologically confirmed prostate cancer (odds ratio, 7.8; 95% CI, 4.8–12.8), whereas no biopsy-related changes could be detected in men without confirmed prostate cancer. Multivariable analysis showed that biopsy-related increase of CTCs was significantly correlated with a worse progression-free survival (hazard ratio, 12.4; 95% CI, 3.2–48.6) within the median follow-up of 41 months. CONCLUSIONS Prostate biopsies may lead to a tumor-associated release of CTCs into the blood circulation. Larger confirmatory trials with longer follow-up periods are required before any change in clinical practice can be recommended.

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Profiling of Circulating microRNAs in Prostate Cancer Reveals Diagnostic Biomarker Potential

Diagnostics ◽

10.3390/diagnostics10040188 ◽

2020 ◽

Vol 10 (4) ◽

pp. 188 ◽

Cited By ~ 1

Author(s):

Jacob Fredsøe ◽

Anne K. I. Rasmussen ◽

Peter Mouritzen ◽

Marianne T. Bjerre ◽

Peter Østergren ◽

...

Keyword(s):

Prostate Cancer ◽

Minimally Invasive ◽

Specific Antigen ◽

Transrectal Ultrasound ◽

Digital Rectal Examination ◽

Area Under The Curve ◽

Diagnostic Tools ◽

Test Set ◽

Localized Disease ◽

Clinically Significant

Early detection of prostate cancer (PC) is paramount as localized disease is generally curable, while metastatic PC is generally incurable. There is a need for improved, minimally invasive biomarkers as current diagnostic tools are inaccurate, leading to extensive overtreatment while still missing some clinically significant cancers. Consequently, we profiled the expression levels of 92 selected microRNAs by RT-qPCR in plasma samples from 753 patients, representing multiple stages of PC and non-cancer controls. First, we compared plasma miRNA levels in patients with benign prostatic hyperplasia (BPH) or localized prostate cancer (LPC), versus advanced prostate cancer (APC). We identified several dysregulated microRNAs with a large overlap of 59 up/down-regulated microRNAs between BPH versus APC and LPC versus APC. Besides identifying several novel PC-associated dysregulated microRNAs in plasma, we confirmed the previously reported upregulation of miR-375 and downregulation of miR-146a-5p. Next, by randomly splitting our dataset into a training and test set, we identified and successfully validated a novel four microRNA diagnostic ratio model, termed bCaP (miR-375*miR-33a-5p/miR-16-5p*miR-409-3p). Combined in a model with prostate specific antigen (PSA), digital rectal examination status, and age, bCaP predicted the outcomes of transrectal ultrasound (TRUS)-guided biopsies (negative vs. positive) with greater accuracy than PSA alone (Training: area under the curve (AUC), model = 0.84; AUC, PSA = 0.63. Test set: AUC, model = 0.67; AUC, PSA = 0.56). It may be possible in the future to use this simple and minimally invasive bCaP test in combination with existing clinical parameters for a more accurate selection of patients for prostate biopsy.

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Systematic and MRI-Cognitive Targeted Transperineal Prostate Biopsy Accuracy in Detecting Clinically Significant Prostate Cancer after Previous Negative Biopsy and Persisting Suspicion of Malignancy

Medicina ◽

10.3390/medicina57010057 ◽

2021 ◽

Vol 57 (1) ◽

pp. 57

Author(s):

Alvydas Vėželis ◽

Gediminas Platkevičius ◽

Marius Kinčius ◽

Liutauras Gumbys ◽

Ieva Naruševičiūtė ◽

...

Keyword(s):

