Risk Of Prostate Cancer Progression Research Articles

Plant-Based Diets and Disease Progression in Men With Prostate Cancer.

Plant-based diets are associated with many health and environmental benefits, including primary prevention of fatal prostate cancer, but less is known about postdiagnostic plant-based diet patterns in individuals with prostate cancer. To examine whether postdiagnostic plant-based dietary patterns are associated with risk of prostate cancer progression and prostate cancer-specific mortality. This longitudinal observational cohort study included men with biopsy-proven nonmetastatic prostate cancer (stage ≤T3a) from the diet and lifestyle substudy within the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) enrolled at 43 urology practices across the US from 1999 to 2018. Participants completed a comprehensive diet and lifestyle questionnaire (including a validated food frequency questionnaire [FFQ]) between 2004 and 2016. Data were analyzed from August 2022 to April 2023. Overall plant-based diet index (PDI) and healthful plant-based diet index (hPDI) scores were calculated from the FFQ. The primary outcome was prostate cancer progression (recurrence, secondary treatment, bone metastases, or prostate cancer-specific mortality). The secondary outcome was prostate cancer-specific mortality. Among 2062 participants (median [IQR] age, 65.0 [59.0-70.0] years), 61 (3%) identified as African American, 3 (<1%) identified as American Indian or Alaska Native, 9 (<1%) identified as Asian or Pacific Islander, 15 (1%) identified as Latino, and 1959 (95%) identified as White. Median (IQR) time from prostate cancer diagnosis to FFQ was 31.3 (15.9-62.0) months after diagnosis. During a median (IQR) follow-up of 6.5 (1.3-12.8) years after the FFQ, 190 progression events and 61 prostate cancer-specific mortality events were observed. Men scoring in the highest vs lowest quintile of PDI had a 47% lower risk of progression (HR, 0.53; 95% CI, 0.37-0.74; P for trend = .003). The hPDI was not associated with risk of progression overall. However, among 680 individuals with Gleason grade 7 or higher at diagnosis, the highest hPDI quintile was associated with a 55% lower risk of progression compared with the lowest hPDI quintile (HR 0.45; 95% CI, 0.25-0.81; P for trend = .01); no association was observed in individuals with Gleason grade less than 7. In this cohort study of 2062 men with prostate cancer, higher intake of plant foods after prostate cancer diagnosis was associated with lower risk of cancer progression. These findings suggest nutritional assessment and counseling may be recommended to patients with prostate cancer to help establish healthy dietary practices and support well-being and overall health.

The Impact of Physical Activity on the Outcomes of Active Surveillance in Prostate Cancer Patients: A Scoping Review

Introduction: Active surveillance has emerged as a valid therapeutic option in patients with low-risk prostate cancer, allowing for the deferral of definitive treatment until the time of possible disease progression. Although it is known that physical activity plays a protective role in the onset and progression of this tumor, its impact on patients with low-risk disease who are managed with active surveillance remains unclear. Our scoping review aims to summarize the existing evidence on this subject. Evidence Acquisition: On 9 April 2023, a systematic search was conducted using the PubMed and Scopus databases. The search employed the combination of the following terms: (“prostate cancer” OR “prostate tumor”) AND (“active surveillance”) AND (“physical activity” OR “physical exercise” OR “physical intensive activity” OR “intensive exercise”) AND (“lifestyle”). Out of the 506 identified articles, 9 were used for the present scoping review, and their results were reported according to the PRISMA-ScR statement. Evidence Synthesis: We discovered a lack of uniformity in the assessment of PA and its stratification by intensity. There was no consensus regarding what constitutes cancer progression in patients choosing expectant management. In terms of the impact of PA on AS outcomes, conflicting results were reported: some authors found no correlation, while others (six of total studies included) revealed that active men experience smaller increases in PSA levels compared to their sedentary counterparts. Additionally, higher levels of exercise were associated with a significantly reduced risk of PCa reclassification. Conclusion: Due to the heterogeneity of the methodologies used in the available studies and the conflicting results reported, it is not possible to draw definitive conclusions concerning the role physical activity may play in the risk of prostate cancer progression in men managed with active surveillance.

