ExoDx Prostate Research Articles

Profiling Extracellular Long RNA Transcriptome in Human Plasma and Extracellular Vesicles for Biomarker Discovery.

SummaryThe recent discovery of extracellular RNAs in blood, including RNAs in extracellular vesicles (EVs), combined with low-input RNA-sequencing advances have enabled scientists to investigate their role in human disease. To date, most studies have been focusing on small RNAs, and methodologies to optimize long RNAs measurement are lacking. We used plasma RNA to assess the performance of six long RNA sequencing methods, at two different sites, and we report their differences in reads (%) mapped to the genome/transcriptome, number of genes detected, long RNA transcript diversity, and reproducibility. Using the best performing method, we further compare the profile of long RNAs in the EV- and no-EV-enriched RNA plasma compartments. These results provide insights on the performance and reproducibility of commercially available kits in assessing the landscape of long RNAs in human plasma and different extracellular RNA carriers that may be exploited for biomarker discovery.

Clinical utility of the exosome based ExoDx Prostate(IntelliScore) EPI test in men presenting for initial Biopsy with a PSA 2\u201310\u2009ng/mL

BackgroundThe ExoDx Prostate(IntelliScore) (EPI) test is a non-invasive risk assessment tool for detection of high-grade prostate cancer (HGPC) that informs whether to proceed with prostate biopsy. We sought to assess the impact of EPI on the decision to biopsy in a real-world clinical setting.MethodsWe conducted a prospective, randomized, blinded, two-armed clinical utility study that enrolled 1094 patients with 72 urologists from 24 urology practices. Patients were considered for prostate biopsy at enrollment based on standard clinical criteria. All patients had an EPI test; however, patients were randomized into EPI vs. control arms where only the EPI arm received results for their biopsy decision.ResultsIn the EPI arm (N = 458), 93 patients received negative EPI scores of which 63% were recommended to defer biopsy by the urologist and 74% ultimately deferred. In contrast, 87% of patients with positive EPI scores were recommended to undergo biopsy with a 72% compliance rate to the urologist’s recommendation. This led to detection of 30% more HGPC compared to the control arm, and we estimate that 49% fewer HGPC were missed due to deferrals compared to standard of care (SOC). Overall, 68% of urologists reported that the EPI test influenced their biopsy decision. The primary reason not to comply with EPI results was rising PSA.ConclusionTo our knowledge this is the first report on a PC biomarker utility study with a blinded control arm. The study demonstrates that the EPI test influences the overall decision to defer or proceed with a biopsy and improves patient stratification.

MP27-08 URINARY EXOSOME TEST AND MP-MRI FOR PROSTATE CANCER SCREENING: BALANCING COSTS AND BENEFITS

INTRODUCTION AND OBJECTIVE:Concern for over-treatment of prostate cancer has led to the development of new biomarkers that risk-stratify patients prior to biopsy. ExoDx Prostate IntelliScore (ExoDx...

Beyond PSA: The Role of Prostate Health Index (phi).

Background: Widespread use of prostate specific antigen (PSA) in screening procedures allowed early identification of an increasing number of prostate cancers (PCas), mainly including indolent cancer. Availability of different therapeutic strategies which have a very different impact on the patient’s quality of life suggested a strong need for tools able to identify clinically significant cancer at diagnosis. Multi-parametric magnetic resonance showed very good performance in pre-biopsy diagnosis. However, it is an expensive tool and requires an experienced radiologist. In this context, a simple blood-based test is worth investigating. In this context, researchers focused their attention on the development of a laboratory test able to minimize overdiagnosis without losing the identification of aggressive tumors. Results: Recent literature data on PCa biomarkers revealed a clear tendency towards the use of panels of biomarkers or a combination of biomarkers and clinical variables. Phi, the 4Kscore, and Stockholm3 as circulating biomarkers and the Mi-prostate score, Exo DX Prostate, and Select MD-X as urinary biomarker-based tests have been developed. In this scenario, phi is worthy of attention as a noninvasive test significantly associated with aggressive PCa. Conclusions: Literature data showed that phi had good diagnostic performance to identify clinically significant (cs) PCa, suggesting that it could be a useful tool for personalized treatment decision-making. In this review, phi potentialities, limitations, and comparisons with other blood- and urinary-based tests were explored.

