Integration of Urinary EN2 Protein & Cell-Free RNA Data in the Development of a Multivariable Risk Model for the Detection of Prostate Cancer Prior to Biopsy

The objective is to develop a multivariable risk model for the non-invasive detection of prostate cancer prior to biopsy by integrating information from clinically available parameters, Engrailed-2 (EN2) whole-urine protein levels and data from urinary cell-free RNA. Post-digital-rectal examination urine samples collected as part of the Movember Global Action Plan 1 study which has been analysed for both cell-free-RNA and EN2 protein levels were chosen to be integrated with clinical parameters (n = 207). A previously described robust feature selection framework incorporating bootstrap resampling and permutation was applied to the data to generate an optimal feature set for use in Random Forest models for prediction. The fully integrated model was named ExoGrail, and the out-of-bag predictions were used to evaluate the diagnostic potential of the risk model. ExoGrail risk (range 0–1) was able to determine the outcome of an initial trans-rectal ultrasound guided (TRUS) biopsy more accurately than clinical standards of care, predicting the presence of any cancer with an area under the receiver operator curve (AUC) = 0.89 (95% confidence interval(CI): 0.85–0.94), and discriminating more aggressive Gleason ≥ 3 + 4 disease returning an AUC = 0.84 (95% CI: 0.78–0.89). The likelihood of more aggressive disease being detected significantly increased as ExoGrail risk score increased (Odds Ratio (OR) = 2.21 per 0.1 ExoGrail increase, 95% CI: 1.91–2.59). Decision curve analysis of the net benefit of ExoGrail showed the potential to reduce the numbers of unnecessary biopsies by 35% when compared to current standards of care. Integration of information from multiple, non-invasive biomarker sources has the potential to greatly improve how patients with a clinical suspicion of prostate cancer are risk-assessed prior to an invasive biopsy.

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KEABSAHAN ENGRAILED-2 DI KANKER PROSTAT

INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY ◽

10.24293/ijcpml.v20i2.1084 ◽

2018 ◽

Vol 20 (2) ◽

pp. 150

Author(s):

Elsa Yulius ◽

Ida Parwati ◽

Anna Tjandrawati ◽

Dewi Kartika T

Keyword(s):

Prostate Cancer ◽

Protein Level ◽

Predictive Value ◽

Specific Antigen ◽

Digital Rectal Examination ◽

Enzyme Linked Immunosorbent Assay ◽

Cross Sectional ◽

Protein Levels ◽

Trus Biopsy ◽

Study Results

Prostate cancer is one of the most common malignancy of males found worldwide including in Asia, and is the second most commoncause of male death in Western countries. Specific cause of prostate cancer is not yet elucidated, but there are several risk factors as well.The diagnosis of prostate cancer is confirmed by digital rectal examination (DRE), prostate-specific antigen (PSA), and a biopsy withtrans-rectal ultrasonography (TRUS). However, the sensitivity of DRE and PSA examinations are low and not good enough to detectprostate cancer. Currently there is a new test called Engrailed-2 (EN2) examination with enzyme-linked immunosorbent assay (ELISA)micro method. The test is simple and uninvasive one. This study is aimed to know the validity of urinary EN2 protein level measurementto detect prostate cancer by analysing. This study was conducted at Dr. Hasan Sadikin Hospital Bandung between November 2012 untilMarch 2013. This study was a diagnostic test with cross sectional design. The subjects of study were men whom suspected to have prostatecancer by DRE, PSA value (≥4 ng/mL) and TRUS biopsy. Urinary EN2 protein levels were measured using ELISA micro method. Statisticalanalysis used Mann-Whitney test, table 2×2 and ROC curve. In this study there are 50 subjects, where the result of positive biopsy forprostate cancer were found on 17 subjects and the negative were on 33 subjects. The study results on cut off value of >0.7 ng/mL gavethe sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 94.12%, 63.64%, 57.1%, 95.5% and 74%,respectively. In conclusion of this study, that the urinary EN2 protein level examination using ELISA micro method has the high sensitivityand moderate specificity, thus these procedure primarily can be used for the screening of prostate cancer.

