Impact of combined lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC).

Background: We previously identified that elevated circulating ceramides and a validated 3-lipid signature are associated with shorter overall survival (OS) in men with mCRPC. Several somatic gene aberrations in mCRPC are also linked to worse outcomes. This study examines the combined impact of a poor prognostic lipid profile and somatic aberrations on clinical outcomes in mCRPC. Method(s): Plasma lipidomic profiling of >700 lipids and deep targeted sequencing of circulating cell-free DNA was performed on (1) discovery cohort of 121 men with mCRPC starting taxanes or androgen receptor signalling inhibitors and (2) validation cohort of 69 men with mCRPC starting chemotherapy. Associations with radiological progression-free survival (rPFS) and OS were examined. Result(s): The 3-lipid signature was associated with shorter rPFS (HR 1.6, 95% CI 1.0-2.4, p=0.037) and OS (HR 1.9, 95% CI 1.3-2.9, p=0.001) in the discovery cohort and shorter OS (HR 2.3, 95% CI 1.6-3.4, p<0.001) in the validation cohort. In both cohorts, elevated ceramides were correlated with gene aberrations in AR, cell cycle and PI3K pathway (p<0.05). Men with both AR aberrations and 3-lipid signature had worse OS than men with either characteristic (median OS 12.5 vs 21.6m, p=0.005). This was also seen in men with PI3K aberrations (median OS 11.9 vs 21.8m, p=0.003), suggesting an additive effect. The biomarker combination of 3-lipid signature and genetic aberration was independently associated with worse rPFS +/- OS in multivariable analysis with clinicopathologic factors (see the table). The C-index for OS prediction using the Halabi model was improved by addition of the biomarker combination (see the table). [Formula presented] Conclusion(s): Elevated ceramides are associated with AR, cell cycle and PI3K pathway aberrations in mCRPC, and the combination of lipid and gene abnormalities confer a poorer prognosis. This suggests that targeting lipid metabolism in addition to actionable genetic mutations may