Basic characteristics and features of the molecular genetic test systems designed for non-invasive diagnostics and prognosis of prostate cancer and bladder cancer

Improving the laboratory diagnosis of prostate cancer and bladder cancer are still an actual problem in modern urologic oncology. Test systems for DNA or RNA alterations that occurred during carcinogenesis and associated with the malignant tumor and the prognosis of disease have been actively developed in recent years. Here we reviewed the data published mainly in the last 5 years about the molecular genetic kits for diagnosis (Progensa, SelectMDx, ExoDx Prostate Test, Prosta-Test, Confirm MDx) and assessment of prognosis (Prolaris, Decipher, Oncotype DX) in patients with prostate cancer, discussed their sensitivity and specificity. The characteristics of analogous kits and panels for bladder cancer (UroVysion, CertNDx Bladder Cancer Assay, UroSEEK, mutations in the FGFR3 and TERT genes, and the Cxbladder Monitor/Detect/Triage kit's line) were systematized. Particularly we focused on the description of the patient cohorts for whom kits mentioned above have greater diagnostic accuracy, described limitations of these test systems in consequence both a methodological and registration aspects, and their use in combination with other tumor markers. This review is aimed at oncologists, urologists, laboratory geneticists and specialists in related professions.

A critical appraisal of biomarkers in prostate cancer.

A number of urine and blood-based biomarker tests have been described for prostate cancer, although to date there has only been a limited exploration of the methodology behind the validation studies that underpin these tests. In this review, a selection of commercially available urine and blood-based biomarker tests for prostate cancer are described, and the underlying key validation studies for each test are critically appraised using the Standards for Reporting Diagnostic Accuracy (STARD) 2015 statement. The ExoDx Prostate Intelliscore, SelectMDx, Progensa PCA3, Mi-Prostate Score, 4K Score, and Prostate Health Index (PHI) tests were reviewed. Most of the validation studies supporting these tests perform exploratory analyses to determine cut-off values in a post hoc manner, comprise cohorts that are primarily Caucasian, report receiver operating characteristic curves that combine the biomarker's result with established clinical nomograms and are based on a reference standard (prostate biopsy) that lacks central pathology review. Deficiencies in STARD reporting guidelines include frequent failure to provide a published study protocol, prospective study registration in a registry, a flow diagram, justification for sample size determination, a discussion of adverse events with testing, and information on how missing or indeterminate test results should be managed. Key validation studies that support many commercially available urine and blood-based biomarkers for prostate cancers have deficiencies in transparency based on STARD reporting guidelines, and limitations in methodology must be considered when deciding when these tests should be applied in clinical practice.

Performance of a validated urine exosome gene expression test (EPI) in men within the USPSTF suggested age-group of 55 to 69 years at initial biopsy with a PSA 2-10 ng/mL.

53 Background: Prostate-specific antigen (PSA) plays a key-role in prostate cancer (PCa) risk stratification but leads to over-diagnosis of low grade PCa. Recently, the USPSTF recommended that the decision to undergo PSA-based screening for men aged 55 to 69 years should be an individual one. We have developed and validated a non-invasive diagnostic test (ExoDx Prostate(IntelliScore), EPI) as a decision aid to guide the initial prostate biopsy decision process for men in the PSA gray zone of 2-10 ng/mL. The EPI test is a urine exosome gene expression assay to discriminate high-grade (GG 2) from low-grade (GG 1) and benign disease, thereby reducing the number of unnecessary biopsies. Methods: Patient data from two clinical trials were merged and constrained by age (55-69) according to the USPSTF suggested age-group resulting in a cohort of 701 patients with PSA 2-10 ng/mL, scheduled for initial prostate needle biopsy. EPI test results as well as PCPT2.0 risk calculator, ERSPC risk calculator and PSA results are compared with biopsy outcomes. Performances are reported using the area under the receiver operating characteristic curve (AUC), Negative predictive value (NPV), Positive predictive value (PPV), Sensitivity, and Specificity for discriminating ≥GG2 from GG1 and benign disease. Results: EPI showed a superior AUC of 0.70 compared to PSA (AUC: 0.57), PCPT2.0 (AUC: 0.60) and ERSPC (AUC: 0.58) (all p-values < 0.001) for discriminating ≥GG2 PCa from benign and GG1. The previously validated EPI cut-point of 15.6 would avoid 22% of all prostate biopsies and 29% of unnecessary biopsies, with an NPV of 93% and miss only 5.4% of ≥GG2, respectively. Conclusions: EPI is a non-invasive, easy to use urine exosome RNA expression assay to discriminate high-grade (GG2) from low-grade (GG1) PCa and benign disease. EPI significantly outperformed the other standard of care parameters tested and applying the EPI test for risk stratification of patients in the USPSTF suggested age group, should reduce the number of unnecessary biopsies.

