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Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13-1.31; P trend < 0.001). However, this association varied by disease aggressiveness (P heterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease.

The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. Cancer Res; 76(8); 2288-300. ©2016 AACR.

BackgroundIndividual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease.ObjectiveThe objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, α-tocopherol, and γ-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors.DesignPrincipal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets.ResultsData were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated with overall risk of prostate cancer, but there was statistically significant heterogeneity by stage of disease, and the OR for aggressive disease for the highest compared with the lowest fifth of lycopene was 0.65 (95% CI: 0.46, 0.91; P-trend = 0.032). No other carotenoid was significantly associated with overall risk of prostate cancer or with risk of advanced-stage or aggressive disease. For retinol, the OR for the highest compared with the lowest fifth was 1.13 (95% CI: 1.04, 1.22; P-trend = 0.015). For α-tocopherol, the OR for the highest compared with the lowest fifth was 0.86 (95% CI: 0.78, 0.94; P-trend < 0.001), with significant heterogeneity by stage of disease; the OR for aggressive prostate cancer was 0.74 (95% CI: 0.59, 0.92; P-trend = 0.001). γ-Tocopherol was not associated with risk.ConclusionsOverall prostate cancer risk was positively associated with retinol and inversely associated with α-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and α-tocopherol. Whether these associations reflect causal relations is unclear.

Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 × 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 × 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 × 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.

Background: The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial assessed the effect of screening with prostate-specific antigen and a digital rectal examination on prostate cancer mortality. Another endpoint of interest was the burden of total metastatic disease.Methods: All men in PLCO were assessed for metastatic prostate cancer at diagnosis; men with clinical stage I/II disease were assessed for metastatic progression. The rate of total metastatic disease was defined as metastases found either at diagnosis or through progression divided by person-years (PYs) of follow-up for all men in the trial. Metastatic progression rates were computed among men with clinical stage I/II prostate cancer. Survival among men with metastases at diagnosis was compared with survival among men with metastatic progression.Results: Among 38,340 men in the intervention arm and 38,343 men in the control arm in PLCO, there were 4974 and 4699 prostate cancer cases, respectively. The rates of total metastatic disease were 4.72 and 4.83 per 10,000 PYs in the intervention and control arms, respectively (rate ratio, 0.98; 95% CI, 0.81-1.18). The rates of metastatic progression among men with clinical stage I/II prostate cancer were 43.7 and 50.5 per 10,000 PYs in the intervention and control arms, respectively (P = .30). Prostate cancer-specific 5- and 10-year survival rates were significantly worse for men with metastatic progression (24% and 19%, respectively) than men with metastases at diagnosis (40% and 26%, respectively).Conclusions: Rates of total metastatic disease and metastatic progression were similar across arms in PLCO. Survival was worse for men with metastatic progression in comparison with those with metastatic disease at diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease-risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin. Methods: Statistical analyses of individual participant data from 12,330 male controls aged 25–85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates. Results: Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones. Conclusion: Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption. [ABSTRACT FROM AUTHOR]