Abstract B028: Vigorous physical activity associated changes in immune cell infiltrate are linked with reduced prostate tumour aggressiveness

Abstract Vigorous physical activity has been associated with lower risk of fatal prostate cancer and improved cancer-specific outcomes. However, the mechanisms contributing to this relationship are not understood. The current study characterized inflammation in prostate cancer tissue and evaluated features of the immune microenvironment related to physical activity and prostate cancer aggressiveness. We studied 119 men with prostate cancer participating in the University of North Carolina Health Registry/Cancer Survivorship Cohort who underwent radical prostatectomy. Structured questionnaires were administered at patients' study entry to assess physical activity. Digital image analysis of H&amp;E-stained tissue sections using QuPath was applied to quantify Tumour Infiltrating Lymphocytes (TILs) in glands and stroma of tumor and adjacent normal regions. Nanostring gene expression profiling was performed on tumour tissue and a 50-gene signature utilized to predict immune cell types. ERG gene expression was used as a surrogate of TMPRSS2:ERG fusion status. Logistic regression was used to test associations of inflammation features with tumour aggressiveness and recreational physical activity measures. Cox proportional hazards analysis was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between immune cell types and risk of prostate cancer progression, with validation in a separate study of 101 radiation-treated prostate cancer patients. Our study comprised 77% white and 23% black men, and 25% of men had Gleason grade ≥4+3, 29% men reported recreational vigorous activity prior to diagnosis of prostate cancer. Acute tumour inflammation affected 30% of men, while 53% showed acute inflammation of adjacent tissue. TILs were more abundant in glands than stroma; two-fold more in tumour and five-fold more in adjacent tissue. Frequency of inflammation was similar between ERG-positive and ERG-negative tumours. An inverse relationship was observed between recreational vigorous activity and TILs abundance. Expression of the immune gene signature was also significantly lower in men reporting any recreational vigorous activity compared to those reporting none (P=0.044), driven by reduced gene expression-predicted abundance of Th cells, exhausted CD8 T cells, macrophages and neutrophils. Moreover, T cells, Tfh, Treg, exhausted CD8 T cells and macrophages were significantly increased in men with Gleason grade ≥4+3 or clinical stage ≥III. Treg abundance was positively associated with prostate cancer progression (HR, 1.35; 95%CI 1.03-1.78) after adjusting for age and race, which was further strengthened in ERG-positive patients (HR, 1.60; 95%CI 1.03-2.47). We show that the immune landscape in prostate cancer is altered in men reporting vigorous physical activity. Immune cell types associated with an immunosuppressive microenvironment, including exhausted CD8 T cells, Tregs, and macrophages, may be potential candidate mechanisms linking recreational vigorous activity with reduced prostate tumour aggressiveness and improved outcomes. Citation Format: Lanshan Huang, Sophia Halliday, Linnea Olsson, Alina Hamilton, Erin Kirk, Laura Farnan, Adrian Gerstel, Stephanie Craig, Stephen Finn, Melissa Wilson, Melissa Troester, Eboneé Butler, Jeannette Bensen, Sara Wobker, Emma Allott. Vigorous physical activity associated changes in immune cell infiltrate are linked with reduced prostate tumour aggressiveness [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B028.

Post-diagnostic health behaviour scores and risk of prostate cancer progression and mortality

BackgroundIndividual behaviours are associated with prostate cancer (PC) progression. Behavioural scores, comprised of multiple risk factors, allow assessment of the combined impact of multiple behaviours.MethodsWe examined the association between six a priori scores and risk of PC progression and mortality among 2156 men with PC in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) cohort: two scores developed based on the PC survivorship literature (‘2021 Score [+ Diet]’); a score developed based on pre-diagnostic PC literature (‘2015 Score’); and three scores based on US recommendations for cancer prevention (‘WCRF/AICR Score’) and survival (‘ACS Score [+ Alcohol]’). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for progression and PC mortality via parametric survival models (interval censoring) and Cox models, respectively.ResultsOver a median (IQR) of 6.4 (1.3, 13.7) years, we observed 192 progression and 73 PC mortality events. Higher (i.e., healthier) 2021 Score + Diet and WCRF/AICR Scores were inversely associated with risk of PC progression (2021 + Diet: HRcontinuous = 0.76, 95% CI: 0.63–0.90. WCRF/AICR: HRcontinuous = 0.83, 95% CI: 0.67–1.02) and mortality (2021 + Diet: HRcontinuous = 0.65, 95% CI: 0.45–0.93. WCRF/AICR: HRcontinuous = 0.71; 95% CI: 0.57–0.89). The ACS Score + Alcohol was only associated with progression (HRcontinuous = 0.89, 95% CI: 0.81–0.98) while the 2021 Score was only associated with PC mortality (HRcontinuous = 0.62, 95% CI: 0.45–0.85). The 2015 was not associated with PC progression or mortality.ConclusionFindings strengthen the evidence that behavioural modifications following a prostate cancer diagnosis may improve clinical outcomes.