A Prospective Adaptive Utility Trial to Validate Performance of a Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer in Patients with Prostate-specific Antigen 2–10 ng/ml at Initial Biopsy

BackgroundDiscriminating indolent from clinically significant prostate cancer (PCa) in the initial biopsy setting remains an important issue. Prospectively evaluated diagnostic assays are necessary to ensure efficacy and clinical adoption. ObjectivePerformance and utility assessment of ExoDx Prostate (IntelliScore) (EPI) urine exosome gene expression assay versus standard clinical parameters for discriminating Grade Group (GG) ≥2 PCa from GG1 PCa and benign disease on initial biopsy. Design, setting, and participantsA two-phase adaptive clinical utility study (NCT03031418) comparing EPI results with biopsy outcomes in men, with age ≥50 yr and prostate-specific antigen (PSA) 2–10ng/ml, scheduled for initial prostate biopsy. After EPI performance assessment during phase I, a clinical implementation document (ie, CarePath) was developed for utilizing the EPI test in phase II, where the biopsy decision is uncertain. Outcome measurements and statistical analysisPerformance evaluation of the EPI test in patients enrolled in phase I and publication of a consensus CarePath for phase II. Results and limitationsIn a total of 503 patients, with median age of 64 yr, median PSA 5.4ng/ml, 14% African American, 70% Caucasian, 53% positive biopsy rate (22% GG1, 17% GG2, and 15% ≥ GG3), EPI was superior to an optimized model of standard clinical parameters with an area under the curve (AUC) 0.70 versus 0.62, respectively, comparable with previously published results (n=519 patients, EPI AUC 0.71). Validated cut-point 15.6 would avoid 26% of unnecessary prostate biopsies and 20% of total biopsies, with negative predictive value (NPV) 89% and missing 7% of ≥GG2 PCa. Alternative cut-point 20 would avoid 40% of unnecessary biopsies and 31% of total biopsies, with NPV 89% and missing 11% of ≥GG2 PCa. The clinical investigators reached consensus recommending use of the 15.6 cut-point for phase II. Outcome of the decision impact cohort in phase II will be reported separately. ConclusionsEPI is a noninvasive, easy-to-use, gene expression urine assay, which has now been successfully validated in over 1000 patients across two prospective validation trials to stratify risk of ≥GG2 from GG1 cancer and benign disease. The test improves identification of patients with higher grade disease and would reduce the total number of unnecessary biopsies. Patient summaryIt is challenging to predict which men are likely to have high-grade prostate cancer (PCa) at initial biopsy with prostate-specific antigen 2–10ng/ml. This study further demonstrates that the ExoDx Prostate (IntelliScore) test can predict ≥GG2 PCa at initial biopsy and defer unnecessary biopsies better than existing risk calculator's and standard clinical data.

Urinary biomarkers of prostate cancer.

The development of more specific biomarkers for prostate cancer and/or high-risk prostate cancer is necessary, because the prostate-specific antigen test lacks specificity for the detection of prostate cancer and can lead to unnecessary prostate biopsies. Urine is a promising source for the development of new biomarkers of prostate cancer. Biomarkers derived from prostate cancer cells are released into prostatic fluids and then into urine. Urine after manipulation of the prostate is enriched with prostate cancer biomarkers, which include prostate cancer cells, DNAs, RNAs, proteins and other small molecules. The urinary prostate cancer antigen3 test is the first Food and Drug Administration-approved RNA-based urinary marker, and it helps in the detection of prostate cancer on repeat biopsy. The SelectMDx test is based on messenger RNA detection of DLX1 and HOXC6 in urine after prostate massage, and helps in the detection of high-risk prostate cancer on prostate biopsy. Exosomes are extracellular vesicles with a diameter of 30-200nm that are secreted from various types of cells. Urinary prostate cancer-derived exosomes also contain RNAs and proteins specific for prostate cancer (e.g. PCA3 and TMPRSS2-ERG), and could be promising sources of novel biomarker discovery. The ExoDx Prostate test is a commercially available test based on the detection of three genes (PCA3, ERG and SPDEF) in urinary exosomes. Advancement of comprehensive analysis (microarray, mass spectrometry and next-generation sequencing) has resulted in the discovery of several urinary biomarkers. Non-invasive urinary markers can help in the decision to carry out prostate biopsy or in the design of a therapeutic strategy.

