# Genetic Risk Score Screening for Prostate Cancer: How It Compares to PSA and MRI Methods A genetic-based approach to prostate cancer screening called a polygenic risk score (PRS) performed worse than current standard methods that use PSA blood tests, MRI scans, and blood biomarkers, according to a new comparative analysis. When researchers compared the BARCODE1 study results (PRS-based screening) against two large European screening trials (Göteborg-2 and ProScreen), they found that PRS screening led to more men undergoing biopsy, detected fewer aggressive (high-grade) cancers, and overdiagnosed more low-risk tumors. The authors conclude that current PRS tools should not be adopted for prostate cancer screening in clinical practice at this time. # Genetic Risk Score Screening for Prostate Cancer: How It Compares to PSA and MRI Methods ## Table of Contents - Key Points - Background: The Prostate Cancer Screening Dilemma - What Is a Polygenic Risk Score (PRS)? - The Three Screening Approaches Compared - How This Comparison Was Done - Key Findings: Numbers for 10,000 Men Screened - The Overdiagnosis Problem - Why the PRS Approach Underperforms - How PRS Compares to Other Cancer Screening Tests - The Crucial Problem: PRS Cannot Target Aggressive Cancers - Cost-Effectiveness Concerns - Study Limitations - Clinical Implications: What This Means for Patients - Recommendations for Patients and Doctors - Frequently Asked Questions - Source Information ## Key Points - In a comparison of the BARCODE1 PRS study with two European trials, PRS screening led to more biopsies, fewer aggressive cancers detected, and more harmless low-grade tumors found. - Per 10,000 men screened, PRS led to 704 biopsies and 155 high-grade cancers, versus 386 biopsies and 178 high-grade cancers with PSA plus MRI. - At the threshold used in BARCODE1, an AUC of 0.67 means the PRS correctly identified only about 1 in 4 men who actually had prostate cancer. - Current prostate cancer PRS tools do not preferentially detect aggressive disease; the proportions of high-grade and low-grade cancers are similar across all PRS risk levels. - The authors recommend not adopting PRS-based screening in clinical practice and continuing validated PSA, biomarker, and MRI-based approaches. ## Background: The Prostate Cancer Screening Dilemma Screening for prostate cancer using prostate-specific antigen (PSA), a blood test that measures a protein produced by the prostate gland, has long been debated. The problem is that PSA testing alone has questionable net benefit. A relatively high number of men must undergo biopsy and be diagnosed with prostate cancer to prevent even one prostate cancer-specific death. This is because PSA testing finds many cancers that are slow-growing and would never cause harm. Treating these harmless cancers leads to unnecessary procedures and side effects like incontinence and erectile dysfunction. This phenomenon is called overdiagnosis. These concerns have pushed researchers to develop ways to "risk-stratify" PSA screening. The goal is to improve the ratio of benefits to harms by identifying which men are most likely to develop aggressive prostate cancer and focusing screening efforts on them. ## What Is a Polygenic Risk Score (PRS)? A polygenic risk score (PRS) is a genetic test that estimates a person's overall inherited risk for a disease. It combines information from many common genetic variants (small differences in DNA), each of which contributes only a tiny amount of risk on its own. When combined, these variants produce a single score reflecting an individual's genetic predisposition. For prostate cancer, researchers have proposed that men with a high PRS could be offered more intensive screening, while men with a low PRS could be screened less often or not at all. This personalized approach, advocates argue, could better balance the benefits and harms of screening by targeting higher-risk individuals. The BARCODE1 study, led by McHugh and colleagues, recently tested this idea in the United Kingdom and published results in the New England Journal of Medicine in 2025. It was a single-group study (meaning there was no comparison group receiving standard care). All men aged 55–69 years from 69 primary care practices were invited to participate. Volunteers underwent PRS testing, and those in the top 10% of the risk distribution were invited for PSA measurement, magnetic resonance imaging (MRI), and biopsy. Importantly, a biopsy was offered to all men at high PRS risk, regardless of their PSA level or imaging findings. If MRI-visible lesions were present, additional targeted biopsy cores were taken. The BARCODE1 authors claimed that the percentage of men "found to have clinically significant disease [on PRS-based screening] was higher than the percentage that would have been identified with the use of PSA or MRI." The authors of this new analysis point out that such a conclusion is questionable without a comparator arm (a control group receiving standard screening methods). That lack of comparison prompted them to conduct this study. ## The Three Screening Approaches Compared To place BARCODE1 in context, the researchers compared its outcomes with two contemporaneous (occurring around the same time), large-scale screening