Rianne J. Hendriks

Detection of High-grade Prostate Cancer Using a Urinary Molecular Biomarker-Based Risk Score.

BACKGROUND To reduce overdiagnosis and overtreatment, a test is urgently needed to detect clinically significant prostate cancer (PCa). OBJECTIVE To develop a multimodal model, incorporating previously identified messenger RNA (mRNA) biomarkers and traditional risk factors that could be used to identify patients with high-grade PCa (Gleason score ≥7) on prostate biopsy. DESIGN, SETTING, AND PARTICIPANTS In two prospective multicenter studies, urine was collected for mRNA profiling after digital rectal examination (DRE) and prior to prostate biopsy. The multimodal risk score was developed on a first cohort (n=519) and subsequently validated clinically in an independent cohort (n=386). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The mRNA levels were measured using reverse transcription quantitative polymerase chain reaction. Logistic regression was used to model patient risk and combine risk factors. Models were compared using the area under the curve (AUC) of the receiver operating characteristic, and clinical utility was evaluated with a decision curve analysis (DCA). RESULTS AND LIMITATIONS HOXC6 and DLX1 mRNA levels were shown to be good predictors for the detection of high-grade PCa. The multimodal approach reached an overall AUC of 0.90 (95% confidence interval [CI], 0.85-0.95) in the validation cohort (AUC 0.86 in the training cohort), with the mRNA signature, prostate-specific antigen (PSA) density, and previous cancer-negative prostate biopsies as the strongest, most significant components, in addition to nonsignificant model contributions of PSA, age, and family history. For another model, which included DRE as an additional risk factor, an AUC of 0.86 (95% CI, 0.80-0.92) was obtained (AUC 0.90 in the training cohort). Both models were successfully validated, with no significant change in AUC in the validation cohort, and DCA indicated a strong net benefit and the best reduction in unnecessary biopsies compared with other clinical decision-making tools, such as the Prostate Cancer Prevention Trial risk calculator and the PCA3 assay. CONCLUSIONS The risk score based on the mRNA liquid biopsy assay combined with traditional clinical risk factors identified men at risk of harboring high-grade PCa and resulted in a better patient risk stratification compared with current methods in clinical practice. Therefore, the risk score could reduce the number of unnecessary prostate biopsies. PATIENT SUMMARY This study evaluated a novel urine-based assay that could be used as a noninvasive diagnostic aid for high-grade prostate cancer (PCa). When results of this assay are combined with traditional clinical risk factors, risk stratification for high-grade PCa and biopsy decision making are improved.

Comparative analysis of prostate cancer specific biomarkers PCA3 and ERG in whole urine, urinary sediments and exosomes.

Abstract Background: PCA3 and ERG are mRNA-based prostate cancer (PCa) specific biomarkers that can be detected in urine. However, urine is a complex substrate that can be separated in several fractions. In this study we compared the levels of PCa-specific biomarkers (PCA3 and ERG) and KLK3 as prostate-specific reference gene in three urine substrates–whole urine, urinary sediment (cell pellet) and exosomes–and evaluated the influence of performing a digital rectal examination (DRE) prior to urine sampling. Methods: First-voided urine samples were prospectively obtained before and after DRE from 29 men undergoing prostate biopsies. The urine was separated in whole urine, cell pellet and exosomes and the biomarker levels were measured with RT-qPCR. Results: PCa was identified in 52% (15/29) of men. In several samples the mRNA levels were below the analytical limit of detection (BDL). The biomarker levels were highest in whole urine and significantly higher after DRE in all substrates. In PCa patients higher levels of PCA3 and ERG were found in all urine substrates after DRE compared to non-PCa patients. Conclusions: This is the first study in which urinary PCa-specific biomarker levels were compared directly in three separate urine fractions. These results suggest that whole urine could be the urine substrate of choice for PCa-diagnostics based on analytical sensitivity, which is reflected directly in the high informative rate. Moreover, the significant positive effect of performing a DRE prior to urine sampling is confirmed. These findings could be of influence in the development of PCa-diagnostic urine tests.

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

BACKGROUND: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.METHODS: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.RESULTS: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.CONCLUSIONS:Future research should focus on independent validation of promising fluid-based biomarkers/models, and prospective comparison of biomarkers with each other.

Pharmacokinetic Aspects of the Two Novel Oral Drugs Used for Metastatic Castration-Resistant Prostate Cancer: Abiraterone Acetate and Enzalutamide

Two novel oral drugs that target androgen signaling have recently become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate inhibits the synthesis of the natural ligands of the androgen receptor, whereas enzalutamide directly inhibits the androgen receptor by several mechanisms. Abiraterone acetate and enzalutamide appear to be equally effective for patients with mCRPC pre- and postchemotherapy. Rational decision making for either one of these drugs is therefore potentially driven by individual patient characteristics. In this review, an overview of the pharmacokinetic characteristics is given for both drugs and potential and proven drug–drug interactions are presented. Additionally, the effect of patient-related factors on drug disposition are summarized and the limited data on the exposure–response relationships are described. The most important pharmacological feature of enzalutamide that needs to be recognized is its capacity to induce several key enzymes in drug metabolism. The potency to cause drug–drug interactions needs to be addressed in patients who are treated with multiple drugs simultaneously. Abiraterone has a much smaller drug–drug interaction potential; however, it is poorly absorbed, which is affected by food intake, and a large interpatient variability in drug exposure is observed. Dose reductions of abiraterone or, alternatively, the selection of enzalutamide, should be considered in patients with hepatic dysfunction. Understanding the pharmacological characteristics and challenges of both drugs could facilitate decision making for either one of the drugs.