Improving the Specificity of PSA Screening with Serum and Urine Markers.

Prostate cancer remains a significant public health burden. In order to decrease the morbidity and mortality associated with prostate cancer, serum prostate-specific antigen (PSA) screening has been used since the 1990s. However, there is concern for overdiagnosis of prostate cancer with widespread PSA screening, which could lead to overtreatment and its attendant morbidities. In order to avoid unnecessary biopsy and downstream effects including treatment of insignificant prostate cancer, a number of tests have been proposed to improve upon PSA screening. Increasing the specificity of prostate cancer screening above that of PSA testing should reduce the incidence of unnecessary prostate biopsy. However, an increase in specificity is associated with a decrease in sensitivity, so these tests must be balanced with the concern for missing the diagnosis of potentially significant disease. In this context, we present a review of six common biomarkers proposed to improve the specificity of prostate cancer screening-free PSA, prostate health index, 4Kscore, PCA3, Select MDx, and ExoDx Prostate(Intelliscore).

Are localized prostate cancer biomarkers useful in the clinical practice?

Prostate cancer presents itself in a heterogeneous way with both aggressive and indolent forms. Despite the controversy surrounding its use, prostate-specific antigen screening ultimately leads to a greater number of diagnosed patients. One of the biggest challenges in clinical practice is to select the right patients for biopsy and, among diagnosed patients, to differentiate tumors with an indolent course from those with an unfavorable prognosis, in order to determine the best therapeutic decision for each case, avoiding unnecessary interventions. Currently, several types of biomarkers are available for clinical use in patients with prostate cancer, which include blood-based (prostate-specific antigen, Prostate Health Index®, 4K score®); urine sample-based (PCA3, SelectMDx®, ExoDx Prostate IntelliScore®); and biopsy, transurethral resection, or radical prostatectomy tissue-based (ConfirmMDx®, Oncotype®, Prolaris®, Decipher®). The aim of this review is to provide an overview of the current state of evidence and to highlight recent advances in the evaluation and diagnosis of prostate cancer, with emphasis on biomarkers related to diagnosis and to prognostic evaluation of localized prostate cancer.

Performance of a clinically validated urine exosome gene expression test to predict high grade prostate cancer in men with a prior negative biopsy.

119 Background: The over-diagnosis of low grade, indolent prostate cancer (PCa) initiates significant patient anxiety regarding treatment options and health risk. To address this clinical need, we developed and subsequently validated a noninvasive, easy to administer, supportive diagnostic test (ExoDx Prostate(IntelliScore), EPI) to guide the initial prostate biopsy decision process for men with PSA 2-10ng/mL. The EPI test is a urine exosome gene expression assay to discriminate high-grade (GS 7 PCa) from low-grade (GS 6) and benign disease, thereby potentially reducing the number of unnecessary biopsies. As many men have had prior negative/ benign biopsies, we sought to understand the performance of EPI in this selected population. Methods: Utilizing men with prior negative biopsies from two clinical trials we evaluated performance of the EPI test with respect to subsequent biopsy outcomes. We used the previously validated and alternative EPI cut-points of 15.6 and 20, respectively, to assess performance with AUC, sensitivity, and NPV. Results: A total of N = 286 patients with a prior negative biopsy; mean age 65 years, mean PSA 6.2 ng/mL, 22% positive family history, 15% African American; 32% positive biopsy rate: 20% GS6 (ISUP1) and 12% > / = GS7 PCa (ISUP≥2). AUC 0.68 vs. AUC 0.59 for standard of care (i.e. PSA, age, race, family history) and AUC 0.51 for PSA alone. By comparison the EPI initial biopsy AUC was 0.71. Using the previously validated EPI cut-points of 15.6 (or alternative 20) yielded NPVs of 92% and 95%, and number of avoided biopsies of 23% and 32%, respectively, and sensitivity of 85.7% for both cut-points. Notably, EPI in the initial biopsy setting had a sensitivity of 92 vs. 87% and an NPV of 91 vs. 90%, for the 15.6 and 20 cut-points, respectively. Conclusions: The EPI test is a noninvasive, first-catch, non-DRE gene expression array that accurately discriminates low-grade and benign biopsy outcomes from high-grade prostate cancer. The test performs well in both the initial and prior negative biopsy patients and has the potential to reduce the overall number of unnecessary biopsies in both settings.