trials from Scandinavia. ### Göteborg-2 (Sweden) Göteborg-2 is a randomized, population-based screening trial conducted in Sweden. Men aged 50–60 years undergo repeated PSA testing. Those with PSA of 3.0 ng/ml or higher proceed to prostate MRI. Participants are then randomized to either systematic biopsy (samples taken from multiple standard locations in the prostate) with additional targeted biopsy if MRI-visible lesions are present, or MRI-targeted biopsy alone. ### ProScreen (Finland) ProScreen is a randomized, population-based screening trial in Finland that enrolled men aged 50–63 years. In the intervention arm, men undergo PSA testing. Those with PSA of 3.0 ng/ml or higher receive further risk stratification using a prostate cancer blood marker called a four-kallikrein panel (a test measuring four proteins in the blood related to prostate cancer). Men with a kallikrein score of 7.5% or higher proceed to MRI, followed by targeted biopsy if indicated. ### BARCODE1 (United Kingdom) As described above, this single-group study invited men aged 55–69. All volunteers had PRS testing. Only men in the top 10% of PRS risk proceeded to PSA testing, MRI, and biopsy. Notably, BARCODE1 also allowed analysis of combinations: PRS plus PSA (biopsy if high PRS and high PSA), PRS plus MRI (biopsy if high PRS and positive MRI), or all three together. ## How This Comparison Was Done From each trial, the researchers extracted data on the number of men screened and biopsied, plus the number of high-grade and low-grade prostate cancers detected. **High-grade (clinically significant) prostate cancer** was defined as Gleason 7 or higher (grade group 2 or above). Gleason score is the standard grading system for prostate cancer; higher scores mean more aggressive tumors. **Low-grade (clinically insignificant) prostate cancer** was defined as Gleason 6 (grade group 1). These cancers are generally considered harmless if left untreated. To make fair comparisons across studies, outcomes were standardized and reported per 10,000 screened individuals. For example, in BARCODE1, 468 biopsies were performed among 6,644 men screened. That works out to 704 biopsies per 10,000 men (468 divided by 6,644, multiplied by 10,000). Similarly, 103 high-grade cancers were detected, which equals 155 per 10,000 men screened, and 84 low-grade cancers were detected, which equals 126 per 10,000 men screened. All results in the analysis are presented as standardized outcomes per 10,000 men screened. ## Key Findings: Numbers for 10,000 Men Screened The results, shown in the table below, reveal clear differences among the three approaches. - **Men biopsied:** BARCODE1 biopsied 704 men per 10,000 screened, compared to 386 in Göteborg-2 and 338 in ProScreen. PRS screening led to nearly double the number of biopsies. - **High-grade cancers detected:** BARCODE1 found 155 high-grade cancers per 10,000 men, versus 178 in Göteborg-2 and 165 in ProScreen. PRS screening found fewer aggressive cancers despite doing more biopsies. - **Low-grade cancers detected (overdiagnosis):** BARCODE1 found 126 low-grade cancers per 10,000 men, versus 103 in Göteborg-2 and 41 in ProScreen. PRS screening overdiagnosed substantially more harmless cancers, especially compared to ProScreen. The full comparison from the study's Table 1, expressed per 10,000 individuals screened, is as follows: - **Göteborg-2** (men aged 50–60; PSA + MRI with targeted biopsy): 386 men biopsied; 178 clinically significant (high-grade) cancers diagnosed; 103 clinically insignificant (low-grade) cancers diagnosed. - **ProScreen** (men aged 50–63; PSA, four-kallikrein panel, and MRI): 338 men biopsied; 165 clinically significant cancers diagnosed; 41 clinically insignificant cancers diagnosed. - **BARCODE1 – PRS alone** (men aged 55–69): 704 men biopsied; 155 clinically significant cancers diagnosed; 126 clinically insignificant cancers diagnosed. - **BARCODE1 – PRS + PSA** (men biopsied only if high PRS plus elevated PSA): 170 men biopsied; 78 clinically significant cancers diagnosed; 26 clinically insignificant cancers diagnosed. - **BARCODE1 – PRS + MRI** (men biopsied only if high PRS plus positive MRI): 146 men biopsied; 68 clinically significant cancers diagnosed; 24 clinically insignificant cancers diagnosed. - **BARCODE1 – PRS, PSA, and MRI combined** (men biopsied only if high PRS plus high PSA, positive MRI, or both): 54 men biopsied; 42 clinically significant cancers diagnosed; 3 clinically insignificant cancers diagnosed. Combining PRS with PSA or MRI in the BARCODE1 population reduced the detection of high-grade cancers by 50–75% compared to Göteborg-2 and ProScreen. In other words, when researchers required both a high PRS and an abnormal PSA or MRI before biopsying, they missed more than half of the aggressive cancers that standard screening approaches would have found. ## The Overdiagnosis Problem A good screening strategy should achieve two goals simultaneously: maximize the number of high-grade (aggressive) cancers detected, while minimizing both the number of men biopsied and the number of low-grade (harmless) cancers found. Low-grade cancer detection generally represents overdiagnosis, which leads to unnecessary treatment and anxiety. By this standard, the PRS-based strategy