Plasma proteomics to predict taxane-induced peripheral neuropathy

Aim: Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting toxicity of paclitaxel in patients with cancer. Prediction of which patients will experience TIPN is challenging, though patients with higher systemic paclitaxel exposure have higher TIPN risk. This study aimed to use plasma proteomics to identify predictors of TIPN and paclitaxel pharmacokinetics (PK). Methods: This is a retrospective analysis of a prospective observational study of female patients with early-stage breast cancer receiving weekly paclitaxel treatment. TIPN was assessed at each dose via the sensory subscale of the EORTC Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (CIPN8). A blood sample was collected within ten minutes before the end of the first paclitaxel infusion to measure plasma proteomes using a liquid chromatography-mass spectrometry-based global proteomics approach and to estimate maximum systemic paclitaxel concentration (Cmax). A second sample was collected approximately 24 hours after infusion to estimate paclitaxel time above threshold (Tc>0.05). Linear mixed-effect and linear regression models were utilized to identify proteins predictive of TIPN and paclitaxel PK parameters, respectively, using a Bonferroni-adjusted α=0.0006 to correct for multiple testing. Results: Data from 36 participants were included in the analysis testing for an association of 83 proteins with TIPN or PK. Higher levels of complement C3 were associated with more severe TIPN trajectories (p=0.0002). No protein was significantly associated with either PK parameter (all p>0.0006). Conclusion: Complement C3 concentration at the end of initial paclitaxel infusion may be useful in identifying patients who could benefit from TIPN prevention strategies to improve long-term treatment outcomes.