Prostate Cancer Risk Stratification Research Articles

68Ga-PSMA-617 PET/CT: a promising new technique for predicting risk stratification and metastatic risk of prostate cancer patients.

The purpose of this study was to investigate the performance of 68Ga-PSMA-617 PET/CT in predicting risk stratification and metastatic risk of prostate cancer. Fifty newly diagnosed patients with prostate cancer as confirmed by needle biopsy were continuously included, 40 in a train set and ten in a test set. 68Ga-PSMA-617 PET/CT and clinical data of all patients were retrospectively analyzed. Semi-quantitative analysis of PET images provided maximum standardized uptake (SUVmax) of primary prostate cancer and volumetric parameters including intraprostatic PSMA-derived tumor volume (iPSMA-TV) and intraprostatic total lesion PSMA (iTL-PSMA). According to prostate cancer risk stratification criteria of the NCCN Guideline, all patients were simplified into a low-intermediate risk group or a high-risk group. The semi-quantitative parameters of 68Ga-PSMA-617 PET/CT were used to establish a univariate logistic regression model for high-risk prostate cancer and its metastatic risk, and to evaluate the diagnostic efficacy of the predictive model. In the train set, 30/40 (75%) patients had high-risk prostate cancer and 10/40 (25%) patients had low-to-moderate-risk prostate cancer; in the test set, 8/10 (80%) patients had high-risk prostate cancer while 2/10 (20%) had low-intermediate risk prostate cancer. The univariate logistic regression model established with SUVmax, iPSMA-TV and iTL-PSMA could all effectively predict high-risk prostate cancer; the AUC of ROC were 0.843, 0.802 and 0.900, respectively. Based on the test set, the sensitivity and specificity of each model were 87.5% and 50% for SUVmax, 62.5% and 100% for iPSMA-TV, and 87.5% and 100% for iTL-PSMA, respectively. The iPSMA-TV and iTL-PSMA-based predictive model could predict the metastatic risk of prostate cancer, the AUC of ROC was 0.863 and 0.848, respectively, but the SUVmax-based prediction model could not predict metastatic risk. Semi-quantitative analysis indexes of 68Ga-PSMA-617 PET/CT imaging can be used as "imaging biomarkers" to predict risk stratification and metastatic risk of prostate cancer.

Difference in prostate cancer incidence around sixty years: effects of age and metabolic diseases.

We examined the risk of prostate cancer in the Korean population stratified on the basis of age group and risk based on metabolic diseases, using National Health Insurance System (NHIS) data. Of the 51,827,813 people from the NHIS data in 2015, 10,879,591 men without prostate cancer who underwent a health examination were analyzed. The risk of prostate cancer was analyzed with stratification by age. Multivariate‐adjusted Cox regression analysis was conducted to examine the association between prostate cancer and metabolic diseases by age groups. The risk of prostate cancer increased continuously with age and 59 years may be a point of inflection. The hazard ratio (HR) of prostate cancer development rose sharply as that age point passed. The population with metabolic diseases was more likely to develop prostate cancer than the population without any of these components. In addition, the incidence rate ratio (IRR) decreased from the youngest age group to the age group comprising 55–59 year olds. Beyond this age group, there was a plateau. The relative risk for prostate cancer associated with metabolic diseases also showed divergent associations with age. The risk of prostate cancer increased continuously with age and the peak Youden index was at 59 years. The relative risk for prostate cancer according to metabolic diseases also showed divergent associations beyond 59 years of age. Therefore, setting the age threshold at 59 years would improve the present clinical risk stratification for prostate cancer in Korea.

The prostate cancer focal therapy.

Despite prostate cancer (PCa) is the leading form of non-cutaneous cancer in men, most patients with PCa die with disease rather than of the disease. Therefore, the risk of overtreatment should be considered by clinicians who have to distinguish between patients with high risk PCa (who would benefit from radical treatment) and patients who may be managed more conservatively, such as through active surveillance or emerging focal therapy (FT). The aim of FT is to eradicate clinically significant disease while protecting key genito-urinary structures and function from injury. While effectiveness studies comparing FT with conventional care options are still lacking, the rationale supporting FT relies on evidence-based advances such as the understanding of the index lesion's central role in the natural history of the PCa and the improvement of multiparametric magnetic resonance imaging (mpMRI) in the detection and risk stratification of PCa. In this literature review, we want to highlight the rationale for FT in PCa management and the current evidence on patient eligibility. Furthermore, we summarize the best imaging modalities to localize the target lesion, describe the current FT techniques in PCa, provide an update on their oncological outcomes and highlight trends for future research.