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Prostate Cancer Liquid Biopsy Biomarkers’ Clinical Utility in Diagnosis and Prognosis

Cancers ◽

10.3390/cancers13133373 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3373

Author(s):

Milena Matuszczak ◽

Jack A. Schalken ◽

Maciej Salagierski

Keyword(s):

Prostate Cancer ◽

Liquid Biopsy ◽

Current Knowledge ◽

Prostate Gland ◽

Specific Antigen ◽

Transrectal Ultrasound ◽

Digital Rectal Examination ◽

Cost Effective ◽

Non Invasive ◽

Diagnosis And Prognosis

Prostate cancer (PCa) is the most common cancer in men worldwide. The current gold standard for diagnosing PCa relies on a transrectal ultrasound-guided systematic core needle biopsy indicated after detection changes in a digital rectal examination (DRE) and elevated prostate-specific antigen (PSA) level in the blood serum. PSA is a marker produced by prostate cells, not just cancer cells. Therefore, an elevated PSA level may be associated with other symptoms such as benign prostatic hyperplasia or inflammation of the prostate gland. Due to this marker’s low specificity, a common problem is overdiagnosis, which leads to unnecessary biopsies and overtreatment. This is associated with various treatment complications (such as bleeding or infection) and generates unnecessary costs. Therefore, there is no doubt that the improvement of the current procedure by applying effective, sensitive and specific markers is an urgent need. Several non-invasive, cost-effective, high-accuracy liquid biopsy diagnostic biomarkers such as Progensa PCA3, MyProstateScore ExoDx, SelectMDx, PHI, 4K, Stockholm3 and ConfirmMDx have been developed in recent years. This article compares current knowledge about them and their potential application in clinical practice.

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Evaluation of MicroRNAs as Non-Invasive Diagnostic Markers in Urinary Cells from Patients with Suspected Prostate Cancer

Diagnostics ◽

10.3390/diagnostics10080578 ◽

2020 ◽

Vol 10 (8) ◽

pp. 578

Author(s):

Angelika Borkowetz ◽

Andrea Lohse-Fischer ◽

Jana Scholze ◽

Ulrike Lotzkat ◽

Christian Thomas ◽

...

Keyword(s):

Prostate Cancer ◽

Molecular Markers ◽

Diagnostic Performance ◽

Operating Characteristic ◽

Clinical Performance ◽

Diagnostic Value ◽

Non Invasive ◽

Diagnostic Potential ◽

Specificity And Sensitivity ◽

Diagnostic Power

Currently used tumor markers for early diagnosis of prostate cancer (PCa) are often lacking sufficient specificity and sensitivity. Therefore, the diagnostic potential of selected microRNAs in comparison to serum PSA levels and PSA density (PSAD) was explored. A panel of 12 PCa-associated microRNAs was quantified by qPCR in urinary sediments from 50 patients with suspected PCa undergoing prostate biopsy, whereupon PCa was detected in 26 patients. Receiver operating characteristic (ROC) curve analyses revealed a potential for non-invasive urine-based PCa detection for miR-16 (AUC = 0.744, p = 0.012; accuracy = 76%) and miR-195 (AUC = 0.729, p = 0.017; accuracy = 70%). While serum PSA showed an insufficient diagnostic value (AUC = 0.564, p = 0.656; accuracy = 50%) in the present cohort, PSAD displayed an adequate diagnostic performance (AUC = 0.708, p = 0.031; accuracy = 70%). Noteworthy, the combination of PSAD with the best candidates miR-16 and miR-195 either individually or simultaneously improved the diagnostic power (AUC = 0.801–0.849, p < 0.05; accuracy = 76–90%). In the sub-group of patients with PSA ≤ 10 ng/mL (n = 34), an inadequate diagnostic power of PSAD alone (AUC = 0.595, p = 0.524; accuracy = 68%) was markedly surpassed by miR-16 and miR-195 individually as well as by their combination with PSAD (AUC = 0.772–0.882, p < 0.05; accuracy = 74–85%). These findings further highlight the potential of urinary microRNAs as molecular markers with high clinical performance. Overall, these results need to be validated in a larger patient cohort.