Abstract 5261: Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression

Abstract Prostate cancer is the most common cancer in men. Commensurate with risk, current approaches to localized prostate cancer include prostatectomy, prostate radiation with or without radiation therapy or active surveillance. Recent data suggest that systemic anti-androgen therapy with enzalutamide reduced the risk of prostate cancer progression in men on active surveillance but was associated with considerable side effects. We developed a novel polymer-based drug delivery method to provide sustained localized drug administration of anti-androgens selectively to the prostate. In vitro and in vivo mouse and canine studies show that this drug eluting implant delivers sustained high prostate to plasma therapeutic anti-androgen levels for an anticipated range of 2 years while preventing accumulation of anti-androgens in the liver, lungs, heart and brain. We performed a proof of concept study in a canine prostate model implanting an 15mm x 1mm bicalutamide eluting implant into each lobe of the prostate. Bicalutamide levels in the prostate measured near the implant at 6 months were 3250 ± 1622 ng/g, n = 3 compared to 3809 ± 638 ng/g, n = 3 to those achieved at steady-state oral administration. Plasma and other off target levels were over 1000-fold lower in the implant cohort compared to oral administration: Plasma: 5.9 ± 0.2 ng/ml, liver: 11.3 ±4.3 ng/g, and brain: 5.4 ±0.8 ng/g versus plasma: 18170 ± 3820 ng/ml, liver: 35407 ±8510 ng/g, and brain: 8870 ±1797 ng/g. The implants were well tolerated without local toxicity and imaged easily with ultrasound. The design characteristics of the implant facilitates minimally invasive surgical implantation under standard image guidance and withstands the concomitant use of prostate radiation. This novel technology warrants future clinical exploration of prostate specific anti-androgen therapy for (neo)adjuvant therapy or in active surveillance. Tissue Bicalutamide oral (2m)(ng/g) Bicalutamide implant (6m)(ng/g) Plasma 18,170 (3820) 5.9 (0.2) Prostate 3,809 (638) 3,250 (1622) Liver 35,407 (8510) 11.3 (4.3) Cerebrum 8,870 (1797) 5.4 (0.8) Cerebellum 8,737 (1550) 6.2 (1.3) Spleen 7,727 (1288) 4.2 (0.9) Lung 27,013 (2896) 11.3 (4.3) Heart 11,737 (3491) 10.0 (1.9) Kidneys 17,413 (6581) 8.5 (2.0) Citation Format: Pujan Desai, Maithili Rairkar, Nela Pawlowska, Scott Thomas, Pamela N. Munster. Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5261.

Preoperative endogenous total testosterone predicts prostate cancer progression: results in 580 consecutive patients treated with robot assisted radical prostatectomy for clinically localized disease

To test the role of endogenous total testosterone (ETT) as a predictor of prostate cancer (PCa) progression in patients treated with robot assisted radical prostatectomy for clinically localized disease. Between November 2014 and December 2019, 580 consecutive patients were evaluated. Preoperative ETT levels were classified as ≤ 350ng/dL vs. > 350ng/dL. The associations between ETT levels and the risk of PCa progression, defined as any event of biochemical recurrence and/or local recurrence and/or distant metastases, or other clinical and pathological factors were evaluated by regression analyses. Preoperative ETT levels resulted ≤ 350ng/dL in 173 (29.8%) patients. Disease progression occurred in 101 (17.1%) cases. Progressing patients were more likely to present with PSA levels > 10ng/mL, as well as with unfavorable tumor grade (ISUP 4-5) and stage (pT3b) at final pathology, but less likely to have ETT levels ≤ 350ng/mL. On clinical multivariable Cox regression models, ETT ≤ 350ng/mL exhibited a statistically significant protective effect on tumor progression (hazard ratio: 0.57, p = 0.013). Subjects presenting with ETT levels ≤ 350ng/mL were less likely to harbor ISUP 4-5 tumor grade either at biopsy (odds ratio [OR]: 0.46, p = 0.028) or final pathology (OR: 0.45, p = 0.032). At PCa diagnosis, ETT, which associates with ISUP tumor grade, is an independent predictor of disease progression. Accordingly, as ETT decreases to levels ≤ 350ng/dL, the risk of unfavorable tumor grade decreases, and a more favorable prognosis is expected. Preoperative ETT levels may allow further patient stratification along prognostic risk groups.