MP53-01 CONTEMPORARY NATIONAL TRENDS IN LOCALIZED PROSTATE CANCER RISK PROFILE AT DIAGNOSIS

You have accessJournal of UrologyProstate Cancer: Staging I1 Apr 2018MP53-01 CONTEMPORARY NATIONAL TRENDS IN LOCALIZED PROSTATE CANCER RISK PROFILE AT DIAGNOSIS Sean A. Fletcher, Nicolas von Landenberg, Alexander P. Cole, Sebastian Berg, Philipp Gild, Joachim Noldus, Mani Menon, Quoc-Dien Trinh, and Adam S. Kibel Sean A. FletcherSean A. Fletcher More articles by this author , Nicolas von LandenbergNicolas von Landenberg More articles by this author , Alexander P. ColeAlexander P. Cole More articles by this author , Sebastian BergSebastian Berg More articles by this author , Philipp GildPhilipp Gild More articles by this author , Joachim NoldusJoachim Noldus More articles by this author , Mani MenonMani Menon More articles by this author , Quoc-Dien TrinhQuoc-Dien Trinh More articles by this author , and Adam S. KibelAdam S. Kibel More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1672AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In the years following the introduction of PSA screening in the early 1990s, there was a documented "stage migration" toward lower risk prostate cancer (PCa) at initial diagnosis that persisted through the 2000s. National policy guidelines such as the US Preventative Services Task Force's (USPSTF) recommendation against PSA screening for men over 75 in 2008, and for all men in 2012, has led to a decline in both screening for and incidence of PCa. The extent to which these policy changes may have impacted contemporary trends in PCa risk stratification at diagnosis is not well known. METHODS We used the National Cancer Database to identify men diagnosed with localized PCa (cT1-4N0M0) from 2010 through 2014. The Cancer of the Prostate Risk Assessment (CAPRA) score was used to define PCa risk stratification into low, intermediate, and high-risk categories. This risk score incorporates age and PSA at diagnosis, Gleason score of biopsy, clinical T-stage, and percent of biopsy cores positive for cancer; we excluded individuals missing any of this information. We measured the estimated annual percent change (EAPC) in PCa risk profile for each risk category. RESULTS A total of 265,150 patients were included in the final cohort. From 2010 to 2014 the proportion of patients presenting with low-risk PCa decreased from 43.7% to 33.9%; EAPC: -6.29 (95% CI: -3.95, -8.57), p=0.004. Conversely, the proportion of high-risk PCa diagnoses increased from 16.5% to 22.0%; EAPC: 8.02 (5.09, 11.03), p=0.003. The proportion of intermediate-risk PCa diagnoses also increased, from 39.8% to 44.1%; EAPC: 2.49 (1.99, 3.90), p=0.002. CONCLUSIONS From 2010 to 2014, the proportion of men presenting with low-risk PCa decreased significantly, and there was a concomitant increase in the proportion of men presenting with intermediate and high-risk PCa. Nationwide changes in PSA screening practices may be contributing to these findings. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e704 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Sean A. Fletcher More articles by this author Nicolas von Landenberg More articles by this author Alexander P. Cole More articles by this author Sebastian Berg More articles by this author Philipp Gild More articles by this author Joachim Noldus More articles by this author Mani Menon More articles by this author Quoc-Dien Trinh More articles by this author Adam S. Kibel More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD42-10 PROGNOSTIC VALUE OF CELL CYCLE PROGRESSION SCORE IN PROSTATE CANCER PATIENTS WITH LOCALLY ADVERSE PATHOLOGY AFTER RADICAL PROSTATECTOMY: IMPLICATIONS FOR TREATMENT GUIDANCE

