A Polygenic Risk Score Predicts Incident Prostate Cancer Risk in Older Men but Does Not Select for Clinically Significant Disease

Abstract

Despite the high prevalence of prostate cancer in older men, the predictive value of a polygenic risk score (PRS) remains uncertain in men aged ≥70 years. We used a 6.6 million-variant PRS to predict the risk of incident prostate cancer in a prospective study of 5701 men of European descent aged ≥70 years (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial. The study endpoint was prostate cancer, including metastatic or non-metastatic disease, confirmed by an expert panel. After excluding participants with a history of prostate cancer at enrolment, we used a multivariable Cox proportional hazards model to assess the association between the PRS and incident prostate cancer risk, adjusting for covariates. Additionally, we examined the distribution of Gleason grade groups by PRS group to determine if a higher PRS was associated with higher grade disease. We tested for interaction between the PRS and aspirin treatment. Logistic regression was used to independently assess the association of the PRS with prevalent (pre-trial) prostate cancer, reported in medical histories. During a median follow-up time of 4.6 years, 218 of the 5701 participants (3.8%) were diagnosed with prostate cancer. The PRS predicted incident risk with a hazard ratio (HR) of 1.52 per standard deviation (SD) (95% confidence interval (CI) 1.33–1.74, p < 0.001). Men in the top quintile of the PRS distribution had an almost three times higher risk of prostate cancer than men in the lowest quintile (HR = 2.99 (95% CI 1.90–4.27), p < 0.001). However, a higher PRS was not associated with a higher Gleason grade groups. We found no interaction between aspirin treatment and the PRS for prostate cancer risk. The PRS was also associated with prevalent prostate cancer (odds ratio = 1.80 per SD (95% CI 1.65–1.96), p < 0.001).While a PRS for prostate cancer is strongly associated with incident risk in men aged ≥70 years, the clinical utility of the PRS as a biomarker is currently limited by its inability to select for clinically significant disease.

Bringing Prostate Cancer Polygenic Risk Scores to the Clinic

“…Although polygenic risk scores have been associated with prevalent and incident disease, 1 prior studies have shown that they do not improve risk prediction for aggressive prostate cancers with the potential to be fatal. 2,3 In this study, we compared the polygenic risk score (PRS 269 ) as defined by Conti et al 4 to the Prostate Biopsy Collaborative Group risk calculator, 5 a clinical tool that computes the probabilities of finding (1) any cancer and (2) high-grade (GG ≥2) cancer on biopsy results in men undergoing a first prostate biopsy.…”

“…It is both notable and reassuring that the inclusion of a modest amount of men with African ancestry, East Asian ancestry, and Hispanic ethnicity in building the PRS 2 resulted in a score that appears to perform as well in men with European and African ancestry in this independent replication. 1 Further increasing representation of non-European participants in these genetic studies and more sophisticated algorithms for including multiancestry data 3 will help ensure that PRS will be valid and useful among all populations.…”

“…However, flecainide-induced widened QRS complex can contribute to hemodynamic instability at lower heart rates. 3 Given that the widened QRS complex induced by this class Ic antiarrhythmic drug is among the most lifethreatening electrocardiography warning indicators (regardless of heart rate), 4 what matters most is to manage flecainide toxicity. The discontinuation of flecainide and sodium bicarbonate therapy has been proposed as a treatment for sodium channel blocker toxicity.…”

“…For example, right bundle-branch block morphology with QRS complex of 200 or fewer milliseconds, left bundle-branch block morphology with QRS complex of 200 or more milliseconds, or a heart rate out of proportion with the degree of hemodynamic instability. 3 Zhenyu Dong, MD Yanmei Lu, MD, PhD Baopeng Tang, MD, PhD…”

Value of machine learning-based transrectal multimodal ultrasound combined with PSA-related indicators in the diagnosis of clinically significant prostate cancer

“…Hormonal therapy, radiotherapy, chemotherapy, and surgical treatment should be chosen according to the stage of the illness ( 8 ). The incidence of CS-PCa is higher in older men and men with no family history ( 9 ). Early detection of CS-PCa is of profound significance for the effective treatment of patients.…”