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The Association of the Long Prostate Cancer Expressed PDE4D Transcripts to Poor Patient Outcome Depends on the Tumour’s TMPRSS2-ERG Fusion Status

Prostate Cancer ◽

10.1155/2019/8107807 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Dianne van Strijp ◽

Christiane de Witz ◽

Birthe Heitkötter ◽

Sebastian Huss ◽

Martin Bögemann ◽

...

Keyword(s):

Prostate Cancer ◽

Patient Outcome ◽

Logistic Regression ◽

Risk Model ◽

Curve Analysis ◽

Net Benefit ◽

Decision Curve Analysis ◽

Kaplan Meier ◽

Biological Outcomes ◽

Prognostic Power

Objectives. To investigate the added value of assessing transcripts for the long cAMP phosphodiesterase-4D (PDE4D) isoforms, PDE4D5 and PDE4D9, regarding the prognostic power of the ‘CAPRA & PDE4D7’ combination risk model to predict longitudinal postsurgical biological outcomes in prostate cancer.Patients and Methods. RNA was extracted from both biopsy punches of resected tumours (606 patients; RP cohort) and diagnostic needle biopsies (168 patients; DB cohort). RT-qPCR was performed in order to determine PDE4D5, PDE4D7, and PDE4D9 transcript scores in both study cohorts. By RNA sequencing, we determined the TMPRSS2-ERG fusion status of each tumour sample in the RP cohort. Kaplan-Meier survival analyses were then applied to correlate the PDE4D5, PDE4D7 and PDE4D9 scores with postsurgical patient outcomes. Logistic regression was then used to combine the clinical CAPRA score with PDE4D5, PDE4D7, and PDE4D9 scores in order to build a ‘CAPRA & PDE4D5/7/9’ regression model. ROC and decision curve analysis was used to estimate the net benefit of the ‘CAPRA & PDE4D5/7/9’ risk model.Results. Kaplan-Meier survival analysis, on the RP cohort, revealed a significant association of the PDE4D7 score with postsurgical biochemical recurrence (BCR) in the presence of the TMPRSS2-ERG gene rearrangement (logrank p<0.0001), compared to the absence of this gene fusion event (logrank p=0.08). In contrast, the PDE4D5 score was only significantly associated with BCR in TMPRSS2-ERG fusion negative tumours (logrank p<0.0001 vs. logrank p=0.4 for TMPRSS2-ERG+ tumours). This was similar for the PDE4D9 score although less pronounced compared to that of the PDE4D5 score (TMPRSS2ERG- logrank p<0.0001 vs. TMPRSS2ERG+ logrank p<0.005). In order to predict BCR after primary treatment, we undertook ROC analysis of the logistic regression combination model of the CAPRA score with the PDE4D5, PDE4D7, and PDE4D9 scores. For the DB cohort, this demonstrated significant differences in the AUC between the CAPRA and the PDE4D5/7/9 regression model vs. the CAPRA and PDE4D7 risk model (AUC 0.87 vs. 0.82; p=0.049) vs. the CAPRA score alone (AUC 0.87 vs. 0.77; p=0.005). The CAPRA and PDE4D5/7/9 risk model stratified 19.2% patients of the DB cohort to either ‘no risk of biochemical relapse’ (NPV 100%) or the ‘start of any secondary treatment (NPV 100%)’, over a follow-up period of up to 15 years. Decision curve analysis presented a clear, net benefit for the use of the novel CAPRA & PDE4D5/7/9 risk model compared to the clinical CAPRA score alone or the CAPRA and PDE4D7 model across all decision thresholds.Conclusion. Association of the long PDE4D5, PDE4D7, and PDE4D9 transcript scores to prostate cancer patient outcome, after primary intervention, varies in opposite directions depending on the TMPRSS2-ERG genomic fusion background of the tumour. Adding transcript scores for the long PDE4D isoforms, PDE4D5 and PDE4D9, to our previously presented combination risk model of the combined ‘CAPRA & PDE4D7’ score, in order to generate the CAPRA and PDE4D5/7/9 score, significantly improves the prognostic power of the model in predicting postsurgical biological outcomes in prostate cancer patients.