PNFLBA-15 INTERIM RESULTS OF A NOVEL ‘ADAPTIVE’ REGISTRATION-UTILITY TRIAL ASSESSING THE PERFORMANCE OF EXODX ® (PROSTATE) INTELLISCORE (EPI); A NON-DRE URINE EXOSOME GENE EXPRESSION ASSAY TO PREDICT HIGH GRADE DISEASE ON INITIAL BIOPSY.

You have accessJournal of UrologyPlenary: Next Frontier (PNFLBA)1 Apr 2017PNFLBA-15 INTERIM RESULTS OF A NOVEL ‘ADAPTIVE’ REGISTRATION-UTILITY TRIAL ASSESSING THE PERFORMANCE OF EXODX® (PROSTATE) INTELLISCORE (EPI); A NON-DRE URINE EXOSOME GENE EXPRESSION ASSAY TO PREDICT HIGH GRADE DISEASE ON INITIAL BIOPSY. Alan Partin, Phillipp Torkler, Mikkel Noerholm, Johan Skog, and Michael Donovan Alan PartinAlan Partin More articles by this author , Phillipp TorklerPhillipp Torkler More articles by this author , Mikkel NoerholmMikkel Noerholm More articles by this author , Johan SkogJohan Skog More articles by this author , and Michael DonovanMichael Donovan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.03.041AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Overdetection and overtreatment of indolent prostate cancer (PCa) remains a significant health issue requiring noninvasive assays to guide the prostate biopsy decision process. We previously demonstrated that a non-DRE urine exosome gene expression assay (ExoDx Prostate (IntelliScore) (EPI) discriminates GS 7 PCa from GS 6 and benign disease, potentially reducing the number of unnecessary biopsies. We initiated a novel prospective, phase-adaptive two cohort trial design: Group 1 (G1), men scheduled for a biopsy and Group 2 (G2), men for which the decision to biopsy is uncertain. The G1 consensus results including EPI cut-point recommendation will be applied to G2 patients with clinical utility, ease of adoption, patient response and health economic data collected. Here we report interim results from G1 with initial cut-point comparison to the original validation trial. METHODS The trial was activated on Sept. 2016 at 9 sites (8 community practice, 1 academic), geographically distributed across the U.S. We plan to enlist up to 20 sites by April 2017. Enrollment is limited to initial biopsy patients only, >/=50 years with PSA 2-10 ng/mL. The EPI test is performed at Exosome Diagnostics’ CLIA laboratory in Cambridge, MA; G1 results are collected for consensus review and G2 recommendation. RESULTS The average biopsy rate across all sites is 1-2 / week. Demographics of the 96 (of targeted) 500 G1 patients enrolled thus far are comparable to the validation study (mean age 64 years, mean PSA 5.78; 75% white, 17% African American, 23% positive family history of PCa, 81% non-suspicious DRE). Of note, we have observed a higher positive biopsy rate of 59% (vs. 47% in validation study); 22% ISUP 1 (GS 3+3) and 37% >/=ISUP 2. The EPI test validated (15.6) vs. adjusted (20) cut-points both result in NPV 90, with sensitivity of 94% and 92%, respectively. The number of avoided biopsies is greater (30%) with the adjusted cut-point of 20 vs. the original validated cut-point (21%); while missing only 1>/=ISUP 3 case. The original validated cut-point would have avoided biopsies in 30% of men with GS6 or benign disease while the adjusted cut-point would have avoided 43% of biopsies in this population. CONCLUSIONS Interim results from a prospective adaptive trial of the EPI test demonstrate consistent performance as identified in the original validation study. The adjusted cut-point continues to provide added benefit without risk of missing significant disease. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e916-e917 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Alan Partin More articles by this author Phillipp Torkler More articles by this author Mikkel Noerholm More articles by this author Johan Skog More articles by this author Michael Donovan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP33-05 RADICAL PROSTATECTOMY OUTCOMES FROM A VALIDATED URINE EXOSOME GENE EXPRESSION ASSAY WHICH PREDICTS HIGH-GRADE (GS7) PROSTATE CANCER SUGGESTS UTILITY FOR MEN ENROLLED IN ACTIVE SURVEILLANCE.

