prostate cancer screening research paper

Screening for prostate cancer: evidence, ongoing trials, policies and knowledge gaps

Author affiliations

Anssi Auvinen 3 ,

Rebecka Arnsrud Godtman 1 2 ,

Mikael Hellström 4 5 ,

Jonas Hugosson 1 2 ,

Hans Lilja 6 7 ,

Jonas Wallström 4 5 ,

Monique J Roobol 8 .

Long-term screening with serum prostate-specific antigen (PSA) and systematic prostate biopsies can reduce prostate cancer mortality but leads to unacceptable overdiagnosis. Over the past decade, diagnostic methods have improved and the indolent nature of low-grade prostate cancer has been established. These advances now enable more selective detection of potentially lethal prostate cancer. This non-systematic review summarises relevant diagnostic advances, previous and ongoing screening trials, healthcare policies and important remaining knowledge gaps.

Evidence synthesis and conclusions: The strong association between low serum PSA values and minimal long-term risk of prostate cancer death allows for adjusting screening intervals. Use of risk calculators, biomarkers and MRI to select men with a raised PSA value for biopsy and lesion-targeting rather than systematic prostate biopsies reduce the detection of low-grade cancer and thereby overdiagnosis. These improvements recently led the European Union to recommend its member states to evaluate the feasibility and effectiveness of organised screening programmes for prostate cancer. Nonetheless, important knowledge gaps remain such as the performance of modern diagnostic methods in long-term screening programmes and their impact on mortality. The knowledge gaps are currently being addressed in three large randomised screening trials. Population-based pilot programmes will contribute critical practical experience.

Introduction

Prostate cancer is one of the leading causes of cancer death in many countries. 1 The disease has a long, asymptomatic, organ-confined stage and is usually incurable when symptomatic. Serum prostate-specific antigen (PSA) testing was introduced in the late 1980s to identify asymptomatic men with prostate cancer. 2 Although serum PSA is a sensitive marker of potentially lethal prostate cancer, its specificity is low. 3 Moderately elevated PSA values (3–10 ng/mL) are more often caused by benign prostatic hyperplasia than prostate cancer. 4 5 As digital rectal examination and transrectal ultrasound cannot rule out clinically significant prostate cancer, a systematic prostate biopsy became the standard diagnostic investigation for men with raised PSA values (≥3 or 4 ng/mL). A European, multinational, randomised screening trial shows that prostate cancer mortality can be reduced by screening but also that the use of systematic biopsies leads to unacceptably high rates of overdiagnosis. 6 As latent, microscopic prostate cancer is common in middle-aged and elderly men, 7 this is not surprising.

Over the past couple of decades, research has been devoted to developing diagnostic methods that more selectively identify men with a potentially lethal prostate cancer. An important progress was the introduction of pre-biopsy MRI and lesion-targeting biopsies. 8–13 Other important advances include biomarkers and nomograms that can aid in identifying men who despite a moderately raised PSA value are unlikely to have a potentially lethal prostate cancer. 14 Moreover, modifications of the Gleason prostate cancer grading system have led to a definition of the lowest grade (Gleason score 6) that now exclusively includes clinically insignificant, slowly progressing cancers with minimal metastatic potential. 15–18

These advances recently led the Council of the European Union to recommend the member states to evaluate the feasibility and effectiveness of organised prostate cancer screening. 19 Our review summarises the results from previous prostate cancer screening trials, relevant diagnostic research, ongoing prostate cancer screening trials and current healthcare policies, and outlines remaining scientific knowledge gaps and practical issues.

PubMed was searched on 2 January 2023 for clinical trials, systematic reviews and meta-analyses with the terms “screening” AND “prostatic neoplasm” OR “prostate cancer” AND (“biopsy” OR “diagnosis” OR “mortality” OR “detection”) published since 1 January 2018. Similar searches were done for the diagnostic methods described in the review. Relevant articles were selected by OB. Additional articles were identified in reference lists. On the same day, a search was done on ClinicalTrials.gov and IRSCTN.com for ‘prostate cancer screening’ to identify ongoing trials.

Previous screening trial results

Except for a few older studies, all randomised prostate cancer screening trials reporting on prostate cancer mortality outcomes used serum PSA as the primary screening test followed by systematic biopsy. 20 Currently relevant trials are summarised below.

The European Randomized Study of Screening for Prostate Cancer (ERSPC)

The multinational European Randomized study of Screening for Prostate Cancer (ERSPC) was initiated in 1993. 21 Recruitment and randomisation procedures differed across countries. Three centres designed population-based effectiveness trials (randomisation before consent) and four centres efficacy trials (consent before randomisation). The core age group for endpoint analyses was 55–69 years at randomisation. The primary endpoint was prostate cancer mortality. Secondary endpoints included metastatic disease and quality of life

The primary screening test was serum PSA. Men with PSA ≥3.0 ng/mL were referred for a systematic prostate biopsy (in Finland, men with PSA 3.0–3.9 ng/mL had an ancillary test to select for biopsy). The screening interval was 4 years in most centres.

After 9 years of median follow-up of 162 242 men, the rate ratio for prostate cancer death in the screening versus the control group was 0.80 (95% CI 0.65 to 0.98). The absolute prostate cancer mortality risk difference was 0.71 prostate cancer deaths per 1000 men. This, together with an excess incidence of 34 prostate cancer cases per 1000 men, translates into 1410 invited men and 48 additional prostate cancer diagnoses (numbers needed to invite and diagnose) to avert one death from prostate cancer. 22 The main results of this and three later publications are shown in table 1 . 6 22–24 With longer follow-ups, the absolute prostate cancer mortality risk difference increased and the numbers needed to invite and diagnose decreased. Twelve-year follow-up data from four centres showed a 50% reduction of metastatic disease at the time of diagnosis and a 30% reduction overall, that is, including also metastasis detected during follow-up. 25 An analysis accounting for non-compliance and PSA testing in the control group, based on the Dutch part of ERSPC, shows that the net mortality reduction among screening participants was 51% (intention-to-screen analysis: 32%). 26

Gothenburg-1 screening trial

The Gothenburg-1 trial started in 1995 as an independent trial but since 1996 constitutes the Swedish branch of the ERSPC. A population-based sample of 20 000 men aged 50–64 years was randomised 1:1 to either biennial PSA screening with a 3 ng/mL threshold for a systematic 6-core biopsy, or to a control group. As many as 93% of the screened men with a PSA ≥3.0 ng/mL had at least one prostate biopsy. 27 Despite that PSA testing was common in the control group (72% had at least 1 PSA test 28 ), the Gothenburg-1 trial reported the greatest prostate cancer mortality reduction of all screening trials. After 14 years, the relative reduction was 44% (95% CI 28% to 64%) 27 ; the absolute prostate cancer mortality was reduced from 0.9% to 0.5% (difference 0.4%, 95% CI 0.17% to 0.64%). 27 After 22 years, the relative reduction was 29% (95% CI 9.0% to 0.45%) and the absolute reduction was 0.6% (95% CI 0.15% to 1.0%). 29 Younger age at screening start (50–55 years vs 60 years) and primary school education only were both associated with a greater relative mortality reduction. 30–32 The number needed to diagnose to prevent one prostate cancer death was 12 after 14 years and 9 after 22 years. 27 29

A mere 0.6% of the men with a moderately raised PSA (3–9.9 ng/mL) and a negative first biopsy died from prostate cancer within 20 years. 33 Most men (79%) in the screening group who died from prostate cancer either started screening after the age of 60 years, did not attend or were diagnosed with prostate cancer after screening had stopped. 29 The protective effect of screening on prostate cancer mortality waned off 10–12 years after screening cessation. 34

The prostate cancer incidence in the control group had after 24 years still not reached the incidence in the screening group, which means that many screening-detected cancers would never have been clinically diagnosed. 31

The Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial

The PLCO cancer screening trial recruited 76 693 US men aged 55–74 years from 1993 to 2001. Men in the screening group underwent annual PSA testing for 6 years and annual digital rectal examination for 4 years. After 13 years, the relative prostate cancer incidence was 1.12 (95% CI 1.07 to 1.17) and the relative risk of prostate cancer death was 1.09 (95% CI 0.87 to 1.36) in the screening group compared with the control group. 35 These results cannot, however, be used for evaluating the effect of screening versus no screening, as almost half of the enrolled men had been PSA tested before entering the study, 90% of the control men were PSA tested and less than half of the men with raised PSA underwent a prostate biopsy. 36–38

The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) trial

The UK-based CAP invited 75 707 men aged 50–69 years for a single PSA test via their primary care practice from 2001 to 2009, of whom 36% participated. 39 A control group of almost 350 000 men received standard care, of whom 25% were PSA-tested at least once. 40 After 10 years, a greater proportion of men in the intervention group (6.0%) than in the control group (3.6%) had been diagnosed with prostate cancer, but there was no difference in prostate cancer mortality (rate ratio 0.96, 95% CI 0.85 to 1.08).

Improved diagnostic methods

Psa for risk stratification.

PSA levels within the ‘normal’ range (<3 ng/mL) at age 45–60 years are strongly associated with up to 25-year risks of advanced, metastatic and lethal prostate cancer. 3 41–47 For example, PSA values below the age-specific median (eg, 1.1 ng/mL at age 60) are associated with 15-year and 25-year risks of lethal prostate cancer far below the population average. 3 41 42 46 47 PSA levels can therefore be used to adapt screening intervals and stop-age to men’s predicted long-term risk of lethal prostate cancer. 48 49

PSA density

Serum PSA is a non-specific test for prostatic disease. Gleason score ≥7 cancer is, however, associated with a higher serum PSA rise per unit volume than Gleason score 6 cancer and benign prostatic tissue. 5 50 This ratio between serum PSA and prostate volume (PSA density) is therefore a better marker for Gleason score ≥7 cancer than serum PSA alone. 51 PSA density can be used for selecting men with an unsuspicious or equivocal prostate MRI for biopsy. 52 Men with a moderately raised PSA value, an unsuspicious MRI and a PSA density <0.1 ng/mL/cm 3 are not more likely to have a Gleason score ≥7 prostate cancer than men in the general population. 52

Other biomarkers

Conventional serum PSA tests measure both free and complexed forms. Assays detecting free PSA, 53 54 the subfractions intact PSA 55 or −2 proPSA, 56 or the closely related hK2 protein 57 may be used to improve test specificity, either alone or in combination such as in the Prostate Health Index (PHI) and 4Kscore tests. 58–63

Two statistical models based on biomarker measurements in serum with or without clinical data have been evaluated in large screening populations: the Stockholm-3 test and 4Kscore test. The Stockholm-3 test measures total and free serum PSA, hK2, microseminoprotein-β, macrophage inhibitory cytokine-1, a polygenic risk score calculated from single-nucleotide polymorphisms, age, first-degree family history and previous biopsy. 64 The Stockholm-3 test may reduce unnecessary systematic biopsies by 44% and detection of Gleason score 6 cancer by 17%, compared with a systematic biopsy for all men with PSA ≥3 ng/mL. 64 The test may also be used to select men for MRI, which in a randomised trial reduced the need for MRI by 36%. 65 The Stockholm-3 test has not been externally validated and there has been some variation in the cut-offs and test components. 66–68

The 4Kscore test is based on measuring free, intact, total PSA and hK2 in blood and information about age, digital rectal examination and prior biopsy. 63 Use of the 4Kscore test decreases unnecessary biopsies by 30%–50% while maintaining >90% detection of Gleason score ≥7 and >97% of Gleason score ≥4+3=7 cancer. 69 70 Furthermore, the 4Kscore predicts a 10–20-year risk of lethal prostate cancer among healthy middle-aged men with ‘normal’ or moderately high PSA values. 42 46

MRI and lesion-targeting biopsy

Use of MRI and lesion-targeting biopsies substantially reduce the detection of Gleason score 6 prostate cancer and somewhat increase the detection of Gleason score ≥7 cancer, compared with a systematic prostate biopsy. 10 12 13 71 A systematic review and meta-analysis of 5831 patients from 26 clinical practice studies compared MRI and lesion-targeting biopsies with systematic biopsies and showed a relative detection rate of 0.65 (95% CI 0.55 to 0.77) for Gleason score 6 and 1.3 (95% CI 1.2 to 1.4) for Gleason score ≥7 cancer. 12

Recently, also data from screening settings have been reported. The population-based Stockholm-3-MRI study randomly allocated 1532 men aged 50–75 years with PSA ≥3 ng/mL to either a systematic biopsy only or an MRI and targeted plus systematic biopsies. 13 Gleason score ≥7 cancer detection was similar in both groups. Gleason score 6 cancer was detected in 4% of the MRI group in 12% of the systematic biopsy group (8% difference, 95% CI 5% to 11%). Fifty-six per cent of the men with PSA ≥3 ng/mL had an unsuspicious MRI and avoided biopsy. Results from the Gothenburg-2 trial are reported below. 10

MRI has also been evaluated as the primary screening test: the IP-Prostagram study screened 403 men aged 50–69 years with PSA, transrectal ultrasound and an MRI. 72 All men with at least one positive screening test had a systematic biopsy; men with an MRI or ultrasound lesion also had a targeted biopsy. The diagnostic pathway with an MRI threshold of ≥4 on the 5-tier Prostate Imaging—Reporting and Data System (PI-RADS) score resulted in 10.6% positive tests, 2.7% detection of Gleason score ≥7 cancer and 1.2% Gleason score 6 cancer. A PSA threshold of ≥3 ng/mL resulted in 23.7% positive tests and the detection of Gleason score ≥7 cancer in 1.7% and Gleason score 6 cancer in 1.6% of the men. Similar results were recently reported from the MRI Versus PSA in Prostate Cancer Screening (MVP) study. 73

Several meta-analyses conclude that prostate MRI without contrast enhancement (bi-parametric MRI) has similar diagnostic accuracy as multiparametric MRI with intravenous contrast medium. 74–78 A pooled analysis of 17 studies directly comparing bi-parametric with multiparametric MRI showed no significant differences in sensitivity or specificity. 75 In a prospective, paired study of 551 men in a screening trial, bi-parametric MRI was non-inferior to multiparametric MRI, with a relative risk for detection of any prostate cancer 0.99 (95% one-sided CI: 0.95 to 1.0). 79

Risk calculators

The first wave of diagnostic prostate cancer risk calculators included clinical variables to select men with a moderately raised serum PSA value for biopsy. 80 Few of them are externally validated, which is a prerequisite to properly assess their clinical value. 81–87 Risk calculators also incorporating prostate volume assessed by transrectal ultrasound better identify men with Gleason score ≥7 cancer. 51 88 89 More recently, risk calculators substituting digital rectal examination with MRI have been developed, some of which also include new biomarkers. 90 91 A recent systematic review identified 18 risk calculators incorporating MRI results. 91 All improved prediction of Gleason score ≥7 cancer better than risk calculators without MRI, but only seven were externally validated and even fewer met requirements for routine use. 91

Ongoing screening trials

Three large, ongoing randomised screening trials and some smaller trials are described below. The designs of the three large trials are summarised in table 2 .

Gothenburg-2 trial (Sweden)

Gothenburg-2 is a population-based, randomised screening trial evaluating three main research questions 92 :

Does a screening algorithm with a pre-biopsy MRI in men with PSA ≥3.0 ng/mL and lesion-targeted biopsies reduce detection of clinically insignificant cancer while maintaining sufficient detection of clinically significant cancer, compared with a systematic biopsy in all men with PSA ≥3.0 ng/mL?

Does a PSA cut-off of 1.8 ng/mL detect more clinically significant cancer without increasing overdiagnosis?

Does screening with PSA, pre-biopsy MRI and lesion-targeted biopsies reduce prostate cancer mortality compared with a non-invited control group?

In 2015–2020, 58 225 men aged 50–60 years without a prostate cancer diagnosis were identified from the population register and randomly allocated 2:1 to a screening group or a control group without prior consent (Zelen design). Of 38 775 men in the screening group invited to the first round 17 980 (46%) participated and were further randomly allocated to one of three screening algorithms ( figure 1 ). The men are re-invited with 2–8 years’ interval until age 63–76 years. Screening intervals and stop age depend on the PSA value.

Gothenburg-2 screening trial flow chart. PSA, prostate-specific antigen.

Diagnostic outcomes of the first screening round for men with PSA ≥3.0 ng/mL were recently published. 10 In arms 2 and 3 combined (MRI-targeted biopsies only), 2.8% of the invited men had a biopsy, compared with 6.8% in arm 1 (systematic biopsy). Clinically insignificant (Gleason score 3+3=6) cancer was detected in 66 men in arms 2 and 3, and in 72 men in arm 1: relative risk 0.46 (95% CI 0.33 to 0.64), absolute risk difference 0.7%). Gleason score ≥7 cancer was detected in 110 men in arms 2 and 3, and in 68 men in arm 1: relative risk 0.81 (95% CI 0.6 to 1.1), absolute risk difference 0.2%. Of 10 Gleason score 3+4=7 cancers detected on systematic biopsy cores only, 7 were stage T1c and 6 had <5% Gleason pattern 4; none had Gleason score ≥4+3=7. Results from repeated screening rounds are planned for publication in 2023–2024 and prostate cancer mortality data in 2027.

ProScreen (Finland)

The ProScreen trial investigates a screening algorithm including PSA, a four-kallikrein serum panel (4Kscore) and MRI with targeted biopsies. The primary endpoint is prostate cancer mortality after 15 years of follow-up. Secondary endpoints include the cumulative incidences of low-grade cancer and of locally advanced or metastatic prostate cancer after 5 years.

ProScreen covers the target age group 55–63 years in the entire male population of the study areas. A total of 117 000 men (initial protocol: 67 000 men) are randomised 1:3 to a screening group or a control group (inclusion is ongoing). To ensure a representative study population randomisation is done before consent in the screening arm and without consent in the control arm (Zelen design). Men in the screening group with a PSA ≥3.0 ng/mL have a 4Kscore test and those with a positive 4Kscore (≥7.5%) are referred for a prostate MRI ( figure 2 ). Men with a suspicious lesion on MRI (PI-RADS score ≥3) are referred for a targeted prostate biopsy; those with an unsuspicious MRI and a PSA density ≥0.15 ng/mL/cm 3 are referred for a systematic prostate biopsy. Men with PSA <1.0 ng/mL are re-invited after 6 years, men with PSA 1.0–2.9 ng/mL after 4 years and men with PSA ≥3.0 ng/mL and no cancer after 2 years. Results from repeated screening rounds are expected within a few years.

