Which men benefit from prostate cancer screening? Prostate cancer mortality by subgroup in the European Randomised Study of Screening for Prostate Cancer.

OBJECTIVE: To evaluate whether a subgroup of men can be identified that would benefit more from screening than others. MATERIALS AND METHODS: This retrospective cohort study was based on three European Randomised Study of Screening for Prostate Cancer (ERSPC) centres, Finland, the Netherlands and Sweden. We identified 126 827 men aged 55-69 years in the study who were followed for maximum of 16 years after randomisation. The primary outcome was prostate cancer (PCa) mortality. We analysed three age groups 55-59, 60-64 and 65-69 years and PCa cases within four European Association of Urology (EAU) risk groups: low, intermediate, high risk, and advanced disease. RESULTS: The hazard ratio (HR) for PCa mortality in the screening arm relative to the control arm for men aged 55-59 years was 0.96 (95% confidence interval [CI] 0.75-1.24) in Finland, 0.70 (95% CI 0.44-1.12) in the Netherlands and 0.42 (95% CI 0.24-0.73) in Sweden. The HR for men aged 60-64 years was 1.03 (95% CI 0.77-1.37) in Finland, 0.76 (95% CI 0.50-1.16) in the Netherlands and 0.97 (95% CI 0.64-1.48) in Sweden. The HR for men aged 65-69 years was 0.80 (95% CI 0.62-1.03) in Finland and 0.57 (95% CI 0.38-0.83) in the Netherlands, and this age group was absent in Sweden. In the EAU risk group analysis, PCa mortality rates were materially lower for men with advanced disease at diagnosis in all three countries: 0.67 (95% CI 0.56-0.82) in Finland, 0.28 (95% CI 0.18-0.44) in the Netherlands, and 0.48 (95% CI 0.30-0.78) in Sweden. CONCLUSION: We were unable to unequivocally identify the optimal age group for screening, as mortality reduction differed among centres and age groups. Instead, the screening effect appears to depend on screening duration, and the number and frequency of screening rounds. PCa mortality reduction by screening is largely attributable to stage shift.

Key learning on the promise and limitations of MRI in prostate cancer screening.

MRI retains its ability to reduce the harm of prostate biopsies by decreasing biopsy rates and the detection of indolent cancers in population-based screening studies aiming to find clinically significant prostate cancers. Limitations of low positive predictive values and high reader variability in diagnostic performance require optimisations in patient selection, imaging protocols, interpretation standards, diagnostic thresholds, and biopsy methods. Improvements in diagnostic accuracy could come about through emerging technologies like risk calculators and polygenic risk scores to select men for MRI. Furthermore, artificial intelligence and workflow optimisations focused on streamlining the diagnostic pathway, quality control, and assurance measures will improve MRI variability. CLINICAL RELEVANCE STATEMENT: MRI significantly reduces harm in prostate cancer screening, lowering unnecessary biopsies and minimizing the overdiagnosis of indolent cancers. MRI maintains the effective detection of high-grade cancers, thus improving the overall benefit-to-harm ratio in population-based screenings with or without using serum prostate-specific antigen (PSA) for patient selection. KEY POINTS: • The use of MRI enables the harm reduction benefits seen in individual early cancer detection to be extended to both risk-stratified and non-stratified prostate cancer screening populations. • MRI limitations include a low positive predictive value and imperfect reader variability, which require standardising interpretations, biopsy methods, and integration into a quality diagnostic pathway. • Current evidence is based on one-time point use of MRI in screening; MRI effectiveness in multiple rounds of screening is not well-documented.

[Prostate cancer - diagnostics and screening]. / Prostatacancer ­ utredning, klinisk diagnostik och screening.

Prostate-specific antigen (PSA) based screening is controversial, even though randomised trials show that screening can reduce prostate cancer mortality. The main reason is that screening leads to overdiagnosis of indolent cancers that would never have surfaced clinically in the absence of screening. Recently, several large studies have shown that magnetic resonance imaging (MRI) improves prostate cancer diagnostics. With MRI, up to half of all men with elevated PSA values can be spared a biopsy. When a biopsy is needed, the needles can be directed towards the suspicious area in the prostate, which increases the detection of clinically significant tumors. In Sweden, regional programmes with organised prostate cancer testing were introduced in 2020. These programmes aim to make prostate cancer testing more standardized, efficient, and equitable. In the future, biomarkers and AI-based systems will likely be important to further improve prostate cancer diagnostics.

Prostate Cancers in the Prostate-specific Antigen Interval of 1.8-3 ng/ml: Results from the Göteborg-2 Prostate Cancer Screening Trial.