You have accessJournal of UrologyProstate Cancer: Detection & Screening III1 Apr 2017MP33-05 RADICAL PROSTATECTOMY OUTCOMES FROM A VALIDATED URINE EXOSOME GENE EXPRESSION ASSAY WHICH PREDICTS HIGH-GRADE (GS7) PROSTATE CANCER SUGGESTS UTILITY FOR MEN ENROLLED IN ACTIVE SURVEILLANCE. Michael Donovan, Phillipp Torkler, Mikkel Noerholm, Johan Skog, and James McKiernan Michael DonovanMichael Donovan More articles by this author , Phillipp TorklerPhillipp Torkler More articles by this author , Mikkel NoerholmMikkel Noerholm More articles by this author , Johan SkogJohan Skog More articles by this author , and James McKiernanJames McKiernan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1001AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES With over-diagnosis and over-treatment of indolent prostate cancer, non-invasive screening tools that predict low-grade (= Gleason score 6, GS 6) from high-grade (=GS 7) prostate cancer (PCa) will play a significant role in the treatment decision process. Recently, we demonstrated that a urine exosome gene expression assay (ExoDx Prostate (IntelliScore) (EPI)) was able to discriminate high-grade (=GS 7) from low-grade (GS 6) and benign disease biopsy outcomes, thereby improving the identification of men with higher-grade PCa, potentially reducing the number of unnecessary biopsies. In a parallel study, we had also shown that EPI scores were associated with pathologic stage (PS) and radical prostatectomy Gleason score (RP-GS). We now sought to expand these results and further examine outcomes from men enrolled in the biopsy validation trial who had selected surgery. METHODS 430 patients from a previous RP cohort study were re-evaluated using urine EPI scores and ISUP 2014 criteria with respect to RP-GS, PS and cancer volume. Specifically, urine EPI scores from men with biopsy ISUP 1 (i.e. potential candidates for Active Surveillance), were examined along with various clinical variables (including PSA, age, race, family history) for predicting RP upgrading. Additionally, RP outcomes were evaluated from men enrolled in the 519-validation cohort. Preliminary assessment using Spearman and Pearson correlation along with AUC was used to evaluate performance. RESULTS In the 430 RP cohort: 16% ISUP1, 45% ISUP2 (GS3+4),and 37% = ISUP3 (GS4+3); 85% PSA <10ng/mL and 32% upgrading upon RP. Higher pre-RP urine EPI scores were associated with higher RP-ISUP groups, RP-PS and RP tumor volume (p-value<0.001). In patients from the 519-validation cohort who had a biopsy ISUP1 and chose RP, one third were upgraded and once again higher pre-RP urine EPI scores were significantly associated with a higher RP-ISUP group and higher RP-PS (p-value<0.001). Pre-RP PSA was not able to discriminate RP ISUP upgrading. CONCLUSIONS The EPI test is a noninvasive, first-catch non-DRE gene expression array that accurately discriminates low-grade from high-grade PCa in ISUP and traditional Gleason score based grading systems. Improved discrimination for predicting higher ISUP groups suggests a potential role in longitudinal monitoring of patients enrolled in Active Surveillance and warrants further validation. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e419 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Michael Donovan More articles by this author Phillipp Torkler More articles by this author Mikkel Noerholm More articles by this author Johan Skog More articles by this author James McKiernan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Blood-based and urinary prostate cancer biomarkers: a review and comparison of novel biomarkers for detection and treatment decisions.

