Background: Lipids are known to influence tumour survival, inflammation, and chemoresistance. This is the first study to profile the plasma lipidome of men with metastatic castrate resistant prostate cancer (CRPC) to assess if differences in lipid profiles are associated with outcome.
Methods: Plasma samples were obtained from a Phase 1 discovery cohort of 96 CRPC patients, at baseline before cycle 1 of docetaxel. Lipidomic profiling of the plasma samples was performed by liquid chromatography and electrospray ionisation-tandem mass spectrometry detecting 323 lipid species. Results were subsequently assessed in an independent Phase 2 validation cohort of 63 patients.
Results: Unsupervised latent class analysis of baseline lipidomic profiles classified the Phase 1 patients into two subgroups. Lipidomic Profile 2 patients had a significantly shorter overall survival (OS) compared to Lipidomic Profile 1 patients (hazard ratio (HR) 2·3, 95% CI 1·4-3·7, p=0·0005). The baseline levels of 46 lipids were individually prognostic (p<0.05, FDR≤10%), and from these a prognostic three-lipid signature was derived (ceramide (d18:1/24:1), sphingomyelin (d18:2/16:0), phosphatidylcholine (16:0/16:0)). Patients with this three-lipid signature had a shorter median survival (11·7 months versus 21·7 months, p=0·00001; HR 2·9, 95% CI 1·8-4·8). The signature was also independently associated with shorter OS (p=0·00006) when modeled with known clinicopathological prognostic markers of baseline levels of alkaline phosphatase (p=0·01), haemoglobin (p=0·03), and serum PSA (p=0·6). Of the 46 lipids that were prognostic in the Phase 1 cohort, 19 were significantly associated with overall survival in the Phase 2 validation cohort (p≤0.03). The three-lipid signature was also associated with shorter OS in the Phase 2 cohort (HR 4·8, 95% CI 2·1-11·1, p=0·0003), and was an independent prognostic factor (p=0·02) when modeled with baseline alkaline phosphatase (p=0·83) and haemoglobin (p=0·11). In both Phase 1 and Phase 1 cohorts, the 3-lipid signature (p<0.05) was independent of body mass index, cholesterol and triacylglycerol levels, diabetes as a co-morbidity, statin and metformin use (p>0.05).
Conclusion: This study has identified and validated a novel plasma lipid signature associated with worse overall survival in men with CRPC. Therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.