Plant-Based Diet May Lower Risk of Prostate Cancer Progression

Plant-Based Diet May Lower Risk of Prostate Cancer Progression

Normal preoperative endogenous testosterone levels predict prostate cancer progression in elderly patients after radical prostatectomy.

The impact of senior age on prostate cancer (PCa) oncological outcomes following radical prostatectomy (RP) is controversial, and further clinical factors could help stratifying risk categories in these patients. We tested the association between endogenous testosterone (ET) and risk of PCa progression in elderly patients treated with RP. Data from PCa patients treated with RP at a single tertiary referral center, between November 2014 and December 2019 with available follow-up, were retrospectively evaluated. Preoperative ET (classified as normal if >350 ng/dl) was measured for each patient. Patients were divided according to a cut-off age of 70 years. Unfavorable pathology consisted of International Society of Urologic Pathology (ISUP) grade group >2, seminal vesicle, and pelvic lymph node invasion. Cox regression models tested the association between clinical/pathological tumor features and risk of PCa progression in each age subgroup. Of 651 included patients, 190 (29.2%) were elderly. Abnormal ET levels were detected in 195 (30.0%) cases. Compared with their younger counterparts, elderly patients were more likely to have pathological ISUP grade group >2 (49.0% versus 63.2%). Disease progression occurred in 108 (16.6%) cases with no statistically significant difference between age subgroups. Among the elderly, clinically progressing patients were more likely to have normal ET levels (77.4% versus 67.9%) and unfavorable tumor grades (90.3% versus 57.9%) than patients who did not progress. In multivariable Cox regression models, normal ET [hazard ratio (HR) = 3.29; 95% confidence interval (CI) = 1.27-8.55; p = 0.014] and pathological ISUP grade group >2 (HR = 5.62; 95% CI = 1.60-19.79; p = 0.007) were independent predictors of PCa progression. On clinical multivariable models, elderly patients were more likely to progress for normal ET levels (HR = 3.42; 95% CI = 1.34-8.70; p = 0.010), independently by belonging to high-risk category. Elderly patients with normal ET progressed more rapidly than those with abnormal ET. In elderly patients, normal preoperative ET independently predicted PCa progression. Elderly patients with normal ET progressed more rapidly than controls, suggesting that longer exposure time to high-grade tumors could adversely impact sequential cancer mutations, where normal ET is not anymore protective on disease progression.

The effect of epistatic interactions between genetic variants located in microRNA and silencing complex genes on prostate cancer progression risk

Previous studies conducted in Asian and European populations have provided evidence of the association between microRNA-related genetic variants and prostate cancer (PCa) risk and/or progression. Nevertheless, the results obtained in these studies are inconsistent, which could be explained by the limitations of single-locus main effect evaluations to detect joint effects of multiple genetic variants, reflected in statistical epistases. Therefore, we conducted the analysis of potential epistatic interactions between variants located in microRNA genes and in genes encoding the components of RNA-induced silencing complex (RISC) in relation with PCa risk/aggressiveness. Raw data on genotyping results from our previous studies involving four microRNA polymorphisms and five variants in RISC genes were subjected to the exclusion of samples based on missing data criterion, followed by the re-evaluation of Hardy-Weinberg equilibrium. Afterwards, these genotyping results were included in the Multifactor dimensionality reduction (MDR) analysis. Permutation testing was conducted in order to assess statistical significance of the best models from MDR tests. MDR tests on the risk of developing PCa yielded statistically insignificant results. Nevertheless, the MDR results for comparison of PCa patients with high and low cancer progression risk were statistically significant for the analysis that included rs11614913, with the 3-locus best model comprising this genetic variant, rs7813 and rs784567. We conclude that statistical epistasis between rs11614913 in hsa-miR-196a2, rs7813 in GEMIN4 and rs784567 in TARBP2 shows association with the invasiveness of PCa.