Participant flow through the ProScreen trial and expected distribution of men by test results. PSA, prostate-specific antigen.

The ProScreen trial is embedded in routine clinical practice and the screening intervention is the only component unique to the screening arm. This approach improves feasibility and comparability across the trial arms, reduces costs and facilitates implementation of the study results. Further, changes in clinical diagnostic or therapeutic practices over time are automatically incorporated.

PROBASE (Germany)

PROBASE investigates the efficacy of PSA-based screening with MRI and systematic plus targeted biopsies, comparing start age 45 versus 50 years. 93 94 The primary endpoint is metastatic prostate cancer before age 60 years.

Over 400 000 men were invited from 2014 through 2019, of whom approximately 11% agreed to participate. Of 23 301 participants randomly allocated to screening from age 45 years, 1.5% had an initial PSA ≥3.0 ng/mL. These men had had a second PSA test 2 weeks later; only half of them then still had a PSA ≥3.0 ng/mL. The 179 men with a repeated PSA ≥3.0 ng/mL (0.8% of the initially PSA-tested men) and 7 who did not have a repeat PSA test were referred for MRI and prostate biopsy. Of 120 men who had a biopsy, 33 had Gleason score ≥7 cancer (0.1% of the initially PSA tested men). 93

Men with PSA <1.5 ng/mL are re-invited after 5 years, men with PSA 1.5–2.9 ng/mL after 2 years. Attendance to scheduled screening visits over the first 6 years varied from 70% to 79% across risk groups. 95

Other ongoing prostate cancer screening studies

Many non-randomised, prospective prostate cancer screening studies are ongoing. Several evaluate screening of high-risk populations: The UK BARCODE-1 investigates a polygenic risk score for targeting a high-risk population. 96 The international IMPACT trial includes men with a mismatch repair gene or BRCA1/2 mutation. 97 98 Similar studies are ongoing in the USA (eg, NCT05129605 , NCT04472338 ) and Canada ( NCT01990521 ).

Single-arm studies evaluating the feasibility and cost-effectiveness of population-based screening with PSA and MRI include the ReIMAGINE study in the UK 99 and studies in Switzerland ( NCT03749993 ), Czechia ( NCT05603351 , also evaluating the PHI test to select for MRI) and China ( NCT03891732 , NCT04251546 ).

Prostate cancer screening policies

Almost all national healthcare authorities recommend against population-based prostate cancer screening but acknowledge that individual men may weigh the potential benefits and harms of PSA testing differently. Men may therefore be offered testing on request, after appropriate counselling. 100 The US and European Union policies and the unique policies in Lithuania and Sweden are summarised below.

United States Preventive Services Task Force recommendation

The United States Preventive Services Task Force in 2012 recommended against PSA testing of asymptomatic men, regardless of age. 101 In 2018, the recommendation was changed to: ‘For men aged 55 to 69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician’. 102

European Union recommendation

The 2003 European Union (EU) Council Recommendation for Cancer Screening did not include prostate cancer. Based on an evidence review concluding that screening with PSA testing and bi-parametric MRI for PSA-positive men reduces overdiagnosis and is likely to be cost-effective for many EU member states, 103 and the significant amount of ongoing opportunistic screening, the EU Council in December 2022 recommended that ‘countries should consider a stepwise approach, including piloting and further research, to evaluate the feasibility and effectiveness of the implementation of organised programmes aimed at ensuring appropriate management and quality on the basis of PSA testing for men in combination with additional MRI scanning’. 19

Lithuania: opportunistic PSA screening in primary care

The Lithuanian Early Prostate Cancer Detection Programme started in 2006. 104 A PSA test is offered to all men aged 50–74 years who visit a general practitioner. Men with PSA ≥3 ng/mL are referred to a urologist. During the first 10 years of the programme, 70% of the target population had at least one PSA test. 104 The Lithuanian prostate cancer incidence doubled 2 years after the introduction of the programme. 105

Sweden: population-based organised prostate cancer testing (OPT)

The Swedish Ministry of Health and Social Affairs in 2018 commissioned the Confederation of Regional Cancer Centres in Sweden to standardise the widespread prostate cancer testing and make it more efficient. The Confederation outlined organised prostate cancer testing (OPT) programmes for men aged 50–74 years within the public, tax-financed, regionally provided healthcare. The first two OPT programmes were launched in 2020 in two of Sweden’s most populated regions. 106 As of March 2023, 7 of the 21 regions have started an OPT programme; a further 10 are planned to start over the next year. Men invited to OPT receive a letter with a brief, neutral description of the potential advantages and disadvantages. 49 All steps from invitation to prostate biopsy are organised by an OPT office. PSA testing intervals, use of MRI, indication and extent of prostate biopsies and follow-up are algorithm-based ( online supplemental figure 1 ). All results are registered for quality control and research. 49 A national working group coordinates the programmes and evaluates their outcomes.

Scientific knowledge gaps

Important knowledge gaps remain about many aspects related to screening for prostate cancer ( Box 1 ). The PSA test effectively identifies a large proportion of men at very low risk of clinically significant prostate cancer and will most likely remain the primary screening test. However, the optimal PSA threshold for further diagnostic evaluation is not known. Gleason score ≥7 prostate cancer may be detected also in men with PSA below the commonly used biopsy threshold, that is, ≥3.0 or ≥4.0 ng/mL. 64 107 Delaying detection of these cancers in a structured screening programme may, however, not significantly affect prostate cancer mortality. 108 The ongoing Gothenburg-2 trial is evaluating cancer detection in men with PSA 1.8–2.9 ng/mL. 92

Key knowledge gaps about screening for prostate cancer with modern diagnostic methods

How best to inform men about the potential advantages and disadvantages of screening.

Optimal PSA cut-off.

Optimal start and stop ages.

Diagnostic results from repeated screening rounds.

Optimal screening intervals after negative investigations of men with PSA ≥3 ng/mL.

Optimal use of ‘intermediate tests’ to select men for MRI and biopsy.

Cost-effectiveness of different screening algorithms.

Long-term effects on mortality and overdiagnosis.

Health-economics.

The use of MRI and lesion-targeted biopsies reduces both the proportion of men who have a prostate biopsy and the detection of low-grade prostate cancer, but current evidence is limited to a single diagnostic evaluation without follow-up testing. 10 12 As most of the benefit from a screening programme is gained from repeated testing, 6 31 results from single testing studies cannot be used to reliably estimate how screening with modern diagnostic methods will affect overdiagnosis and cancer-specific mortality. Diagnostic results from repeated screening rounds in the ongoing screening trials are expected within a few years. 10 93 109

The optimal start and stop age of a screening programme are not known. Mortality results from the Gothenburg-1 trial suggest that screening should start at age 50–55 years. 31 Diagnostic results from PROBASE show that very few Gleason score ≥7 cancers are detected among men aged 45 years, 93 which suggests that starting at age 45 is not cost-effective. As the protective effect of screening on prostate cancer mortality does not persist more than 10–12 years after screening cessation, 34 stopping screening at age 70 years may be too early for healthy men in countries with a long life expectancy. Results from the ERSPC suggest that selective screening of men aged 70–75 years may lead to the diagnosis of a greater proportion of Gleason score ≥7 cancer than screening of younger men. 110

Prostate cancer mortality reduction is the definite indicator of screening benefit. A key issue is whether diagnostic outcomes can be used to reliably model mortality and overdiagnosis. Prostate cancer-specific models have been developed, 111 112 but estimating mortality reduction and overdiagnosis from diagnostic results is challenging because these measures can be reliably defined only on a population level. Many cancers currently labelled ‘clinically significant’ represent overdiagnosis (the man would die before experiencing any cancer symptoms) and some cancers labelled ‘clinically insignificant’ may over time dedifferentiate and metastasise. On the other hand, if we wait for long-term results from the ongoing trials, their screening algorithms may be obsolete when mortality results become available. It is obviously not possible to prospectively evaluate every refined screening algorithm in a new randomised trial with mortality as the endpoint.

Cost-effectiveness of different screening algorithms will be essential when healthcare authorities decide if, when and how a screening programme is to be implemented. Availability of MRI resources (equipment and qualified staff) is in many countries a limiting factor for implementing MRI-based screening algorithms. It is therefore important to further evaluate biomarkers and risk calculators for the selection of men with a raised PSA for an MRI. 113 The Finnish ProScreen trial evaluates one such biomarker. 109 Healthcare providers short of MRI machines but not staff may use transrectal ultrasound for prostate volume measurement and calculation of PSA density to select men for MRI, 114 but this approach has not yet been prospectively evaluated in a screening context. The length of screening intervals much affects the need for MRI resources. A report from the Gothenburg-2 trial suggests that most men with PSA ≥3.0 ng/mL and a negative MRI do not need to be re-screened for at least 2 years. 115

Finally, there is scarce evidence for how men who are offered screening are best informed about the potential advantages and disadvantages. This is of course essential for men’s choices. 116 Even with modern prostate cancer diagnostics, positive test results, overdiagnosis and overtreatment remain important potential harms. Explaining these issues to laypeople is a challenge.

Practical considerations on implementation

Unorganised PSA testing is less effective and may be more socioeconomically unequal than an organised screening programme. 32 117–123 Organising population-wide testing may, however, be a Herculean challenge. One challenge is related to the simplicity and availability of the primary screening test PSA. Men can easily obtain PSA tests in the screening intervals and after the programme’s stop age, but PSA testing and urology consultations in parallel with the screening programme are probably not cost-effective.

The optimal use of prostate MRI in a population-based screening setting differs from its use in the standard clinical setting. A shorter protocol without contrast enhancement (ie, bi-parametric MRI) is clearly advantageous from a resource perspective, but the resulting images may be more difficult for non-expert readers to interpret. 124 Screening usually involves younger men who have smaller prostates with a different signal intensity compared with older men’s prostates. 125 Younger men also have a lower prevalence of clinically significant cancer and suspicious MRI lesions. 79 These differences, together with the large variability in MRI interpretation, 126 127 entail a compelling need for quality assurance such as structured training, central review, audits and continuous feedback of biopsy results to reporting radiologists.

Population-based, pilot screening projects were recently recommended by the EU. They will provide experiences that can be used to improve screening algorithms and processes. Such projects are already ongoing in Sweden. Similar, nationally tailored projects will be started within the EU funded PRAISE-U project after a needs-assessment in all 27 EU member states. PRAISE-U will rely on a comprehensive test algorithm with multiple options for risk stratification ( figure 3 ). 113 128 Prerequisites for generating internally and externally valid results include strict adherence to algorithms for PSA testing and diagnostic investigations, and that all results are prospectively registered, analysed and reported, both internally and to some external governance body. Public sharing of protocols, experiences and results is strongly encouraged.

Test algorithm planned for use in the European PRAISE-U project. Reprinted from reference 113 with permission from Springer Nature. PI-RADS, Prostate Imaging—Reporting and Data System; PSA, prostate-specific antigen.

Conclusions

Screening for prostate cancer using PSA and systematic biopsies reduces prostate cancer-specific mortality but also leads to unacceptable overdiagnosis and overtreatment. Recent advances in diagnostic methods have now reduced these harms. Overdiagnosis can be reduced by risk stratified, organised screening, ancillary testing (risk calculators, biomarkers, MRI) to select men with a raised PSA value for biopsy, and lesion-targeting rather than systematic biopsies. In contrast, the current widespread unorganised PSA testing is ineffective and is more likely to harm than organised screening. Therefore, the EU recently recommended the initiation of pilot projects that evaluate the feasibility and effectiveness of organised screening for prostate cancer. Nonetheless, important knowledge gaps remain. For instance, it is not known to which extent the pre-biopsy selection process and omission of systematic biopsies reduce overdiagnosis or delay detection of curable, potentially lethal cancers that progress to an incurable disease before detection in subsequent screening rounds. Results from ongoing randomised screening trials and population-based pilot screening projects will fill these and some other knowledge gaps over the next few years, but reliable assessment of the impact of screening on cancer mortality requires longer follow-ups.

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Prostate Cancer Screening

PMID: 28343840
DOI: 10.1016/j.soncn.2017.02.003

Objective: To review the current state of prostate cancer screening and future directions.

Data sources: Nursing, medical and scientific literature related to prostate cancer screening, and national and international professional recommendations.

Conclusion: Prostate cancer screening has been a topic of robust discussion for a number of years. Research continues to examine novel options for prostate cancer screening to either replace or compliment the prostate specific antigen test, but require additional validation before they will be widely accepted into clinical practice.

Implications for nursing practice: As new data emerges and professional organizations update their recommendations, it is important for oncology nurses to keep abreast of the latest developments to educate patients.

Keywords: prostate cancer; prostate cancer screening; prostate specific antigen (PSA).

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Striking the Right Balance With Prostate Cancer Screening

1 Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City
2 Holden Comprehensive Cancer Center, University of Iowa, Iowa City
Original Investigation Trends in Incidence of Metastatic Prostate Cancer in the US Mihir M. Desai, MD, MPH; Giovanni E. Cacciamani, MSc, MD; Karanvir Gill, MS; Juanjuan Zhang, PhD; Lihua Liu, PhD; Andre Abreu, MD; Inderbir S. Gill, MD, MCh JAMA Network Open

Desai and colleagues, 1 analyzing Surveillance, Epidemiology, and End Results data from 2004 through 2018, found significantly increasing incidence rates of metastatic prostate cancer (mPCa) among men aged 45 to 74 years (during the period 2010-2018) and among men ages 75 and older (during the period 2011-2018). In the earlier periods, incidence rates of mPCa disease were stable in younger men and decreasing in older men. The authors highlighted the temporal association between the mPCa incidence trends and preceding US Preventive Services Task Force (USPSTF) recommendations.

In 2008, the USPSTF recommended against any screening of men aged 75 years and older (grade D), but concluded that evidence was insufficient to make recommendations for younger men (grade I). 2 PCa incidence rates subsequently began declining, most notably in older men. 3 In the fall of 2011, the USPSTF issued a draft recommendation against PCa screening for men of all ages. This grade D recommendation was based on evidence that the PCa mortality benefits of screening were small to none and that screening resulted in harms related to false-positives, biopsy and treatment complications, overdiagnosis, and overtreatment. The final recommendation, published in the spring of 2012, remained a grade D. 4 The draft USPSTF recommendation was clearly influential, being associated with an astounding reduction in PCa incidence. Jemal and colleagues 5 estimated that 33 519 fewer US PCas were diagnosed in 2012 compared with 2011. Those authors also presented results from the National Health Interview Surveys showing decreasing PCa screening rates from 2008 to 2013. These findings strongly suggest an association between declining incidence rates and the USPSTF recommendations on screening practices.

Less screening reduces the risks of overdiagnosis and overtreatment, but there is a trade-off. The decreased overall incidence of PCa was followed by a rising incidence of mPCa that Desai and colleagues 1 show had persisted at least through 2018. When prostate-specific antigen testing was first introduced in the early 1990s, the overall incidence rate of PCa, particularly early-stage, markedly increased. An early sign that screening could be effective was a concomitant decline in mPCa, though there was a several-year lag period before mortality declines were observed. 3 Analyses of longer-term trends data will be needed to provide the important coda to the 2012 USPSTF guideline story—specifically, whether the changes in screening practices impacted PCa mortality rates. These rates have substantially declined since the early 1990s, but the rising incidence of mPCa could well herald a reversal in mortality trends.

Any observed trends, however, might be transitory because the screening guidelines have again changed. In 2018, the USPSTF withdrew its previous objections to screening and gave a grade C recommendation, advising personalized decision-making, for screening men aged 55 to 69 years. 6 The USPSTF cited recent clinical trial evidence showing that screening had a greater benefit in reducing PCa mortality than was previously recognized as well as a benefit in preventing metastatic disease. Additionally, observational data demonstrated increased uptake of active surveillance, a strategy of deferring active treatment in the absence of disease progression, among men with low-risk PCas. Overall, they concluded with moderate certainty that there was a small net benefit for screening. This revised guideline should be encouraging clinicians to more consistently address screening with men who are healthy enough to benefit, engaging them in shared decision-making discussions to determine their screening preferences.

Along with the 2018 USPSTF guideline, emerging practice changes around diagnosing and treating PCa might also impact the burden from PCa. The risk of overdiagnosis could decrease because some urological guidelines are now recommending using results from multiparametric magnetic resonance imaging to avoid unnecessary biopsies. 7 The harms of overtreatment could be mitigated if men with low-risk PCas routinely engage in shared decision-making around treatment choices and are supported in considering active surveillance. Although the overall number of cancer diagnoses might not rebound to the level seen before the guideline change, the number of men discussing screening and receiving diagnoses of clinically important treatable cancers could increase. Achieving these outcomes might further reduce morbidity and mortality from PCa, reversing recent mPCa trends and minimizing the harms of overdiagnosis and overtreatment.

Published: March 14, 2022. doi:10.1001/jamanetworkopen.2022.2174

Corresponding Author: Richard M. Hoffman, MD, MPH, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 200 Hawkins Dr, SE618 GH, Iowa City, Iowa 52242 ( [email protected] ).

Conflict of Interest Disclosures: Dr Hoffman reported receiving royalties from UpToDate to write the prostate cancer screening chapter and fees from law firms for serving as an expert witness in prostate cancer screening cases outside the submitted work. No other disclosures were reported.

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Hoffman RM. Striking the Right Balance With Prostate Cancer Screening. JAMA Netw Open. 2022;5(3):e222174. doi:10.1001/jamanetworkopen.2022.2174

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Prostate cancer...

