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Active surveillance for prostate cancer relies on regular prostate specific antigen tests and surveillance biopsies. Compliance rates with biopsies vary but the subsequent impact on oncologic outcomes is not known. The objective of this study was to determine whether noncompliance with the confirmatory biopsy negatively impacts prostate cancer specific outcomes.A retrospective analysis was performed on a prospective single-arm cohort of men enrolled in active surveillance for prostate cancer between 1995 and 2018 with a median followup of 9.1 years. A total of 1,275 patients were enrolled and 1,043 had a minimum of 3 years of followup and were included in the analysis. Patients were stratified by compliance with a confirmatory biopsy within 24 months of enrollment in active surveillance. The primary outcome was recurrence-free survival. Secondary outcomes included metastatic-free survival and cause specific survival.A total of 1,275 patients were enrolled, and 1,043 had a minimum of 3 years of followup and were included in the analysis, of whom 425 were treated for localized prostate cancer. Patients noncompliant with the confirmatory biopsy had higher rates of recurrence after treatment (19% vs 12%, HR 1.64, 95% CI 1.19-2.26, p=0.003) and metastases (7% vs 2%, HR 3.56, 95% CI 1.8-7.0, p=0.0003) even after accounting for age, prostate specific antigen and Grade Group. Cause specific survival was not significantly different between the 2 groups. The results were consistent even in the subset of patients with Grade Group 1 disease at study entry.Noncompliance with a confirmatory biopsy compromises the control of prostate cancer in men followed on active surveillance. Patients and physicians should be aware of the importance of adhering to protocol for men on active surveillance.

Purpose:We report our experience with transperineal prostate biopsy as well as the cancer diagnosis rate, complications and patient tolerability in 1,287 consecutive patients at risk for prostate c...

Conventional clinical variables cannot accurately differentiate indolent from aggressive prostate cancer in patients on active surveillance. We investigated promising circulating miRNA biomarkers to predict the reclassification of active surveillance cases.We collected serum samples from 2 independent active surveillance cohorts of 196 and 133 patients for the training and validation, respectively, of candidate miRNAs. All patients were treatment naïve and diagnosed with Gleason score 6 prostate cancer. Samples were collected prior to potential reclassification. We analyzed 9 circulating miRNAs previously shown to be associated with prostate cancer progression. Logistic regression and ROC analyses were performed to assess the predictive ability of miRNAs and clinical variables.A 3-miR (miRNA-223, miRNA-24 and miRNA-375) score was significant to predict patient reclassification (training OR 2.72, 95% CI 1.50-4.94 and validation OR 3.70, 95% CI 1.29-10.6). It was independent of clinical characteristics in multivariable models. The ROC AUC was maximized when combining the 3-miR score and prostate specific antigen, indicating additive predictive value. The 3-miR score plus the prostate specific antigen panel cutoff achieved 89% to 90% negative predictive value and 66% to 81% specificity.The 3-miR score combined with prostate specific antigen represents a noninvasive biomarker panel with high negative predictive value. It may be used to identify patients on active surveillance who have truly indolent prostate cancer.

Patients with prostate cancer on active surveillance are monitored by repeat prostate specific antigen measurements, digital rectal examinations and prostate biopsies. A subset of patients on active surveillance will later reclassify with disease progression, prompting definitive treatment. To minimize the risk of under treating such patients on active surveillance minimally invasive tests are urgently needed incorporating biomarkers to identify patients who will reclassify.We assessed post-digital rectal examination urine samples of patients on active surveillance for select DNA methylation biomarkers that were previously investigated in radical prostatectomy specimens and shown to correlate with an increasing risk of prostate cancer. Post-digital rectal examination urine samples were prospectively collected from 153 men on active surveillance who were diagnosed with Gleason score 6 disease. Urinary sediment DNA was analyzed for 8 DNA methylation biomarkers by multiplex MethyLight assay. Correlative analyses were performed on gene methylation and clinicopathological variables to test the ability to predict patient risk reclassification.Using backward logistic regression a 4-gene methylation classifier panel (APC, CRIP3, GSTP1 and HOXD8) was identified. The classifier panel was able to predict patient reclassification (OR 2.559, 95% CI 1.257-5.212). We observed this panel to be an independent and superior predictor compared to current clinical predictors such as prostate specific antigen at diagnosis or the percent of tumor positive cores in the initial biopsy.We report that a urine based classifier panel of 4 methylation biomarkers predicts disease progression in patients on active surveillance. Once validated in independent active surveillance cohorts, these promising biomarkers may help establish a less invasive method to monitor patients on active surveillance programs.

Purpose: To assess the applicability of active surveillance in patients with intermediate risk prostate cancer, we compared the survival outcomes of patients with low risk and intermediate risk disease.Materials and Methods: Active surveillance was offered to all patients with low risk (cT1-T2b and Gleason score 6 and prostate specific antigen 10 ng/ml or less) and select intermediate risk disease (age greater than 70 years with cT2c or prostate specific antigen 15 ng/ml or less, or Gleason score 3+4 or less). Data from November 1995 to May 2013 were extracted from a prospectively collected database. The primary outcome was metastasis-free survival, and secondary outcomes were overall survival, cause specific survival and treatment-free survival.Results: A total of 213 intermediate risk and 732 low risk cases were identified. Median age was 72 years (IQR 67.3, 76.8) in the intermediate risk cohort and 67 years (IQR 60.6, 71.9) in the low risk group. Median followup was comparable (6.7 years for intermedia...

