Fankhauser, Christian D.Parry, Matthew G.Ali, AdnanCowling, Thomas E.Nossiter, JulieSujenthiran, ArunBerry, BrendanMorris, MelanieAggarwal, AjayPayne, Heathervan der Meulen, JanClarke, Noel W.2025-05-302025-05-300959-8049PubMed:36641896ORCID:/0000-0002-8344-3776/work/167893665http://www.scopus.com/inward/record.url?scp=85146167289&partnerID=8YFLogxKhttps://hdl.handle.net/1885/733755422Objective: The relationship between prostate-specific antigen (PSA) and prostate cancer (PCa) grade was traditionally thought to be linear but recent reports suggest this is not true in high-grade cancers. We aimed to compare the association between PSA and PCa-specific mortality (PCSM) in clinically localised low/intermediate and high-grade PCa. Subjects/patients and methods: Retrospective cohort study using the National Prostate Cancer Audit database in England of men treated with external beam radiotherapy (EBRT), EBRT and brachytherapy boost (EBRT + BT), radical prostatectomy or no radical local treatment between 2014 and 2018. Multivariable competing-risk regression was used to examine the association between PSA, Gleason, and PCSM. Multivariable restricted cubic spline regression was used to explore the non-linear associations of PSA and PCSM. Results: 102,089 men were included, of whom 71,138 had low/intermediate-grade and 22,425 had high-grade PCa. In high-grade, 4-year PCSM was higher with PSA ≤5 than PSA 5.1–10 for men treated with EBRT (hazard ratio 1.96 (95% confidence interval 1.15–3.34) or no radical local treatment (hazard ratio 1.99 (95% confidence interval 1.33–2.98). Restricted cubic spline regression showed that PSA and PCSM have a non-linear association in high-grade but a linear association in low/intermediate-grade PCa. Conclusion: The low-PSA/high-grade combination in M0 PCa treated with EBRT has a higher PCSM than those with high-grade and intermediate PSA levels. In high-grade disease, the PSA association was non-linear; by contrast, low/intermediate-grade had a linear relationship. This confirms a more aggressive biology in low PSA secreting high-grade PCa and a worse outcome following treatment.M.G.P. was supported by the National Institute of Health Research (DRF-2018-11-ST2-036). The National Prostate Cancer Audit is commissioned by the Healthcare Quality Improvement Partnership (HQIP) as part of the National Clinical Audit and Patient Outcomes Programme, and funded by NHS England and the Welsh Government . Neither the funders nor HQIP had any involvement in the study design, in the collection, analysis, and interpretation of the data, in the writing of this report. T.E.C was supported by the Medical Research Council (grant number MR/S020470/1). C.D.F. was supported by the Walter und Gertrud Siegenthaler Stiftung.9enPublisher Copyright: © 2022 The Author(s)Androgen deprivation therapyBrachytherapyProstate cancerProstate-specific antigenProstatectomyRadiotherapy202310.1016/j.ejca.2022.12.01785146167289