Cost‐effectiveness of a new urinary biomarker‐based risk score compared to standard of care in prostate cancer diagnostics – a decision analytical model

To assess the cost‐effectiveness of a new urinary biomarker‐based risk score (SelectMDx; MDxHealth, Inc., Irvine, CA, USA) to identify patients for transrectal ultrasonography (TRUS)‐guided biopsy and to compare this with the current standard of care (SOC), using only prostate‐specific antigen (PSA) to select for TRUS‐guided biopsy.

A urinary biomarker-based risk score correlates with multiparametric MRI for prostate cancer detection

Prostate cancer (PCa) diagnostics would greatly benefit from more accurate, non‐invasive techniques for the detection of clinically significant disease, leading to a reduction of over‐diagnosis and over‐treatment. The aim of this study was to determine the association between a novel urinary biomarker‐based risk score (SelectMDx), multiparametric MRI (mpMRI) outcomes, and biopsy results for PCa detection.

Epigenetic markers in circulating cell-free DNA as prognostic markers for survival of castration-resistant prostate cancer patients

: Noninvasive biomarkers to guide personalized treatment for castration‐resistant prostate cancer (CRPC) are needed. In this study, we analyzed hypermethylation patterns of two genes (GSTP1 and APC) in plasma cell‐free DNA (cfDNA) of CRPC patients. The aim of this study was to analyze the cfDNA concentrations and levels of the epigenetic markers and to assess the value of these biomarkers for prognosis.

MP33-17 POTENTIAL ROLE OF A NOVEL URINARY BIOMARKER-BASED RISK SCORE TO SELECT PATIENTS FOR MULTIPARAMETRIC MRI FOR PROSTATE CANCER DETECTION.

INTRODUCTION AND OBJECTIVES: Prostate cancer (PCa) diagnostics would greatly benefit from more accurate, non-invasive techniques for the detection of clinically significant disease, leading to a reduction of over-diagnosis and over-treatment. Multiparametric MRI (mpMRI) is being used increasingly and has proven to be a valuable addition to the PCa diagnostic pathway. A novel biomarker-based risk score (SelectMDx) assessing urinary HOXC6 and DLX1 mRNA expression levels combined with traditional clinical risk factors, was recently developed to predict high-grade PCa (Gleason score >/1⁄47) upon prostate biopsy and to reduce the number of unnecessary biopsies. The aim of this study was to investigate the correlation between the risk score and mpMRI outcomes. METHODS: The patients in this retrospective observational cohort were previously included in the validation study of the SelectMDx risk score, in which urine was collected after digital rectal examination (DRE) from men undergoing prostate biopsies based on an elevated serum PSA level (>/1⁄43.0 ng/ml) and/or suspicious DRE. A subset of patients underwent an mpMRI after prostate biopsies were performed (n1⁄4174). The indications for performing MRI were based on persistent clinical suspicion of PCa after negative prostate biopsies or staging after PCa was found upon biopsy. RESULTS: 102 of 174 patients (59%) had PCa detected upon prostate biopsy, of which 54 (53%) had high-grade disease and a significantly higher SelectMDx risk score (p<0.001). The median SelectMDx risk score was also significantly higher in patients who had a suspicious lesion on MRI (p<0.001). For 81 mpMRI’s the PIRADS classification was reported and there was a positive correlation observed between the risk score and the PIRADS classification (Figure 1). A Kruskal-Wallis test indicated a statistically significant difference in SelectMDx risk scores between the different PIRADS groups (p<0.001). CONCLUSIONS: The novel urinary biomarker-based risk score is a promising tool in PCa detection. This study showed promising results regarding the correlation between the SelectMDx risk score with MRI outcomes. This risk score could potentially guide clinicians in selecting patients at risk for significant PCa for mpMRI.

18 Een directe vergelijking van prostaatkankerbiomarkers in drie urinefracties: onbewerkte urine, sediment en exosomen

SamenvattingHet prostaatspecifiek antigeen (PSA) wordt gebruikt als tumormarker voor prostaatkanker, maar heeft als belangrijk nadeel dat het niet specifiek is. PCA3 en TMPRSS2-ERG zijn prostaatkankerspecifieke biomarkers die gedetecteerd kunnen worden in urine. Urine is een complex substraat en bestaat uit meerdere fracties.