Prostate cancer incidence and mortality in Europe and implications for screening activities: population based study

Related content
Peer review
Freddie Bray , scientist 1 ,
Rune Kvale , senior researcher 3 4 ,
Valentina Lorenzoni , visiting scientist 6 ,
1 Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France
2 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
3 The Cancer Registry of Norway, Oslo, Norway
4 Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
5 Cancer Epidemiology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
6 Institute of Management, Scuola Superiore Sant’Anna, Pisa, Italy
7 Tampere University, Faculty of Social Sciences, Unit of Health Sciences, Tampere, Finland
8 Tampere University Hospital and FiCan-Mid Regional Cancer Centre, Tampere, Finland
Correspondence to: S Vaccarella vaccarellas{at}iarc.who.int
Accepted 4 July 2024

Objective To provide a baseline comparative assessment of the main epidemiological features of prostate cancer in European populations as background for the proposed EU screening initiatives.

Design Population based study.

Setting 26 European countries, 19 in the EU, 1980-2017. National or subnational incidence data were extracted from population based cancer registries from the International Agency for Research on Cancer’s Global Cancer Observatory, and mortality data from the World Health Organization.

Population Men aged 35-84 years from 26 eligible countries.

Results Over the past decades, incidence rates for prostate cancer varied markedly in both magnitude and rate of change, in parallel with temporal variations in prostate specific antigen testing. The variation in incidence across countries was largest around the mid-2000s, with rates spanning from 46 (Ukraine) to 336 (France) per 100 000 men. Thereafter, incidence started to decline in several countries, but with the latest rates nevertheless remaining raised and increasing again in the most recent quinquennium in several countries. Mortality rates during 1980-2020 were much lower and less variable than incidence rates, with steady declines in most countries and lesser temporal differences between countries. Overall, the up to 20-fold variation in prostate cancer incidence contrasts with a corresponding fivefold variation in mortality. Also, the inverse U-shape of the age specific curves for incidence contrasted with the mortality pattern, which increased progressively with age. The difference between the highest and lowest incidence rates across countries ranged from 89.6 per 100 000 men in 1985 to 385.8 per 100 000 men in 2007, while mortality rates across countries ranged from 23.7 per 100 000 men in 1983 to 35.6 per 100 000 men in 2006.

Conclusions The epidemiological features of prostate cancer presented here are indicative of overdiagnosis varying over time and across populations. Although the results are ecological in nature and must be interpreted with caution, they do support previous recommendations that any future implementation of prostate cancer screening must be carefully designed with an emphasis on minimising the harms of overdiagnosis.

Introduction

Prostate cancer is currently the most diagnosed malignancy among men and the third most common cause of death from male specific cancers in EU member states. 1 In the European Economic Area, which includes the 26 EU member states, Iceland, Lichtenstein, and Norway, and comprises 219 million men, around 341 000 men were diagnosed as having prostate cancer in 2020 (equivalent to 23% of all cancers in men) and about 71 000 men died from the disease (10% of all deaths from male specific cancers) in the same year. 1

Screening men to check their prostate specific antigen (PSA) levels aims to reduce mortality from prostate cancer. 2 The European Randomized Study of Screening for Prostate Cancer found a reduction in deaths from prostate cancer (after around 10 years), 3 4 whereas the other large randomised trials—the Prostate, Lung, Colorectal and Ovarian trial, 4 5 which reported no reduction in mortality (although likely the results were affected by contamination), 6 and the CAP (cluster randomised trial of PSA testing for prostate cancer) in the UK—found similarly negative results based on a single screen. In addition, PSA based screening may lead to overdiagnosis through the detection of low risk tumours that are unlikely to progress, with the risk of overtreatment and adverse effects that could lower men’s quality of life. 7 8 The potential for overdiagnosis and overtreatment is higher when screening for prostate cancer than when screening for breast, cervix, and colorectal cancers, with autopsy studies reporting that up to one third of men of screening age harbour an indolent prostate cancer. 9

Because of the delicate risk-benefit balance, almost all European countries, except Lithuania, have thus far opted against establishing prostate cancer screening programmes in favour of shared decision making about PSA testing between men and their doctors. 10 Differing individual attitudes and local practices towards PSA testing against a backdrop of on-demand and opportunistic screening unguided by clear protocols (in particular, the testing of older men) are likely to have a less than optimal effect on the population, with a possibly different net balance between the benefits and harms at population level than that observed in randomised clinical trials. 11 12

The EU Beating Cancer Plan recently released the European Commission’s council recommendations proposing a gradual and well planned implementation of screening programmes for prostate cancer in men younger than 70. 13 14 The suggested approach involves PSA testing initially, followed by magnetic resonance imaging (MRI) or other diagnostic tests for men with raised PSA levels before considering biopsy. The aim of the proposed approach is to maintain the benefit of mortality reduction while reducing overdiagnosis. 15 Modelling studies have suggested that this could be a cost effective procedure. 16

Given that opportunistic PSA testing has largely been carried out in Europe, it is important to assess the effect on prostate cancer incidence and mortality at population level. In addition, baseline data on national levels and trends in prostate cancer outcomes before the possible initiation of screening with new approaches are needed. We therefore carried out a comparative assessment of the main epidemiological features of prostate cancer in 26 European countries, quantifying the range of variability in incidence rates against temporal variations in PSA testing and relative to mortality rates as a contribution to the evaluation of the population level impact of the EU initiative.

Data sources

We obtained long term data on the annual incidence of prostate cancer (international classification of diseases, 10th revision, ICD-10 code C61) from the International Agency for Research on Cancer’s CI5plus (Cancer Incidence in Five Continents Plus) database and the Global Cancer Observatory. 1 17 18 From population based cancer registries we retrieved national or subnational recorded incidence data for 26 European countries during 1980-2017. Countries with populations less than 1 000 000 (Iceland and Malta) were not analysed. Coverage and availability of data within this period varied by country, but for most of the countries, the last year with incidence data was 2017 (see supplementary table S1). We obtained mortality data for the 26 European countries for 1980-2020 based on national vital registration from the World Health Organization. 19 Population coverage of the mortality database was nearly 100% in all selected countries, except Cyprus (86%). 19 Supplementary table S2 shows data availability and missing data points within the study period. We also extracted the most recent (2020) national incidence and mortality estimates from GLOBOCAN 2020 (with UK countries combined). 1

Review on PSA testing

We carried out a review of the literature on PSA testing across European countries. PubMed was searched using keywords (time trend OR trend) AND (prostate-specific antigen) AND (testing OR screening OR testing rate). The reference lists of relevant articles were also checked to identify additional eligible studies. We selected only studies that provided information on trends in PSA testing in European countries for at least three years. When several studies reported the time trends of PSA testing for one country, we selected the study with the longest periods of data. Overall, information on trends in PSA testing was available for 12 countries (see supplementary table S3), although quality and type of information varied. Therefore we were unable to derive precise characterisation of prevalence, patterns, and trends in PSA testing from the literature, and the available estimates were not directly comparable across countries because they referred to different indicators, age groups, and data sources across populations. Consequently, it was not possible to carry out a quantitative analysis linking levels of PSA testing with incidence of prostate cancer across countries but only to provide a visual assessment of the temporal trajectory of PSA testing against that of incidence by country.

Statistical analysis

We restricted all analyses to the age group 35-84 years, with missing mortality data points removed. Annual age standardised rates of prostate cancer incidence and mortality per 100 000 men were calculated using the world standard population as a reference. 20 To assess the temporal trends of prostate cancer incidence and mortality by country, we plotted the line chart of annual age standardised rates against calendar years based on all available data points. We assessed trends by country continuously by single year, whereas when emphasis was put on the range of variability in incidence and mortality across the continent, we smoothed trends using Loess regression. The average annual percentage change was calculated as 100×( e β −1), where β is the regression coefficient in the generalised linear regression models between natural logarithm of annual age standardised rate and year, with a gaussian distribution and identity link function. 21

Information on trends in PSA testing was retrieved from the literature for the 12 studied countries and is displayed against the corresponding trend in incidence. To assess the discrepancy between incidence and mortality, we grouped calendar years into four periods of five years each (1998-2002, 2003-07, 2008-12, and 2013-17). We calculated the standardised rate ratios of annual age standardised rates between incidence and mortality and then compared the standardised rate ratio across periods. 22 Age curves were also plotted for both incidence and mortality over the four periods.

All analyses were performed using R software (version 4.0.3).

Patient and public involvement

This study used deidentified and aggregated registration data provided by patients and collected by staff from local registries in the countries studied. No patients were involved in the development of the research question, outcome measures, study design, or implementation of the study, as it is not possible nor permitted to attempt to identify and engage them. Although no patients were directly involved in this paper, one impetus for this research was the clinical context of the proposed prostate cancer screening programmes in the EU. Results will be disseminated to the public through media and a press release written using layman’s terms.

Time trends of prostate cancer incidence and mortality rates

Figure 1 , figure 2 , figure 3 , and supplementary figure S1 show trends in prostate cancer incidence and mortality by country on an arithmetic scale (more suitable to assess and compare absolute values) and semi-log scale (more suitable to assess and compare relative changes over time), respectively. Supplementary figure S2 shows the trajectory of incidence and mortality over time by country. Increases in incidence were seen in almost every country, although the pace of increase varied greatly across countries. Increases in incidence were highest in northern Europe, France, and the Baltic countries—notably in Lithuania where the rates peaked at 435 per 100 000 men in 2007. In several countries (France, Switzerland, Italy, and Lithuania) the rates showed a parabolic increase, culminating after the mid-2000s and followed by subsequent declines, whereas in other countries the rates stabilised (Denmark, Sweden, Norway, Ireland, Spain, and Slovenia). Increases in incidence were, however, observed in the most recent quinquennium (2013-17) in several countries. In contrast, mortality rates decreased in most countries after the early 2000s, except in the Baltic countries and eastern Europe (eg, Estonia, Latvia, Belarus, Bulgaria, Poland, and Ukraine), where marked increasing trends, from previously low rates, were observed.

Time trends of age standardised incidence and mortality rates for prostate cancer per 100 000 men aged 35-84 years on an arithmetic scale in northern Europe

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Time trends of age standardised incidence and mortality rates for prostate cancer per 100 000 men aged 35-84 years on an arithmetic scale in central and southern Europe

Time trends of age standardised incidence and mortality rates for prostate cancer per 100 000 men aged 35-84 years on an arithmetic scale in the Baltic countries and eastern Europe

Three patterns can be distinguished in trends for prostate cancer incidence and mortality. Among the European countries included, nearly half exhibited upward trends in incidence (generally from the early 1990s to the late 2000s), followed by stable or downward trends, with corresponding mortality rates in uniform decline (such as the Nordic countries, France, Switzerland, and Italy). A second pattern involved increasing incidence rates throughout the study period, accompanied by downward mortality trends, as was observed in Britain (England, Wales, and Scotland) and the Czech Republic. The incidence of prostate cancer increased with stable or increasing mortality in the remaining countries, particularly in eastern and Baltic Europe (including Croatia, Estonia, Latvia, Belarus, Ukraine, Poland, Slovakia, and Bulgaria). Supplementary table S4 shows the average annual percentage changes of prostate cancer incidence and mortality.

Range of geographical and temporal variations in incidence and mortality rates

Figure 4 shows the range of variability in the annual age standardised rates for prostate cancer incidence and mortality across European countries and over time, highlighting the contrasting levels and magnitudes of differences in incidence versus mortality. Overall, prostate cancer incidence rates tended to rise during the study period, but with a variable pace and peak incidence in different countries and calendar periods. Consequently, the range varied considerably over time, the lowest rates being at the beginning of the study period in 1980 (from 17.6 in Belarus to 109.4 in Sweden per 100 000), then increasing substantially up until around 2005 (from 46.0 in Ukraine to 335.6 in France) and thereafter somewhat narrowing (from 62.7 in Ukraine to 299.3 in Lithuania) until around 2012, although rising trends were observed thereafter in several countries. The difference between the highest and lowest incidence rates across countries ranged from 89.6 per 100 000 men in 1985 to 385.8 per 100 000 men in 2007.

Range of age standardised incidence and mortality rates of prostate cancer per 100 000 men aged 35-84 years over time among the included European countries. Lines are smoothed by the Loess regression algorithm (bandwidth: 0.4)

Compared with incidence, mortality rates were much lower in absolute terms and, despite the declines observed in most countries, presented a smaller range of values, spanning from 12 (Ukraine and Belarus) in 1981 to 53 (Latvia) deaths per 100 000 men in 2006. Considering all countries and periods, the 20-fold maximum variation in prostate cancer incidence contrasts with the fivefold variation in mortality. The difference between the highest and lowest mortality rates across countries ranged from 23.7 per 100 000 men in 1983 to 35.6 per 100 000 men in 2006.

Trends in incidence against trends in PSA testing

Supplementary figure S3 shows the trends in incidence of prostate cancer against trends in PSA testing for the 12 countries where information on both indicators was available. A correlation was evident between the direction and rate of change in incidence relative to PSA testing across all countries assessed, although data on PSA trends are subject to major limitations. Supplementary table S3 provides detailed information on the review of PSA testing in Europe.

Divergence between incidence and mortality

The divergence between incidence and mortality increased in all countries over two decades ( fig 5 ). The standardised rate ratios between incidence and mortality were around 2~4 in most countries during 1998-2002, but higher values (5~7) were observed for several central European countries (Germany, Austria, France, Switzerland, Italy, and Spain). The standardised rate ratios almost doubled by 2013-17 compared with 1998-2012 and reached over 5 for almost all included countries other than Croatia, Latvia, and several countries in eastern Europe. High standardised rate ratios (>10) were found in Ireland, France, Italy, and Spain in 2013-17.

Standardised rate ratios between incidence and mortality for prostate cancer across different periods among men aged 35-84 years

Supplementary figure S4 also shows age standardised incidence rates for incidence and mortality in Europe in 2020, ranked by increasing order of incidence. Higher incidence rates were not consistently associated with the level of mortality rates.

Changes in age curves of prostate cancer incidence and mortality over time

Figure 6 , figure 7 , figure 8 (all on arithmetic scale), and supplementary figure S5 (on logarithmic scale) show the temporal change in age specific incidence and mortality. The age specific profiles changed markedly for incidence, but not for mortality. The incidence curves resembled an inverse U-shape peaking at around 70 years of age during the period 1998-2017, as seen in France, Sweden, Denmark, Norway, Ireland, Estonia, Lithuania, Slovenia, and the Czech Republic. The corresponding age specific curves in the central European countries decreased in 2008-12 after an earlier peak around 2003-07, although increases were observed in the recent quinquennium 2013-17 in some countries in the region. In contrast, the mortality curves remained relatively stable over time, showing a consistent increase with age in all European countries.

Age specific incidence and mortality rates of prostate cancer per 100 000 men during 1998-2002, 2003-07, 2008-12, and 2013-17 in northern Europe

Age specific incidence and mortality rates of prostate cancer per 100 000 men during 1998-2002, 2003-07, 2008-12, and 2013-17 in central and southern Europe

Age specific incidence and mortality rates of prostate cancer per 100 000 men during 1998-2002, 2003-07, 2008-12, and 2013-17 in the Baltic countries and eastern Europe

Our study found noticeable differences in both the magnitude of prostate cancer incidence rates across Europe and the rate of change in the generally upward trends over the past decades. The divergence between countries reached its maximum around the period 2000-10. Thereafter the rates declined in several countries, with somewhat reduced variability in rates, even though they remained high, and even increased in several countries in the most recent years. Such temporal variations in prostate cancer incidence correlated with the national variations in PSA testing. In contrast, mortality rates were substantially lower and showed less variability than incidence, with a more homogeneous pattern over time. Uniform declines in mortality were generally seen across the European continent, although less marked than the increases in incidence. In the Baltic countries and eastern Europe, however, mortality trends remained relatively flat.

The delivery and uptake of PSA testing have been shown to have a rapid effect on the number of new diagnoses of prostate cancer and corresponding incidence rates at the population level. It is widely acknowledged that in the US the large increase (starting in the 1970s and peaking around 2000) and subsequent decline in incidence resulted from the initial increasing use of transurethral resections of the prostate (from the 1970s) and subsequent use of PSA testing (from the mid-1980s) 23 and was followed by a decline, partly as a result of the US Preventive Services Task Force’s recommendation aimed to discourage the practice. 24 Our study confirmed this pattern for incidence in Europe yet also found large heterogeneity across countries. Conversely, the extent of the effect of PSA testing on mortality at the population level is less clear. In the US, the decline in mortality from the mid-1990s followed by a period of stability could be attributed to the use of PSA testing as well as to advances in effective treatment for late stage prostate cancer (whereas the cancers are localised at diagnosis). Yet, disentangling the contribution of the two components is challenging. The patterns of prostate cancer in Europe appear to replicate the earlier observations in the US. This suggests the same mechanism and implicates the potential contributions of both PSA testing and improved treatment outcomes.

In this respect, this comparative assessment should help to improve the understanding of the effect of PSA testing on incidence and mortality in Europe by highlighting consistent patterns across countries. Specifically, our results suggest that the intensity and coverage of PSA testing has been a critical driver for the increasing trends in prostate cancer incidence in Europe. Nevertheless, the possible benefits in terms of reduced mortality appeared to be relatively consistent everywhere, regardless of the extent of the increase in incidence as an indicator of PSA testing. 25 In addition, the magnitude of prostate cancer incidence showed little interdependence with mortality at the national level.

The changes in the age specific incidence curves showed a progressively younger age at peak incidence and increasing resemblance to an inverted U-shape. Older data from the 1960s and 1970s suggest that before the initiation of PSA testing, the incidence of prostate cancer increased strongly with age. 1 In contrast, in our study the age specific mortality curves did not substantially change over time and increased steadily with age. The decline in mortality rates affected all age groups proportionally, and the trend towards earlier diagnosis in younger men seemed to have only a negligible impact on subsequent mortality in older age groups.

In most Baltic and eastern European countries, mortality rates were relatively stable, in contrast with the declines elsewhere. Explanations may include the limited extent of PSA testing, as well as a slower adoption of therapeutic advances (compared with more affluent areas on the continent). Lithuania was an exception, with minor declines in mortality in the most recent period, possibly because it is the only country in Europe offering population screening using the PSA test (since 2006). 26 As the national programme has been accompanied by a substantial amount of opportunistic testing, prostate cancer incidence in Lithuania has increased rapidly, reaching the highest levels ever recorded in Europe.