in BARCODE1 failed on all three counts. It resulted in more men being biopsied and more overdiagnoses of low-grade prostate cancer per 10,000 men screened, yet it detected fewer cases of high-grade disease compared with both Göteborg-2 (PSA plus MRI) and ProScreen (PSA plus blood markers plus MRI). This finding is especially striking given that BARCODE1 screened an older population. The men in BARCODE1 were aged 55–69, while Göteborg-2 enrolled men aged 50–60 and ProScreen enrolled men aged 50–63. Prostate cancer incidence rises steeply with age, so a higher number of clinically significant cancers would be expected in the older BARCODE1 cohort. Instead, BARCODE1 detected fewer high-grade cancers per 10,000 men screened than either trial with younger participants. ## Why the PRS Approach Underperforms The poor performance of PRS-based screening is perhaps unsurprising given its modest diagnostic properties, the authors explain. A central limitation is the weak risk discrimination offered by PRS, reflected in two ways. First, the BARCODE1 data show only modest stratification of 10-year absolute risk across PRS percentiles. In plain language, the difference in actual prostate cancer risk between men at the top and bottom of the PRS distribution was not dramatic enough to guide screening decisions reliably. Second, the area under the receiver operating characteristic curve (AUC) was only 0.67. The AUC is a standard measure of a test's ability to distinguish between people who have a disease and those who do not. An AUC of 0.5 means the test is no better than a coin flip. An AUC of 1.0 means perfect discrimination. A score of 0.67 is considered modest at best. To make this number clinically meaningful, the researchers converted the AUC into two practical metrics: the detection rate (DR, also called sensitivity) and the false positive rate (FPR). The detection rate is the proportion of people with the disease who are correctly identified by the test. The false positive rate is the proportion of people without the disease who are incorrectly classified as high risk. Using a risk-screening converter tool, an AUC of 0.67 corresponds to a detection rate of only 24% and a false positive rate of 9% when the threshold is set at the 90th percentile of PRS distribution (the cutoff used in BARCODE1). This means that, at the BARCODE1 threshold, the PRS correctly identifies only about 1 in 4 men who actually have prostate cancer, while incorrectly flagging about 1 in 11 healthy men as high risk. ## How PRS Compares to Other Cancer Screening Tests To put these numbers in perspective, the authors compared the PRS performance to well-established cancer screening tests used in general populations. - **Fecal immunochemical testing (FIT)** for colorectal cancer screening has a detection rate of 79% and a false positive rate of 6%. This test looks for hidden blood in the stool. - **Digital mammography** for breast cancer screening has a detection rate of 75% and a false positive rate of 8%. Both of these widely accepted screening tests offer substantially stronger performance than the PRS approach used in BARCODE1, which achieved only a 24% detection rate at a comparable false positive rate. Expressed differently, most prostate cancers in the general population occur in men below the 90th percentile of PRS risk. These men would be missed by the BARCODE1 PRS approach, which only screens the top 10%. However, those same cancers would be detected by the screening strategies used in Göteborg-2 and ProScreen, which screen all participants with PSA and then use MRI or blood markers to decide who needs biopsy. Consequently, at the population level, the PRS as implemented in BARCODE1 cannot reliably identify which men would benefit from continued PSA-based screening. This is in contrast to baseline PSA measured at ages 40–60, which has been shown in prior research to predict long-term prostate cancer risk and guide screening decisions effectively. ## The Crucial Problem: PRS Cannot Target Aggressive Cancers Perhaps the most important limitation, the authors stress, is that current prostate cancer PRSs do not preferentially detect aggressive disease. This is not just a quirk of BARCODE1; it is a fundamental property of how PRS works for prostate cancer. Research has shown that the proportions of high-grade and low-grade cancers are similar across all PRS risk strata. This makes biological sense: the genetic variants captured in a PRS are associated with developing prostate cancer in general, not specifically with developing lethal or aggressive forms of the disease. A man with a high PRS is about equally likely to develop a harmless low-grade cancer as an aggressive high-grade one. The authors note that they have previously demonstrated mathematically that the net benefit of screening can only be improved if the relative proportion of aggressive to indolent (harmless) disease increases with higher risk scores. In other words, a useful screening tool must preferentially detect dangerous cancers. This is true for PSA, blood markers, and MRI, which is why screening approaches based on these methods have superior properties. It is not true for PRS. Therefore, restricting screening to higher-risk groups defined by PRS will not improve