Title | Statin Use Is Associated with Lower Risk of PTEN-Null and Lethal Prostate Cancer. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Allott EH, Ebot EM, Stopsack KH, Gonzalez-Feliciano AG, Markt SC, Wilson KM, Ahearn TU, Gerke TA, Downer MK, Rider JR, Freedland SJ, Lotan TL, Kantoff PW, Platz EA, Loda M, Stampfer MJ, Giovannucci E, Sweeney CJ, Finn SP, Mucci LA |
Journal | Clin Cancer Res |
Volume | 26 |
Issue | 5 |
Pagination | 1086-1093 |
Date Published | 2020 03 01 |
ISSN | 1557-3265 |
Keywords | Adult, Aged, Biomarkers, Tumor, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Incidence, Male, Middle Aged, Neoplasm Metastasis, Prospective Studies, Prostatic Neoplasms, PTEN Phosphohydrolase, Risk Assessment, Risk Factors, Survival Rate, Transcriptional Regulator ERG, United States |
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; heterogeneity = 0.01). Associations did not differ by ERG. Inflammation and immune pathways were enriched in normal prostate tissue of statin ever ( = 10) versus never users ( = 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. |
DOI | 10.1158/1078-0432.CCR-19-2853 |
Alternate Journal | Clin Cancer Res |
PubMed ID | 31754047 |
PubMed Central ID | PMC7056554 |
Grant List | P30 CA008748 / CA / NCI NIH HHS / United States P50 CA090381 / CA / NCI NIH HHS / United States R01 CA136578 / CA / NCI NIH HHS / United States U01 CA167552 / CA / NCI NIH HHS / United States P30 CA006516 / CA / NCI NIH HHS / United States P30 CA006973 / CA / NCI NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.