You have accessJournal of UrologyProstate Cancer: Localized: Surgical Therapy VI1 Apr 2018PD42-10 PROGNOSTIC VALUE OF CELL CYCLE PROGRESSION SCORE IN PROSTATE CANCER PATIENTS WITH LOCALLY ADVERSE PATHOLOGY AFTER RADICAL PROSTATECTOMY: IMPLICATIONS FOR TREATMENT GUIDANCE Xun Shangguan, Wei Xue, Baijun Dong, Jiahua Pan, Hongyang Qian, and Fan Xu Xun ShangguanXun Shangguan More articles by this author , Wei XueWei Xue More articles by this author , Baijun DongBaijun Dong More articles by this author , Jiahua PanJiahua Pan More articles by this author , Hongyang QianHongyang Qian More articles by this author , and Fan XuFan Xu More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1963AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate cancer (PCa) patients with locally adverse pathologic features (including extracapsular extension (ECE), seminal vesicle invasion (SVI), or positive surgical margins (PSM)) are considered as poor prognostic factors. Evidences form randomized trials (SWOG-8794, EORTC 22911, and ARO 96-02) suggests that adjuvant radiotherapy is appropriate for patients with high-risk features because it can significantly improve disease-free survival. However, the outcomes of surgically treated patients with locally adverse pathologic features are not invariably poor, with not every patient will suffer eventual cancer recurrence and the policy of adjuvant radiotherapy could lead to the potential for overtreatment. Therefore, correct identification of patients who most likely to benefit from adjuvant therapy is of paramount importance. Tissue-based genomic tests, such as the cell cycle progression (CCP) score, can help decrease prognostic uncertainty and improve risk stratification of PCa. The aim of this study was to determine the prognostic utility of the CCP score in men with locally adverse pathology undergoing radical prostatectomy. METHODS Data on 100patients with locally adverse pathologic features (including ECE, SVI, or PSM) who had been treated with wait and see policy after RP were retrospectively analyzed for biochemical recurrence (BCR)-free survival. CCP score were retrospectively derived from prostatectomy specimens. Kaplan–Meier survival analysis and Cox proportional hazard regression models were used to test the association between the CCP score and BCR. RESULTS Among the 100 men identified, 47(46.5%) had BCR. Five-year BCR-free survival for the vary low (<-1), low (<0), intermediate (0–1), high (>1) and vary high (>2) CCP score groups was 100%, 82.9%, 38.8%, 28.7%, 0% respectively (p<0.001). In multivariable models adjusting for clinical and pathological variables with the Cancer of the Prostate Risk Assessment (CAPRA) score, the CCP score was an independent predictor of BCR (HR:1.67; P = 0.001). In addition, CCP score had higher predictive accuracy for BPFS (increment in Harrell concordance index by 0.026–0.036), compared with the CAPRA score. CONCLUSIONS For the appropriate patient, depending on age, physical condition, patient desire, etc., could be a candidate for wait and see policy with low specimen CCP score, so to distinguish this from high CCP score may facilitate discussions at the point of treatment decision making. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e818 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Xun Shangguan More articles by this author Wei Xue More articles by this author Baijun Dong More articles by this author Jiahua Pan More articles by this author Hongyang Qian More articles by this author Fan Xu More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

A 17-Gene Genomic Prostate Score Assay Provides Independent Information on Adverse Pathology in the Setting of Combined Multiparametric Magnetic Resonance Imaging Fusion Targeted and Systematic Prostate Biopsy

Multiparametric magnetic resonance imaging and biopsy based molecular tests such as the 17-gene Oncotype DX® Genomic Prostate Score™ assay are increasingly performed to improve risk stratification in men with clinically localized prostate cancer. The prostate score assay was previously shown to be a significant independent predictor of adverse pathology findings at radical prostatectomy in men diagnosed by systematic biopsies only. Therefore, we investigated the ability of the prostate score assay to predict adverse pathology findings in the setting of magnetic resonance imaging guided prostate biopsy. We identified men diagnosed with NCCN® (National Comprehensive Cancer Network®) very low, low or intermediate risk prostate cancer who underwent simultaneous multiparametric magnetic resonance imaging fusion targeted and systematic prostate biopsy with subsequent radical prostatectomy within 6 months. Prostate score assay testing was performed on biopsy tissue with the highest Gleason score. The primary outcome of the study was adverse pathology findings, defined as Gleason score 4 + 3 or greater disease and/or pT3+ at radical prostatectomy. Independent predictors of adverse pathology findings were determined in a multivariable model to adjust for clinical parameters. A total of 134 men were eligible for primary analysis. On univariable analysis the UCLA score, magnetic resonance imaging, prostate score assay results and biopsy Gleason score were significant predictors of adverse pathology findings. After multivariable adjustment prostate score assay values remained a significant predictor of adverse pathology results (prostate score assay per 20 U OR 3.28, 95% CI 1.74-6.62, p <0.001). A wide and overlapping distribution of prostate score assay results was seen across PI-RADS® (Prostate Imaging Reporting and Data System) version 2 scores. The prostate score assay result is an independent predictor of adverse pathology findings in patients who were diagnosed with very low, low or intermediate risk prostate cancer in the setting of multiparametric magnetic resonance imaging fusion prostate biopsy. This assay can be useful as an independent technology or an adjunct technology to multiparametric magnetic resonance imaging to individualize risk stratification of low and intermediate risk prostate cancer.

Improving risk-stratification of localized prostate cancer in a prospective active surveillance cohort.