The diagnosis of prostate cancer (PCa) is currently based on serum PSA testing and/or abnormal digital rectal examination and histopathologic evaluation of prostate biopsies. The main drawback of PSA testing is the lack of specificity for PCa. To improve early detection of PCa more specific biomarkers are needed. In the past few years, many new promising biomarkers have been identified; however, to date, only a few have reached clinical practice. In this review, we discuss new blood-based and urinary biomarker models that are promising for usage in PCa detection, follow-up and treatment decision-making. These include Prostate Health Index (PHI), prostate cancer antigen 3 (PCA3), four-kallikrein panel (4K), transmembrane protease serine 2-ERG (TMPRSS2-ERG), ExoDx Prostate Intelliscore, SelectMDx and the Mi-Prostate score. Only few head-to-head studies are available for these new fluid-based biomarkers and/or models. The blood-based PHI and urinary PCA3 are two US Food and Drug Administration-approved biomarkers for diagnosis of PCa. In the second part of this review, we give an overview of published studies comparing these two available biomarkers for prediction of (1) PCa upon prostate biopsy, (2) pathological features in radical prostatectomy specimen and (3) significant PCa in patients eligible for active surveillance. Studies show opposing results in comparison of PHI with PCA3 for prediction of PCa upon initial and repeat prostate biopsy. PHI and PCA3 are able to predict pathological findings on radical prostatectomy specimen, such as tumor volume and Gleason score. Only PHI could predict seminal vesicle invasion and only PCA3 could predict multifocality. There is some evidence that PHI outperforms PCA3 in predicting significant PCa in an active surveillance population. Future research should focus on independent validation of promising fluid-based biomarkers/models, and prospective comparison of biomarkers with each other.

Improving Prostate Cancer Screening and Diagnosis: Health Policy and Biomarkers Beyond PSA.

The initial goal of prostate cancer screening with prostatespecific antigen (PSA) was to identify men with early-stage disease according to the general oncologic principle of secondary prevention that early diagnosis and treatment would prevent disease progressionand improve survival. However, 2 randomized clinical trials evaluating PSA screening and a large body of literature have identified unintended harms of overdiagnosis and overtreatment of potentially indolentprostatecancer.1,2TherevisedUSPreventiveServices Task Force grade D recommendation for PSA screening in 2012, stating that there is a lack of evidence that its benefits outweigh itsharms, further thrustprostate cancer screening into the spotlight of health policy in the United States.3 Recently, one of the intended consequences of the US Preventive ServicesTaskForce recommendationwas realized in that fewer men are being screened for and diagnosed with prostate cancer,withanestimated33000fewer incident cases in 2012 than in 2011.4 Although a uniform recommendation against screeningcan reduceoverdiagnosis andovertreatment of low-riskdisease, it also reduces theopportunity todiagnose higher-riskdisease, inwhich treatmenthas beenproven to reduce deaths from prostate cancer. Amore nuanced approach toPSAscreeningbasedona systematic reviewof the literature was proposed in 2013 by theAmericanUrological Association guideline for the earlydetectionof prostate cancer.5Although the review also investigated other serum and urine biomarkersofprostatecancer, suchasPSAisoforms, theProstateHealth Index, prostate cancer antigen 3 assay, and TMPRSS2-ERG fusion,6 the quality of the reviewed data was insufficient for determining their role in screening. In the current prospective cohort study reported in JAMA Oncology,McKiernanand colleagues7 demonstrate thepotential utility of a urine-based 3-gene exosome expression assay utilizing SAM pointed domain containing ETS transcription factor, ERG, and PCA3 (ExoDx Prostate IntelliScore, Exosome Diagnostics) to discriminate prostate cancer with a Gleason score of 7 ormore from that with a Gleason score of 6 and benign disease at initial biopsy. The population forwhich use of the assaywas intended includedmenolder than50yearswith no prior biopsy and a PSA value between 2 and 10 ng/mL (to convert tomicrograms per liter,multiply by 1.0). Similar estimates of the area under the curve were seen in the training (0.74) and validation (0.71) cohorts for the assay, with statistically significant improvements inmodel areaunder thecurve when the test was added to standard-of-care variables alone. Inapracticalapplication,applyingacutoffvalue fromthetraining cohort to serve as a threshold for biopsy in the validation cohort showed that 27% (138 of 519) of initial biopsies could havebeenavoidedat the cost ofmissing8%(12of 148) of prostate cancers of a Gleason score of 7 or more. A cutoff adjustment avoided 37% (192 of 519) of biopsies at a cost ofmissing 13% (19 of 148) of prostate cancers of a Gleason score of 7 or more (only 4 of the 19 patients had prostate cancer with a Gleason score including dominant pattern 4 disease). McKiernan and colleagues7 suggest that this 3-gene expression signature assay and similar tests could provide a route to reducing thediagnosis of low-riskprostate cancer and decreasing the number of unnecessary prostate biopsies. Instead of uniformly halting efforts to screen for early-stage prostate cancer, the focus shifts to detecting clinically significant disease.Notably, thepopulation included23% (55of 237) of menwith digital rectal examinations that raised the suspicionof prostate cancer and25% (64of 255) ofmenwith a familyhistoryofprostatecancer.These factors, combinedwithPSA values, led to the decision to perform a biopsy of the prostate, which resulted in a diagnosis of prostate cancer in almost half of the men in the study population and the finding that more than one-fourth of the study population had a Gleason score of 7 or more. The performance of the 3-gene expressionassay ina randomsampleofmennot scheduled for biopsy is unknown, making it uncertain whether the assay holds promise as an independent screening modality. Longitudinal assessment of the assay in a screening cohort will provide more data. Therefore, the current role of the 3-gene expression signature assay, if validated in external cohorts, would be as a secondary or reflex test for risk stratification in the setting of exercising stewardship with PSA screening, as suggested in theAmericanUrological Association guidelines, rather than as ameans of completely stopping PSA screening. The introduction of an effective reflex test for risk stratification adds an additional procedure to health policy efforts to combat overdiagnosis and overtreatment of prostate cancer. Health policy considerations in these efforts can be listed in downstream order from population-based screening to individualizedmanagementdecisions. The first step in this process includes guideline statements by the American Urological Association advocating shared decision making for men aged 55 to 69 years and PSA screening intervals of 2 years or more,5 resembling the2009USPreventiveServicesTaskForce recommendation for screeningmammography.A second step is effective risk stratification before conducting a diagnostic biopsy by using a validated gene-expression signature, such Related article page 882 Opinion

A Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer at Initial Biopsy.

Overdiagnosis and overtreatment of indolent prostate cancer (PCA) is a serious health issue in most developed countries. There is an unmet clinical need for noninvasive, easy to administer, diagnostic assays to help assess whether a prostate biopsy is warranted. To determine the performance of a novel urine exosome gene expression assay (the ExoDx Prostate IntelliScore urine exosome assay) plus standard of care (SOC) (ie, prostate-specific antigen [PSA] level, age, race, and family history) vs SOC alone for discriminating between Gleason score (GS)7 and GS6 and benign disease on initial biopsy. In training, using reverse-transcriptase polymerase chain reaction (PCR), we compared the urine exosome gene expression assay with biopsy outcomes in 499 patients with prostate-specific antigen (PSA) levels of 2 to 20 ng/mL. The derived prognostic score was then validated in 1064 patients from 22 community practice and academic urology clinic sites in the United States. Eligible participants included PCA-free men, 50 years or older, scheduled for an initial or repeated prostate needle biopsy due to suspicious digital rectal examination (DRE) findings and/or PSA levels (limit range, 2.0-20.0 ng/mL). Evaluate the assay using the area under receiver operating characteristic curve (AUC) in discrimination of GS7 or greater from GS6 and benign disease on initial biopsy. In 255 men in the training target population (median age 62 years and median PSA level 5.0 ng/mL, and initial biopsy), the urine exosome gene expression assay plus SOC was associated with improved discrimination between GS7 or greater and GS6 and benign disease: AUC 0.77 (95% CI, 0.71-0.83) vs SOC AUC 0.66 (95% CI, 0.58-0.72) (P < .001). Independent validation in 519 patients' urine exosome gene expression assay plus SOC AUC 0.73 (95% CI, 0.68-0.77) was superior to SOC AUC 0.63 (95% CI, 0.58-0.68) (P < .001). Using a predefined cut point, 138 of 519 (27%) biopsies would have been avoided, missing only 5% of patients with dominant pattern 4 high-risk GS7 disease. This urine exosome gene expression assay is a noninvasive, urinary 3-gene expression assay that discriminates high-grade (≥GS7) from low-grade (GS6) cancer and benign disease. In this study, the urine exosome gene expression assay was associated with improved identification of patients with higher-grade prostate cancer among men with elevated PSA levels and could reduce the total number of unnecessary biopsies.