Plasma lipidomic profiling of chemotherapy-induced peripheral neuropathy

3031 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment. This may result in dose reduction (DR) or chemotherapy discontinuation (CD) and ultimately decrease the efficacy of therapy. There is a lack of studies examining the role of lipids in relation to CIPN, despite the association of obesity with worse CIPN, and hyperlipidaemia with diabetic neuropathy. The aim of this study is to determine if circulating lipids are associated with CIPN severity. Methods: Pre-chemotherapy plasma samples from 137 patients with CIPN from docetaxel or paclitaxel-based treatment underwent lipidomic analysis (788 lipids). CIPN severity was measured using the neurological grading scale Total Neuropathy Score-clinical version (TNSc score; John Hopkins University) and patient-reported outcome measure EORTC QLQ-CIPN20. The association of baseline lipid levels with severe CIPN, as defined by high TNSc and CIPN20 scores, was performed using linear modelling (LIMMA). Baseline lipids associated with shorter time to dose reduction (DR) or chemotherapy discontinuation (CD) due to CIPN was determined by Cox regression, with adjustment for body mass index (BMI), age and diabetes. Lipid profiles were identified using latent class analysis (LCA) of significant lipids from the Cox regression. Results: Higher TNSc or CIPN20 scores were associated with 107 and 43 lipid species respectively (LIMMA p<0.05), of which only 3 species were in common. Triacylglycerols (TG) represented a significant proportion of lipids with elevated levels associated with higher TNSc (32.5%) or CIPN20 (9.1%) scores (Fisher’s exact test p<0.001). 70 lipid species were associated with shorter time to DR/CD (Cox regression p<0.05), which included 15 TG with higher levels associated with shorter time to DR/CD. Unsupervised LCA identified a specific lipid profile associated with worse CIPN [Hazard ratio 2.61 (95% CI 1.40 – 4.84, p=0.002)]. This lipid profile also had higher levels of TG (t-test p<0.05). The high risk CIPN lipid profile was independently associated with shorter time to DR/CD when modelled with clinical factors (diabetes, age, BMI or prior numbness/tingling; Cox regression p<0.006); however, these clinical factors were not associated with time to DR/CD in the multivariable models (p>0.08). Conclusions: Higher levels of baseline plasma TG are associated with increased CIPN severity and shorter time to DR/CD in taxane-treated patients. These findings are consistent with other reports regarding the association of hyperlipidaemia with neuropathy. Further research is required to determine if TG-lowering medication can reduce the risk of CIPN development.