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Proteomic analyses Identify Major Vault Protein as a Prognostic Biomarker for Fatal Prostate Cancer

Carcinogenesis ◽

10.1093/carcin/bgab015 ◽

2021 ◽

Author(s):

Håkon Ramberg ◽

Elin Richardsen ◽

Gustavo A de Souza ◽

Mehrdad Rakaee ◽

Maria Ekman Stensland ◽

...

Keyword(s):

Prostate Cancer ◽

Prognostic Biomarker ◽

Mass Spectrometry Analysis ◽

Major Vault Protein ◽

Net Benefit ◽

Demographic Shift ◽

Spectrometry Analysis ◽

Protein Levels ◽

Post Surgery ◽

Risk Parameters

Abstract The demographic shift towards an older population will increase the number of prostate cancer cases. A challenge in the treatment of prostate cancer is to avoid undertreatment of patients at high risk of progression following curative treatment. These men can benefit from early salvage treatment. An explorative cohort consisting of tissue from 16 patients who underwent radical prostatectomy, and were either alive or had died from prostate cancer within 10 years post-surgery, was analyzed by mass spectrometry analysis. Following proteomic and bioinformatic analyses, major vault protein was identified as a putative prognostic biomarker. A publicly available tissue proteomics dataset and a retrospective cohort of 368 prostate cancer patients were used for validation. The prognostic value of the major vault protein was verified by scoring immunohistochemical staining of a tissue microarray. High level of major vault protein was associated with more than four-fold higher risk for death from prostate cancer (HR=4.41, 95% CI: 1.45-13.38; p = 0.009) in a Cox proportional hazard models, adjusted for Cancer of the Prostate Risk Assessments Post-surgical (CAPRA-S) score and perineural invasion. Decision curve analyses suggested an improved standardized net benefit, ranging from 0.06-0.18, of adding major vault protein onto CAPRA-S score. This observation was confirmed by receiver operator characteristics curve analyses for the CAPRA-S score versus CAPRA-S and major vault protein score (AUC: 0.58 vs. 0.73). From these analyses one can infer that major vault protein levels in combination with CAPRA-S score might add onto established risk parameters to identify patients with lethal prostate cancer.

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Identification of Biomarkers for Prostate Cancer

The Indonesian Biomedical Journal ◽

10.18585/inabj.v6i3.26 ◽

2014 ◽

Vol 6 (3) ◽

pp. 123

Author(s):

Anna Meiliana ◽

Andi Wijaya

Keyword(s):

Prostate Cancer ◽

Treatment Response ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Digital Rectal Examination ◽

Treatment Decision ◽

Common Type ◽

Non Invasive ◽

Specific Mortality ◽

Multiple Biomarkers

BACKGROUND: Prostate cancer (PCa) was the second most common type of cancer and the fifth leading cause of cancer-related death in men. The great challenge for physicians is being able to accurately predict PCa prognosis and treatment response in order to reduce PCa-specific mortality while avoiding overtreatment by identifying of when to intervene, and in which patients.CONTENT: Currently, PCa prognosis and treatment decision of PCa involved digital rectal examination, Prostate-Speciic Antigens (PSA), and subsequent biopsies for histopathological staging, known as Gleason score. However, each procedure has its shortcomings. Efforts to find a better clinically meaningful and non-invasive biomarkers still developed involving proteins, circulating tumor cells, nucleic acids, and the ‘omics' approaches.SUMMARY: Biomarkers for PCa will most likely be an assay employing multiple biomarkers in combination using protein and gene microarrays, containing markers that are differentially expressed in PCa.KEYWORDS: prostate cancer, PSA, biomarkers, nomograms, miRNA, proteomic, genomic, metabolomic