104 Background: Prospective active surveillance (AS) studies in men with low- and intermediate-risk prostate cancer (PCa) have demonstrated feasibility, but no consensus supports an optimal monitoring scheme. To expand our findings on AS disease reclassification, we examined predictors of disease reclassification in a prospective single-institution AS study. Methods: Men with localized PCa diagnosed within 6 months (mos) of AS enrollment were stratified into four groups: group 1 (Gr 1) was defined by a Gleason score (GS) ≤6 (3+3), one positive (pos) core ( &lt; 3 mm), and a prostate-specific antigen (PSA) level &lt; 4 ng/mL (adjusted by prostate size); Gr IIa by GS 6, one pos core, and either tumor length ≥3 mm or PSA ≥4 ng/mL; Gr IIb by GS6, &gt; one pos core, and any PSA level or tumor length; Gr IIc by GS7, &gt; one pos core or any PSA. Monitoring included PSA and digital rectal exam every 6 mo. Biopsy (BX) was repeated at 1 year and then on a predetermined BX scheme. Patients with reclassified disease (upgrading, increase in pos cores and/or tumor length) were offered treatment. Cox proportional hazards modeling was used to determine the association of baseline clinicopathologic parameters with time to reclassification. Results: Between 2006 and 2015, 803 patients met criteria for inclusion: Gr I, 242; Gr IIa, 67; Gr IIb, 376; Gr IIc, 118. Median age was 64 years (range, 36–83), 662 (82.4%) were white, 703 (87.5%) had cT1c disease, 687 (85.6%) had GS 6, and median PSA level was 4.2 ng/mL (range 0.2–34). At a median follow-up of 2.9 years, 249 (31.0%) men had disease reclassification and 258 (32.1%) left AS to pursue curative treatment. Overall, 82% of reclassifications occurred within 3 years of study enrollment. Stratification to group IIb/IIc was significantly associated with time to reclassification compared to Gr I/IIa (HR 2.13, 95 CI 1.63-2.80, p &lt; 0.001) while CAPRA score did not show a significant difference (p = 0.27). Conclusions: Grouping patients on characteristics including tumor length and pos core number may improve risk stratification in localized PCa. Risk-based surveillance protocols merit further evaluation. Clinical trial information: NCT00490763.

Patched 1 Expression Correlates with Biochemical Relapse in High-Risk Prostate Cancer Patients

There is an unmet clinical need for adequate biomarkers to aid risk stratification and management of prostate cancer (PCa) patients. Even within the high-risk PCa category, not all patients will invariably have a poor prognosis, and improved stratification of this heterogeneous group is needed. In this context, components of the hedgehog (Hh) pathway may have promise as biomarkers, because the available evidence suggests increased Hh pathway activity may confer a poorer outcome in advanced and castrate-resistant PCa. In this study, potential associations between Hh pathway protein expression and clinicopathological factors, including time to biochemical recurrence (BCR), were investigated using a tissue microarray constructed from benign and malignant prostate samples from 75 predominantly high-risk PCa patients who underwent radical prostatectomy. Hh signaling activity was found to differ between benign and malignant prostate tissue, with a greater amount of active Hh signaling present in malignant than benign prostate epithelium. High expression of Patched 1 in malignant prostate epithelium was found to be an independent predictor of BCR in high-risk PCa patients. Glioma-associated oncogene 1 may potentially represent a clinically useful biomarker of an aggressive tumor phenotype. Evaluation of Hh signaling activity in PCa patients may be useful for risk stratification, and epithelial Patched 1 expression, in particular, may be a prognostic marker for BCR in high-risk PCa patients.

High BCAR1 expression is associated with early PSA recurrence in ERG negative prostate cancer

BackgroundBreast cancer anti-estrogen resistance 1 (BCAR1/p130cas) is a hub for diverse oncogenic signaling cascades and promotes tumor development and progression.MethodsTo understand the effect of BCAR1 in prostate cancer, we analyzed its expression on more than 11,000 prostate cancer samples. BCAR1 expression levels were compared with clinical characteristics, PSA recurrence, molecular subtype defined by ERG status and 3p, 5q, 6q and PTEN deletion.ResultsBCAR1 staining was barely detectable in normal prostate glands but seen in 77.6% of 9472 interpretable cancers, including strong expression in 38.5%, moderate in 23.2% and weak in 15.9% of cases. BCAR1 up regulation was associated with positive ERG status (p < 0.0001), high Gleason score (p < 0.0001), advanced pathological tumor stage (p = 0.0082), lower preoperative PSA level (p < 0.0001), increased cell proliferation (p < 0.0001), early PSA recurrence (p = 0.0008), and predicted prognosis independently from clinico-pathological parameters available at the time of the initial biopsy. However, subset analyses revealed that the prognostic impact of BCAR1 expression was limited to ERG-negative cancer. That BCAR1 up regulation was linked to almost all analyzed deletions (p < 0.0001 each for PTEN, 5q, 6q deletion) may suggest a functional link to genomic instability.ConclusionThe results of our study identify BCAR1 as a prognostic biomarker with potential clinical value for risk stratification of ERG-negative prostate cancer.

Promoter hypermethylation of SOX11 correlates with adverse clinicopathological features of human prostate cancer.