Selected Articles from This Issue

Inflammatory and insulinemic pathways have been linked to prostate cancer; thus, health behaviors that activate these pathways may impact prostate cancer survivorship. In this study, Langlais and colleagues predicted biomarker levels of inflammation, hyperinsulinemia, and insulin resistance pathways from questionnaire data among 2,056 men with prostate cancer. The authors examined the scores in relation to risk of prostate cancer progression. Over a median of 6.4 years of follow-up, the most pro-inflammatory and pro-insulinemic behaviors following a prostate cancer diagnosis were associated with a 1.6- to 2.8-fold increased risk of prostate cancer progression. Limiting inflammation and insulin hypersecretion through diet and physical activity may improve prostate cancer survivorship.Testicular germ cell tumors (TGCTs), whose etiology is largely unknown, are believed to arise from primordial gonocytes with an altered DNA methylation reprogramming. Grasso and colleagues evaluated the association between 273 single-nucleotide polymorphisms (SNPs) from 28 DNA methylation-related genes and TGCT risk using summary statistics from the Genome Wide Association Study meta-analysis of the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls. Four MTHFR SNPs, potentially affecting DNA methylation pattern, were associated with TGCT risk. This suggests that TGCT pathogenesis could be linked to folate cycle status, and this relation could be partly due to hereditary factors.In the United States (US), the incidence of Hodgkin lymphoma (HL) differs by ethnicity. In a large population-based case-control study, Graham and colleagues found that having a foreign-born mother (versus a US-born mother) was associated with an increased risk of early onset HL among non-Hispanic White individuals and a decreased risk among Hispanic individuals. In addition, sex, birthweight and parental age were also linked to risk of early onset HL. The findings suggest that the etiology of early onset HL is multi-faceted, and the observed disparity warrants further evaluation.This article describes the randomized transition from established cytology-based screening to primary HPV-based screening in Norway. This programmatic change required substantial modifications to existing infrastructure and screening protocols, affecting activity volumes, staff training, and changes in the data-flow and communication systems. Nygård and colleagues report a relative increase of 60% in the detection of cervical precancers and 40% in cancer using HPV-based screening as compared to the cytology-based screening. Introducing new screening technology gradually and in a controlled manner should be considered in both established and novel population-based cancer screening programs and specifically implementing HPV-based screening to advance the cervical cancer elimination.

Pelvic lymphadenectomy for radical prostatectomy: perioperative and oncological results

Background. Currently, in men suffering from prostate cancer, histological examination of the material obtained during pelvic lymphadenectomy (PLAE) is the most accurate and reliable method for staging the tumor process and postoperative prognosis of disease outcomes, an important factor influencing the choice of the most rational treatment tactics after radical prostatectomy. However, today questions about the therapeutic (oncological) expediency of PLAE and its safety in terms of the development of intra- and postoperative complications remain debatable.Aim. To was to compare the perioperative and therapeutic (oncological) results of radical prostat ectomy performed in combination with standard or extended PLAE.Materials and methods. The study materials were the data of medical records of 812 men aged 43 to 78 years, at different times (from January 2009 to December 2018) who were hospitalized for localized or locally advanced prostate cancer in stages cT1a–cT3bN0M0. The research method was a retrospective analysis of the data contained in the selected medical records.Results and conclusion. The results of our studies, firstly, confirm the conclusions of the European Association of Urology (EAU) experts on the justification and necessity of performing an extended PLAE with radical prostatectomy in order to diagnose metastatic lesions of the pelvic lymph nodes in individuals with an intermediate or high risk of prostate cancer progression; secondly, they indicate a higher therapeutic efficacy of extended PLAE compared to that for standard PLAE, which is expressed in a statistically significantly three times lower incidence of biochemical relapses and an 11.4 % longer relapse-free period after extended PLAE than after standard PLAE. Extended PLAE, performed in one surgical session with radical prostatectomy, is not a risk factor for the development of various intra- and postoperative complications, with the exception of the lymphocele, which is formed in 3.7–13.5 % of cases of extended PLAE due to intraoperative transection of lymphatic vessels and lymph accumulation at the site of the removed adipose tissue.

