Ontology highlight
ABSTRACT: Purpose
Statins are associated with lower risk of aggressive prostate cancer, but lethal prostate cancer is understudied and contributing mechanisms are unclear. We prospectively examined statins and lethal prostate cancer risk in the Health Professionals Follow-up Study (HPFS), tested associations with molecular subtypes, and integrated gene expression profiling to identify putative mechanisms.Experimental design
Our study included 44,126 men cancer-free in 1990, followed for prostate cancer incidence through 2014, with statin use recorded on biennial questionnaires. We used multivariable Cox regression to examine associations between statins and prostate cancer risk overall, by measures of clinically significant disease, and by ERG and PTEN status. In an exploratory analysis, age-adjusted gene set enrichment analysis identified statin-associated pathways enriched in tumor and adjacent normal prostate tissue.Results
During 24 years of follow-up, 6,305 prostate cancers were diagnosed and 801 (13%) were lethal (metastatic at diagnosis or metastatic/fatal during follow-up). Relative to never/past use, current statin use was inversely associated with risk of lethal prostate cancer [HR, 0.76; 95% confidence interval (CI), 0.60-0.96] but not overall disease. We found a strong inverse association for risk of PTEN-null cancers (HR, 0.40; 95% CI, 0.19-0.87) but not PTEN-intact cancers (HR, 1.18; 95% CI, 0.95-1.48; P heterogeneity = 0.01). Associations did not differ by ERG. Inflammation and immune pathways were enriched in normal prostate tissue of statin ever (n = 10) versus never users (n = 103).Conclusions
Molecular tumor classification identified PTEN and inflammation/immune activation as potential mechanisms linking statins with lower lethal prostate cancer risk. These findings support a potential causal association and could inform selection of relevant biomarkers for statin clinical trials.
SUBMITTER: Allott EH
PROVIDER: S-EPMC7056554 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
Allott Emma H EH Ebot Ericka M EM Stopsack Konrad H KH Gonzalez-Feliciano Amparo G AG Markt Sarah C SC Wilson Kathryn M KM Ahearn Thomas U TU Gerke Travis A TA Downer Mary K MK Rider Jennifer R JR Freedland Stephen J SJ Lotan Tamara L TL Kantoff Philip W PW Platz Elizabeth A EA Loda Massimo M Stampfer Meir J MJ Giovannucci Edward E Sweeney Christopher J CJ Finn Stephen P SP Mucci Lorelei A LA
Clinical cancer research : an official journal of the American Association for Cancer Research 20191121 5
<h4>Purpose</h4>Statins are associated with lower risk of aggressive prostate cancer, but lethal prostate cancer is understudied and contributing mechanisms are unclear. We prospectively examined statins and lethal prostate cancer risk in the Health Professionals Follow-up Study (HPFS), tested associations with molecular subtypes, and integrated gene expression profiling to identify putative mechanisms.<h4>Experimental design</h4>Our study included 44,126 men cancer-free in 1990, followed for pr ...[more]