Polygenic risk score (PRS) as prostate cancer screening: ready for primetime?

Prostate cancer remains a major health concern around the world and is currently the second most common cancer diagnosis in men. Despite its rising incidence, there is no globally accepted population-wide screening program for early prostate cancer detection. The prostate-specific antigen (PSA) assay has been revolutionary in the identification of prostate cancer, but its use remains controversial due to equivocal mortality benefits as evidenced by multiple PSA screening trials over the last decade (see Table 1) (1-6), as well as possible false-positive results which is estimated to be at least as high as 10% in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial or 18% in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, the complications of prostate biopsies, and overdiagnosis or resulting overtreatment of indolent prostate cancer. While prostate cancer screening guidelines mainly include PSA screening in the United States (7), the United Kingdom National Screening Committee recommends against universal PSA screening. However, it remains important to note that while the 5-year survival rate for those with early localized prostate cancer is nearly 100% (8), those with stage IV prostate cancer remains to have worse prognosis with 5-year survival rates of 37% (9). Therefore, early detection of prostate cancer remains crucial, highlighting the urgent need for an effective screening tool to identify clinically significant cancers at an earlier stage where intervention might result in improving mortality outcomes.

Age, ethnicity, and family history are the few consistently recognized risk factors linked to more aggressive forms of prostate cancer, pointing to its strong genetic component. While rare pathogenic variants in DNA-repair genes such as BRCA1 and BRCA2 can increase risk, they account for only a small proportion of inherited prostate cancer. Increasing adoption of genome-wide association study (GWAS) have identified many prostate cancer susceptibility loci (10). The majority of genetic risk is attributable to the additive effect of numerous low-risk variants known as single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF), which confers increasing genetic risk with the greater number of risk alleles an individual carries (11). The overall effect of these variants can be summarized using a polygenic risk score (PRS), which does not contribute to a diagnosis of prostate cancer but rather serves as a valuable instrument for refining individual risk stratification.

The BARCODE1 study (12), published in The New England Journal of Medicine, was the first population-based effort to use a PRS to identify men at higher risk for prostate cancer and direct them to targeted screening using prostate magnetic resonance imaging (MRI) and prostate biopsy irrespective of their PSA results. The study was conducted in the United Kingdom and recruited men aged 55 to 69 years from primary care centers. Participants submitted saliva samples from which their DNA was extracted and genotyped using a panel consisting of 130 European-ancestry prostate cancer predisposition SNPs. The weighted alleles for the 130 SNPs were used to calculate the PRS for each participant. Those found to have a PRS in the 90^th percentile or higher were then invited to the clinic for PSA testing, multiparametric MRI, and transperineal biopsy. Diagnosed cases with prostate cancer were assigned to a corresponding Gleason score that ranges from 6 to 10, with a score of 7 (3+4) or higher, considered clinically significant. The initial pilot study that led to the BARCODE1 trial tested feasibility which showed a 26% uptake in a total of 25 men who had a PRS above the 90^th percentile (13). This pilot study showed 38.8% prostate cancer detection in these men (14,15).

Among the 40,292 men invited to take part, 8,953 expressed interest and 6,393 provided saliva samples for PRS calculation. Of those, 745 men (11.7%) were found to have a PRS in the 90^th percentile or higher and were invited for further screening, and 468 agreed to undergo prostate MRI and biopsy. Prostate cancer was detected in 187 of these participants (40.0%), with a median age at diagnosis of 64 years with a median PSA at diagnosis of 2.1 ng/mL. Notably, 103 men (55.1%) had intermediate (favorable at 33.7% and unfavorable at 14.9%) or high-risk cancers (6.4%) based on the 2024 National Comprehensive Cancer Network (NCCN) risk classification that necessitated treatment in 21.3% of patients. Importantly, 74 (71.8%) of these clinically significant cancers would have been missed using the United Kingdom’s current standard screening approach, which focuses mainly on elevated PSA levels and positive MRI findings. This compares favorably to a 35.3% detection of a Gleason score of 7 prostate cancer based on a PSA-directed ERSPC screening schema. Additionally, 125 men with MRI results that would not typically prompt a biopsy were still found to have prostate cancer, and 57 of those had a Gleason score of 7 or above which indicated more aggressive disease. This suggests that 30 additional prostate cancer cases were picked up using the PRS compared to just PSA and MRI screening alone and 17 (44%) of these constitute clinically significant cancer.