Postdiagnostic Inflammatory, Hyperinsulinemic, and Insulin-Resistant Diets and Lifestyles and the Risk of Prostate Cancer Progression and Mortality.

Inflammatory and insulin pathways have been linked to prostate cancer; postdiagnostic behaviors activating these pathways may lead to poor outcomes. The empirical dietary inflammatory pattern (EDIP), empirical dietary index for hyperinsulinemia (EDIH), and empirical dietary index for insulin resistance (EDIR), and associated lifestyle indices (ELIH, ELIR) predict biomarkers of inflammation (EDIP: IL6, TNFaR2, CRP) and insulin secretion (EDIH/ELIH: c-peptide; EDIR/ELIR: TAG:HDL) from whole foods and behaviors. Associations of these indices with time to prostate cancer progression (primary, n = 2,056) and prostate cancer-specific mortality (PCSM; secondary, n = 2,447) were estimated among men diagnosed with nonmetastatic prostate cancer in the Cancer of the Prostate Strategic Urologic Research Endeavor cohort diet and lifestyle sub-study. Because the true (versus clinically documented) date of progression is unobserved, we used parametric (Weibull) survival models to accommodate interval-censoringand estimated adjusted HR and 95% confidence intervals (CI) for prostate cancer progression per 1-SD increase in index. Cox proportional hazards models were used to estimate PCSM associations. During a median [interquartile range (IQR)] 6.4 years (IQR, 1.3-12.7), 192 progression and 73 PCSM events were observed. Inflammatory (EDIP: HR, 1.27; CI, 1.17-1.37), hyperinsulinemic (EDIH: HR, 1.24; CI, 1.05-1.46. ELIH: HR, 1.34; CI, 1.17-1.54), and insulin-resistant (EDIR: HR, 1.22; CI, 1.00-1.48. ELIR: HR, 1.36; CI, 1.12-1.64) indices were positively associated with risk of prostate cancer progression. There was no evidence of associations between the indices and PCSM. Both inflammatory and insulinemic dietary and lifestyle patterns are associated with risk of prostate cancer progression. For men with prostate cancer, consuming dietary patterns that limit chronic systemic inflammation and insulin hypersecretion may improve survivorship, especially when coupled with active lifestyle and healthy body weight. See related commentary by Kucuk, p. 1673.

Enzalutamide Monotherapy vs Active Surveillance in Patients With Low-risk or Intermediate-risk Localized Prostate Cancer

There are few published studies prospectively assessing pharmacological interventions that may delay prostate cancer progression in patients undergoing active surveillance (AS). To compare the efficacy and safety of enzalutamide monotherapy plus AS vs AS alone in patients with low-risk or intermediate-risk prostate cancer. The ENACT study was a phase 2, open-label, randomized clinical trial conducted from June 2016 to August 2020 at 66 US and Canadian sites. Eligible patients were 18 years or older, had received a diagnosis of histologically proven low-risk or intermediate-risk localized prostate cancer within 6 months of screening, and were undergoing AS. Patients were monitored during 1 year of treatment and up to 2 years of follow-up. Data analysis was conducted in February 2021. Randomized 1:1 to enzalutamide, 160 mg, monotherapy for 1 year or continued AS, as stratified by cancer risk and follow-up biopsy type. The primary end point was time to pathological or therapeutic prostate cancer progression (pathological, ≥1 increase in primary or secondary Gleason pattern or ≥15% increased cancer-positive cores; therapeutic, earliest occurrence of primary therapy for prostate cancer). Secondary end points included incidence of a negative biopsy result, percentage of cancer-positive cores, and incidence of a secondary rise in serum prostate-specific antigen (PSA) levels at 1 and 2 years, as well as time to PSA progression. Adverse events were monitored to assess safety. A total of 114 patients were randomized to treatment with enzalutamide plus AS and 113 to AS alone; baseline characteristics were similar between treatment arms (mean [SD] age, 66.1 [7.8] years; 1 Asian individual [0.4%], 21 Black or African American individuals [9.3%], 1 Hispanic individual [0.4%], and 204 White individuals [89.9%]). Enzalutamide significantly reduced the risk of prostate cancer progression by 46% vs AS (hazard ratio, 0.54; 95% CI, 0.33-0.89; P = .02). Compared with AS, odds of a negative biopsy result were 3.5 times higher; there was a significant reduction in the percentage of cancer-positive cores and the odds of a secondary rise in serum PSA levels at 1 year with treatment with enzalutamide; no significant difference was observed at 2 years. Treatment with enzalutamide also significantly delayed PSA progression by 6 months vs AS (hazard ratio, 0.71; 95% CI, 0.53-0.97; P = .03). The most commonly reported adverse events during enzalutamide treatment were fatigue (62 [55.4%]) and gynecomastia (41 [36.6%]). Three patients in the enzalutamide arm died; none were receiving the study drug at the time of death. No deaths were considered treatment-related. The results of this randomized clinical trial suggest that enzalutamide monotherapy was well-tolerated and demonstrated a significant treatment response in patients with low-risk or intermediate-risk localized prostate cancer. Enzalutamide may provide an alternative treatment option for patients undergoing AS. ClinicalTrials.gov Identifier: NCT02799745.