Overall, our findings imply that unregulated and opportunistic PSA testing has had a differential effect at the population level in Europe compared with the results of the randomised screening trials and appear consistent with overdiagnosis. The PSA based screening trials reported a 1.4-fold or smaller increase in incidence, 3 5 27 whereas national incidence rates in most European countries more than doubled from 1990 to 2017 (and in some countries increased up to eightfold, as in Lithuania). The epidemiological features observed in our study, specifically the rapid inconsistent increase in incidence but not mortality and the progressive change in age specific incidence curves, are difficult to explain for factors other than PSA testing. Our findings have commonalities with what has been previously reported for thyroid cancer, where overdiagnosis is an established driver of rapid increases in incidence. 28 Opportunistic examinations of the thyroid (often with ultrasound) have spread rapidly in many countries, 29 30 despite the lack of evidence for a mortality benefit from thyroid screening (in contrast with prostate cancer screening) and of current guidelines, which recommend against population screening for thyroid cancer. 31

The value of early detection of prostate cancer has been debated extensively, and most of the recent guidelines recommend that asymptomatic men should be offered an informed decision making process about the potential benefits and harms of prostate cancer screening. However, it is still not clear how shared decision making should be implemented, or its possible effect on patient outcomes. 32 33 34 In countries where such policies have been introduced, the prevalence of PSA testing is disproportionally higher among older men 11 and among men with a higher socioeconomic position. 35 This limits the benefits, increases the risk of overdiagnosis, and increases social inequalities.

Overtreatment may be a consequence of overdiagnosis, with harms of overdiagnosis exacerbated by aggressive management. Recent improvements in the de-escalation of treatment for low risk men with prostate cancer are observed in some countries. In Norway, for instance, the proportion of low risk men managed primarily by active surveillance instead of immediate treatment increased from 20% to 80% during 2008-21, with only 7% of such men treated radically in 2021 (eg, with surgery or radiotherapy). 36 In England, treatment of low risk men was estimated to be 4% in 2018. 37 Heterogeneity in the management and treatment of low risk and high risk localised prostate cancer is substantial, however, even across high income countries. 37 International society based treatment guidelines should be enforced to minimise overtreatment. In addition, many men initially treated with active surveillance decided to switch to active treatment within a few years. The process of reducing unnecessary treatment for prostate cancer is multifaceted and involves various aspects of health systems and the attitude of decision makers, medical practitioners, and patients and their families. 38 It is important to monitor whether opportunistic use of PSA testing, with the consequent cascade of biopsies, aggressive management, and treatment, will continue in the future, especially in settings where the provision of healthcare services is particularly unregulated.

The European Commission has recently recommended that “countries should take a stepwise approach, including piloting and further research to evaluate the feasibility of implementation of organised programmes aimed at assuring appropriate management and quality on the basis of prostate specific antigen (PSA) testing for men up to 70, in combination with additional magnetic resonance imaging (MRI) scanning as a follow-up test.” 39 The use of pre-biopsy MRI and of targeted prostate biopsies compared with systematic biopsies alone, should reduce the number of men who will receive an unnecessary diagnosis of prostate cancer, and although changes in clinical practice are already occurring in some settings, they are too recent for any potential effect to be observable in our study. To this extent, some proposals have been advanced, including the implementation of systematically designed, risk based national prostate cancer detection programmes aimed at reducing overdiagnosis and overtreatment and increasing equity. 11 40

Limitations of this study

The present analysis may refer to different age groups, periods in time, and indicators of PSA testing, and therefore the results should be interpreted with caution. The limitations of this study include the lack of data on cancer stage (due to problems with comparability across cancer registries) and on treatment modalities. This is of importance as increases in prostate cancer incidence and mortality at more advanced stages have been observed in the US following the USPSTF recommendations against PSA based screening in 2008 and 2012. 41 42 However, the data used in this analysis include IARC’s GLOBOCAN and CI5, for which the underlying sources are commonly robust and internationally comparable. Although data for Cyprus and Slovakia have been available only since the early 2000s and early 1990s, respectively, for all other countries under study, cancer incidence trends could be analysed up until the relatively recent period of 2017. In some countries, mortality data are missing for a few years, but those are generally scattered throughout the study period, their impact on the trends and on the general conclusions of the study are negligible. Ecological studies in multiple settings, such as the present one, are an appropriate approach for quantifying and monitoring overdiagnosis. 43 The current review on PSA testing, as noted, does have several limitations. In addition, although we could retrieve data from the literature on the frequency of PSA testing for 12 out of the 26 countries, the information available could not be synthesised or enable quantitative assessments given the lack of comparability of the measures used. A visual inspection of the trend variations in PSA testing showed a strong parallelism with prostate cancer incidence in countries where both indicators were available, but these findings should also be interpreted with caution. In addition to PSA testing, other factors may have affected incidence and mortality rates. The descriptive nature of the data used in the present study, the incompleteness of the data both geographically and temporally, and the lack of information on confounding factors, mean that causality cannot be assumed. The established risk factors for prostate cancer include age (adjusted for in our analysis) as well as family history and genetic predisposition, but these cannot change rapidly within a population. Putative factors include diet, specific drugs, and occupational factors, 44 45 but overall, the cause remains poorly understood. It is, however, unlikely that changes in the prevalence of one or more risk factors could have caused such a surge in incidence, given the variability internationally, and the contrasting mortality trend.

Conclusions

Overall, our results suggest that several of the epidemiological characteristics of prostate cancer in the Europe countries included, particularly the contrast between large heterogeneity in trends for incidence with the more uniform reduction in mortality, are compatible with the highly variable patterns of PSA testing across Europe. The current high incidence of prostate cancer in many countries may be inflated by unregulated and opportunistic PSA testing that serves to mask any variations due to causal factors and may be indicative of overdiagnosis. The importance of these results is further emphasised by the proposed EU guidelines endorsing prostate cancer screening, assuming that resources are available, and that prostate cancer is a public health priority. Careful monitoring and assessment of the benefits and harms, including overdiagnosis, will be essential for the potential implementation of the guidelines and the prospective introduction of population-wide prostate cancer screening.

What is already known on this topic

Unregulated and opportunistic testing of prostate specific antigen has been, and still is, common in Europe

The EU Beating Cancer Plan recently released the European Commission’s council recommendations proposing a new strategy for prostate cancer screening programmes

A baseline assessment of the main epidemiological features of prostate cancer outcomes in Europe is needed before the possible initiation of screening with new approaches

What this study adds

This study found that the magnitude of prostate cancer incidence rates varied markedly across European countries and over time, in parallel with national trends of prostate specific antigen testing. Conversely, the mild and steady declines in mortality rates were at much lower levels and showed a more homogeneous and less variable pattern

The epidemiological features analysed in this study suggest that unregulated and opportunistic screening with prostate specific antigen likely leads to a population effect on prostate cancer outcomes that is less than optimal compared to that observed in randomised clinical trials

The present results are ecological in nature and should be interpreted with caution, but they reinforce the need for prudently planned prostate cancer screening programmes, especially to mitigate harms from overdiagnosis

Ethics statements

Ethical approval.

Not required as the study used publicly available aggregated data.

Data availability statement

All data used for analyses are available from the International Agency for Research on Cancer at http://ci5.iarc.fr and the World Health Organization at https://www.who.int/data/data-collection-tools/who-mortality-database .

Acknowledgments

We thank Frédéric Lam and Murielle Colombet for technical and data support and the cancer registries and staff for sharing data needed for this study. Where authors are identified as staff of the International Agency for Research on Cancer or the World Health Organization, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer or WHO.

Contributors: SV and ML are joint first authors. SV, ML, and LDM conceived and designed the study. ML contributed to data collection, analyses, and interpretation of the results. SV wrote the first draft of the manuscript. FB, RV, DS, VL, and AA critically discussed and interpreted the results and contributed to the final version of the paper. SV is the guarantor of the study and had final responsibility for the decision to submit the manuscript. All authors read and approved the final version of the paper. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: The Italian Association for Cancer Research supported the work of DS and LDM (grant No 28893).

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: DS and LDM were supported by the Italian Association for Cancer Research; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Transparency: The lead author (SV) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Dissemination to participants and related patient and public communities: Study results will be disseminated to the public, health professionals, and policy makers through a press release written using layman’s terms on the International Agency for Research on Cancer’s website. Findings will be shared through mass media communications and social media postings. We will also present findings at national and international conferences oriented towards researchers and clinicians in the specialty of cancer prevention and control. Since the study is based on deidentified and aggregated registration data, we have no plans to disseminate results to individual study participants beyond the usual channels of publication.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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↵ Kreft Registeret. National Quality Register for Prostate Cancer. https://www.kreftregisteret.no/globalassets/publikasjoner-og-rapporter/arsrapporter/publisert-2023/arsrapport-2022-nasjonalt-kvalitetsregister-for-prostatakreft.pdf .
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Ethiop J Health Sci
v.33(3); 2023 May
PMC10416328

Knowledge, Awareness and Practice towards Screening for Prostate Cancer: A Systematic Review and Meta-Analysis

Adithya g rao.

1 Department Medical Imaging Technology, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal – 576104, Karnataka, India. Email:

Winniecia Dkhar

2 Department Medical Imaging Technology, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal – 576104, Karnataka, India

3 Department Medical Imaging Technology, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal – 576104, Karnataka, India

Rajagopal Kadavigere

4 Department of Radio diagnosis and Imaging, Kasturba Medical College, Manipal Academy of Higher Education, Manipal – 576104, Karnataka, India

Abhimanyu Pradhan

5 Department Medical Imaging Technology, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal – 576104, Karnataka, India

Globally prostate cancer is one of the most prevalent cancer among men and a leading cause of morbidity and mortality, especially in a developing country, which is mainly due to lack of knowledge and awareness regarding the screening of prostate cancer. The main objective of this review and meta-analysis is to evaluate the knowledge, awareness and practice of adult men about prostate cancer.

An extensive literature search was performed on studies published between January 2000 to 2021. The systematic review initially yielded 137 studies, out of which 7 studies were covered on this meta-evaluation.

We noted that the pooled estimate of knowledge and awareness were respectively 65% [CI: 29%, 100%], and 74% [CI: 66%, 82%] about prostate cancer. However, there were limited practices noted in screening of prostate cancer.

In order to increase the awareness and screening practice rate for prostate cancer, an improved health education is highly recommended.

Introduction

Prostate Cancer (prophylaxis-related cancer of the prostate) is one of the most frequent and most prevalent cancer in men worldwide and a leading cause of cancer-related morbidity and mortality. In accordance with the aging process, the probability of developing prostate cancer increases as one ages. Prostate cancer is more likely to develop among those older than 39 years of age, increasing to 2.2% (1 in 45) for those between the ages of 40 and 59 years and 13.7% (1 in 7) for those ages 60 to 79 years. Overall, 16.7% of men will develop prostate cancer in their lifetime (1 in 6). As per GLOBACON census report of 2020, the number of new cases of Prostate cancer are 14,259 and 3, 74,304 deaths have been recorded in the world. It has been reported that prostate cancer is the third most frequently occurring cancer which also stands eight in terms of mortality ( 1 ). In India 34,540 new cases of prostate cancer have been reported with 16,783 deaths. The incidence of prostate cancer has been increasing during the last decades especially in industrialised countries like India ( 2 ).

The advanced prostate cancer symptoms may include unexplained weight loss, frequent need to urinate, blood in urine or semen, pain in lower back or hips or pelvic region( 3 ). The risk factors for developing the Prostate cancer include – age, geography, race/ethnicity, family history, gene changes like men with lynch syndromes. Along with these there are lesser clear risk factors such as diet, obesity, smoking, prostatitis, sexually transmitted infections, vasectomy, etc.( 4 ). Male-assigned non-binary individuals and transgender women are also at risk of developing prostate cancer ( 3 ).

Prostate Specific Antigen (PSA) tests measure the amount of PSA protein in the blood, which is an early indicator of prostate cancer. There are a few other conditions that can cause an elevated PSA level, such as benign prostatic hyperplasia (enlarged prostate) and prostatitis (prostate inflammation). Men without prostate cancer may also have positive PSA screening results (i.e., “false-positive” results). The most effective way to diagnose prostate cancer in men with positive PSA tests is to perform a trans-rectal ultrasound-guided needle biopsy of prostate tumors or lesions. PSA testing can have adverse effects on the psychological well-being due to the frequency of false-positive results ( 5 ).

In addition to digital rectal examinations, MRIs, and CT scans, prostate cancer can also be detected with other tests. The risk of prostate cancer growing and spreading is categorized according to the diagnostic grading and PSA level before the biopsy, this is known as the risk of progression. It is important to take into account the probability of progression when determining treatment and management ( 3 ).

Even though the incidence rate in India is not so high compared to other cancers, but however according to the census the mortality rate is comparatively high. The most important reason for the increase in mortality rate especially in a developing country is the lack of knowledge and awareness regarding the prostate cancer and a tool to screen the prostate cancer. As a means of reducing the mortality rates, it is crucial to raise awareness among the population about prostate cancer, screening tool for prostate cancer, and the benefits of screenings, so that prostate cancer can be diagnosed at an earlier stage for better treatment and management especially for the high risk population. This would significantly reduce the mortality rate. The main objective of this review is to find out the knowledge, awareness and practice of adult men for prostate cancer.

Literature Search

An extensive search on Scopus, Web of Science and PubMed databases were performed on studies published between January 2000 to 2021. To find additional relevant research papers, we manually cross-checked the reference lists of all retrieved articles. The database searches used the subsequent as clinical concern heading phrases and medical text words: “Knowledge” (and) “Awareness” (and) “Practice” (and) “Screening” (and) “Prostate Cancer” (and) “English” (and) “2000:2021”.

Selection criteria: The inclusion criteria considered for analyses in this study were (a) Articles dated from 2000 – 2021 (b) Published research with authentic facts in peer-reviewed journals (c) Studies published in English language only. The selection of the articles were conducted with accordance to the guidelines of the systematic reviews of the diagnostic test (Devillé et al., 2002)( 6 ), (Campbell et al., 2019)( 7 ). The articles underwent screening of the title and abstract fulfilling all the exclusion and inclusion standards. Based on the same inclusion and exclusion criteria's applied to the entire document, a final set of studies were included in the meta-analysis. The excluded articles were those that were published before 2000, case reports, review articles, unpublished articles were excluded as described in PRISMA Chart ( Figure 1 ).

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PRISMA chart depicting the search strategies and procedure for studies selection for the systematic review and meta-analysis

Study selection and quality assessment : The systematic seek initially yielded 137 studies, out of which 7 were covered on this meta-evaluation ( Figure 1 ). All research studies have been published between 2000 to 2021.

Study characteristics : The 7 included studies involved 15854 participants within Africa and Europe. All 7 studies used cross-sectional study design. All studies have been executed in the form of a questionnaire. A detailed description of the participant's knowledge, awareness, and practice towards the screening of Prostate cancer ( Table 1 ).

Characteristics of the selected studies

Author	Year	Country	Study design	No of Participants	Age	Knowledge	Awareness	Awareness of PSA test	Screening Practice
Genevieve Benurugo	2020	Rwanda	Cross-sectional	257	>40	NA	75%	77%	45%
Asfaw N Erena	2019	Kenya	Cross-sectional	12803	15 – 54	NA	61.90%	NA	3.90%
Paraskevi A Farazi	2018	Nigeria	Cross-sectional	600	NA	NA	66.7%	NA	29.40%
Marianna Morlando	2017	Italy	Cross-sectional	625	27 – 71	82.10%	NA	72.70%	29.60%
J Sutton	2016	UK	Cross-sectional	708	NA	NA	NA	NA	NA
Belinda F. Morrison	2016	Jamaica	Cross-sectional	300	>40	84%	NA	NA	NA
Oladepo Oladimeji	2010	Nigeria	Cross-sectional	561	>50	28.70%	80%	NA	4.50%

Knowledge on prostate cancer : Random effect meta-analysis was performed to pool the proportion of knowledge as heterogeneity found to be high (I 2 =99.6%). In this meta-analysis random effects model analysis showed that the pooled estimate of knowledge among the studies conducted by Marianna et al, Belinda F Morrison et al, and Oladepo Oladimeji et al, was found to be 65% [CI: 29%, 100%] ( Figure 2 )

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Knowledge Random-effects REML Model.

Awareness of signs, symptom and treatment of Prostate cancer : Random effect meta-analysis was performed to pool the proportion of awareness as heterogeneity found to be high (I 2 =91.05%). The pooled estimate found to be 74% [CI: 66%, 82%] ( Figure 3a ).

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Awareness Random-effects REML Model.

Awareness on PSA : Fixed effect meta-analysis is performed to pool the proportion of awareness of PSA as heterogeneity found to be less (I 2 =45.56%). In this meta-analysis random effects model analysis showed that the pooled estimate of awareness of PSA among the studies conducted by Genevieve et al, Marianna et al showed the pooled estimate of 74% [CI: 71%, 77%] ( Figure 3b ).

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Awareness of PSA Fixed-effects inverse-variance model.

Practice of undergoing screening of prostate cancer : Random effect meta-analysis was performed to pool the proportion of practice as heterogeneity found to be high (I 2 =99.16%). The pooled estimate found to be 14% [CI: 13%, 15%] ( Figure 4 ).

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Practice Fixed-effects inverse-variance model.

In this review, the articles from the year 2000 to 2021 based on Knowledge, Awareness and Practice of screening for Prostate cancer and PSA test were included. These studies were conducted on various geographical regions like Kenya, Nigeria, Italy, UK, and Jamaica. This review identified seven articles in a span of two decades. The studies were conducted in human participants and cross-sectional study design was implemented.

According to our meta-analysis, we noted the proportion of knowledge as heterogeneity found to be high with I 2 =99.6% with a pooled estimate of 65% ( Figure 2 ). A survey across Jamaica demonstrated a pooled estimate of 0.84( 8 ) while the study conducted across Italy showed the pooled estimate of 0.82( 9 ). A considerable difference was noted in the pooled estimate in the study conducted in Nigeria that showed a pool estimate of 0.29( 10 ). The pooled estimate was higher in the studies done post 2015 than the one done in 2010 may be due to the time frame between the two studies. The study done in Jamaica demonstrated a pooled estimate of 0.84( 8 ) which was higher while the study done in Nigeria showed the pooled estimate of 0.29( 10 ) which was comparatively very low. The pooled estimate was higher in the studies done post 2015 than the one done in 2010 may be due to the time period when the study was conducted.