BACKGROUND AND OBJECTIVE: Magnetic resonance imaging(MRI) and targeted biopsies reduce overdiagnosis of prostate cancer(PC). It is uncertain how this strategy performs for low PSA levels. The objective was to investigate the PI-RADS distribution, frequency and characteristics of screen-detected PC with PSA of 1.8-<3ng/ml and 3-<10ng/ml. METHODS: In the population-based Göteborg-2 screening study, 17 974 men choose to participate by having a PSA(2015-2020). One-third of the participants(n=6006) were randomized to Arm 3, men with a PSA ≥1.8ng/ml were recommended MRI. Men with positive MRI(PI-RADS3-5) had four targeted biopsies from each MRI-visible lesion. Clinically significant PC was defined as Gleason score ≥3+4. KEY FINDINGS AND LIMITATIONS: 6006 men were included. Median age was 55.9 years. 670(11%) had PSA of 1.8-<3ng/ml(low-PSA group), median PSA 2.1ng/ml, and 377(6.3%) had PSA of 3-<10ng/ml(high-PSA group), median PSA 3.9ng/ml. PI-RADS scores of 3, 4, and 5 were observed in 7.8%, 15%, and 1.0% in the low-PSA group, and in 6.9%, 17%, and 5.3% in the high-PSA group, respectively. PC was found in 64 men (41%, 95%CI 0.33-0.49) with positive MRI findings in the low-PSA group, 33(21%) had Gleason 6 and 31(20%) had Gleason ≥7. In the high-PSA group, PC was detected in 61men (56%, 95%CI 0.46-0.66), 26(24%) had Gleason 6 and 35(32%) had Gleason ≥7. Limitations include results from only a single screening round. CONCLUSIONS AND CLINICAL IMPLICATIONS: A non-negligible number of men with PSA 1.8-3ng/ml have clinically significant PC. Whether a delay in the diagnosis of these tumors until they reached PSA ≥3ng/ml would impair their chance of cure remains to be evaluated.

Performance of 4Kscore as a Reflex Test to Prostate-specific Antigen in the GÖTEBORG-2 Prostate Cancer Screening Trial.

BACKGROUND AND OBJECTIVE: We investigated whether adding 4Kscore as a reflex test to prostate-specific antigen (PSA) could improve the screening algorithm for prostate cancer (PC). METHODS: In the GÖTEBORG-2 PC screening trial, 38 000men (50-60 yr) were invited to PSA testing and, if elevated, followed by magnetic resonance imaging (MRI). For 571 men with PSA ≥3.0 ng/ml and evaluable outcomes, 4Kscore was calculated. The performance using a prespecified 4Kscore cutoff of 7.5% was evaluated. KEY FINDINGS AND LIMITATIONS: The area under the curve for 4Kscore to identify intermediate- and high-risk PC was 0.84 (95% confidence interval 0.79-0.89), and the positive predictive value, and negative predictive value were 15% (0.12-0.20) and 99% (97-100%), respectively. Of the 54 men diagnosed with intermediate- or high-grade PC, two had a 4Kscore cutoff below 7.5%, both with organ-confined intermediate-risk PC. Per 1000 men with elevated PSA, adding 4Kscore would have resulted in avoidance of MRI for 408 (41%) men, biopsies for 95 (28% reduction) men, and diagnosis of 23 low-grade cancers (23% reduction) while delaying the diagnosis of four men with intermediate-grade cancers (4%). CONCLUSIONS AND CLINICAL IMPLICATIONS: Including 4Kscore as a reflex test for men with elevated PSA reduces the need for MRI and biopsy markedly, and results in less overdiagnosis of low-grade PC at the cost of delaying the diagnosis of intermediate-grade PC in a few men. These results add further evidence for including new blood-based biomarkers in addition to PSA to improve the harm and benefit ratio of PC screening and reduce the need for resource-demanding MRI and biopsies. PATIENT SUMMARY: In this study, 4Kscore, a blood-based biomarker, as a reflex test for men with elevated prostate-specific antigen (PSA), reduces the need for magnetic resonance imaging and biopsy. These results support the inclusion of new blood-based biomarkers in addition to PSA.

How a population-based cohort of men estimate lifetime risk of prostate cancer in a survey before entering a prostate cancer screening trial in Sweden?

OBJECTIVES: Investigating men's perceived lifetime risk of prostate cancer. DESIGN: Survey-based study to men invited for prostate-specific antigen (PSA) screening in the GÖTEBORG-2 trial between September 2015 and June 2020. SETTING: 38 775 men in the Gothenburg area, Sweden, were invited for PSA-testing and participated in a survey. PARTICIPANTS: 17 980 men participated in PSA-testing, of whom 13 189 completed the survey. In addition, 1264 men answered the survey only. INTERVENTIONS: Before having the PSA-test, men answered an electronic survey and estimated their lifetime risk of receiving a prostate cancer diagnosis on a visual analogue scale from 0% to 100%. MAIN OUTCOME MEASURES: The primary outcome was the median lifetime risk estimation, which was compared with Wilcoxon test to an anticipated lifetime risk of 20% (based on GÖTEBORG-1 trial). The secondary outcome was to determine factors associated with risk estimation in a multivariable linear regression model: previous prostate examination, family history, physical exercise, healthy diet, comorbidity, alcohol consumption, smoking, education level, marital status, urinary symptoms and erectile dysfunction. RESULTS: Among PSA-tested men, the median estimated lifetime risk of prostate cancer was 30% (IQR 19% to 50%), corresponding to a 10 percentage-points higher estimation compared with the anticipated risk (p<0.001). Family history of prostate cancer, moderate to severe urinary symptoms and mild to moderate erectile dysfunction were associated with >5 percentage-points higher risk estimation. Similar results were obtained for non-PSA-tested men. CONCLUSIONS: Most men overestimated their prostate cancer risk which underscores the importance of providing them accurate information about prostate cancer. TRIAL REGISTRATION NUMBER: ISRCTN94604465.