The results of the BARCODE1 study suggest that incorporating a PRS into the screening process could help detect clinically significant prostate cancers that might otherwise be missed using current, traditional screening methods. Compared to PSA as a screening method using the ERSPC criteria, the positive predictive value (PPV) of PSA screening was 24.1% while the PPV of PRS screening was 40% (P<0.001). While PRS is not intended to replace tools like PSA and MRI, it shows promise as an initial step to risk stratify individuals for prostate cancer. Incorporating PRS as a tool for screening has already previously shown to lower the chances of finding a low-risk indolent cancer that has little potential to harm men in their lifetime (16). Since a person’s PRS remains constant throughout their lifetime, it only needs to be calculated once and is not subject to variability and fluctuations in the same manner as PSA does. All participants in this study were aged 55 years or older and additional research is needed to determine the most appropriate and beneficial age for PRS assessment in clinical practice. A key limitation of BARCODE1 is that this study was comprised of participants who were of European ancestry only since PRS was based on a genotyping panel validated in men of European ancestry (17). As a result, this gene signature and performance in men of other non-European backgrounds as well as applicability to the global male population may be limited. However, this remains true in any population-wide study, including the PLCO cancer screening trial which is considered the biggest screening trial in the United States, in which non-Hispanic Black men only represented 4.4% of the whole trial population (18). As genetic testing becomes more accessible and affordable, the potential to use PRS in screening programs appears viable and beneficial, but questions around cost-effectiveness and implementation still need to be addressed. Overall, the BARCODE1 study offers valuable insight into assessing new variables for prostate cancer screening and how genetic information could enhance other disease screening pathways in the future.

Limitations and unanswered questions remain. By analyzing the relationship between PRS and prostate cancer outcomes, the study contributes to a broader understanding of how genetic factors influence cancer risk. This knowledge can inform future research and clinical practices regarding genetic counseling and risk assessment. However, cost-analysis studies, including how much financial cost in addition to PSA testing and MRI, must be determined. While genetic testing is becoming more accessible and economically feasible, the use of PRS as a screening tool is envisioned to be adjunctive, rather than replacing PSA and/or MRI for prostate cancer screening. In addition, attempts at applying PRS as an augmentative tool in personalized prediction models particularly in other patient populations such as Asians has been attempted but rather limited (19). On the other hand, a study evaluating a polygenic hazard score, which is a means to adapt a version compatible with OncoArray genotypes to look at a multi-ethnic database that including men of European, Asian and African descent, showed that risk-stratifying men into aggressive or even fatal phenotypes was possible in this multi-ethnic group (20). However, while genetic testing has been more widely incorporated in most national guidelines depending on risk factors for hereditary prostate cancer or whenever personal diagnosis of high-risk or metastatic disease is rendered, PRS testing based on genome-wide association study (GWAS) is still largely considered population-specific by design, hence highly subject to variability and influenced by allelic effect size based on the spread of population in the validation cohort. It is therefore not yet incorporated in major screening guidelines. Ultimately, success will be measured by mortality benefits along with lower incidence or diagnosis of low-risk prostate cancers, which has not yet thus far been demonstrated in any of the aforementioned studies. Therefore, given the lack of widespread adoption or integration into clinical guidelines, randomized trial affirming mortality benefit, and cost-effectiveness validation, the PRS as a tool remains promising but not ready for primetime use. Regardless, the correlation between high PRS and significant disease highlights the usefulness of PRS in identifying individuals who may require closer monitoring and early intervention.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-25-84/prf

Funding: This study was supported by the Wohlscheid Fund.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-25-84/coif). J.B.A-C. served as an unpaid Editorial Board Member of Annals of Translational Medicine from June 2023 to May 2025. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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