In terms of awareness and perception towards prostate cancer among men, the proportion of awareness as heterogeneity was found to be high (I 2 =91.05%). The pooled estimate found to be 74% [CI: 66%, 82%] ( Figure 3a ). A study was conducted across Nigeria to assess the awareness showed the pooled estimate of 0.80( 10 ) while the study done in Rwanda showed the pooled estimate of 0.75( 11 ) and the study done in Abuja showed a pooled estimate of 0.67( 12 ). However, the study done in Nigeria showed higher pooled estimate than the ones done in Rwanda and Abuja.

In a study conducted by Marianna Morlando et al in Italy, the knowledge and awareness towards prostate cancer screening and PSA test was higher among the older men with higher education level, in which the PSA test has already been practiced by 29.6% of men, and 59.4% intend to do so in the future. In response to the survey, the majority of respondents had a reasonable understanding of prostate cancer and were likely to undergo the PSA test. The studies showed good awareness for PSA in the study done in Rwanda showed 0.77 pooled estimate( 11 ) and the study done in Italy showed a pooled estimate of 0.73( 9 ). Both the studies showed almost equal pooled estimate.

With respect to practice of screening for prostate cancer a study which was done in Rwanda showed the pooled estimate of 0.45( 11 ), the study done in Italy showed the pooled estimate of 0.30( 9 ), the study done in Abuja showed the pooled estimate of 0.29( 12 ) whereas the study done in Nigeria showed the pooled estimate of 0.04( 10 ). The study done in the Rwanda showed the highest pooled estimate for the screening practice while the study done in Nigeria showed the lowest. The studies done post 2015 had better screening practices than the one done in 2010, which may be due the time period when the studies were conducted.

Subgroup analysis was conducted for the studies done in African Continent, the study done in Rwanda showed the pooled estimate of 0.45, the study done in Abuja showed the pooled estimate of 0.29( 12 ) whereas the study done in Nigeria showed the pooled estimate of 0.04 ( 10 ). The study done in the Rwanda showed the highest pooled estimate in African Continent for the screening practice while the study done in Nigeria showed the lowest.

However, we also noted regarding the practice of prostate cancer screening, according to the sensitivity analysis, the studies done in Rwanda showed the pooled estimate of 0.45( 11 ) whereas the study done in Italy showed the pooled estimate of 0.30( 9 ) and the study done in Abuja showed the pooled estimate of 0.29( 12 ). The study done in the Rwanda showed the highest pooled estimate for the practice-sensitivity comparatively to the study done in Italy and Abuja.

Hence, it was clearly observed that the development of the tool to assess the knowledge, awareness and practice for prostate cancer is highly significant in order to increase the information on the risks, benefits of the signs and symptoms of prostate cancer and the also the screening practice of prostate cancer at an early stage.

In conclusion, it was found that there is a high level of knowledge and awareness about prostatic cancer according to the study. However, participants showed low screening practices in prostate cancer prevention, as well as a low ability to identify the risk factors and determine when prostate cancer is more likely to occur. In addition, all socio-demographic factors were strongly related to cancer screening practices. Furthermore, televisions, radios, and other mass media may not have been effective at communicating health information to men, leading to low screening rates for men. As a consequence, increasing knowledge and screening rates of prostate cancer need to be improved in the community.

Hence, the results indicate the need for developing a tool for to educate and create awareness among the men regarding the prostate cancer in both rural and urban areas in order to reduce the burden of advanced cancer by practising early screening and curb the mortality rate.

Prostate Cancer Screening (PDQ®)–Patient Version

What is screening.

Screening is looking for cancer before a person has any symptoms . This can help find cancer at an early stage . When abnormal tissue or cancer is found early, it may be easier to treat. By the time symptoms appear, cancer may have begun to spread.

Scientists are trying to better understand which people are more likely to get certain types of cancer. They also study the things we do and the things around us to see if they cause cancer. This information helps doctors recommend who should be screened for cancer, which screening tests should be used, and how often the tests should be done.

It is important to remember that your doctor does not necessarily think you have cancer if he or she suggests a screening test. Screening tests are given when you have no cancer symptoms. Screening tests may be repeated on a regular basis.

If a screening test result is abnormal, you may need to have more tests done to find out if you have cancer. These are called diagnostic tests .

General Information About Prostate Cancer

Prostate cancer is a disease in which malignant (cancer) cells form in the tissues of the prostate., prostate cancer is the most common nonskin cancer among men in the united states., different factors increase or decrease the risk of developing prostate cancer..

Drawing of the male reproductive system and urinary system anatomy showing the front and side views of the ureters, bladder, prostate gland, vas deferens, urethra, penis, and testicles. A side view of the seminal vesicle and ejaculatory duct is also shown. The drawing also shows front and side views of the rectum and lymph nodes in the pelvis.

See the following PDQ summaries for more information about prostate cancer:

Prostate Cancer Prevention
Prostate Cancer Treatment

Prostate cancer is found mainly in older men. In the United States, about one out of every 8 men will be diagnosed with prostate cancer. Most men diagnosed with this disease do not die from it. Prostate cancer causes more deaths in men than any other cancer except lung cancer . Prostate cancer occurs more often in African American men than in White men. African American men with prostate cancer are more likely to die from the disease than White men with prostate cancer.

Anything that increases a person's chance of developing a disease is called a risk factor . Anything that decreases your chance of getting a disease is called a protective factor .

For information about risk factors and protective factors for prostate cancer, see Prostate Cancer Prevention .

Prostate Cancer Screening

Tests are used to screen for different types of cancer when a person does not have symptoms., digital rectal exam, prostate-specific antigen test, a prostate cancer gene 3 (pca3) rna test may be used for certain patients., screening tests for prostate cancer are being studied in clinical trials..

Scientists study screening tests to find those with the fewest harms and most benefits. Cancer screening trials also are meant to show whether early detection (finding cancer before it causes symptoms ) helps a person live longer or decreases a person's chance of dying from the disease. For some types of cancer, the chance of recovery is better if the disease is found and treated at an early stage .

There is no standard or routine screening test for prostate cancer.

Although there are no standard or routine screening tests for prostate cancer , the following tests are being used or studied to screen for it:

Digital rectal exam; drawing shows a side view of the male reproductive anatomy and the urinary anatomy, including the prostate, rectum, and bladder. Also shown is a gloved, lubricated finger inserted into the rectum to feel the rectum, anus, and prostate.

A prostate-specific antigen (PSA) test is a test that measures the level of PSA in the blood . PSA is a substance made mostly by the prostate that may be found in an increased amount in the blood of men who have prostate cancer. The level of PSA may also be high in men who have an infection or inflammation of the prostate or benign prostatic hyperplasia (BPH; an enlarged, but noncancerous, prostate).

A PSA test or a DRE may be able to detect prostate cancer at an early stage, but it is not clear whether early detection and treatment decrease the risk of dying from prostate cancer.

Studies are being done to find ways to make PSA testing more accurate for early cancer detection.

If a man had a high PSA level and a biopsy of the prostate did not show cancer and the PSA level remains high after the biopsy, a prostate cancer gene 3 (PCA3) RNA test may be done. This test measures the amount of PCA3 RNA in the urine after a DRE. If the PCA3 RNA level is higher than normal, another biopsy may help diagnose prostate cancer.

Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Risks of Prostate Cancer Screening

Screening tests have risks., finding prostate cancer may not improve health or help a man live longer., follow-up tests, such as a biopsy, may be done to diagnose cancer., false-negative test results can occur., false-positive test results can occur..

Decisions about screening tests can be difficult. Not all screening tests are helpful and most have risks. Before having any screening test, you may want to discuss the test with your doctor. It is important to know the risks of the test and whether it has been proven to reduce the risk of dying from cancer .

The risks of prostate screening include the following:

Screening may not improve your health or help you live longer if you have cancer that has already spread to the area outside of the prostate or to other places in your body.

Some cancers never cause symptoms or become life-threatening, but if found by a screening test, the cancer may be treated. Finding these cancers is called overdiagnosis . It is not known if treatment of these cancers would help you live longer than if no treatment were given.

Treatments for prostate cancer , such as radical prostatectomy and radiation therapy , may have long-term side effects in many men. The most common side effects are erectile dysfunction and urinary incontinence .

Some studies of patients with newly diagnosed prostate cancer showed these patients had a higher risk of death from cardiovascular (heart and blood vessel ) disease or suicide . The risk was greatest in the first weeks or months after diagnosis .

If a PSA test is higher than normal, a biopsy of the prostate may be done. Complications from a biopsy of the prostate may include fever , pain, blood in the urine or semen , and urinary tract infection . Even if a biopsy shows that a patient does not have prostate cancer, he may worry more about developing prostate cancer in the future.

Magnetic resonance imaging (MRI)−guided biopsy is being studied in the diagnosis of prostate cancer, either in place of, or in addition to, standard prostate needle biopsy .

Screening test results may appear to be normal even though prostate cancer is present. A man who receives a false-negative test result (one that shows there is no cancer when there really is) may delay seeking medical care even if he has symptoms.

Screening test results may appear to be abnormal even though no cancer is present. A false-positive test result (one that shows there is cancer when there really isn't) can cause anxiety and is usually followed by more tests, (such as biopsy) which also have risks.

Your doctor can advise you about your risk for prostate cancer and your need for screening tests.

About This PDQ Summary

Physician Data Query (PDQ) is the National Cancer Institute's (NCI's) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish .

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about prostate cancer screening. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

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PDQ® Screening and Prevention Editorial Board. PDQ Prostate Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/prostate/patient/prostate-screening-pdq . Accessed <MM/DD/YYYY>. [PMID: 26389306]

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JSmol Viewer

From oncogenesis to theranostics: the transformative role of psma in prostate cancer.

Simple Summary

1. oncogenesis, 2. introduction to prostate cancer, 3. psma and prostate cancer diagnosis, 4. psma pet imaging, 5. theranostics, 7. 177. lupsma-617, 8. 177. lu-psma-i&t, 11. conclusions, author contributions, conflicts of interest.

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Click here to enlarge figure

Clinical Trial Identifier/Authors	Study Objective	Phase	Status
Bander et al. [ ]	177Lu-J591 in androgen-independent prostate cancer	1	Complete
NCT00195039	177Lu-J591 in mCRPC	2	Complete
NCT00538668	177Lu-J591 in mCRPC	1/2	Complete
NCCT04786847 (ProstACT SELECT)	177Lu-TLX591 with SoC in mCRPC	1	Complete
NCT05146973 (ProstACT Target)	177Lu-TLX591 with external beam radiation therapy in biochemically recurrent, oligometastatic PSMA prostate cancer	2	Active, not recruiting
NCT04876651 (PROSTACT)	177Lu-TLX591 with Soc versus Soc alone in mCRPC	3	Not yet recruiting

Criteria	Full Name	Details
RECIST	Response Evaluation Criteria in Solid Tumors	Evaluates tumors’ reactions to treatments by monitoring changes in their size through anatomical imaging techniques. It primarily focuses on measurable tumor lesions.
PERCIST	PET Response Criteria in Solid Tumors	Assesses metabolic response to treatments using PET scans by monitoring changes in standardized uptake values (SUV) of tumors, emphasizing metabolic changes over size alterations.
PCWG3	Prostate Cancer Working Group 3	Provides guidelines tailored to prostate cancer for assessing treatment response and disease progression by considering PSA levels, imaging results, and clinical status.
PPP	PSMA PET Progression	Focuses on disease progression in PSMA PET, monitoring biochemical or clinical progression along with lesion counts observed through PSMA-ligand PET.
RECIP	Response Evaluation Criteria in PSMA Imaging	Specifically designed for PSMA PET, these criteria evaluate treatment effectiveness in metastatic castration-resistant prostate cancer by focusing on new lesions and overall PSMA tumor volume changes.

Clinical Trial Identifier/Authors	Study Objective	Phase	Status
VISION (NCT03511664)	177Lu-PSMA-617 and Soc versus Soc alone in mCRPC	3	Complete
UpfrontPSMA (NCT04343885)	177Lu-PSMA-617 followed by docetaxel versus docetaxel	2	Active, not recruiting
LuTectomy (NCT04430192)	177Lu-PSMA-617 before radical prostatectomy and pelvic lymph node dissection	1/2	Active, not recruiting
LuPSMA (ACTRN12615000912583)	177Lu-PSMA-617 in mCRPC	2	Complete
TheraP (NCT03392428)	177Lu-PSMA617 versus cabazitaxel in mCRPC	2	Complete
PSMAfore (NCT04689828)	177Lu-PSMA-617 vs. change in ART in taxane-naïve mCRPC	3	Active, not recruiting

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Hameed, M.Y.; Gul, M.; Chaudhry, A.; Muzaffar, H.; Sheikh, M.; Chee, W.; Ayyash, S.; Ayyash, J.; Al-Hindi, M.; Shahare, H.; et al. From Oncogenesis to Theranostics: The Transformative Role of PSMA in Prostate Cancer. Cancers 2024 , 16 , 3039. https://doi.org/10.3390/cancers16173039

Hameed MY, Gul M, Chaudhry A, Muzaffar H, Sheikh M, Chee W, Ayyash S, Ayyash J, Al-Hindi M, Shahare H, et al. From Oncogenesis to Theranostics: The Transformative Role of PSMA in Prostate Cancer. Cancers . 2024; 16(17):3039. https://doi.org/10.3390/cancers16173039

Hameed, Muhammad Y., Maryam Gul, Abbas Chaudhry, Huma Muzaffar, Mubashir Sheikh, Winson Chee, Sondos Ayyash, Jenna Ayyash, Mohannad Al-Hindi, Humam Shahare, and et al. 2024. "From Oncogenesis to Theranostics: The Transformative Role of PSMA in Prostate Cancer" Cancers 16, no. 17: 3039. https://doi.org/10.3390/cancers16173039

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Prostate Cancer Awareness Month: The History and Impact

September is recognized as Prostate Cancer Awareness Month, designed to promote increased awareness, education, and research on one of the most common forms of cancer. An estimated 13 out of every 100 American men will develop prostate cancer in their lifetime, and the risk increases with age.¹

In addition to how common prostate cancer is compared to other cancers, its incidence continues to increase. According to the US Centers for Disease Control and Prevention (CDC), there were 236,659 new cases of prostate cancer in 2021 and 33,363 prostate cancer-related deaths in 2022.² The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program estimates higher totals for 2024: 299,010 cases and 35,250 deaths.³ This would make prostate cancer the second most common cancer in the US in 2024, after breast cancer.

Because it often is slow-growing, prostate cancer has one of the highest 5-year survival rates of any cancer at 97.5%.³ Still, with prostate cancer incidence on the rise, awareness of and education about risk factors and screening remain vital. What is the history of prostate cancer, when was the first Prostate Cancer Awareness Month, and what has been the impact of this campaign?

The History of Prostate Cancer

The prevalence of prostate cancer in past centuries is unclear. The oft-cited first case described as prostate cancer was reported in 1853, documented by London surgeon John Adams in a patient who had died 3 years after the onset of the disease. 4 However, in a study published in the International Journal of Paleopathology in 2011, researchers reported finding lesions on a Ptolemaic Egyptian male mummy suggestive of osteoblastic secondary cancer, with a distribution pattern that suggested origin within the prostate. 5

The fight to cure prostate cancer began much later, after Marie and Pierre Curie discovered radium and polonium in 1898; a decade later, Henri Minet published a paper describing treating patients with prostate cancer by inserting tubes containing radium through urethral or suprapubic catheters. 4 Internal radiation therapy was not a popular treatment option because it was a difficult procedure for clinicians to perform, and it was painful for patients. The first radical prostatectomy was performed in 1904 by Hugh Hampton Young, who reported 15 successful recoveries out of the 19 prostatectomies he performed using a transperineal approach.

In 1938, prostate-specific acid phosphatase was discovered. It was the first biomarker that health care professionals found useful for diagnosing prostate cancer, though it was only helpful for identifying metastatic disease . 4 A few years later, in 1941, Charles Huggins and Clarence V. Hodges made a major leap forward in treatment when they demonstrated that estrogen injections could delay the progression of prostate cancer. Another leap forward occurred in 1945, when Terrence Millin reported a new prostatectomy technique that used a retropubic approach, which provided a more accessible route to the pelvic lymph nodes that were used to stage the disease. 4 This technique remained a part of prostate cancer treatment for decades after.

As radiation therapy advanced, so did techniques for prostate cancer treatment. In 1965, researchers reported the results of using external beam radiotherapy (EBRT) to treat 81 patients with prostate cancer that was inoperable but had not spread to distant organs. 4 The 5-year survival rate was 54%, which was an impressive rate for that era. 4

The 1980s and 1990s saw a notable increase in prostate cancer incidence. According to the CDC, from 1980 to 1988 the age-adjusted incidence rate of prostate cancer in the US rose by 8% among Black men and 30% among White men. 6 The increase in incidence, particularly in the early 1990s, has been attributed to the widespread introduction of prostate-specific antigen (PSA) screening, which led to an increase in early detection. 7 This meant finding prostate cancers when they were more likely to be successfully treated, which improved the mortality rate.

Advances in chemotherapeutic treatment options, such as mitoxantrone and docetaxel , also helped reduce mortality rates in the mid-1990s and early 2000s. 4 The development of laparoscopic prostatectomy procedures in the 1990s and robotic-assisted prostatectomy in 2001 also improved outcomes. In addition, recent advances in EBRT now allow for more specific and accurate dose planning.

When Was the First Prostate Cancer Awareness Month?

September was officially named National Prostate Cancer Awareness Month in the United States by President George W. Bush in September 2003. 8 Bush’s proclamation referenced the importance of using screening for early detection, and urged men (particularly those age 50 years and older) to discuss preventive screening with their health care professionals.