Active surveillance is an approach to low and low intermediate risk prostate cancer that is designed to decrease overtreatment. Despite close monitoring a small subset of patients progress to metastatic disease. We analyzed the clinical and pathological correlates of surveillance in patients who eventually experienced metastasis.This was a single center, prospective cohort study. Eligible patients were treated with an expectant approach. The main outcome measure was metastasis-free survival. Predictive factors for metastasis were identified.Metastasis developed in 30 of 980 patients, of whom 211 were classified at intermediate risk, including 14 who progressed to metastatic disease. Median followup was 6.3 years, median age was 70 years, median prostate specific antigen was 6.2 ng/ml and median time to metastasis was 8.9 years. Metastases developed in bone in 18 patients (60%) and in lymph nodes in 13 (43%). Prostate specific antigen doubling time less than 3 years (HR 3.7, 95% CI 1.4-9.4, p = 0.0006), Gleason score 7 (HR 3.0, 95% CI 1.2-7.3, p = 0.0018) and a total of 3 or more positive cores (HR 2.7, 95% CI 1.1-6.8, p = 0.0028) were independent predictors of metastasis. Although the intermediate risk group was at higher risk for metastasis, those with Gleason score 6 and prostate specific antigen greater than 10 ng/ml were not at increased risk for metastasis. Metastasis developed in only 2 patients with Gleason score 6 and neither had surgical pathology grading.Active surveillance appears safe in patients at low risk and in select patients at intermediate risk, particularly those with Gleason score 6 and prostate specific antigen greater than 10 ng/ml. Patients with elements of Gleason pattern 4 on diagnostic biopsy are at increased risk for eventual metastasis when treated with an initial conservative approach.

INTRODUCTION AND OBJECTIVES: The majority of men with prostate cancer (PCa) are diagnosed with low-risk disease given effective PSA screening. To avoid over-treatment, men with low-risk PCa are encouraged to be followed on an Active Surveillance (AS) protocol in which repeated blood tests, digital rectal examinations (DRE) and prostate biopsies are utilized to monitor disease progression. Aberrant DNA methylation is a common feature in a variety of tumours. Tumour-specific gene methylation would be an ideal biomarker since only minute amounts of DNA are required which could be extracted from post-DRE urine samples, thus being a much less invasive method for PCa screening as compared to frequent biopsies. Our group previously identified and validated a panel of DNA methylation biomarkers that predicted the presence of high risk disease and/or post treatment biochemical recurrence in radical prostatectomy samples. In the current study, we investigated if this same panel of biomarkers can be detected in post-DRE urine samples of PCa patients participating in an AS program, and whether methylation of these biomarkers could have prognostic value in predicting development of high-risk PCa. METHODS: We collected post DRE urine samples from PCa patients with lowand intermediate-risk PCa patients followed in an AS program. DNA extracted from urine cell pellets was analyzed for selected methylation biomarkers by multiplex MethyLight, a highly sensitive, methylation specific qPCR assay. Patients were stratified using Chi-square analysis by the percent of methylated reference (PMR). Correlative studies were performed on methylation data and clinical variables such as Gleason score and clinical stage. RESULTS: DNA extracted from DRE urine cell pellets of 142 patients was analyzed for the presence of 9 DNA methylation biomarkers. DNA methylation in one or more biomarkers was seen in 73% of patients. Methylation of 3 independent biomarkers was able to distinguish between low(GS6) and intermediate-risk (GS7) PCa (p

Prostate specific antigen doubling time was used to stratify patients into groups at low and high risk for progression. The prostate specific antigen kinetics in these 2 groups were modeled.In this prospective, single-arm cohort study patients with favorable clinical parameters (stage T1b-T2b N0M0, Gleason score 7 or less, prostate specific antigen 15 ng/ml or less) were conservatively treated with watchful waiting. Evolution of serial prostate specific antigen measurements over time was estimated from a general linear mixed model of the natural log of prostate specific antigen. The corresponding average and individual prostate specific antigen doubling times were also calculated.Since November 1995 a total of 231 patients had at least 6 months of followup and at least 3 prostate specific antigen measurements. Based on prostate specific antigen doubling time and repeat biopsy, 93 patients fulfilled the criteria for high risk of disease progression and 138 were defined as low risk. Given the baseline status of these individuals, 2 reference average lines (high risk and low risk) were derived to model the evolution of prostate specific antigen levels and permit more rational decision making regarding the need for definitive intervention. The average prostate specific antigen doubling time was 2.97 years (95% CI 2.2-4.4) in patients allocated to the high risk group and 6.54 years (95% CI 4.8-12.3) in those at low risk.By applying the dynamic prognostic rule in combination with serial biopsy, a rational decision for definitive intervention based on the risk of disease progression could be optimally recommended about 2.3 years after initiated surveillance.