Background: A 3-lipid signature has been recently proposed to predict for prognosis in pts with mCRPC. This study aimed at assessing the lipidomic profiles of pts with mCRPC to identify new prognostic and predictive biomarkers.
Methods: Plasma samples were collected from pts with mCRPC starting a 1st-line (1L) (n=29) and pretreated with >2 lines (>2L) (n=19). Lipids were extracted and analyzed with an untargeted lipidomic approach. T-test was applied to identify lipids differentially expressed. ROC curves and X-Tile were used to identify lipids’ threshold and to test association with overall survival (OS). Kaplan-Meier curves were constructed and Cox regression was used to adjust for prognostic variables.
Results: We identified and quantified a total of 789 plasma lipids. 75 lipid specieswere significantly dysregulated in >2L compared to 1L samples. 63 species were upregulated, and 12 were downregulated. >2L pts showed higher levels of acylcar-nitine, diacylglycerols, phosphatidylethanolamine, triacylglycerols and ceramides (Cer). We tested the effect on OS of lipids included in the 3-lipid signature: Cer(d18:1/24:1), sphingomyelin (d18:2/16:0) and phosphatidylcholine (16:0/16:0). Only Cer (d18:1/24:1) was associated with OS, but without statistical significance in the multivariate model. Among upregulated lipids in >2L cohort, Cer (d18:1/18:0) (C18), Cer (d18:1/16:0), Cer (d18:2/18:0), Cer (d18:1/24:1) and Cer (d20:1/24:1) all showed proportional relative risk of death and significant association with OS in univariate models. However, only C18 retained significant association with OS after adjustmentfor basal PSA and line of treatment (HR: 3.26 [95% CI 1.37-7.76]). The association of C18 with OS was consistent in both subgroups 1L and >2L, separately analyzed. Biochemical response was only seen in 4/14 (28.6%) evaluable pts with high levels of C18.
Conclusions: Using a quantitative mass spectrometry approach, we characterized the lipidomic profile of highly pretreated mCRPC pts. We found that C18 is increased in these pts compared to therapy-naïve men, and significantly associated with OS, paving the way for further investigations on its prognostic and predictive value
