The Impact of Atorvastatin on Intraprostatic Biomarkers - Prognostic Value of 3LS-score - Follow-up of ESTO1-Trial

Abstract

Background: Prostate cancer (PCa) remains a global health burden, with limited reliable biomarkers beyond prostate-specific antigen (PSA). Statins have been associated with survival benefits in advanced Pca, potentially by modulating cholesterol metabolism and tumor biology. However, the causal mechanisms are not well understood. A distinct three-lipid signature (3LS) has previously been proposed as a prognostic biomarker for PCa.

Objective: This study investigates the effects of atorvastatin intervention on PCa tissue markers, long-term clinical outcomes, and the prognostic value of the 3LS derived from prostate tissue lipidome.

Methods: The ESTO1 trial randomized 158 statin-naïve PCa patients to receive high-dose atorvastatin (80 mg daily) or placebo before prostatectomy. Long term outcomes were assessed for 102 patients through medical records review. Prostate tissue samples were pathologically characterized, and lipidome quantified. Cox regression models were used to analyse clinical outcomes between the groups. The 3LS score was calculated by identifying the constituent lipids from the prostate lipidome.

Findings: Higher intraprostatic atorvastatin lactone concentrations were associated with reduced Ki67 expression and PSA levels. After a median follow-up of seven years, no significant differences were observed in biochemical recurrence, overall mortality, or initiation of hormonal therapy. However, the atorvastatin arm had a lower risk of major acute cardiovascular events (HR 0.11, 95% CI 0.01-1.01). The intraprostatic 3LS correlated with higher baseline tumor aggressiveness but did not predict subsequent outcomes.

Conclusion: Higher atorvastatin lactone concentrations in the prostate tissue were linked to improved pathological variables. Pre-surgery statin intervention reduced MACE risk but no impact on other clinical outcomes was observed. The 3LS from prostate tissue does not seem to be prognostic marker in localized Pca.

Keywords: Biochemical recurrence; Cardiovascular risk; Ki67; Lipidomics; Prostate cancer; Statins; Three-lipid signature.

Fig. 1

Study flow-chart of the follow-up of patients with prostate cancer treated with radical prostatectomy and participating in ESTO1 clinical trial. legend: Participants in the ESTO1 trial were randomized to use a daily dose of either 80 mg atorvastatin or a placebo from the day of recruitment until surgery. Long term follow-up information was not reliably available for patients residing outside the Pirkanmaa district. 3LS is a distinct lipid signature calculated in this study from the in from the intraprostatic concentrations of three lipids that have been previously shown to have prognostic value in prostate cancer as measured from serum.