Prostate Cancer ◽

Prostate Biopsy ◽

Specific Antigen ◽

Transrectal Ultrasound ◽

Targeted Biopsy ◽

Negative Biopsy ◽

Prostate Biopsies ◽

Clinically Significant ◽

Systematic Biopsy ◽

Targeted Biopsies

Background and objectives: Overdiagnosis, overtreatment, and the need for repeated procedures caused by transrectal ultrasound guided prostate biopsies and their related complications places a heavy burden on healthcare systems. This was a prospective cohort validating study to access the clinical accuracy of systematic and MRI-cognitive targeted transperineal prostate biopsies in detecting clinically significant prostate cancer after a previous negative biopsy and persistent suspicion of malignancy. The primary goal was to assess the ability of multiparametric magnetic resonance imaging (mpMRI) to detect clinically significant prostate cancer with an additional goal to assess the diagnostic value of systematic and MRI-cognitive transperineal biopsies. Materials and Methods: In total, 200 patients were enrolled who had rising serum prostate specific antigen (PSA) levels for at least 4 months after a previous negative transrectal ultrasound (TRUS) biopsy. All eligible men underwent 1.5T prostate mpMRI, reported using the Prostate Imaging Reporting and Data System version 2 (PI-RADS v2), followed by a 20-region transperineal prostate systematic biopsy and additional targeted biopsies. Results: Systematic 20-core transperineal prostate biopsies (TPBs) were performed for 38 (19%) patients. Systemic 20-core TPB with additional cognitive targeted biopsies were performed for 162 (81%) patients. Clinically significant prostate cancer (csPC) was detected for 31 (15.5%) patients, of which 20 (64.5%) cases of csPC were detected by systematic biopsy, eight (25.8%) cases were detected by targeted biopsy, and three (9.7%) both by systematic and targeted biopsies. Conclusions: Cognitive mpMRI guided transperineal target biopsies increase the detection rate of clinically significant prostate cancer after a previously negative biopsy. However, in a repeat prostate biopsy setting, we recommend applying a cognitive targeted biopsy with the addition of a systematic biopsy.

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Current Status of MRI and PET in the NCCN Guidelines for Prostate Cancer

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2019.7306 ◽

2019 ◽

Vol 17 (5) ◽

pp. 506-513 ◽

Cited By ~ 5

Author(s):

Brandon R. Mason ◽

James A. Eastham ◽

Brian J. Davis ◽

Lance A. Mynderse ◽

Thomas J. Pugh ◽

...

Keyword(s):

Prostate Cancer ◽

Active Surveillance ◽

Specific Antigen ◽

Transrectal Ultrasound ◽

The United States ◽

Current Status ◽

Low Grade ◽

Nccn Guidelines ◽

Psa Testing ◽

Pet Ct

Prostate cancer (PCa) represents a significant source of morbidity and mortality for men in the United States, with approximately 1 in 9 being diagnosed with PCa in their lifetime. The role of imaging in the evaluation of men with PCa has evolved and currently plays a central role in diagnosis, treatment planning, and evaluation of recurrence. Appropriate use of multiparametric MRI (mpMRI) and MRI-guided transrectal ultrasound (MR-TRUS) biopsy increases the detection of clinically significant PCa while decreasing the detection of clinically insignificant PCa. This process may help patients with clinically insignificant PCa avoid the adverse effects of unnecessary therapy. In the setting of a known PCa, patients with low-grade disease can be observed using active surveillance, which often includes a combination of prostate-specific antigen (PSA) testing, serial mpMRI, and, if indicated, follow-up systematic and targeted TRUS-guided tissue sampling. mpMRI can provide important information in the posttreatment setting, but PET/CT is creating a paradigm shift in imaging standards for patients with locally recurrent and metastatic PCa. This article examines the strengths and limitations of mpMRI for initial PCa diagnosis, active surveillance, recurrent disease evaluation, and image-guided biopsies, and the use of PET/CT imaging in men with recurrent PCa. The goal of this review is to provide a rational basis for current NCCN Clinical Practice Guidelines in Oncology for PCa as they pertain to the use of these advanced imaging modalities.

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The Prostate Gland and PSA (Prostate Specific Antigen)

European Journal of Interdisciplinary Studies ◽

10.26417/ejis.v2i2.p74-80 ◽

2016 ◽

Vol 2 (2) ◽

pp. 74

Author(s):

Serfa Faja ◽

Amir Shoshi

Keyword(s):

Prostate Cancer ◽

Prostate Specific Antigen ◽

Quantitative Measurement ◽

Prostate Gland ◽

Specific Antigen ◽

Transrectal Ultrasound ◽

High Sensitivity ◽

Psa Test ◽

Psa Testing ◽

Very High

The PSA test is used primarily to screen for prostate cancer. A PSA test measures the amount of prostate-specific antigen (PSA) in your blood. PSA is a protein produced in the prostate, a small gland that sits below a man's bladder. PSA is mostly found in semen, which also is produced in the prostate. Small amounts of PSA ordinarily circulate in the blood. The PSA test can detect high levels of PSA that may indicate the presence of prostate cancer. However, many other conditions, such as an enlarged or inflamed prostate, can also increase PSA levels. We use ImmunoAssay for Quantitative Measurement of PSA in Human Blood / Serum / Plasma with i-CHROMA TM Reader System with high sensitivity and specifity. We have analysed 120 patients and only 2 of them had very high value of PSA so we can determine for a prostate cancer. Additional factors increase the accuracy of PSA testing and it is not sufficient only the PSA to determine a prostate cancer so we need a rectal examination and transrectal ultrasound.

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