Developing a consensus statement for psychosocial support in active surveillance for prostate cancer.

Our objective was to prioritise the psychosocial support needs of men on active surveillance for prostate cancer and to develop a consensus statement to provide guidance on best practice psychosocial support for men choosing active surveillance and their families. We undertook a patient and public involvement Delphi process over two rounds, informed by qualitative data and a comprehensive literature review, to prioritise the information and support needs of men on active surveillance for prostate cancer. Two panels were surveyed, a patient/carer panel (n = 55) and a health care provider panel (n = 114). Based on the findings of the Delphi surveys, an expert active surveillance discussion group developed a consensus statement to guide best practice. Patients and health care professionals differed slightly in their ideas concerning priorities for active surveillance psychosocial support. Broadly, agreed priority areas included -patients being involved in decision-making, continuity of care, more streamlined access to health care teams, improved understanding of the risk of prostate cancer progression and information and support provided through both health care professionals and peers. Based on the identified priorities, the expert discussion group agreed on 22 consensus statements for best practice in psychosocial care for active surveillance in respect of (1) principles of an active surveillance programme; (2) structure of consultations; (3) content of information and support; and (4) delivery of information. This consensus statement provides a framework for patient-focused psychosocial support, which, if adopted, should increase uptake and adherence to active surveillance among men with prostate cancer.

Development and validation of a cell cycle progression signature for decentralized testing of men with prostate cancer.

Aim: The 46-gene Prolaris® cell cycle progression test provides information on the risk of prostate cancer progression. Here we developed and validated a 16-gene kit-based version. Methods: RNA was extracted from prostate cancer biopsy tissue. Amplification efficiency, minimum tumor content, repeatability, reproducibility and equivalence with the 46-gene test were evaluated. Results: Amplification efficiencies for all genes were within the acceptable range (90-110%), and samples with ≥50% tumor content were appropriate for the 16-gene test. Results were repeatable (standard deviation: 0.085) and reproducible (standard deviation: 0.115). Instrument, operator and kit lot had minimal impact on results. Cell cycle progression scores from the 46- and 16-gene tests were highly correlated (r=0.969; bias=0.217). Conclusion: The 16-gene test performs consistently and similarly to the 46-gene test.

Identification of UAP1L1 as a critical factor for prostate cancer and underlying molecular mechanism in tumorigenicity

BackgroundProstate cancer is the second most common cancer in men, and some new target genes are needed to predict the risk of prostate cancer progression and the treatment.MethodsIn this study, the effects of UAP1L1 (UAP1-like-1) on prostate cancer were investigated by detecting the proliferation, migration, invasion and apoptosis of prostate cancer cells in vitro using MTT, wound healing, Transwell and flow cytometry assay, and the tumor growth in vivo. The downstream genes and pathways of UAP1L1 were explored using Ingenuity Pathway Analysis (IPA), and screened by qRT-PCR and western blot. The effects of CDCA8 on prostate cancer cells were also verified in vitro, which was through detecting the change of proliferation, migration, invasion and apoptosis of prostate cancer cells after CDCA8 knockdown.ResultsThe results indicated that UAP1L1 promoted the proliferation, migration and invasion of prostate cancer cells, which was inhibited by downregulating CDCA8. Furthermore, the promotion of CDCA8 knockdown on cell apoptosis was reduced when UAP1L1 was simultaneously overexpressed.ConclusionsIn conclusion, the results in this study revealed that UAP1L1 promoted the progression of prostate cancer through the downstream gene CDCA8.