Currently available tools for early diagnosis and prognosis of prostate cancer lack sufficient accuracy. There is a need to identify novel biomarkers for this common malignancy. SOX family genes play an important role in embryogenesis and are also implicated in various cancers. SOX11 has been recently recognized as a potential tumour suppressor that is downregulated in prostate cancer. We hypothesized that hypermethylation may be responsible for SOX11 silencing in human prostate cancer. The aim of the study was to investigate SOX11 promoter methylation in prostate adenocarcinoma by comparing it with benign prostatic hyperplasia (BPH). A total of 143 human prostate tissue samples, 62 from patients with prostate cancer and 81 from patients with BPH were examined by methylation-specific PCR. Associations between SOX11 promoter methylation and clinicopathological parameters were assessed by univariate statistics. Detection rates of SOX11 promoter methylation were 80.6% and 35.8% in prostate cancer and BPH respectively (P<0.001). SOX11 hypermethylation was associated with adverse clinicopathological characteristics of prostate cancer, including higher PSA level (P<0.01), Gleason score ≥ 7 (P=0.03) and perineural invasion (P=0.03). SOX11 methylation was positively correlated with the PSA level (P=0.001). Our data indicated that SOX11 can be a promising methylation marker candidate for differential diagnosis and risk stratification for prostate cancer.

Nuclear magnetic resonance spectroscopy as a new approach for improvement of early diagnosis and risk stratification of prostate cancer.

Prostate cancer (PCa) is the second most common male cancer worldwide and the fifth leading cause of death from cancer in men. Early detection and risk stratification is the most effective way to improve the survival of PCa patients. Current PCa biomarkers lack sufficient sensitivity and specificity to cancer. Metabolite biomarkers are evolving as a new diagnostic tool. This review is aimed to evaluate the potential of metabolite biomarkers for early detection, risk assessment, and monitoring of PCa. Of the 154 identified publications, 27 and 38 were original papers on urine and serum metabolomics, respectively. Nuclear magnetic resonance (NMR) is a promising method for measuring concentrations of metabolites in complex samples with good reproducibility, high sensitivity, and simple sample processing. Especially urine-based NMR metabolomics has the potential to be a cost-efficient method for the early detection of PCa, risk stratification, and monitoring treatment efficacy.

Optimising preoperative risk stratification tools for prostate cancer using mpMRI

PurposeTo improve preoperative risk stratification for prostate cancer (PCa) by incorporating multiparametric MRI (mpMRI) features into risk stratification tools for PCa, CAPRA and D’Amico.Methods807 consecutive patients operated on by robot-assisted radical prostatectomy at our institution during the period 2010–2015 were followed to identify biochemical recurrence (BCR). 591 patients were eligible for final analysis. We employed stepwise backward likelihood methodology and penalised Cox cross-validation to identify the most significant predictors of BCR including mpMRI features. mpMRI features were then integrated into image-adjusted (IA) risk prediction models and the two risk prediction tools were then evaluated both with and without image adjustment using receiver operating characteristics, survival and decision curve analyses.Results37 patients suffered BCR. Apparent diffusion coefficient (ADC) and radiological extraprostatic extension (rEPE) from mpMRI were both significant predictors of BCR. Both IA prediction models reallocated more than 20% of intermediate-risk patients to the low-risk group, reducing their estimated cumulative BCR risk from approximately 5% to 1.1%. Both IA models showed improved prognostic performance with a better separation of the survival curves.ConclusionIntegrating ADC and rEPE from mpMRI of the prostate into risk stratification tools improves preoperative risk estimation for BCR.Key points• MRI-derived features, ADC and EPE, improve risk stratification of biochemical recurrence.• Using mpMRI to stratify prostate cancer patients improves the differentiation between risk groups.• Using preoperative mpMRI will help urologists in selecting the most appropriate treatment.

Risk Stratification of Equivocal Lesions on Multiparametric Magnetic Resonance Imaging of the Prostate

We systematically analyzed the records of patients with PI-RADS™ (Prostate Imaging Reporting and Data System) 3 lesions, which are called equivocal according to PI-RADS version 2, using prostate multiparametric magnetic resonance imaging and magnetic resonance imaging targeted biopsies. Systematic transrectal ultrasound guided biopsies served as the reference standard. A total of 120 consecutive patients were retrospectively included in the study. In these patients the overall PI-RADS score was 3 after 3 Tesla T2-weighted imaging, diffusion weighted imaging and dynamic contrast enhanced multiparametric magnetic resonance imaging as well as subsequent targeted magnetic resonance imaging/ultrasound fusion guided biopsies plus systematic 12-core transrectal ultrasound guided biopsies. The study end points were the prostate cancer detection rate, the Gleason score distribution, the prostate cancer location and risk stratification by subgroup analyses. Prostate cancer was detected in 13 of 118 patients for a detection rate of 11%, including 5 patients (4.2%) with a Gleason score of 3 + 4 = 7 or greater. Three of the 212 lesions (1.4%) in the transition zone and 6 of the 64 (9.4%) in the peripheral zone were positive for prostate cancer. Multiparametric magnetic resonance imaging revealed patterns of peripheral prostatitis combined with diffuse stromal hyperplasia in 54% of the patients with prostate cancer. Prostate volume was significantly lower in patients with prostate cancer (p = 0.015) but differences in prostate specific antigen levels were not statistically significant (p= 0.87). Prostate specific antigen density was higher in patients with prostate cancer (0.19 vs 0.12 ng/ml/ml). Low grade prostate cancer (Gleason score 3 + 3 = 6) can develop in patients with an overall PI-RADS score of 3. Prostate cancer with a Gleason score of 3 + 4 = 7 or greater can be detected by multiparametric magnetic resonance imaging with a high degree of certainty. Gleason score 4 + 3 = 7 or greater prostate cancer is unlikely in PI-RADS 3 lesions. Therefore, these patients should primarily undergo followup multiparametric magnetic resonance imaging. In patients with a combination of multiparametric magnetic resonance imaging aspects of extensive prostatitis and diffuse stromal hyperplasia low prostate volume and/or high prostate specific antigen density biopsy might be considered.

