Lipidomic analysis of circulating lipidsacross the natural history of prostate cancer identifiesaberrant ceramide metabolism

Background: Obesity is a well established risk factor not only for increased prostate cancer incidence, but for poorersurvival from prostate cancer. However, there is limited knowledge on the role of the circulating lipidome in prostatecancer. In order to target lipid metabolism optimally, it is critical to understand the spectrum of changes in circulatinglipid profiles and the association with clinical outcome across the natural history of prostate cancer. Aim: To assess the relationship between the plasma lipidome and clinical outcome in localized and metastaticprostate cancer. Methods: Liquid chromatography-tandem mass spectrometry was used to quantitate over 500 lipid species inplasma samples from 3 cohorts (1) 389 men with localized prostate cancer, (2) 44 men with metastatic hormone-sensitive prostate cancer (mHSPC), and (3) 137 men with metastatic castration-resistant prostate cancer (CRPC).Associations between circulating lipids with metastatic relapse, androgen-deprivation therapy (ADT) failure or overallsurvival for each relevant disease stage were examined by latent class analysis and cox regression. Results: Circulating lipid profiles displaying elevated levels of ceramides were associated with metastatic relapse inlocalized prostate cancer (HR 5.8, 95% CI 3.0-11, P 1 × 10 ), early ADT failure in mHSPC (HR 2.4, 95% CI 1.1-5.3, P 0.03), and shorter overall survival in CRPC (HR 2.5, 95% CI 1.7-3.7, P 2 × 10 ). ADT failure in mHSPC and shorter overall survival in CRPC were also associated with elevated levels of other sphingolipids (sphingomyelins,hexosylceramides). The prognostic significance of the high risk lipid profiles in localized prostate cancer was independent of clinicopathological characteristics (lipid profile HR 4.7, 95%CI 2.4-9.3, P 7 × 10 ) when modeledwith Gleason score (P<0.0001) and pathological stage (P<0.0001). Furthermore, the circulating lipid profiles were independent of metabolic factors (localized prostate cancer lipid profile HR 8.2, 95% CI 2.6-25, P 0.0003 whenmodeled with diabetes, statin, hypertension, body mass index [BMI]; CRPC lipid profile HR 2.6, 95% CI 1.7-3.8, Px10 when modeled with BMI). Conclusion: Elevated circulating ceramides are associated with poorer clinical outcomes across the natural history of prostate cancer (from localized to metastatic hormone-sensitive to metastatic castration resistant prostatecancer). This demonstrates that aberrant lipid metabolism in the patients occurs early in prostate cancer and couldbe therapeutically targeted in prospective clinical trials to improve prostate cancer outcomes.