The Impact of Prostate Cancer Awareness

Increased awareness and earlier detection of prostate cancer have substantially improved the prognosis of the disease. In an older report, the CDC estimated that in 1992 132,000 men would be diagnosed with prostate cancer and 34,000 men would die from it. 6 The SEER program estimates that in 2024, there will be a similar number of mortalities (35,250) but a much higher incidence (299,010).¹ According to the American Cancer Society’s Cancer Facts & Figures 2024 report, the prostate cancer mortality rate in the US fell from a peak of 39.3 per 100,000 men in 1993 to 18.8 per 100,000 men in 2017. 9 Based on 2018 to 2022 data, the present age-adjusted mortality rate is 19.0 per 100,000 men per year. 3

Greater awareness and knowledge of prostate cancer has also helped improve or maintain the quality of life for patients diagnosed with early stage disease. Many prostate cancers grow slowly or not at all. 2 Active surveillance, which entails closely monitoring the disease until active treatment is deemed necessary, was developed as an option for patients with lower-risk, early stage prostate cancer. 4 This approach is based on evidence that suggested deferring treatment in this manner does not decrease survival rates among patients with lower-risk prostate cancer. 4 It allows patients to avoid potentially unnecessary treatments and adverse effects.

The focus on early detection of prostate cancer remains crucial because in recent years, the incidence rates have started to steadily increase. According to the American Cancer Society, since 2014 the overall prostate cancer incidence rate has increased by 3% per year, including by approximately 5% per year for advanced-stage disease. 9 Worldwide, there is concern that this trend will continue. In 2024, The Lancet Commission on prostate cancer projected that globally, prostate cancer cases would increase from 1.4 million in 2020 to 2.9 million in 2040. 10 Annual deaths were estimated to increase from 375,000 in 2020 to nearly 700,000 in that same timeframe. Many of these cases and deaths are projected to occur in low- and middle-income countries, and the increase may be attributed in part to aging populations. 10

These projections show that despite all of the strides made in screening and treatment, Prostate Cancer Awareness Month remains an essential campaign.

References:

Prostate cancer risk factors. Centers for Disease Control and Prevention. https://www.cdc.gov/prostate-cancer/risk-factors/index.html . Updated February 23, 2024. Accessed August 27, 2024.
U.S. cancer statistics prostate cancer stat bite. Centers for Disease Control and Prevention. https://www.cdc.gov/united-states-cancer-statistics/publications/prostate-cancer-stat-bite.html . Updated June 13, 2024. Accessed August 27, 2024.
Cancer stat facts: Prostate cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. https://seer.cancer.gov/statfacts/html/prost.html . Accessed August 27, 2024.
Lehtonen M, Kellokumpu-Lehtinen PL. . SAGE Open Med . 2023;11:20503121231216837. doi:10.1177/20503121231216837
Prates C, Sousa S, Oliveira C, Ikram S. Prostate metastatic bone cancer in an Egyptian Ptolemaic mummy, a proposed radiological diagnosis . Int J Paleopathol . 2011;1(2):98-103. doi:10.1016/j.ijpp.2011.09.002
Centers for Disease Control (CDC). Trends in prostate cancer–United States, 1980-1988 . MMWR Morb Mortal Wkly Rep . 1992;41(23):401-404.
Brawley OW. . J Natl Cancer Inst Monogr . 2012;2012(45):152-6. doi:10.1093/jncimonographs/lgs035
Bush GW. Proclamation 7700—National Prostate Cancer Awareness Month, 2003 Online by Gerhard Peters and John T. Woolley. The American Presidency Project. Updated September 1, 2003. Accessed August 27, 2024. https://www.presidency.ucsb.edu/node/210994
American Cancer Society. Cancer Facts & Figures 2024. Updated 2024. Accessed August 27, 2024. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf
10. James ND, Tannock I, N’Dow J, et al. The Lancet Commission on prostate cancer: Planning for the surge in cases . Lancet . 2024;403(10437):1683-1722. doi:10.1016/S0140-6736(24)00651-2

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Published: 03 September 2024

Predictive value of polygenic risk score for prostate cancer incidence and prognosis in the Han Chinese

Sheng-Chun Hung 1 , 2 , 3 ,
Li-Wen Chang 1 , 2 , 3 ,
Tzu-Hung Hsiao 4 , 5 , 6 ,
Chia-Yi Wei 4 ,
Shian-Shiang Wang 1 , 3 , 7 ,
Jian-Ri Li 1 , 2 , 3 , 8 &
I-Chieh Chen 4

Scientific Reports volume 14 , Article number: 20453 ( 2024 ) Cite this article

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Cancer genomics

Although prostate cancer is a common occurrence among males, the relationship between existing risk prediction models remains unclear. The objective of this hospital-based retrospective study is to investigate the impact of polygenic risk scores (PRSs) on the incidence and prognosis of prostate cancer in the Han Chinese population. A total of 24,778 male participants including 903 patients with prostate cancer at Taichung Veterans General Hospital were enrolled in the study. PRS was calculated using 269 single nucleotide polymorphisms and their corresponding effect sizes from the polygenic score catalog. The association between PRS and the risk prostate cancer was evaluated using Cox proportional hazards regression model. Among the 24,778 participants, 903 were diagnosed with prostate cancer. The risk of prostate cancer was significantly higher in the highest quartile of PRS distribution compared to the lowest (hazard ratio = 4.770, 95% CI = 3.999–5.689, p < 0.0001), with statistical significance across all age groups. Patients in the highest quartile were diagnosed with prostate cancer at a younger age (66.8 ± 8.3 vs. 69.5 ± 8.8, p = 0.002). Subgroup analysis of patients with localized or stage 4 prostate cancer showed no significant differences in biochemical failure or overall survival. This hospital-based cohort study observed that a higher PRS was associated with increased susceptibility to prostate cancer and younger age of diagnosis. However, PRS was not found to be a significant predictor of disease stage and prognosis. These findings suggest that PRS could serve as a useful tool in prostate cancer risk assessment.

Prostate cancer risk prediction using a polygenic risk score

Common genetic and clinical risk factors: association with fatal prostate cancer in the Cohort of Swedish Men

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations, introduction.

Prostate cancer is the most prevalent cancer among men worldwide and ranks as the second leading cause of cancer-related mortality in men 1 . In Taiwan, there were 7,137 newly diagnosed cases of prostate cancer and 1538 deaths due to prostate cancer in 2019 2 . Although the exact etiology of prostate cancer remains unclear, studies have indicated that genetic and hereditary factors play a crucial role in disease development 3 , 4 . Genome-wide association studies (GWAS) have identified over 100 susceptibility loci for prostate cancer, which collectively account for 28.4% of the familial relative risk of prostate cancer 5 .

Previous studies have identified several common genetic polymorphisms that are associated with the risk of developing prostate cancer, but the relative risk conferred by each loci remains low to modest 6 . Consequently, the concept of the polygenic risk score (PRS) has been introduced. PRS is a composite score that incorporates the presence or absence of multiple genetic variants associated with prostate cancer. By weighting the influence of each single nucleotide polymorphism (SNP) and summing these SNPs into a PRS, researchers can assess the cumulative contribution of these variants to disease prevalence and incidence in population 7 . For instance, men in the ninetieth to ninety-ninth percentiles of PRS would have a 2.69-fold increased risk of developing prostate cancer compared to the population average, and this risk would further increase to 5.71-fold for men in the first percentile 8 . Currently, the predictive value for the area under the curve (AUC) in prostate cancer using PRS alone ranges from 0.56 to 0.67. When combined with established clinical markers, the AUC increases significantly to a range of 0.886–0.880 9 . PRS has been found to be a significant predictor of prostate cancer risk, with higher scores associated with an increased risk of developing the disease.

The application of PRS has shown variations among different ethnic groups. A meta-analysis of trans-ancestry GWAS studies revealed that the top decile of PRS was associated with a 5.06-fold increased risk of prostate cancer in men of European ancestry, while it was 3.74-fold in men of African ancestry 5 . Furthermore, the relative risk was 4.47-fold for men of East Asian ancestry in the same cohort. However, most PRS models have been developed based on GWAS data primarily collected from Caucasian and European populations 10 . Another multi-ethnic cohort study conducted by the PRACTICAL Consortium found that Asian men at the 98th percentile of PRS, compared to those at the 30–70th percentile, had hazard ratios of 3.77 and 4.14 for overall prostate cancer and aggressive prostate cancer development, respectively 11 . Despite the significant results for the Asian population in this study, only a small proportion of participants were of Asian ethnicity. There have been studies on ancestry-specific PRS for the Asian population as well. For instance, Song et al. developed a PRS using 83 candidate SNPs that showed significant association with prostate cancer, enabling the prediction of clinically significant prostate cancer susceptibility in the Korean male population 12 . Akamatsu et al. conducted a study using a PRS derived from the genotypes of 16 common variants, along with sequencing of 8 prostate cancer-associated genes. They found that a high PRS had a comparable impact on biopsy positivity to a positive magnetic resonance imaging finding in Japanese patients with prostate-specific antigen (PSA) levels between 2 and 10 ng/mL 13 . The utilization of ethnicity-specific PRS can be beneficial in predicting prostate cancer incidence within a given population.

Understanding the role of genetics factor, particularly PRS, in prostate cancer risk, clinical outcomes and prognosis has significant clinical implications. Moreover, PRS has been proposed not only as a tool for predicting disease incidence but also for reducing overdiagnosis by identifying potentially lethal prostate cancer 14 . The aim of our study is to investigate the association between PRS and prostate cancer susceptibility in the Asian population, as well as analyze the impact of genome-wide susceptibility variants on clinical outcomes and prognosis of prostate cancer patients in a Han Chinese population.

Patients and methods

Study population.

This hospital-based retrospective cohort study was conducted with the participation of 58,091 Taiwanese individuals aged 20 years or older. The study utilized data from the Taiwan Precision Medicine Initiative (TPMI) project, overseen by Academia Sinica in Taiwan, and took place from June 2019 to May 2021. The study cohort consisted of 903 patients who were identified using the international Codes of Diseases–Ninth Revision–Clinical Modification (ICD-9-CM) code 185, and their genetic profiles were linked to medical claims data from TCVGH. All participants (24,778 males), including 903 prostate cancer patients, were followed for recurrence and mortality until the end of available follow-up period, which extended from January 2009 to January 2022. This comprehensive dataset of TPMI included demographic information, procedures, diagnoses, surgeries, and medication prescriptions. All participants underwent genotyping using the Affymetrix Genome-Wide TWB 2.0 SNP Array. The study was approved by the ethics committee of the TCVGH Institutional Review Board (IRB No. CE23119A), and all participants provided informed consent. All methods were performed in accordance with the relevant guidelines and regulations. Only male participants were included in the analysis. Clinical parameters were obtained from the dataset and electronic medical records from TCVGH using de-identification method.

Genotyping and quality control

This study collected blood samples from all participants to extract DNA and conducted genotyping using the Axiom Genome-Wide TWB 2.0 Array Plate (Affymetrix, Santa Clara, CA, USA) , which contains 714,431 SNPs and is designed specifically for Taiwan’s Han Chinese population 15 . Analysis and quality control were performed using Affymetrix Power Tools software, and markers that failed Hardy–Weinberg equilibrium tests with a P < 1.0 × 10 –5 , had a minor allele frequency < 0.05, or had a genotype missing rate of > 5% were excluded. After quality control, a total of 591,048 SNPs were retained for analysis. The use of high coverage GWAS SNP data from large-scale Han Chinese ancestry in Taiwan using custom arrays has been previously described 16 . The samples with a missingness rate > 0.02, an inbreeding coefficient > 0.15, and those with a sex mismatch were removed. Genotype imputation was carried out across the autosomal chromosomes using the Michigan Imputation Server, which implemented the ‘minimac4’ algorithm 17 . Strand-aligned genotype data were loaded into the server. We performed the imputation using the 1000 Genomes Phase 3 (Version 5) reference panel 18 . All biallelic variants with imputation quality threshold of INFO score ≥ 0.3 were reported.

Polygenic risk score analysis

PRS was calculated by using the ‘score’ function from plink version 1.9 to aggregate the effects of multiple genetic variants weighted by their effects size 19 . The PRS used in this study, PGS000662, was derived from a discovery analysis of 269 variants associated with prostate cancer identified from Trans-ancestry GWAS meta-analyses, including East Asian ancestry case–control analysis 5 . The list of SNPs and effect sizes were downloaded from the Polygenic score (PGS) catalog 20 . PGS000662 was normally distributed among both the cases and non-cases groups (Supplementary Fig. 1 ).

Clinical parameters and outcome evaluation

Patients diagnosed with prostate cancer were identified based on International Classification of Disease, Ninth Revision (ICD-9-CM) code 185, along with pathological proof. The index date was defined as the date of prostate cancer diagnosis, which was determined using the ICD-9-CMcode 185, recorded at least twice during outpatient visits or once during hospitalization between January 2009 and January 2022. All participants with the prostate cancers were incident cases and had not undergone regular follow-up prior to their cancer diagnoses. The study extracted relevant biochemical, lifestyle data and death files from the TCVGH database, and evaluated several covariates including sex, age, comorbidities and smoking. We obtained comorbidity information from the electronic health records of TCVGH based on ICD-9 diagnostic codes for hypertension (ICD-9-CM code 401–405), diabetes mellitus (ICD-9-CM code 250) and hypertension (ICD-9-CM code 401–405) were identified if the diagnostic code was used once during admission or at least twice in the outpatient service. Smoking status was dichotomized into former/current smokers and non-smokers. The incidence of prostate cancer among male participants was analyzed as the first step. Subsequently, the genetic profile was correlated with clinical parameters such as age at diagnosis, PSA levels, clinical stage and Gleason grading. The risk of prostate cancer was categorized based on the D’Amico risk classification 21 . Outcome evaluations included all-cause mortality and prostate cancer specific mortality.

Statistical analysis

Hazard ratios (HRs) and 95% confidence interval (95% CI) were calculated using Cox proportional hazards regression models, with time since study entry serving as the designated timescale. Outcomes were censored if a participant was lost to follow-up or died, or if the end of available follow-up was reached (November 2022). The demographic data are shown as mean ± standard deviation (SD) for continuous variables. An analysis of variance (ANOVA) for continuous variables, while categorical variables were presented as number (percent) and analyzed using Chi-square test. The PRS was assessed as a categorical variable, categorized into four groups based on quartiles of PRS values, namely Q1 (0–25%), Q2 (26–50%), Q3 (51–75%), and Q4 (76–100%). All statistical analyzes were conducted using SAS version 9.4. (SAS Institute Inc. Cary NC) and IBM SPSS statistical software for Windows, version 22.0 (IBM corp., Armonk, NY, United States).

Among the 57,257 participants from the TPMI project in TCVGH, a total of 24,778 male participants were included in the analysis. Among them, 903 patients diagnosed with prostate cancer were enrolled, and no data was missing for these participants (Fig. 1 ). Among the patients with prostate cancer, 508 individuals with clinically localized prostate cancer underwent radical prostatectomy, 156 cases of biochemical recurrence and 352 cases without recurrence. Additionally, there were 143 patients had metastatic disease at diagnosis, 416 patients had localized low-intermediate risk prostate cancer, and 344 patients had localized high risk prostate cancer (Fig. 1 ). Throughout the follow-up period, there were 103 fatalities recorded. Table 1 presents the basic demographic characteristics of the entire cohort. Compared with non-prostate cancer patients, prostate cancer patients exhibit a significantly higher mean age of 75.72 years. The average score of PGS000662 was significantly higher in patients with prostate cancer than in non-prostate cancer patients (− 1.53 vs. − 2.09, p < 0.0001). Additionally, this group demonstrates lower incidences of diabetes mellitus (24.14% vs. 33.45%, p < 0.0001) and hyperlipidemia (23.48% vs. 38.64%, p < 0.0001), yet a higher prevalence of smoking (51.38% vs. 45.02%, p = 0.0002). The mortality analysis reveals that prostate cancer patients have significantly higher all-cause death rates (11.41% vs. 4.55%, p < 0.0001). The patients had a median follow-up duration of 9.63 years (interquartile range [IQR] 5.98–12.52) among those diagnosed with prostate cancer, and 9.4 years (IQR 4.94–12.52) among those without prostate cancer.

Flow chart for enrolled participants in the study. Among the 57,257 participants from the TPMI project in TCVGH, a total of 24,778 male participants were included in the analysis, with 903 patients diagnosed with prostate cancer as cases and controls. Among the patients with prostate cancer, 143 patients had metastatic disease at diagnosis, 416 patients had localized low-intermediate risk prostate cancer, and 344 patients had localized high-risk prostate cancer.

The participants were categorized into four groups (Q1–Q4) by quartile of PRS. The characteristics of the four quartiles of PRS among the 903 prostate cancer patients are presented in Table 2 . The diagnosis age was found to be significantly younger in Q4 (Q1, 69.5 ± 8.8 years old; Q2, 68.0 ± 7.9 years old; Q3, 69.3 ± 8.1 years old; Q4, 66.8 ± 8.3 years old, p = 0.002). The patients were confirmed as developing prostate cancer with a median follow-up time of 10.28 years (IQR 6.01–12.54) in Q1, 9.25 years (IQR 5.76–12.64) in Q2, 9.92 years (IQR 6.41–12.67) in Q3 and 8.83 years (IQR 5.90–12.05) in Q4, respectively. However, there was no statistically significant association between the four quartiles of PRS and the disease severity, as indicated by PSA level [Q1–Q4: median 13.4, interquartile range (IQR) 6.3–35.6 ng/ml; median 11.8, IQR 72–33.8 ng/ml; median 12.3, IQR 6.7–27.8 ng/ml; median 15.4, IQR 8.0–53.1 ng/ml, p = 0.07], clinical stage (stage I to stage IV, p = 0.71), Gleason grade (grade 1, 2 + 3, 4 + 5, p = 0.23) and Risk classification (low-intermediate, high, metastatic, p = 0.55). A total of 103 patients expired during the follow-up period, and 72 of them expired due to prostate cancer. There was no statistically significant association observed among the four quartiles in terms of all-cause death ( p = 0.73) or cancer-specific death ( p = 0.29) (Table 2 ).