BACKGROUND Two large-scale prostate cancer screening trials using prostate-specific antigen (PSA) have given conflicting results in terms of the efficacy of such screening. One of those trials, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, previously reported outcomes with 13 years of follow-up. This study presents updated findings from the PLCO trial. METHODS The PLCO trial randomized subjects from 1993 to 2001 to an intervention or control arm. Intervention-arm men received annual PSA tests for 6 years and digital rectal examinations for 4 years. This study used a linkage with the National Death Index to extend mortality follow-up to a maximum of 19 years after randomization. RESULTS Men were randomized to the intervention arm (n = 38,340) or the control arm (n = 38,343). The median follow-up time was 14.8 years (25th/75th, 12.7/16.5 years) in the intervention arm and 14.7 years (25th/75th, 12.6/16.4 years) in the control arm. There were 255 deaths from prostate cancer in the intervention arm and 244 deaths from prostate cancer in the control arm; this meant a rate ratio (RR) of 1.04 (95% confidence interval [CI], 0.87-1.24). The RR for all-cause mortality was 0.977 (95% CI, 0.950-1.004). It was estimated that 86% of the men in the control arm and 99% of the men in the intervention arm received any PSA testing during the trial, and the estimated yearly screening-phase PSA testing rates were 46% and 84%, respectively. CONCLUSIONS Extended follow-up of the PLCO trial over a median of 15 years continues to indicate no reduction in prostate cancer mortality for the intervention arm versus the control arm. Because of the high rate of control-arm PSA testing, this finding can be viewed as showing no benefit of organized screening versus opportunistic screening. Cancer 2017;123:592-599. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: There is a body of evidence indicating that aspirin may reduce the risk of cancer mortality. However, to the authors' knowledge, the optimal exposure timing and mechanism of action remain unclear. In the current study, the authors investigated associations between prediagnostic aspirin use and breast cancer-specific mortality in a US population.Methods: Postmenopausal women diagnosed with stage I to III breast cancer (1993-2009) were identified (2925 women with a total of 18,073 person-years) from the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Prediagnostic aspirin use (1274 women) was identified from study questionnaires. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs) for associations between aspirin use and breast cancer-specific mortality. Effect modification by lymph node status was evaluated.Results: Prediagnostic aspirin use was not found to be associated with lower breast cancer-specific mortality (HR, 0.95; 95% CI, 0.68-1.31 [P = .74]). In analyses stratified by lymph node status, aspirin use was found to be associated with lower breast cancer-specific mortality among women with lymph node-negative tumors (HR, 0.54; 95% CI, 0.32-0.93 [P = 0.02]), but not those with lymph node-positive tumors (HR, 1.41; 95% CI, 0.92-2.16 [P = 0.11]). Tests for interaction were found to be statistically significant (P for interaction =.006). No association was noted between aspirin use and lymph node status.Conclusions: Prediagnostic aspirin use was not found to be associated with a reduction in breast cancer-specific mortality overall. However, effect modification by lymph node status was observed and mortality was found to be reduced by approximately one-half among aspirin users with lymph node-negative disease. This represents a clinically significant reduction in breast cancer mortality. These findings contribute to the understanding of aspirin's mechanism of action in breast cancer. However, further etiologic research to understand this association is warranted. Cancer 2016;122:2067-75. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Follow-through of a positive screening test is necessary to reap the potential benefits of cancer screening. Racial variation in follow-through diagnostic care may underlie a proportion of the known disparity in prostate cancer mortality. The authors used data from the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial to determine whether race is associated with the use of follow-up diagnostic testing after a positive initial screening evaluation. METHODS Men who had a prostate-specific antigen (PSA) level >4 ng/mL at any time during the study were included. The proportion of men who underwent follow-up evaluation with a repeat PSA, a prostate biopsy, or either test within 9 months was determined, and the authors tested for differences in follow-through according to race using mixed-effects multivariate models with a random effect for accrual site to account for clustering. Models were stratified according to age (<65 years and ≥65 years). RESULTS Among 6294 men who had a PSA elevation during the study period, 70% underwent a repeat PSA or prostate biopsy within 9 months. Non-Hispanic black men aged <65 years had 45% lower odds of undergoing a repeat PSA test or prostate biopsy compared with non-Hispanic white men (odds ratio, 0.55; 95% confidence interval, 0.37-0.82), whereas there was no racial difference in follow-through among older men. CONCLUSIONS The current results suggest that limitations in access to care among non-Hispanic black men under the age of Medicare eligibility may underlie the paradoxically low use of follow-through diagnostic care among non-Hispanic black men in the United States. Cancer 2013;119:2223-2229. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND. Two recent chemoprevention trials demonstrated significant reductions in overall prostate cancer incidence. However, a possible increase in high-grade disease has raised concerns that the harms of the drugs, including mortality because of high-grade disease, may outweigh the benefits. The authors attempted to estimate the effect of these drugs on prostate cancer mortality to be able to better evaluate the cost-benefit tradeoff. METHODS. The authors analyzed prostate cancer incidence in the Prostate Cancer Prevention Trial (PCPT) and Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which evaluated finasteride and the related compound dutasteride, respectively (both vs placebo). They used 13-year prostate cancer survival data from the Prostate, Lung, Colorectal and Ovarian (PLCO) trial to project prostate cancer mortality from incidence patterns; survival rates were applied to incident cancers according to prognostic strata, which were defined by Gleason score, prostate-specific antigen level, and clinical stage. For PCPT, the analysis was performed using both original trial results and previously published adjusted analyses that attempted to account for artifacts related to the drugs' effect on prostate volume. RESULTS. For the PCPT trial, the estimated relative risk (RR) for prostate cancer mortality was 1.02 (95% confidence interval [95% CI], 0.85-1.23) using the original trial results and 0.87 (95% CI, 0.72-1.06) and 0.91 (95% CI, 0.76-1.09) based on the adjusted PCPT analyses. For the REDUCE trial, the RR for prostate cancer mortality was 0.93 (95% CI, 0.80-1.08). CONCLUSIONS. Projecting a mortality outcome of the PCPT and REDUCE trials as an approach to weighing benefits versus harms suggests at most a small increase in prostate cancer mortality in the treatment arms, and possibly a modest decrease. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Prostate cancer, like many diseases, is more common in older men. Although an estimated 1 in 7 men will be diagnosed with it, the majority of these men will not die from prostate cancer. The latent nature of this disease, the use of screening with prostate-specific antigen (PSA) testing and the greater risk of dying from causes other than prostate cancer contribute to this disparity. As the US population continues to age, prostate cancer screening and disease management presents an increasingly important public health issue. We discuss the current PSA screening recommendations and practices in the USA and the benefits and harms of screening older populations. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: A recent ovarian cancer genome-wide association study (GWAS) identified a locus on 9p22 associated with reduced ovarian cancer risk. The single nucleotide polymorphism (SNP) markers localize to the BNC2 gene, which has been associated with ovarian development. Methods: We analyzed the association of 9p22 SNPs with transvaginal ultrasound (TVU) screening results and CA-125 blood levels from participants without ovarian cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO); 1,106 women with adequate ultrasound screening results and available genotyping information were included in the study Results: We observed a significantly increased risk of abnormal suspicious TVU results for seven SNPs on 9p22, with odds ratios between 1.68 (95% CI: 1.04-2.72) for rs4961501 and 2.10 (95% CI: 1.31-3.38) for rs12379183. Associations were restricted to abnormal suspicious findings at the first TVU screen. We did not observe an association between 9p22 SNPs and CA-125 levels. Conclusions: Our findings suggest that 9p22 SNPs, which were found to be associated with decreased risk of ovarian cancer in a recent GWAS, are associated with sonographically detectable ovarian abnormalities. Our results corroborate the relevance of the 9p22 locus for ovarian biology. Further studies are required to understand the complex relationship between screening abnormalities and ovarian carcinogenesis and to evaluate whether this locus can influence the risk stratification of ovarian cancer screening. [ABSTRACT FROM AUTHOR]