The EEF1A2 gene expression as risk predictor in localized prostate cancer

BackgroundBesides clinical stage and Gleason score, risk-stratification of prostate cancer in the pretherapeutic setting mainly relies on the serum PSA level. Yet, this is associated with many uncertainties. With regard to therapy decision-making, additional markers are needed to allow an exact risk prediction. Eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) was previously suggested as driver of tumor progression and potential biomarker. In the present study its functional and prognostic relevance in prostate cancer was investigated.MethodsEEF1A2 expression was analyzed in two cohorts of patients (n = 40 and n = 59) with localized PCa. Additionally data from two large expression dataset (MSKCC, Cell, 2010 with n = 131 localized, n = 19 metastatic PCa and TCGA provisional data, n = 499) of PCa patients were reanalyzed. The expression of EEF1A2 was correlated with histopathology features and biochemical recurrence (BCR). To evaluate the influence of EEF1A2 on proliferation and migration of metastatic PC3 cells, siRNA interference was used. Statistical significance was tested with t-test, Mann-Whitney-test, Pearson correlation and log-rank test.ResultsqRT-PCR revealed EEF1A2 to be significantly overexpressed in PCa tissue, with an increase according to tumor stage in one cohort (p = 0.0443). In silico analyses in the MSKCC cohort confirmed the overexpression of EEF1A2 in localized PCa with high Gleason score (p = 0.0142) and in metastatic lesions (p = 0.0038). Patients with EEF1A2 overexpression had a significantly shorter BCR-free survival (p = 0.0028). EEF1A2 expression was not correlated with serum PSA levels. Similar results were seen in the TCGA cohort, where EEF1A2 overexpression only occurred in tumors with Gleason 7 or higher. Patients with elevated EEF1A2 expression had a significantly shorter BCR-free survival (p = 0.043). EEF1A2 knockdown significantly impaired the migration, but not the proliferation of metastatic PC3 cells.ConclusionThe overexpression of EEF1A2 is a frequent event in localized PCa and is associated with histopathology features and a shorter biochemical recurrence-free survival. Due to its independence from serum PSA levels, EEF1A2 could serve as valuable biomarker in risk-stratification of localized PCa.

Perineural invasion by prostate cancer on MR/US fusion targeted biopsy is associated with extraprostatic extension and early biochemical recurrence after radical prostatectomy

In recent years, multiparametric magnetic resonance imaging and magnetic resonance/ultrasound fusion targeted biopsy (TB) have become more widely adopted to aid in prostate cancer (PCa) detection. Previously, TB has been found to increase the yield of clinically significant PCa and is more likely to sample the index tumor compared with traditional 12-core extended sextant biopsies. Currently, the prognostic significance of perineural invasion (PNI) when identified on TB (PNI-TB) is unknown. We identified 95 men at 2 tertiary referral centers who underwent TB followed by radical prostatectomy between January 2014 and January 2017. Clinical, radiological, and pathological variables were retrospectively reviewed. PNI was identified on TB in 27 of 95 (28.4%) patients. On multivariable logistic regression, independent predictors of extraprostatic extension were prostate-specific antigen, TB maximum % core involvement, and PNI-TB (all P<.05). Furthermore, Kaplan-Meier analysis demonstrated that PNI-TB was associated with early biochemical recurrence events within 12 months after prostatectomy (log-rank P=.049). Given the increasing adoption of TB for PCa detection in clinical practice, PNI-TB may be useful for PCa risk stratification.

