Prospectively assessing serum neurofilament light chain levels as a biomarker of paclitaxel‐induced peripheral neurotoxicity in breast cancer patients

Abstract

Our aim was to assess the significance of measuring serum neurofilament light chain (sNfL) levels as a biomarker of paclitaxel‐induced peripheral neurotoxicity (PIPN). We longitudinally measured sNfL in breast cancer patients, scheduled to receive the 12‐weekly paclitaxel‐based regimen. Patients were clinically examined by means of the Total Neuropathy Score‐clinical version (TNSc), while sNfL were quantified, using the highly sensitive Simoa technique, before starting chemotherapy (baseline), after 2 (week 2) and 3 (week 3) weekly courses, and at the end of chemotherapy (week 12). Among 59 included patients (mean age: 53.1 ± 11.5 years), 33 (56%) developed grade 0‐1 and 26 (44%) grade 2‐3 PIPN at week 12. A significant longitudinal increase of sNfL levels from baseline to week‐12 was determined, whereas patients with TNSc grade 2‐3 PIPN had significantly increased sNfL levels at week 12, compared to those with grade 0‐1. receiver‐operated characteristics (ROC) analysis defined a value of NfL of >85 pg/mL at week 3 as the best discriminative determination to predict the development of grade 2‐3 PIPN at week 12 (sensitivity 46.2%, specificity 84.8%). The logistic binary regression analysis revealed that age > 50 years and the cutoff of >85 pg/mL of sNfL levels at week 3 independently predicted the development of grade 2‐3 PIPN at week 12 with a sensitivity of 46%, a specificity of 91%, and a positive and negative predictive values of 75% and 67%, respectively. sNfL levels seem to be a valuable biomarker of neuro‐axonal injury in PIPN. An early increase of this biomarker after a 3‐weekly chemotherapy course can be a predictive marker of final PIPN severity.

Neurofilaments contribution in clinic: state of the art

“…The increase correlated with the development and severity of polyneuropathy (Huehnchen et al, 2022 ; Karteri et al, 2022 ). However, no association between increased blood NfL and cognitive impairment could be demonstrated in this context (Argyriou et al, 2022 ).…”

“…Further studies will determine whether the combination of the two biomarkers is worthwhile, but studies have already described increased levels of sNfL and GFAP in patients with CNS tumors with disease in progression vs. CNS with stable disease ( p = 0.03 and p = 0.01, respectively; Hepner et al, 2019 ). Regarding chemotherapy toxicity, an increase in serum NfL concentration (assessed by Simoa) of more than 36 pg/ml (Huehnchen et al, 2022 ) or an elevated level at 3 or 4 weeks (>50 pg/ml and >85 pg/ml) is associated with high risk of developing polyneuropathy (Huehnchen et al, 2022 ; Karteri et al, 2022 ). In addition, high level of blood NfL could predict the occurrence of ICANS in case of CAR-T cell treatment (a threshold value of 75 pg/ml determined by the Simoa approach has been proposed; Schoeberl et al, 2022 ).…”

Neurological Complications of Conventional and Novel Anticancer Treatments

“…In CIPN, NfL levels were initially tested in animal models with promising results [ 10 , 19 , 68 ] and subsequently explored in small clinical studies. Karteri et al [ 74 ] prospectively followed paclitaxel-treated patients demonstrating a significant longitudinal increase in NfL levels that were also significantly more increased in patients most severely affected. Huehnchen et al [ 75 ] showed similar data in paclitaxel-treated patients.…”

Neurons: The Interplay between Cytoskeleton, Ion Channels/Transporters and Mitochondria

“…On the basis of these results, NfL were then tentatively tested in a clinical setting and very recently some groups suggested their use at the bedside. Karteri et al [ 171 ] prospectively followed up 59 patients treated with paclitaxel measuring serum NfL before starting chemotherapy, after 2 and 3 weekly courses, and at the end of chemotherapy (12 weekly cycles in total), a significant longitudinal increase was observed and NfL levels were significantly higher in patients affected by more severe toxicity. Huehnchen et al [ 172 ] monitored NfL levels in a cohort of 31 patients treated with paclitaxel and compared NfL levels with healthy control (n = 6) and breast cancer patients not treated with chemotherapy ( n = 25); they observed a specificity and sensibility higher than 80%, giving promising results even if the low number of subjects included in the analysis make a validation necessary in larger cohorts.…”