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MiR-93/miR-375: Diagnostic Potential, Aggressiveness Correlation and Common Target Genes in Prostate Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21165667 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5667

Author(s):

Ewa Ciszkowicz ◽

Paweł Porzycki ◽

Małgorzata Semik ◽

Ewa Kaznowska ◽

Mirosław Tyrka

Keyword(s):

Prostate Cancer ◽

Operating Characteristic ◽

Target Genes ◽

Diagnostic Value ◽

Tissue Samples ◽

Non Invasive ◽

Diagnostic Potential ◽

Diagnostic Applications ◽

First Time ◽

Common Target

Dysregulation of miRNAs has a fundamental role in the initiation, development and progression of prostate cancer (PCa). The potential of miRNA in gene therapy and diagnostic applications is well documented. To further improve miRNAs’ ability to distinguish between PCa and benign prostatic hyperplasia (BPH) patients, nine miRNA (-21, -27b, -93, -141, -205, -221, -182, -375 and let-7a) with the highest reported differentiation power were chosen and for the first time used in comparative studies of serum and prostate tissue samples. Spearman correlations and response operating characteristic (ROC) analyses were applied to assess the capability of the miRNAs present in serum to discriminate between PCa and BPH patients. The present study clearly demonstrates that miR-93 and miR-375 could be taken into consideration as single blood-based non-invasive molecules to distinguish PCa from BPH patients. We indicate that these two miRNAs have six common, PCa-related, target genes (CCND2, MAP3K2, MXI1, PAFAH1B1, YOD1, ZFYVE26) that share the molecular function of protein binding (GO:0005515 term). A high diagnostic value of the new serum derived miR-182 (AUC = 0.881, 95% confidence interval, CI = 0.816–0.946, p < 0.0001, sensitivity and specificity were 85% and 79%, respectively) is also described.

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Comparison among different precursor prostatespecific antigen isoform derivatives on prostate cancer prediction in patients with serum prostatespecific antigen bellow 10 ng/ml

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh180918106s ◽

2020 ◽

Vol 148 (3-4) ◽

pp. 160-166

Author(s):

Milorad Stojadinovic ◽

Damnjan Pantic ◽

Marija Andjelkovic ◽

Miroslav Stojadinovic

Keyword(s):

Prostate Cancer ◽

Characteristic Curve ◽

Specific Antigen ◽

Digital Rectal Examination ◽

Predictive Performance ◽

Clinicopathological Characteristics ◽

Net Benefit ◽

Free Psa ◽

Prostate Biopsies ◽

Prostate Health

Introduction/Objective. The precursor prostate-specific antigen (proPSA) especially its isoform p2PSA is useful in the detection of prostate cancer (PCa). However, the prediction value of different p2PSA derivatives remains unclear. The aim of the study was to compare the performance of the p2PSA, percentage of p2PSA to free PSA (%p2PSA), prostate health index (Phi), and one prostate dimension-adjusted index, p2PSA density (p2PSAD), with each other for PCa prediction in patients with serum PSA 10 ng/ml or less. Methods. This prospective study included patients who had undergone ultrasound-guided prostate biopsies and p2PSA testing. The data about patients? clinicopathological characteristics were collected and %p2PSA, p2PSAD and Phi were calculated. Different aspect of predictive performance was assessed using the area under the receiver operating characteristic curve (AUC), the specificities at set sensitivities, and clinical utility using decision curve analyses (DCA). Results. PCa was diagnosed in 23 (32.4%) out of 71 patients. Results of multivariate analysis showed that only the Phi and digital rectal examination were independent predictors of PCa. The AUC of p2PSA, %p2PSA, p2PSAD and Phi were 76.2%, 81.5%, 88.7%, 89.6%, respectively. At pre-specified sensitivity of 90% and 95%, Phi demonstrated a greater specificity than the other p2PSA derivatives. Phi and p2PSAD lead to the higher net benefit in DCA. Conclusion. Compared with other p2PSA derivatives Phi is the most useful parameter for selection of the patients that do not need to be undergone to biopsy and thereby avoiding unnecessary procedures.