the balance of screening benefits and harms. It will simply shift which men are biopsied, without improving the ratio of aggressive cancers found to unnecessary procedures performed. Looking forward, the authors suggest that future research should explore whether PRS calibrated against prostate cancer mortality (death from the disease), rather than incidence (diagnosis of the disease), could offer better clinical utility. Such a score would ideally identify men at risk for lethal prostate cancer specifically. ## Cost-Effectiveness Concerns Beyond clinical performance, there is also an economic concern. A recent study concluded that, given the additional costs of genotyping (performing the genetic tests) and downstream management, combined with the limited risk discrimination of PRS, realistic implementation of PRS in screening programs is unlikely to be cost-effective. In other words, the expense of testing every man's DNA is not justified by the modest improvement in cancer detection, especially when cheaper and more effective blood and imaging tests already exist. ## Study Limitations The authors acknowledge several limitations in their comparison. Because BARCODE1 did not include a control arm, placing its findings in context requires comparison with other contemporary screening trials. Inevitably, these trials differ in terms of patient characteristics and health care settings. All of these factors can influence outcomes such as cancer detection rates. However, the authors argue that the differences between the PRS approach and the other strategies are consistent and large. The differences in the numbers of biopsies, overdiagnoses, and cancers detected are so substantial that it is unlikely they could be explained by between-trial differences in patient characteristics alone. The fact that BARCODE1 screened an older population, which would be expected to have higher cancer incidence, makes its inferior detection of high-grade cancers even more telling. Additionally, this analysis is based on comparing separate trials rather than a head-to-head randomized study. A randomized controlled trial directly comparing PRS-based screening to PSA/MRI-based screening would provide the strongest evidence, but no such trial has been completed to date. ## Clinical Implications: What This Means for Patients This analysis carries several important messages for men considering prostate cancer screening. First, if you are offered a polygenic risk score test to decide whether you should undergo prostate cancer screening, you should know the evidence does not currently support this approach. The BARCODE1 data show that using PRS alone would mean more men undergo biopsy, more men are diagnosed with harmless cancers they never needed to know about, and fewer aggressive cancers are caught compared to standard approaches. Second, established screening methods that combine PSA blood testing with MRI, and in some cases additional blood markers like the four-kallikrein panel, remain the best available tools. These methods detect more clinically significant cancers and cause fewer unnecessary biopsies. Third, the study's findings highlight a fundamental point: a genetic score that predicts your overall risk of developing prostate cancer is not the same as a test that finds aggressive disease. A high PRS does not mean you are more likely to die from prostate cancer; it simply means you are more likely to be diagnosed with it, including the harmless type. Finally, the existing evidence suggests that PSA measured at ages 40–60 remains a valuable tool for long-term risk assessment. Baseline PSA in this age range can reliably indicate which men would benefit from continued screening, unlike the current generation of PRS tests. ## Recommendations for Patients and Doctors Based on the comparison of BARCODE1 with Göteborg-2 and ProScreen, the authors offer clear guidance: 1. **Do not adopt PRS-based screening in clinical practice.** Given the modest discriminatory ability, lack of preferential detection of aggressive disease, inferior performance compared to established screening strategies, and limited cost-effectiveness, current prostate cancer PRS tools do not offer a favorable balance of benefits to harms. 1. **Continue using validated PSA, biomarker, and MRI-based approaches.** Clinicians should rely on these established methods for prostate cancer screening. The combination of PSA with MRI (as in Göteborg-2) or PSA with blood markers and MRI (as in ProScreen) detects more clinically significant cancers with fewer biopsies. 1. **Reserve PRS for research settings.** Substantial methodological advances are required before the role of PRS in population screening can be reconsidered. In particular, developing PRS calibrated to lethal disease endpoints (prostate cancer mortality rather than incidence) is a key research priority. 1. **Consider baseline PSA testing at ages 40–60.** Current evidence indicates that a single PSA measurement in this age range provides useful long-term risk information, unlike PRS testing. 1. **Understand that more biopsies are not better.