Neurofilament light chain as a biomarker of axonal damage in sensory neurons and paclitaxel-induced peripheral neuropathy in ovarian cancer patients.

Paclitaxel-induced peripheral neuropathy (PIPN) is a barrier to effective cancer treatment and impacts quality of life among cancer patients. We used a translational approach to assess the utility of neurofilament light chain (NFL) as a biomarker of PIPN in a human cell model and in ovarian cancer patients. We measured NFL in medium from human induced pluripotent stem-cell derived sensory neurons (iPSC-SNs) treated with paclitaxel. Serum NFL (sNFL) levels were quantified in 190 ovarian cancer patients receiving paclitaxel/carboplatin chemotherapy at baseline and after each of the following 2 or 6 cycles. PIPN-related adverse outcomes were retrospectively obtained, and Cox regression model was performed with different sNFL cut-offs after first cycle. The apparent elimination half-life of sNFL was estimated in patients that discontinued paclitaxel. Paclitaxel neurotoxicity in iPSC-SNs was accompanied by NFL release in a concentration-dependent manner (P<0.001, ANOVA). sNFL levels increased substantially in patients during paclitaxel/carboplatin chemotherapy with considerable interindividual variability. Patients with sNFL>150 pg/mL after first cycle had increased risk to discontinue paclitaxel early (unadjusted HR: 2.47 (95% CI 1.16-5.22), adjusted HR: 2.25 (95% CI: 0.88-5.79)). Similar trends were shown for risk of severe PIPN and paclitaxel dose reduction due to PIPN. The median elimination half-life of sNFL was 43 days (IQR 27-82 days). NFL constitutes an objective biomarker of neurotoxicity in iPSC-SNs and in ovarian cancer patients with high sNFL predicting PIPN-related adverse outcomes. If prospectively validated, sNFL can be utilized to study PIPN and may guide clinical decision making and personalize treatment with paclitaxel.