Targeting men in the top 10% of genetic risk helped detect high-grade prostate cancer that conventional screening would miss, paving the way for more personalized and effective early detection strategies.
Study: Assessment of a Polygenic Risk Score in Screening for Prostate Cancer. Image Credit: Julien Tromeur / Shutterstock
In a recent study published in The New England Journal of Medicine, a group of researchers assessed whether a polygenic risk score can improve the detection of clinically significant prostate cancer compared to standard screening methods.
Background
What if a simple genetic test could help prevent cancer deaths? Prostate cancer is the second most common cancer among men globally, responsible for over 375,000 deaths in 2020. Yet, current screening tools like the prostate-specific antigen (PSA) test are flawed, prone to false positives, overdiagnosis, and unnecessary treatment.
Early-stage prostate cancer has a near 100% five-year survival rate, but this drops to 50% if detected late. Therefore, accurate, early detection is crucial. While magnetic resonance imaging (MRI) and PSA testing are evolving, they still miss many aggressive cancers. Growing interest in genetic profiling for personalized screening underscores the urgent need for further research.
About the Study
Researchers conducted a prospective, single-group study in the United Kingdom, targeting individuals assigned male sex at birth, aged 55–69 years, exclusively of European ancestry (limiting generalizability to other populations), with no history or current testing for prostate cancer. Invitations were sent to over 40,000 individuals via general practices, and eligible participants provided saliva samples for DNA extraction.
Using a custom genotyping panel, polygenic risk scores were calculated based on 130 prostate cancer–associated single-nucleotide polymorphisms (SNPs). Those in the top 10% of genetic risk (≥90th percentile) were invited for further screening, which included PSA testing, multiparametric MRI, and transperineal biopsy under local anesthesia.
MRI scans were evaluated using the Prostate Imaging Reporting and Data System (PI-RADS), version 2.1. Targeted biopsies were performed if the MRI revealed lesions. Notably, biopsies were also offered to high-risk participants with negative MRI scans, reflecting the study’s protocol to prioritize genetic risk.
Biopsy samples were assessed by a urologic histopathologist and graded using the Gleason score system. Diagnoses were classified according to the 2024 National Comprehensive Cancer Network (NCCN) prostate cancer risk categories.
Participants diagnosed with cancer received treatment based on National Institute for Health and Care Excellence (NICE) guidelines. Those without cancer were offered annual screening for five years. Statistical models evaluated associations between biopsy outcomes and variables like age, PSA levels, MRI scores, and family history.
Study Results
Out of 40,292 people invited, 8,953 (22.2%) expressed interest, and 6,393 underwent genetic risk scoring. Among them, 745 (11.7%) were in the ≥90th percentile for polygenic risk and invited for screening. Of these, 468 (62.8%) underwent MRI and biopsy. Prostate cancer was diagnosed in 187 participants with a detection rate of 40.0%. Most cancers (55.1%) were clinically significant, requiring treatment based on NCCN guidelines. The median age at diagnosis was 64 years.
Strikingly, 71.8% of clinically significant cancers would have been missed using the standard diagnostic pathway in the United Kingdom, which relies on elevated PSA levels and MRI findings alone. This highlights the value of genetic risk-based targeting.
Among the diagnosed cases, 118 (63.1%) had a PSA level ≤3.0 micrograms per liter, below the traditional screening threshold. Even within this "normal" PSA range, 43.2% had aggressive cancers (Gleason score ≥7). MRI also had limitations: 370 participants had negative scans, yet 125 of them still had cancer, 57 of which were clinically significant. Only 16% of detected cancers met both current PSA and MRI criteria.
Further analysis showed that neither age nor family history alone reliably predicted cancer. However, combining PSA level and MRI with polygenic risk improved prediction, yielding an area under the curve (AUC) of 0.78 for clinically significant cancer. PSA density added no benefit.
The Individualized Coherent Absolute Risk Estimator (iCARE) model was used to calculate the 10-year absolute risk of prostate cancer. Nearly all men with a polygenic risk score in the ≥90th percentile had a 10-year risk above 3.8%, a clinically useful threshold derived from quality-adjusted life-year analyses.
Overdiagnosis (identifying cancers that would never cause harm in a person’s lifetime) was estimated in about 20.8% of screen-detected cases using polygenic risk scoring. While this was comparable to traditional methods, the study emphasized that active surveillance for low-risk cases minimized overtreatment. Most men with low-risk cancer (Gleason score 6) were placed under active surveillance, aligning with guidelines to avoid unnecessary interventions.
Few adverse events were reported: one participant had sepsis, two had urinary infections, and one needed temporary catheterization. Most participants were well-educated professionals, a self-selected group that may limit real-world applicability due to potential uptake biases, and only 21% had a family history of prostate cancer.
Conclusions
To summarize, targeting men with a polygenic risk score in the top 10% significantly improved detection of clinically important prostate cancer, even when traditional PSA and MRI screenings failed. This strategy led to fewer missed aggressive cancers and avoided diagnosing many harmless ones.
Incorporating genetic risk profiling into national screening programs could personalize care, reduce unnecessary interventions, and save lives. While promising, further research is needed to expand this approach to diverse populations, including underrepresented racial/ethnic groups, such as Black men, who face higher prostate cancer risk, refine screening age guidelines, and assess long-term impact.
Polygenic risk scoring offers a one-time, stable measure that may revolutionize early cancer detection strategies globally.