** A screening approach that biopsies more men but finds fewer aggressive cancers and more harmless ones is a step backward, not forward. For patients, this means you should have an informed discussion with your doctor about prostate cancer screening that covers the benefits and limitations of PSA testing and MRI. If someone offers you a genetic test to "personalize" your prostate cancer screening, ask what the results will actually change and whether the evidence supports that approach. Based on this analysis, current PRS testing has not yet earned that role. ## Frequently Asked Questions ### What is a polygenic risk score (PRS) for prostate cancer? A polygenic risk score is a genetic test that estimates your overall inherited risk for prostate cancer. It combines many common genetic variants, each contributing a tiny amount of risk, into one score. Researchers proposed that men with a high score could be screened more intensively, while men with a low score could be screened less often or not at all. ### Does a high polygenic risk score mean I am more likely to die from prostate cancer? No. A high polygenic risk score means you are more likely to be diagnosed with prostate cancer, including the harmless slow-growing type. The genetic variants in the score are linked to developing prostate cancer in general, not specifically to aggressive or lethal disease. The proportions of high-grade and low-grade cancers are similar across all PRS risk levels. ### How did PRS-based screening compare with PSA and MRI screening in this analysis? When researchers compared the BARCODE1 PRS study with two European trials, PRS screening led to more men having biopsies, detected fewer aggressive cancers, and found more harmless low-grade tumors. Per 10,000 men screened, PRS led to 704 biopsies and 155 high-grade cancers, versus 386 biopsies and 178 high-grade cancers with PSA plus MRI. ### What does an AUC of 0.67 mean for a prostate cancer risk test? AUC measures how well a test distinguishes people with a disease from those without. An AUC of 0.5 is no better than a coin flip; 1.0 is perfect. An AUC of 0.67 is modest. At the threshold used in BARCODE1, it corresponds to correctly identifying only about 1 in 4 men who actually have prostate cancer. ### What is overdiagnosis in prostate cancer screening and why does it matter? Overdiagnosis means finding slow-growing cancers that would never have caused harm. Treating these harmless tumors leads to unnecessary procedures and side effects like incontinence and erectile dysfunction. In the comparison, PRS screening found 126 low-grade cancers per 10,000 men, versus 103 with PSA plus MRI and 41 with PSA, blood markers, and MRI. ### What screening methods for prostate cancer are supported by current evidence? Established methods combining PSA blood testing with MRI, and in some cases additional blood markers like the four-kallikrein panel, detect more clinically significant cancers with fewer unnecessary biopsies. A single PSA measurement at ages 40 to 60 also provides useful long-term risk information. Discuss these options with your doctor. ### If I'm offered a polygenic risk score test to decide whether I need prostate cancer screening, when should I get a second opinion? A second opinion is worth seeking before agreeing to PRS-based screening decisions. PRS screening led to more biopsies, more harmless low-grade cancers detected, and fewer aggressive cancers found than PSA combined with MRI or blood markers. At the threshold used, PRS correctly identified only about 1 in 4 men who had prostate cancer. Current PRS tools are not recommended for clinical screening; validated PSA, biomarker, and MRI approaches remain the established methods. An independent review can clarify whether a genetic test should change your screening plan. Diagnostic Detectives Network provides independent expert second opinions. ## Source Information **Original article title:** Comparison of Results from the BARCODE1 Study and Contemporary Prostate Cancer Screening Trials **Journal:** European Urology Oncology. Published by Elsevier B.V. on behalf of the European Association of Urology. **Publication details:** Accepted December 18, 2025. DOI: 10.1016/j.euo.2025.12.013 **Funding:** Supported in part by the National Institutes of Health/National Cancer Institute via a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748), a SPORE grant in Prostate Cancer to Dr. H. Scher (P50-CA92629), the Sidney Kimmel Center for Prostate and Urologic Cancers, and David H. Koch through the Prostate Cancer Foundation. Amit Sud is the recipient of a Wellcome Trust Early Career Award (227000/Z/23/Z). **Conflicts of interest:** Amit Sud and Alan McNeill have nothing to disclose. Andrew J. Vickers reports royalties from the sale of the 4Kscore prostate test, a blood-based marker panel for prostate cancer risk assessment. This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not constitute medical advice. Men considering prostate cancer screening should consult their healthcare provider. --- Publisher: Diagnostic Detectives Network (https://diagnosticdetectives.com) — independent multi-expert medical second opinions, worldwide, private-pay. Author byline: Anton Titov, MD, PhD. Contact: https://diagnosticdetectives.com/pages/contact Canonical page: https://diagnosticdetectives.com/products/genetic-risk-score-screening-for-prostate-cancer-how-it-compares-to-psa-and-mri-methods