The relationship between PGS000662 and the prostate cancer using Cox proportional hazard re-gression models, adjusted hazard ratios were calculated for prostate cancer risk factors and polygen-ic risk score in relation to the occurrence of first-onset prostate cancer outcomes. As shown in Table 3 , the baseline characteristics of participants along with HRs for prostate cancer, adjusted for risk factors. Age significantly elevates prostate cancer risk (HR = 1.070, P < 0.0001), while histories of hypertension and diabetes mellitus are associated with a decreased risk (HRs of 0.897 and 0.665, respectively, both P < 0.0001). Hyperlipidemia exhibits a notable protective effect against prostate cancer (HR = 0.476, P < 0.0001). Conversely, cigarette smoking marginally increases the risk (HR = 1.113, P = 0.0413), and a family history of the disease does not significantly alter risk levels (HR = 0.85, P = 0.1956). PGS000662 was normally distributed (Supplementary Fig. 1 ), and exhibited an association with prostate cancer, showing HRs of 2.254 (95% CI = 2.108–2.410, p < 0.001) after adjustment for potential confounders.

The development of prostate cancer increased with higher quartiles of PRS, with rates of 2.42%, 3.91%, 6.15% and 11.03% in Q1 to Q4, respectively ( p < 0.0001, Supplementary Table 1 ). The risk of incident prostate cancer was significantly higher in Q4 compared to Q1 (HR = 4.770, 95% CI = 3.999–5.689, p < 0.0001) by using Cox proportional regression analysis, as shown in Table 4 . After stratification by age group, the prostate cancer incidence remained higher in Q4 compared to Q1 in different age groups, including age ≤ 50 years old (HR = 9.247, 95% CI = 1.171–72.984, p = 0.0348) and age > 50 years old (HR = 4.755, 95% CI = 3.984–5.675, p < 0.0001), age ≤ 60 years old (HR = 5.417, 95% CI = 3.174–9.246, p < 0.0001) and age > 60 years old (HR = 4.731, 95% CI = 3.925–5.702, p < 0.0001), and age ≤ 70 years old (HR = 5.193, 95% CI = 4.061–6.641, p < 0.0001) and age > 70 years old (HR = 4.485, 95% CI = 3.482–5.778, p < 0.0001) (Table 4 ).

Then, we utilized both univariate and multivariate Cox proportional hazards models to assess the risk of survival outcomes among study populations. As shown in Table 5 , distinguishing between Gleason grades 2 + 3 and 4 + 5, showing a significant increase in risk for higher grades in the univariable model (HR = 3.66 for 4 + 5, p < 0.0001), but not in the multivariable model. The results in Table 5 indicate that there was no statistically significant association between the top quartile (Q4) of PRS compared to the bottom quartile (Q1) of PRS with all-cause death (Q4 vs. Q1, HR = 0.895, 95% CI = 0.519–1.543, p = 0.689) or cancer-specific death (Q4 vs. Q1, HR = 0.585, 95% CI = 0.291–1.176, p = 0.132) with Cox regression univariate analysis. Similarly, Cox regression multivariate analysis revealed a no statistically significant association between all-cause death (Q4 vs. Q1, HR = 0.817, 95% CI = 0.458–1.457, p = 0.493), cancer death (Q4 vs. Q1, HR = 0.473, 95% CI = 0.223–1.001, p = 0.0504) and PRS. Adjusted hazard ratios were calculated for age at baseline, Gleason grade, clinical stage, PRS, and cause of death.

In a subgroup analysis, we focused on 508 patients with localized prostate cancer who underwent radical prostatectomy (Supplementary Fig. 2 .) and compared the demographic characteristics between PRS groups (Table 6 ). A median follow-up duration of 9.18 years (IQR 5.34–12.39) in Q1, 7.90 years (IQR 5.61–12.02) in Q2, 8.85 years (IQR 5.78–12.41) in Q3 and 8.85 years (IQR 6.24–11.56) in Q4, respectively. There was no significant difference in diagnosis age among the four quartile groups ( p = 0.12). Among these patients, 156 patients experienced biochemical failure.

Compared with participants in Q1, participants in the highest quartile (Q4) had higher risk of incident prostate cancer ( p < 0.0001) (Fig. 2 ).

Cumulative incidence rate of prostate cancer in the entire cohort by PRS group.

Figure 3 displays the Kaplan–Meier survival curve for overall mortality of the 24,778 male participants (Fig. 3 A) and the 903 patients diagnosed with prostate cancer (Fig. 3 B), respectively. Both Kaplan–Meier survival curves showed no significant differences in all-cause death among the four groups ( p = 0.39 and p = 0.55, respectively). Figure 4 displays the Kaplan–Meier survival curve for the 508 patients who received radical prostatectomy, and no significant differences were observed in terms of biochemical failure among the four groups (Median biochemical failure time: Q1 to Q4: 41.4, 47.0, 47.9 and 51.0 months, respectively, p = 0.27).

The overall mortality (Kaplan–Meier survival curve) for the 24,778 male participants ( A ) and 903 patients ( B ) diagnosed with prostate cancer, respectively. The median overall survival is not reached within the follow-up period.

The Kaplan–Meier survival curve was used to analyze the biochemical failure outcomes of 508 patients who underwent radical prostatectomy. No statistically significant differences were observed among the four groups by quartiles of polygenic risk score. The median times to biochemical failure for patients in quartiles 1–4 were 41.4, 47.0, 47.9, and 51.0 months, respectively ( p = 0.27).

Furthermore, we conducted a survival analysis of 170 patients diagnosed with stage four prostate cancer who underwent hormone therapy (Table 7 ). A median follow-up duration of 8.28 years (IQR 4.90–10.91) in Q1, 7.93 years (IQR 5.19–10.99) in Q2, 8.67 years (IQR 4.22–11.52) in Q3 and 6.94 years (IQR 4.13–10.69) in Q4, respectively. There was no significant for the diagnosis age among the four quartile groups ( p = 0.7). Out of this group, 45 individuals passed away during the follow-up period. Figure 5 showed the Kaplan Meier survival curve for the 170 patients with stage four prostate cancer, and no significant differences were observed in terms of all-cause death among the four groups (Median overall survival time: Q1–Q4: 46.5, 46.4, 40.3 and 44.2 months, respectively, p = 0.99).

The Kaplan–Meier survival curve was used to analyze the overall survival outcomes of 170 patients with stage four prostate cancer. No statistically significant differences were observed among the four groups in terms of all-cause death by quartiles of polygenic risk score. The median overall survival times for patients in quartiles 1–4 were 46.5, 46.4, 40.3, and 44.2 months, respectively ( p = 0.99).

Our study aimed to utilize the PRS method to investigate the association between disease associated variants identified in GWAS and prostate cancer susceptibility and prognosis in Han Chinese individuals from TCVGH-TPMI cohort. We observed that individuals in the top quartile of PRS had a significantly higher risk of prostate cancer compared to those in the bottom quartile. Furthermore, the higher PRS was associated with early onset of prostate cancer. However, we did not find any correlation between PRS and tumor aggressiveness as determined by tumor stage, PSA levels and Gleason score. Additionally, PRS was not predictive of treatment outcomes in patients with localized prostate cancer who received radical prostatectomy or in patients with stage four prostate cancer who were treated with hormone therapy.

The PRS, PGS000662, used in our study consisted of 269 SNPs and was developed by Conti et al. in a trans-ancestry study that included GWAS data from 107,247 cases and 127,006 controls. This PRS comprised 269 single nucleotide polymorphisms (SNPs) and was developed using data from 12 large cohorts of cases and controls, encompassing individuals from various ancestries, including European, African American or Afro-Caribbean, African unspecified, East Asian, and Hispanic or Latin American backgrounds 5 . Conti et al. identified 86 new genetic risk variants independently associated with prostate cancer risk, in addition to the 269 known risk variants. Their PRS has been extensively validated in various cohort studies, consistently demonstrating its predictive value across different populations. In their original research, they found that PRS 90–100% compared to 40–60% increased risk of prostate cancer (OR = 4.47, 95% CI = 3.52–5.68) in EAST Asia. Furthermore, the risk was notably elevated among individuals with a PRS of 99–100% (OR = 9.41, 95% CI = 5.6–15.82).

Conti’s PRS has been utilized in several cohort study with consistent results. For instance, Plym et al. 22 found that men with higher PRS scores, particularly when combined with a family history of prostate or breast cancer, exhibited significantly increased risks of prostate cancer and prostate cancer-specific death. Furthermore, Plym et al. utilized Conti's PRS to examine different ancestries and reported increased prostate cancer risk in European (PRS 90–100% vs. 40–60%, OR = 3.89, 95%CI = 3.24–4.68) and African ancestry populations but no Asian population (PRS 90–100% vs. 40–60%, OR = 3.81, 95%CI = 1.48–10.19). Additionally, Plym et al. found that men in the top quartile of PRS, along with a family history of prostate or breast cancer, had the highest risk of prostate cancer (HR = 6.95, 95% CI = 5.57–8.66) and prostate cancer-specific death (HR = 4.84, 95% CI = 2.59–9.03) compared to men in the bottom quartile with no family history 23 . Furthermore, they reported that by the age of 85, the cumulative incidence of prostate cancer was 7.1% in the bottom decile and 54.1% in the top decile for European American men 22 . In addition to Conti’s 269 PRS, Chen et al. 24 identified nine novel susceptibility loci for prostate cancer in African men, which were strongly associated with prostate cancer risk and aggressive disease in African ancestry populations (PRS 90–100% vs. 40–60%, OR = 3.19, 95% CI = 3.00–3.40). Our study is the first and largest GWAS cohort to examine Conti’s 269 PRS in Han Chinese individuals (PRS Q4 vs. Q1, HR 4.770, 95% CI = 3.999–5.689) and found similar predictive value as observed in European and African ancestries.

To the best of our knowledge, the first PRS for prostate cancer was conducted in 2008, utilizing five SNPs among the Swedish population. Incorporation of this PRS and family history accounted for 46% of prostate cancer cases with an odds ratio of 9.46 25 . Subsequently, numerous studies investigating genetic factors and prostate cancer susceptibility have been published. Nordstrom et al . also reported the potential application of PRS in predicting prostate cancer risk in individuals with PSA levels between 1 and 3 ng/ml 26 . Another cohort study evaluating pathogenic variants in 14 prostate cancer susceptibility genes and 72 validated prostate cancer-associated SNPs further confirmed the predictive value and potential clinical utility of PRS for risk assessment in addition to family history 27 . In conclusion, Siltari et al . summarized a total of 16 PRS prostate cancer studies involving 9 to 448 SNPs, and found that the ability of PRS to identify men with prostate cancer was modest [pooled AUC 0.63, 95% CI 0.62–0.64], and could be improved when combined with clinical variables (AUC 0.74, 95% CI 0.68–0.81) 28 .

In Ho et al., the PGS000662 demonstrated excellent performance in predicting prostate cancer for Han Chinese, with an area under the receiver operating characteristic curve (AUC) of 0.7 29 . Similarly, in this study, the predictive value of PGS000662 for prostate cancer was 0.685 (95% CI = 0.427–0.732) (Supplementary Fig. 3 ). In comparison to the study by Ho et al., our study includes a larger number of male participants (24,778 vs. 9,610) and prostate cancer cases (903 vs. 308). However, we did not observe any significant correlation between the polygenic risk score (PRS) and disease aggressiveness or treatment prognosis. This finding is consistent with previous studies suggesting that while PRS may be associated with disease incidence, it does not necessarily provide predictive value for aggressive disease or cancer-related mortality beyond prostate-specific antigen (PSA) level 30 , 31 . Possible reasons for this lack of correlation include confounding factors such as cancer stage, early cancer screening practices, or treatment availability. Although we specifically focused on localized prostate cancer cases that received radical prostatectomy and stage 4 prostate cancer cases, our sample size for these analyses was limited (508 and 170, respectively). Further large-scale analyses would be beneficial for more robust conclusions.

The incidence of prostate cancer is notably lower in Asian countries compared to Western populations 32 . The discrepancy may be attributed to the lack of systemic PSA screening; however, genetic ethnicities could potentially account for the significant differences in prostate cancer incidence. Zhu et al . conducted a Chinese cohort study comprising 176 cases and 548 controls, which identified 24 prostate cancer-associated SNPs and revealed that the genetic score was able to predict prostate cancer risk in the overall population as well as in individuals aged 60–70 years 33 . Another Chinese cohort study conducted by Na et al . compared seven prostate cancer risk-associated SNPs implicated in East Asians with seventy-six prostate cancer risk-associated SNPs implicated in at least one racial group. They found that the former set of SNPs demonstrated better predictive performance for prostate cancer (AUC 0.602 vs. 0.573, respectively) 34 . Notably, although most PRS studies have been developed in Western countries, they have shown similar predictive performance in Asian populations 9 .

Furthermore, our study has revealed that in addition to supporting the association of PRS with prostate incidence, PRS is also significantly associated with disease development at a younger age. This finding aligns with previous research indicating that the relative risk of PRS for prostate cancer varies depending on age. For instance, Schaid et al . conducted refined analyses on a validated PRS for prostate cancer and reported significantly higher relative risks for younger men (relative risk of 2.56, age 30–55 years) compared with older men (relative risk of 1.86, aged 70–88 years) 35 . Similarly, Varma et al . demonstrated that machine learning algorithms incorporating PRS information and basic patient data could provide risk assessment in men younger than 55 years, for whom screening is not standard practice 36 . Moreover, Seibert et al . reported that PRS based on 54 SNPs was a highly significant predictor of age at diagnosis of aggressive prostate cancer 37 . Consistent with these findings, our study also observed that the diagnosis age in the top quartile of PRS was lower than that in the bottom quartile of PRS in our population (Table 2 ), and PRS had similar impacts across different age groups (Table 4 ).

Although there was a positive correlation between PRS and prostate incidence in our study population, we did not find any significant correlation between PRS and disease aggressiveness or treatment prognosis. This finding is consistent with a population-based study conducted by Klein et al . in Sweden, which shown that PRS was associated with incident of prostate cancer and prostate cancer death, but it did not provide additional utility beyond PSA 30 . Furthermore, the study by Schaffer et al ., which used PRS with 269 SNPs by Conti in a cohort of 655 men who underwent prostate biopsy, found that although PRS 269 improved the prediction of all prostate cancer cases, it did not improve the risk prediction of aggressive disease 31 .

The study by Ou et al . conducted in South Korea utilized a cohort design and demonstrated that a PRS incorporating sixteen SNPs was able to predict biochemical failure following radical prostatectomy. The 10-year biochemical-free survival rate was reported to be 46.3% in the high PRS group compared to 81.8% in the low PRS group 38 . However, another multi-center cohort study from Taiwan presented the opposite conclusions. Wang et al . found that PRS was associated with early onset age of prostate cancer in patients undergoing radical prostatectomy, but it did not predict disease recurrence 39 . Our own results were consistent with this finding, as we did not observe a predictive association between PRS and biochemical failure following radical prostatectomy. Furthermore, we also reported for the first time that PRS was not predictive of overall survival in stage four prostate cancer patients treated with hormone therapy. In contrast, a prospective cohort study conducted in the UK biobank setting, which considered mortality as an endpoint, found that PRS was superior in predicting incidence and mortality compared to family history and rare pathogenic mutation 40 . Despite the promising potential of PRS in predicting prostate cancer incidence and susceptibility, there is currently no consensus on its ability to predict prognosis or treatment outcomes. One possible explanation for this inconsistency is the significant impact of life-prolonging treatments such as androgen receptor targeted agents and chemotherapy on prostate cancer outcomes, which may reduce the contribution of genetic factors. Additionally, the widespread implementation of early screening programs for prostate cancer has resulted in the detection of cancers at earlier stages, thereby further reducing the cancer specific mortality rates in the population.

The value of germline genetic testing for prostate cancer screening strategies has been called into question, as it has not been shown to be superior to other validated biomarkers for prostate cancer prediction, such as PSA or Prostate Health Index 31 . In the BARCODE1 study, which enrolled 5000 men to access their genetic risk of prostate cancer, only 18 out of 25 participants in the top 10% of the PRS distribution underwent Magnetic Resonance Imaging and biopsy, and only seven cases diagnosed with prostate cancer (38.9%). Furthermore, all the identified cancers were low-risk and were managed with active surveillance 41 . As current prostate cancer risk SNPs were primarily designed to predict disease incidence, it may be necessary to expand the polygenic models to include rare coding variants that influence disease aggressiveness and outcome, such as DNA repair genes, in order to improve the prediction of lethal prostate cancer 42 , 43 .

This study has several limitations that should be acknowledged. Firstly, the sample size of the study was relatively small, and the follow-up period was not long enough, which may have limited the generalizability of our findings in terms of disease treatment and prognosis. Enrolled participants consisted of patients who visited our institute, thereby limiting the applicability of the findings to the general population. Furthermore, due to limitations in data collection, we were unable to obtain medical records from sources outside of the hospital where the study was conducted. Additionally, the family history records of prostate cancer patients included in this study were incomplete. This limitation could potentially be overcome by leveraging national-level data. Moreover, we did not include the treatment effects of novel hormone therapy and chemotherapy, which have been proven to be life-prolonging agents for metastatic prostate cancer, and their omission may confound our results. Additionally, the PRS utilized in our study was obtained from cross-ancestry GWAS, which may have potentially diminished its predictive efficacy 5 . A better approach would be to develop a GWAS-based PRS system specifically designed for the Taiwanese population. This can be accomplished by utilizing national-level data from the TPMI study cohort, which is conducted by Academia Sinica in collaboration with 13 medical center-level hospitals across Taiwan. By leveraging this extensive dataset, we can enhance the accuracy of disease incidence and prognosis prediction for the Taiwanese ethnic group. Finally, to develop PRS system not only for cancer incidence but also disease prognosis or drug selection would be helpful for clinician in their decision making and treatment approaches.