Abstract 4448A: MicroRNA profiling of prostate cancer tissue identifies a prognostic 4-miRNA model and implicates one novel microRNA in prostate cancer cell viability

Abstract Purpose: New prognostic biomarkers for prostate cancer (PC) risk stratification are urgently needed. Here, we identify and validate a novel 4-microRNA prognostic ratio model for prostate cancer. We also identify a new microRNA with tumor suppressive characteristics in prostate cancer cell lines. Methods: PC tissue samples from 123 radical prostatectomy (RP) patients, 58 of whom experienced biochemical recurrence, were profiled for genome-wide miRNA expression using RT-qPCR (training cohort). Initially, we identified 11 top candidate prognostic microRNAs (P &amp;lt;0.05, univariate Cox regression). Based on these, all possible 2-4 microRNA ratio models were systematically tested for their potential to predict time to biochemical recurrence (BCR), as assessed by Kaplan-Meier, uni- and multivariate Cox regression analyses. The findings were validated in two independent RP cohorts. A novel microRNA, included in the final ratio model and with previously unknown function in prostate cancer, was over expressed using a microRNA mimic in PC3 and DU145 cells to evaluate its effect on prostate cancer cell viability and proliferation. Results: We identified a new prognostic 4-microRNA ratio model ((miR-23a-3p*miR-10b-5p)/(miR-133a*miR-374b-5p)) that significantly predicted time to BCR independently of established clinicopathological variables in a training RP cohort (n=123). The ratio model was successfully validated in two independent RP cohorts including 112 and 476 patients, respectively. Ectopic expression of one of these microRNAs (miR-374b-5p) significantly inhibited viability and proliferation in two prostate cancer cell lines, suggesting it has a tumor suppressor function in PC. Conclusions: Here, we describe the identification and independent validation of a 4-miRNA ratio model that allows risk stratifications of prostate cancer patients undergoing RP into different prognostic groups. Furthermore, we identify and functionally characterize a novel possible tumor suppressor miRNA in prostate cancer. Citation Format: Linnea Schmidt, Jacob Fredsøe, Helle Kristensen, Anne Rasmussen, Peter Mouritzen, Søren Høyer, Michael Borre, Torben Ørntoft, Karina Dalsgaard Sørensen. MicroRNA profiling of prostate cancer tissue identifies a prognostic 4-miRNA model and implicates one novel microRNA in prostate cancer cell viability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4448A. doi:10.1158/1538-7445.AM2017-4448A

Abstract 4730: Fluorescence in situ hybridization panels for prediction of disease progression in prostate cancer patients on active surveillance

Abstract Background: Overdiagnosis and overtreatment of men with lower-risk Prostate Cancer (PCa) is a concern due to co-morbidities and healthcare costs. Maximizing patient quality of life while recognizing early signs of aggressive disease is essential. There is a need to stratify patients according to the risk of disease progression, identifying with high sensitivity and specificity patients to biopsy, re-biopsy and monitor. Within the high risk population, there is a need to identify when to proceed with treatment. Methods: We performed a retrospective study to evaluate FISH biomarkers on PCa specimens with histologically confirmed, clinically localized disease (T1c-T2c) enrolled in Active Surveillance (AS). AS patients were classified into two categories: Progressive (clinical intervention within 10 years), and non-progressive (did not progress to intervention in 10 years). Cohorts were matched by clinical characteristics (Gleason score, disease stage and grade, PSA level, age, race) as possible. The study objective was to establish a FISH biomarker panel to differentiate non-progressive from progressive prostate cancer in the low and intermediate risk groups. Receiver Operating Characteristics (ROC) curve analysis was performed to obtain the best single parameters based upon Area Under the Curve (AUC). For each FISH parameter cutoffs were determined based on Sensitivity, Specificity and Distance from Ideal (DFI). Further ROC analysis was used to identify the best 3-5 probe combinations. FISH parameters were combined with clinical parameters in the final model. Results: Five combinations of FISH parameters with the highest AUC and sensitivity in discriminating case and control groups were selected based on ROC curve analysis. Combinations were superior in performance to single probes. The best individual parameter, MYC gain, had an AUC of 0.6998. The two best combinations of parameters, MYC Gain/NKX3.1 Gain/NMYC Gain/PTEN Homozygous and MYC Gain/ETV1 Break Apart/NKX3.1 Gain/PTEN Homozygous had AUC of 0.7363 and 0.7236, respectively. In the logistic regression analysis, these combinations contributed significantly to the prediction of PCa outcome (progressive vs non-progressive, odds ratios of 5.522 and 6.118, respectively). The combination of clinical parameters and FISH outperformed clinical parameters or FISH alone, with odds ratios of 5.955 and 6.787 in the final model. Conclusions: Combinations of FISH parameters discriminating cases (progressive) from controls (non-progressive) were selected based on ROC curve analysis. The combination of clinical parameters and FISH outperformed clinical parameters alone, and was complimentary to clinical parameters (NCCN Risk Groups) in the final model, demonstrating potential utility of multi-color FISH panels as an auxiliary tool for PCa risk stratification. Further studies with larger cohorts are planned to confirm these findings. Citation Format: Adam J. Koch, Ying Zhang, Beth Blondin, Svetlana Sitailo, Huixin Fei, Stephen Van Den Eeden, Ekaterina Pestova. Fluorescence in situ hybridization panels for prediction of disease progression in prostate cancer patients on active surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4730. doi:10.1158/1538-7445.AM2017-4730

Automating the Determination of Prostate Cancer Risk Strata From Electronic Medical Records.