Androgen receptor phosphorylated at Ser815: The expression and function in the prostate and tumor-derived cells

Androgen is beneficial for the prostate with normal functions but creates a risk for prostate cancer progression. How androgen receptor (AR) mediates these various androgen actions remains elusive. AR conserves a phosphorylation motif within its ligand-binding domain throughout species. Here, we have found AR phosphorylated at Ser815 (P-AR) is expressed in normal tissues of both human and mouse prostates. P-AR begins expression in association with prostatic development and castration decreases its expression levels in the mouse prostate. Functional analysis of AR in prostate cancer PC-3 cells showed ligand-induced AR nuclear translocation and transactivation were disturbed by its phosphorylation at Ser815. Moreover, P-AR suppressed oncogenic AKT signaling suggesting a suppressive function for prostate cancer development. In fact, AR phosphorylation levels progressively decrease in human prostates as cancer worsens. These findings showed androgen might utilize P-AR to self-antagonize oncogenic signals and cancer progression believed to be regulated by non-phosphorylated AR (NonP-AR). By differing its target genes and signal regulations from those of NonP-AR, P-AR co-expression with NonP-AR may be the molecular basis for androgen to balance its actions and to control disease developments.

Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial

BackgroundIn the phase 2, randomized, double-blind STRIVE trial, enzalutamide significantly reduced the risk of prostate cancer progression or death versus bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic CRPC (nmCRPC). The objective of this protocol-specified subgroup analysis of STRIVE was to investigate the benefit of enzalutamide versus bicalutamide specifically in patients with nmCRPC.MethodsPatients (N = 139) were stratified by disease stage and randomized to enzalutamide 160 mg/day plus androgen deprivation therapy (ADT; n = 70) or bicalutamide 50 mg/day plus ADT (n = 69).ResultsBaseline characteristics of patients with nmCRPC were comparable between groups. At a median of 17 months follow-up, enzalutamide reduced the risk of progression or death by 76% versus bicalutamide in patients with nmCRPC (hazard ratio [HR], 0.24; 95% CI 0.14–0.42). Enzalutamide reduced risk of prostate-specific antigen progression by 82% versus bicalutamide in patients with nmCRPC (HR, 0.18; 95% CI 0.10–0.34). The most frequently reported adverse events by patients receiving enzalutamide were fatigue (36.2%), hot flush (20.3%), decreased appetite (17.4%), dizziness (17.4%), and nausea (17.4%).ConclusionsThis STRIVE subgroup analysis of patients with nmCRPC illustrates the benefit of enzalutamide in reducing the risk of progression or death versus bicalutamide in patients with nmCRPC.Trial registrationClinicalTrials.gov identifier NCT01664923.

This Month in Adult Urology

This Month in Adult Urology

Racial differences in the systemic inflammatory response to prostate cancer.

Systemic inflammation may increase risk for prostate cancer progression, but the role it plays in prostate cancer susceptibility is unknown. From a cohort of over 10,000 men who had either a prostate biopsy or transurethral resection that yielded a benign finding, we analyzed 517 incident prostate cancer cases identified during follow-up and 373 controls with one or more white blood cell tests during a follow-up period between one and 18 years. Multilevel, multivariable longitudinal models were fit to two measures of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), to determine NLR and MLR trajectories associated with increased risk for prostate cancer. For both measures, we found no significant differences in the trajectories by case/control status, however in modeling NLR trajectories there was a significant interaction between race (white or Black and case-control status. In race specific models, NLR and MLR values were consistently higher over time among white controls than white cases while case-control differences in NLR and MLR trajectories were not apparent among Black men. When cases were classified as aggressive as compared to non-aggressive, the case-control differences in NLR and MLR values over time among white men were most apparent for non-aggressive cases. For NLR among white men, significant case-control differences were observed for the entire duration of observation for men who had inflammation in their initial prostate specimen. It is possible that, among white men, monitoring of NLR and MLR trajectories after an initial negative biopsy may be useful in monitoring prostate cancer risk.