Conclusions

In this cohort study conducted in a hospital setting, we observed that individuals in the top quartile of PRS were more susceptible to prostate cancer and tended to be diagnosed at a younger age. However, we did not find any significant associations between PRS and disease stage, PSA level, Gleason grade, or D'Amico risk classification. Furthermore, PRS was not a reliable predictor of biochemical failure in localized prostate cancer patients treated with radical prostatectomy, nor overall death in stage four prostate cancer patients treated with hormone therapy. To further validate our findings, PRS scoring derived from a cohort with a longer follow-up, such as the TPMI cohort, would be preferable.

Data availability

All data used in this study are available in this article. However, the individual-level PRS and prostate cancer information data are not currently available within the paper. However, we are committed to facilitating access to the data for interested researchers. To request access to the underlying data, please contact the corresponding author. We will provide further information regarding the availability and any necessary procedures for obtaining access, taking into account any ethical, legal, or privacy considerations associated with the data. We appreciate your understanding and patience in this matter.

Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 72 , 7–33. https://doi.org/10.3322/caac.21708 (2022).

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Acknowledgements

We thank all of the participants and investigators from the Taiwan Precision Medicine Initiative, which was funded by Academia Sinica (40-05-GMM; AS-GC-110-MD02; 236e-1100202), and National Development Fund, Executive Yuan [NSTC 111-3114-Y-001-001]. The authors sincerely appreciate the assistance of the Center for Translational Medicine of Taichung Veterans General Hospital.

This study was funded by Taichung Veterans General Hospital, Taiwan [grant numbers TCVGH-TCVGH-1127304B, TCVGH-1135003B and TCVGH-1137302B].

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Department of Urology, Taichung Veterans General Hospital, Taichung, Taiwan

Sheng-Chun Hung, Li-Wen Chang, Shian-Shiang Wang & Jian-Ri Li

Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan

Sheng-Chun Hung, Li-Wen Chang & Jian-Ri Li

Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan

Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan

Tzu-Hung Hsiao, Chia-Yi Wei & I-Chieh Chen

Department of Public Health, Fu Jen Catholic University, New Taipei City, Taiwan

Tzu-Hung Hsiao

Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan

Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan

Shian-Shiang Wang

Department of Medicine and Nursing, Hungkuang University, Taichung, Taiwan

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Study design and protocol development: SCH, THH, JRL, ICC; manuscript writing and editing: SCH, ICC; statistical analysis: ICC, CYW; data collection and patient management: SCH, LWC, SSW, JRL; supervision or mentorship: SCH, LWC, THH, CYW, SSW, JRL and ICC. All authors reviewed the final manuscript.

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Correspondence to I-Chieh Chen .

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Hung, SC., Chang, LW., Hsiao, TH. et al. Predictive value of polygenic risk score for prostate cancer incidence and prognosis in the Han Chinese. Sci Rep 14 , 20453 (2024). https://doi.org/10.1038/s41598-024-71544-7

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DOI: 10.1111/jgs.19177
Corpus ID: 272278826

Physician perspectives regarding over-screening for breast, colorectal, and prostate cancers in older adults.

Morgan R. Quinley , Cynthia M. Boyd , +2 authors Nancy L. Schoenborn
Published in Journal of The American… 29 August 2024

2 References

Physician attitudes about using life expectancy to inform cancer screening cessation in older adults-results from a national survey., cancer screening in older adults: individualized decision-making and communication strategies., related papers.

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Understanding prostate cancer screening

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In this article: , when prostate cancer is confined to the prostate, there is an almost 100% chance that it can be cured with treatment., the prostate-specific antigen (psa) test is a good first step in screening for cancer. doctors can also use other tests to determine if a man likely has cancer., men who are at average risk for prostate cancer should start screenings at age 50. .

In the United States, about one in eight men will be diagnosed with prostate cancer in their lifetime. Other than skin cancer, it’s the most common cancer for men in this country. Fortunately, diagnostic tests have advanced tremendously in recent years, which means men who have prostate cancer are much more likely to catch it early. That increases their chance for a cure.

The prostate is a walnut-shaped gland in males that produces semen, the liquid that nourishes and transports sperm. The gland is located below the bladder and in front of the rectum, and it tends to grow larger as a man gets older.

What is prostate cancer?

The vast majority of prostate cancers are adenocarcinomas, which means they develop from the gland cells in the prostate. Many of them grow slowly and are confined to the prostate gland. “We tell patients that as long as the cancer is confined to the prostate, the likelihood of a cure is close to 100%,” says Mehran Movassaghi, M.D. , the division chief of urology and director for men’s health at Providence Saint John’s Health Center in Santa Monica, California.

In some cases, such as when a man is over 75 when he receives his diagnosis, active surveillance may be a better option than treatment. The cancer may be so slow-growing that the man would die from other causes before being affected by the cancer.

Screening for prostate cancer

The screening test that is most closely associated with prostate cancer is the prostate-specific antigen (PSA) test. PSA is a protein produced by the prostate and found mostly in semen.

“PSA has nothing to do with prostate cancer,” says Dr. Movassaghi. “The only reason it was used as a screening tool is because men who have prostate cancer were found to have an elevated PSA level.”

Since doctors didn’t have any other method of screening for prostate cancer 10-20 years ago, they checked a man’s PSA level through a blood test. In the past, a PSA level of 3 or 4 was considered “normal” vs. “abnormal.” But extensive research has shown that high PSA test results don’t always mean there’s cancer— and a low level of PSA doesn’t always guarantee no cancer.

“Because the PSA test is not perfect, there was a while when primary care providers were no longer recommending that men undergo this screening,” says Dr. Movassaghi.

Over the past decade, however, more sensitive prostate cancer tests have been developed, including magnetic resonance imaging (MRI), blood tests and urine tests. “A PSA works really well as a first step,” says Dr. Movassaghi. “If a patient has an elevated PSA, then we will continue other kinds of testing to determine whether he should undergo a prostate biopsy for cancer.”

Another screening tool for prostate cancer is a digital rectal examination (DRE), during which a doctor inserts a gloved finger into the rectum and feels the back wall of the prostate gland for enlargement, hard spots, lumps or tenderness.

When should you undergo prostate cancer screening?

The American Cancer Society recommends that men talk to their health care provider about whether to be screened for prostate cancer. The discussion about screening should take place at:

Age 50 for men who are at average risk of prostate cancer and will likely live another 10 or more years.
Age 45 for men at high risk of developing prostate cancer. This includes African American men and men who have a first-degree relative (father or brother) diagnosed with prostate cancer at an early age (younger than age 65).
Age 40 for men at even higher risk (which includes men who have more than one first-degree relative who had prostate cancer at an early age).

Is it possible to prevent prostate cancer?

Prostate cancer is a “disease of aging,” which means that the older a man becomes, the more likely he is to receive a prostate cancer diagnosis. However, there are other risk factors — in addition to age — that are also unavoidable:

Race – Black men’s chances of developing prostate cancer are double that of white American men.
Genes – If you have a family history of prostate cancer, you are at greater risk of getting it, too.

That said, you can adopt a lifestyle that lowers your risk for prostate cancer. “More and more studies point toward adopting a Mediterranean diet,” says Dr. Movassaghi. That includes eating mostly vegetables, fruits and whole grains, focusing on plant-based foods and healthy fats.

Dr. Movassaghi also recommends participating in regular exercise, including 35 minutes of high-intensity activity every day. Not only can that prevent prostate cancer, he says, but it can also be good for men who already have prostate cancer. “A lot of times men who have prostate cancer feel like they have no control,” he says. “This is a way for them to regain control.”

Contributing caregiver

Mehran Movassaghi, M.D. , is the division chief of urology and director for men’s health at Providence Saint John’s Health Center in Santa Monica, California.

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VIDEO

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COMMENTS

The Risk Factors and Screening Uptake for Prostate Cancer: A Scoping Review
1. Background. Prostate cancer is the second-most prevalent cancer in men and was the fifth-most common cause of cancer-associated death among men in 2020 [1,2].Peripheral zone cancer accounts for 70% of cases, with transition and central zone cancers accounting for 20% and 10%, respectively [].Cancer cells may travel through the blood and lymphatic fluid, causing metastasis mostly commonly ...
Screening for Prostate Cancer
Among 1000 men invited to undergo screening, approximately 5 will die from prostate cancer and 1.3 will avoid death from prostate cancer owing to screening in the 13-year period after initial ...
Prostate Cancer Screening with PSA and MRI Followed by Targeted Biopsy
GÖTEBORG-2, which has been described previously, 20 is a large, population-based, randomized screening trial to evaluate several different research questions with regard to prostate cancer ...
Prostate cancer
Current research aims to improve prostate cancer detection, management and outcomes, including understanding the fundamental biology at all stages of the disease. ... Prostate cancer screening (on ...
Screening for Prostate Cancer
Controversies. PSA screening can have several beneficial effects. Most men have a "normal" PSA value below the cut-off for further evaluation and up to 97% of men report some reassurance with PSA screening. 27 Screening can reduce a man's risk of developing metastatic prostate cancer and dying from the disease. 11,28 For every prevented death from prostate cancer, a life is lengthened by ...
Screening for prostate cancer: evidence, ongoing trials, policies and
Methods. PubMed was searched on 2 January 2023 for clinical trials, systematic reviews and meta-analyses with the terms "screening" AND "prostatic neoplasm" OR "prostate cancer" AND ("biopsy" OR "diagnosis" OR "mortality" OR "detection") published since 1 January 2018. Similar searches were done for the diagnostic ...
Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and
1. Introduction. Prostate cancer affects middle-aged men between the ages of 45 and 60 and is the highest cause of cancer-associated mortalities in Western countries [].Many men with prostate cancer are diagnosed by prostate biopsy and analysis, prostate-specific antigen (PSA) testing, digital rectal examination, magnetic resonance imaging (MRI), or health screening.
Prostate cancer screening with prostate-specific antigen (PSA) test: a
Objective: To investigate the efficacy and safety of prostate-specific antigen (PSA) testing to screen for prostate cancer. Design: Systematic review and meta-analysis. Data sources: Electronic search of Cochrane Central Register of Controlled Trials, Web of Science, Embase, Scopus, OpenGrey, LILACS, and Medline, and search of scientific meeting abstracts and trial registers to April 2018.
Screening for Prostate Cancer
screening on prostate cancer mortality among 162,388 men 55 to 69 years of age.17,18 Planned screening involved assessment of PSA every 4 years with a biopsy-recommendation threshold of 3.0 ng
Prostate Cancer Screening
Conclusion: Prostate cancer screening has been a topic of robust discussion for a number of years. Research continues to examine novel options for prostate cancer screening to either replace or compliment the prostate specific antigen test, but require additional validation before they will be widely accepted into clinical practice ...
Striking the Right Balance With Prostate Cancer Screening
Desai and colleagues, 1 analyzing Surveillance, Epidemiology, and End Results data from 2004 through 2018, found significantly increasing incidence rates of metastatic prostate cancer (mPCa) among men aged 45 to 74 years (during the period 2010-2018) and among men ages 75 and older (during the period 2011-2018). In the earlier periods, incidence rates of mPCa disease were stable in younger men ...
Prostate cancer screening with prostate-specific antigen (PSA) test: a
### What you need to know What is the role of prostate-specific antigen (PSA) screening in prostate cancer? An expert panel produced these recommendations based on a linked systematic review.1 The review was triggered by a large scale, cluster randomised trial on PSA screening in men without a previous diagnosis of prostate cancer published in 2018 (box 1).2 It found no difference between one ...
Prostate cancer
Prostate cancer is a major health issue, with approximately 1·3 million new cases diagnosed worldwide every year. About 10 million men are presently living with a diagnosis of prostate cancer, and approximately 700 000 of these are living with metastatic disease. 1,2 Metastatic prostate cancer accounts for more than 400 000 deaths annually, and this mortality is expected to more than double ...
Landmarks in prostate cancer
Full size image. Age, race, and family history are the strongest established risk factors for prostate cancer 11. On the basis of SEER data, the age-adjusted incidence per 100,000 men in 2014 was ...
Prostate Cancer Foundation Screening Guidelines for Black Men in the
Conclusions. These guidelines recommend that Black men should obtain information about PSA screening for prostate cancer. Among Black men who elect screening, baseline PSA testing should occur between ages 40 and 45. Depending on PSA value and health status, annual screening should be strongly considered.
Prostate cancer incidence and mortality in Europe and ...
Objective To provide a baseline comparative assessment of the main epidemiological features of prostate cancer in European populations as background for the proposed EU screening initiatives. Design Population based study. Setting 26 European countries, 19 in the EU, 1980-2017. National or subnational incidence data were extracted from population based cancer registries from the International ...
The promising role of new molecular biomarkers in prostate cancer: from
An exhaustive search was conducted by Pubmed, Google Scholar and Connected Papers using keywords relating to the genetics, genomics and artificial intelligence in prostate cancer, it includes ...
Advances in Prostate Cancer Research
Advances in Prostate Cancer Research. Nanoparticles are tested as a means to deliver drugs to prostate cancer cells. NCI-funded researchers are working to advance our understanding of how to prevent, detect, and treat prostate cancer. Most men diagnosed with prostate cancer will live a long time, but challenges remain in choosing the best ...
A contemporary review: mpMRI in prostate cancer screening and diagnosis
The biparametric MRI used as a triage test in this study was associated with improved prostate cancer risk stratification and may be used to exclude aggressive disease and avoid unnecessary biopsies in 30% of men with clinical suspicion of prostate cancer, although further studies are needed to fully explore this new diagnostic approach. Expand
Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for
Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these...
Knowledge, Awareness and Practice towards Screening for Prostate Cancer
To find additional relevant research papers, we manually cross-checked the reference lists of all retrieved articles. The database searches used the subsequent as clinical concern heading phrases and medical text words: "Knowledge" (and) "Awareness" (and) "Practice" (and) "Screening" (and) "Prostate Cancer" (and) "English ...
Prostate Cancer Research Articles
Posted: April 23, 2018. In a small clinical trial, researchers compared the efficacy of a much lower dose of the cancer drug abiraterone (Zytiga) taken with a low-fat breakfast with a full dose taken on an empty stomach, as directed on the drug's label. FDA Approves Apalutamide for Some Men with Prostate Cancer.
Prostate Cancer Screening
Prostate cancer is a disease in which malignant (cancer) cells form in the tissues of the prostate. The prostate is a gland in the male reproductive system located just below the bladder (the organ that collects and empties urine) and in front of the rectum (the lower part of the intestine).It is about the size of a walnut and surrounds part of the urethra (the tube that empties urine from the ...
Cancers
Prostate cancer, a leading cause of cancer-related mortality among men, is characterized by complex genetic and epigenetic alterations, dysregulation of oncogenic pathways, and a dynamic tumor microenvironment. Advances in molecular diagnostics and targeted therapies have significantly transformed the management of this disease. Prostate-specific membrane antigen (PSMA) has emerged as a ...
Novel light-based technique shows 90% accuracy in early prostate cancer
Microscopic and histological images of blood smears and prostate tissue biopsies—thin (2-5 µm) films, respectively: (a) and (d) show blood smears and prostate tissue at normal conditions; (b ...
Prostate Cancer Awareness Month: The History and Impact
In 2024, The Lancet Commission on prostate cancer projected that globally, prostate cancer cases would increase from 1.4 million in 2020 to 2.9 million in 2040. 10 Annual deaths were estimated to ...
Predictive value of polygenic risk score for prostate cancer incidence
The value of germline genetic testing for prostate cancer screening strategies has been called into question, as it has not been shown to be superior to other validated biomarkers for prostate ...
Physician perspectives regarding over-screening for breast, colorectal
DOI: 10.1111/jgs.19177 Corpus ID: 272278826; Physician perspectives regarding over-screening for breast, colorectal, and prostate cancers in older adults. @article{Quinley2024PhysicianPR, title={Physician perspectives regarding over-screening for breast, colorectal, and prostate cancers in older adults.}, author={Morgan R. Quinley and Cynthia M. Boyd and Craig E. Pollack and Somnath Saha and ...
What everyone needs to know about prostate cancer
The American Cancer Society guidelines recommend that if no prostate cancer is found as a result of screening, the time between future screenings should depend on the results of the PSA blood test. For example, individuals with a PSA of less than 2.5 ng/mL may only need to be retested every two years.
Understanding prostate cancer screening
The cancer may be so slow-growing that the man would die from other causes before being affected by the cancer. Screening for prostate cancer. The screening test that is most closely associated with prostate cancer is the prostate-specific antigen (PSA) test. PSA is a protein produced by the prostate and found mostly in semen.

Screening for prostate cancer: evidence, ongoing trials, policies and knowledge gaps

Previous screening trial results

The European Randomized Study of Screening for Prostate Cancer (ERSPC)

Gothenburg-1 screening trial

The Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial

The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) trial

Improved diagnostic methods

PSA density

Other biomarkers

MRI and lesion-targeting biopsy

Risk calculators

Ongoing screening trials

Gothenburg-2 trial (Sweden)

ProScreen (Finland)

PROBASE (Germany)

Other ongoing prostate cancer screening studies

Prostate cancer screening policies

United States Preventive Services Task Force recommendation

European Union recommendation

Lithuania: opportunistic PSA screening in primary care

Sweden: population-based organised prostate cancer testing (OPT)

Scientific knowledge gaps

Key knowledge gaps about screening for prostate cancer with modern diagnostic methods

Practical considerations on implementation

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Prostate cancer incidence and mortality in Europe and implications for screening activities: population based study

Introduction

Data sources

Review on PSA testing

Statistical analysis

Patient and public involvement

Time trends of prostate cancer incidence and mortality rates

Range of geographical and temporal variations in incidence and mortality rates

Trends in incidence against trends in PSA testing

Divergence between incidence and mortality

Changes in age curves of prostate cancer incidence and mortality over time

Limitations of this study

Conclusions

What is already known on this topic

What this study adds

Ethics statements

Data availability statement

Acknowledgments

Knowledge, Awareness and Practice towards Screening for Prostate Cancer: A Systematic Review and Meta-Analysis

Winniecia Dkhar

Rajagopal Kadavigere

Abhimanyu Pradhan

Introduction

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Prostate Cancer Screening (PDQ®)–Patient Version

General Information About Prostate Cancer

Prostate Cancer Screening

There is no standard or routine screening test for prostate cancer.

Risks of Prostate Cancer Screening

The risks of prostate screening include the following:

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