Background: Despite the recent publication of results from two randomized clinical trials, prostate specific antigen (PSA) screening for prostate cancer remains a controversial issue. There is lack of agreement across studies that PSA screening significantly reduces prostate cancer mortality. In spite of these facts, the widespread use of PSA testing in the United States leads to overdetection and overtreatment of clinically indolent prostate cancer, and its associated harms of incontinence and impotence. Discussion: Given the inconclusive results from clinical trials and incongruent PSA screening guidelines, the decision to screen for prostate cancer with PSA testing is an uncertain one for patients and health care providers. Screening guidelines from some health organizations recommend an informed decision making (IDM) or shared decision making (SDM) approach for deciding on PSA screening. These approaches aim to empower patients to choose among the available options by making them active participants in the decision making process. By increasing involvement of patients in the clinical decision-making process, IDM/SDM places more of the responsibility for a complex decision on the patient. Research suggests, however, that patients are not wellinformed of the harms and benefits associated with prostate cancer screening and are also subject to an assortment of biases, emotion, fears, and irrational thought that interferes with making an informed decision. In response, the IDM/SDM approaches can be augmented with strategies from the philosophy of libertarian paternalism (LP) to improve decision making. LP uses the insights of behavioural economics to help people better make better choices. Some of the main strategies of LP applicable to PSA decision making are a default decision rule, framing of decision aids, and timing of the decision. In this paper, we propose that applying strategies from libertarian paternalism can help with PSA screening decision-making. Summary: Our proposal to augment IDM and SDM approaches with libertarian paternalism strategies is intended to guide patients toward a better decision about testing while maintaining personal freedom of choice. While PSA screening remains controversial and evidence conflicting, a libertarian-paternalism influenced approach to decision making can help prevent the overdiagnosis and overtreatment of prostate cancer. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate the ability of prostate-specific antigen velocity (PSAV) to predict prostate cancer, and assess the test characteristics of several PSAV thresholds for identifying prostate cancer and high-grade cancers. PATIENTS AND METHODS From a population-based database of PSA results, men with an initial PSA level of <10.0 ng/mL, taken between I January 1994 and 31 December 2003, were identified. Those with three or more PSA tests before diagnosis, taken over ≥18 months, were included. Men were followed for a diagnosis of prostate cancer or histologically confirmed benign disease until 31 December 2003. RESULTS In all, 24 709 men were included, with 716 (2.9%) diagnosed with prostate cancer and 1488 (6.0%) with benign histology. The mean (10.38 vs 0.43 ng/mL/year) and median (1.47 vs 0.03 ng/mL/year) PSAV were considerably higher in men with prostate cancer than in those with no cancer ( P < 0.001). There was no PSAV threshold that could reliably identify prostate cancer or high-grade cancers without requiring many men to proceed to prostate biopsy. CONCLUSION In this population, PSAV had additional value over one PSA value in identifying men with prostate cancer. Many men with prostate cancer might have a ‘normal’ (<0.75 ng/mL/year) PSAV. As with total PSA level, there was no PSAV threshold that could reliably predict prostate cancer, but rather a continuum of risk of cancer associated with PSAV level. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Numerous methods of calculating PSA velocity (PSAV) are used and have the potential to produce differing PSAV results from the same PSA data. We calculated PSAV using three common methods and compared differences between the methods and their predictive value for prostate cancer diagnosis. Methods: From a population-based database of PSA results, men with initial PSA<10.0ng/ml and a subsequent diagnosis of prostate cancer or benign histology were identified. Those with ≥3 PSA tests before diagnosis carried out over a minimum of 18 mo were included. PSAV was calculated by using three methods: [1.] Arithmetic equation of change in PSA over time (AE) [2.] Linear regression (LR) [3.] Rate of PSA change using first and last values only (FL) The differences between the methods and test characteristics of each method were compared. Results: Of the 2204 men included, 716 (32.5%) were diagnosed with prostate cancer and 1488 (67.5%) benign histology. PSAV differed markedly in each method of calculation. The LR and FL methods had similar predictive values, which were higher than the AE method. There was strong agreement for cancer diagnosis between LR and FL (kappa=0.85), with weaker agreement between LR/AE and FL/AE (kappa=0.69 and 0.66, respectively). Conclusions: Methods used to calculate PSAV using the same PSA data can produce markedly different results. Linear regression should be the method of choice for calculating PSAV. Using first and last PSA values only may be adequate for everyday clinical use, as long as measurements are separated by a sufficiently long time period. [Copyright &y& Elsevier]