Risk stratification underlies system-wide efforts to promote the delivery of appropriate prostate cancer care. Although the elements of risk stratum are available in the electronic medical record, manual data collection is resource intensive. Therefore, we investigated the feasibility and accuracy of an automated data extraction method using natural language processing (NLP) to determine prostate cancer risk stratum. Manually collected clinical stage, biopsy Gleason score, and preoperative prostate-specific antigen (PSA) values from our prospective prostatectomy database were used to categorize patients as low, intermediate, or high risk by D'Amico risk classification. NLP algorithms were developed to automate the extraction of the same data points from the electronic medical record, and risk strata were recalculated. The ability of NLP to identify elements sufficient to calculate risk (recall) was calculated, and the accuracy of NLP was compared with that of manually collected data using the weighted Cohen's κ statistic. Of the 2,352 patients with available data who underwent prostatectomy from 2010 to 2014, NLP identified sufficient elements to calculate risk for 1,833 (recall, 78%). NLP had a 91% raw agreement with manual risk stratification (κ = 0.92; 95% CI, 0.90 to 0.93). The κ statistics for PSA, Gleason score, and clinical stage extraction by NLP were 0.86, 0.91, and 0.89, respectively; 91.9% of extracted PSA values were within ± 1.0 ng/mL of the manually collected PSA levels. NLP can achieve more than 90% accuracy on D'Amico risk stratification of localized prostate cancer, with adequate recall. This figure is comparable to other NLP tasks and illustrates the known trade off between recall and accuracy. Automating the collection of risk characteristics could be used to power real-time decision support tools and scale up quality measurement in cancer care.

The combination of histological prostate atrophy and inflammation is associated with lower risk of prostate cancer in biopsy specimens.

To evaluate whether the presence of both prostate atrophy (PA) and chronic prostate inflammation (CPI) in the same biopsy and in the same biopsy core are associated with prostate cancer (PCa) risk and grade in repeat biopsies. Retrospective analyses of 6132 men who were 50-75 years old undergoing 2-year repeat prostate biopsy after a negative baseline biopsy for PCa in the REduction by DUtasteride of prostate Cancer Events (REDUCE) study. PA, CPI and PCa were determined by central pathology. The association of baseline PA and CPI with 2-year repeat biopsy cancer status and grade was evaluated with χ2 test and logistic regression controlling clinicopathological features. PA, CPI and both were detected in 583 (9.5%), 1063 (17.4%) and 3675 (59.9%) baseline biopsies, respectively. Compared with biopsies with neither PA nor CPI, the presence of PA (odds ratio (OR)=0.73, 95% confidence interval (CI)=0.57-0.93), CPI (OR=0.72, 95% CI=0.58-0.88) and both (OR=0.54, 95% CI=0.45-0.64) were associated with lower PCa risk in the 2-year repeat prostate biopsy. Results were similar in multivariable analysis. Among subjects with both PA and CPI, those with both findings in the same core had even lower PCa risk compared with PA and CPI in different cores (univariable OR=0.68, 95% CI=0.51-0.91; multivariable OR=0.73, 95% CI=0.54-0.99). Combination of PA and CPI was associated with lower risk of high-grade PCa. The presence of both PA and CPI in baseline biopsies, especially in the same core, was associated with lower PCa risk and grade. The presence and topographical distribution of PA and CPI may be used in PCa risk stratification.

Association of estrogen receptor α PvuII and XbaI polymorphisms with prostate cancer susceptibility and risk stratification: a meta-analysis from case-control studies.

BackgroundStudies on the association between two single nucleotide polymorphisms (SNPs) in estrogen receptor α (ERα), PvuII (rs2234693 T>C) and XbaI (rs9340799 A>G), and the prostate cancer risk are inconsistent. Therefore, we performed a meta-analysis to derive a more accurate estimation of this relationship.MethodsA literature search of PubMed, Embase, Web of Science databases until October 1, 2016, was conducted. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of this association.ResultsEighteen case-control studies, with a total of 3,317 prostate cancer patients and 8,324 controls, were included. Results showed that both PvuII and XbaI polymorphisms were significantly associated with a higher prostate cancer risk in overall populations. To derive a more accurate estimation, subgroup analysis stratified by ethnicity revealed that this relation-ship existed only in Caucasians, but not in Asians. Furthermore, PvuII polymorphism was significantly associated with high Gleason grade (Gleason score ≥7) cancers.ConclusionThe current meta-analysis demonstrates that ERα PvuII and XbaI polymorphisms are associated with a higher prostate cancer risk in Caucasians, but not in Asians, and PvuII polymorphism is significantly associated with high Gleason grade tumors, indicating the probability of inherited susceptibility to prostate cancer arising from different genomic ERα SNPs, which may help us understand the pathogenesis of prostate cancer in Caucasians.