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A Novel Urine Exosomal lncRNA Assay to Improve the Detection of Prostate Cancer at Initial Biopsy: A Retrospective Multicenter Diagnostic Feasibility Study

Cancers ◽

10.3390/cancers13164075 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4075

Author(s):

Yun Li ◽

Jin Ji ◽

Ji Lyu ◽

Xin Jin ◽

Xing He ◽

...

Keyword(s):

Prostate Cancer ◽

Diagnostic Performance ◽

Digital Rectal Examination ◽

Clinical Parameters ◽

Net Benefit ◽

Clinical Value ◽

Decision Curve Analysis ◽

Initial Biopsy ◽

Clinically Significant ◽

Almost All

Purpose: This study aimed at developing and validating a novel noninvasive urinary exosome-based post-DRE (digital rectal examination) lncRNA assay to diagnose PCa (prostate cancer) and clinically significant PCa (Gleason score ≥ 7) from the initial prostate biopsy. Methods: A total of 602 urine samples from eligible participants were collected. The expression levels of urinary exosomal PCA3 (prostate cancer antigen 3) and MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) were detected by qPCR (quantitative real-time PCR). Receiver operating characteristic (ROC) analysis was applied to evaluate the diagnostic performance of PCA3, MALAT1 and the lncRNA assay. A decision curve analysis (DCA) and waterfall plots were used to assess the clinical value of the lncRNA assay. Results: Urinary exosomal PCA3 and MALAT1 were overexpressed in PCa and clinically significant PCa (p < 0.001). The lncRNA assay combining PCA3 and MALAT1 had a better diagnostic performance (AUC 0.828) than the current clinical parameters in detecting PCa. More importantly, the lncRNA assay yielded an AUC of 0.831 to detect clinically significant PCa, which is much higher than that of the current clinical parameters. The lncRNA assay was superior to PSA, f/tPSA and the base model for detecting PCa and clinically significant PCa, with a higher net benefit for almost all threshold probabilities. At the cutoff value of 95% sensitivity, the lncRNA assay could avoid 24.2% unnecessary biopsies while only missing 1.2% of the cases of clinically significant PCa. Conclusion: We developed and validated a novel noninvasive post-DRE urine-based lncRNA assay that presented good diagnostic power and clinical utility for the early diagnosis of PCa and high-grade PCa.

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Integrin Alpha V in Urine: A Novel Noninvasive Marker for Prostate Cancer Detection

Frontiers in Oncology ◽

10.3389/fonc.2020.610647 ◽

2021 ◽

Vol 10 ◽

Author(s):

Marina Y. Zemskova ◽

Maria V. Marinets ◽

Andrey V. Sivkov ◽

Julia V. Pavlova ◽

Andrey N. Shibaev ◽

...

Keyword(s):

Prostate Cancer ◽

Urine Analysis ◽

Specific Antigen ◽

High Specificity ◽

Control Group ◽

Prostate Hyperplasia ◽

Non Invasive ◽

Diagnostic Potential ◽

Noninvasive Biomarker ◽

Benign Prostate

Prostate cancer (PCa) diagnosis based on patient urine analysis provides non-invasive and promising method as compared to biopsy and a prostate-specific antigen (PSA) test. This study was conceived to investigate whether Integrin alpha V (ITGAV) protein is present in urine and assess the urinary ITGAV diagnostic potential for PCa. Materials and Methods: Urinary ITGAV expression was determined by Western blot analysis and quantified by ELISA in urine from men with PCa (n = 47), benign prostate hyperplasia (n = 42) and age-matched controls (n = 22). Results: The level of ITGAV protein was significantly lower in PCa urine samples as compared to those in the control group (p < 0.00001). The decrease of ITGAV in urine was highly predictive of PCa with 91.5% sensitivity, 91.4% specificity, 0.93 area under the ROC curve, and its specificity was better than that of serum PSA. Conclusion: Urinary ITGAV provides a novel noninvasive biomarker with high specificity.

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