Abstract: Background: The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized screening trial demonstrated no mortality effect of screening. Here we analyze prostate cancer specific survival in PLCO and its relation to screening. Methods: 76,693 men aged 55–74 were randomized to usual care (n =38,350) or intervention (n =38,343). Intervention arm men received annual prostate-specific antigen (6 years) and digital rectal exam (4 years). Men were followed for cancer diagnosis and mortality through 13 years. Medical record abstractors confirmed prostate cancer diagnoses, stage and grade. Prostate-specific survival in PLCO cases was analyzed using Kaplan–Meier analysis and proportional hazards modeling. We utilized data from the Surveillance, Epidemiology and End Results (SEER) program to compute expected survival in PLCO and compared this to observed. Results: There was no significant difference in prostate-specific survival rates between arms; 10 year survival rates were 94.7% (intervention, n =4250 cases) versus 93.5% (usual care, n =3815 cases). Within the intervention arm, cases never screened in PLCO had lower 10 year survival rates (82%) than screen detected or interval (following a negative screen) cases, both around 95.5%. The ratio of observed to expected 10 year prostate-specific death (1-survival) rates was 0.59 (95% CI: 0.51–0.68) for all PLCO cases, 0.66 (95% CI: 0.51–0.81) for Gleason 5–7 cases and 1.07 (95% CI: 0.87–1.3) for Gleason 8–10 cases. Conclusion: Prostate cancer specific survival in PLCO was comparable across arms and significantly better than expected based on nationwide population data. How much of the better survival is due to a healthy volunteer effect and to lead-time and overdiagnosis biases is not readily determinable. [Copyright &y& Elsevier]

Abstract: Background: To estimate the benefits of prostate-specific antigen (PSA) screening on prostate cancer (Pca) metastasis and Pca-specific mortality, we compared two populations with a well-defined difference in intensity of screening. Methods: Between 1997 and 1999, a total of 11,970 men, aged 55–74years, were included in the intervention arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) section Rotterdam. Control population consisted of 133,287 men, aged 55–74years, between 1998 and 1999 in Northern Ireland (NI). Men were followed for Pca incidence, Pca metastasis and cause of death until 31st December 2006. Results: Median age in both groups was 63years at study entry (p =0.184). In Rotterdam 94.2% of men and in NI 6% of men underwent PSA testing. In Rotterdam, 1153 men (9.6%) were diagnosed with Pca with median baseline PSA of 5.1ng/ml. In NI, 3962 men (3.0%, p <0.001) were diagnosed with Pca with median baseline PSA of 18.0ng/ml (p <0.001). The relative risk of Pca metastasis during observation in the intervention population compared to control population was 0.47 (95% confidence interval (CI), 0.35–0.63; p <0.001). The relative risk of Pca-specific mortality was also lower in the intervention population compared to the control population after a median follow-up of 8.5years: 0.63 (95% CI, 0.45–0.88; p =0.008); absolute mortality reduction was 1.8 deaths per 1000 men. Conclusions: A relative reduction in Pca metastasis of 53% and Pca mortality of 37% was observed in the intervention population after 8.5years of observation. The impact of overdiagnosis, quality of life benefits and cost-effectiveness need to be assessed before population-based PSA screening can be recommended. [Copyright &y& Elsevier]