Serum neurofilament light chain levels as biomarker of paclitaxel-induced peripheral neurotoxicity

Background and Objective: There is compelling experimental evidence that neurofilament light chain (NfL) could sensitively be detected in serum as a biomarker of neuro-axonal damage induced by chemotherapy. We sought to assess the significance of measuring serum NfL (sNfL) in the clinical setting of paclitaxel-induced peripheral neurotoxicity (PIPN). Materials and methods: 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 levels were quantified, using the highly-sensitive Simoa technique, before the onset of chemotherapy (baseline), after 2 (week 2) and 3 (week 3) weekly courses, and at the end of chemotherapy (week 12). Results: 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 PIPN. 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 positive and negative predictive values of 75% and 67%, respectively. Conclusions: NfL 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.Εισαγωγή και Σκοπός: Η νευρο-αξονική βλάβη ως αποτέλεσμα της χημειοθεραπείας αυξάνει τα επίπεδα των νευροϊνιδίων χαμηλού μοριακού βάρους σε πειραματόζωα, με αποτέλεσμα να ανιχνεύονται σε δείγματα ορού αίματος (sNfL-serum neurofilament light chain). Μέχρι σήμερα, δεν υπάρχουν διαθέσιμα επαρκή κλινικά δεδομένα. Μελετήσαμε την αξία του προσδιορισμού των επιπέδων των sNfL, ως βιοδείκτη έκβασης της περιφερικής νευροτοξικότητας (ΠΝ) σχετιζόμενης με την πακλιταξέλη. Υλικά και Μέθοδοι: Πραγματοποιήθηκε προσδιορισμός των επιπέδων sNfL σε διαδοχικά δείγματα περιφερικού αίματος ασθενών με καρκίνωμα μαστού που βρίσκονταν σε πρόγραμμα εβδομαδιαίας χημειοθεραπείας με 12 κύκλους πακλιταξέλης. Τα επίπεδα sNfL μετρήθηκαν με την υπερευαίσθητη μέθοδο SIMOA-QUANTERIX, προ της έναρξης χημειοθεραπείας (baseline), μετά τον 2o κύκλο (εβδομάδα 2), τον 3ο (εβδομάδα 3) και στο τέλος της χημειοθεραπείας (εβδομάδα 12). Η κλινική εκτίμηση της περιφερικής νευροπάθειας (ΠΝ) έγινε με την κλίμακα Τotal neuropathy score-clinical (TNSc). Αποτελέσματα: Συμπεριλήφθηκαν 59 ασθενείς (μέση ηλικία: 53.1 ± 11.5 έτη), από τους οποίους οι 33 (56%) παρουσίασαν βαθμού 0-1 και οι 26 (44%) βαθμού 2-3 περιφερική νευροπάθεια την εβδομάδα 12. Αναδείχθηκε σημαντική προοδευτική αύξηση των επιπέδων sNfL από την έναρξη της χημειοθεραπείας μέχρι την εβδομάδα 12, ενώ οι ασθενείς με βαθμού 2-3 περιφερική νευροπάθεια είχαν σημαντικά αυξημένα επίπεδα sNfL την εβδομάδα 12, συγκριτικά με αυτούς που είχαν περιφερική νευροπάθεια βαθμού 0-1. Η ανάλυση καμπύλης ROC έδειξε ότι μία τιμή sNfL > 85 pg/mL την εβδομάδα 3 αποτελεί ανεξάρτητο προγνωστικό παράγοντα ανάπτυξης βαθμού 2-3 ΠΝ την εβδομάδα 12 (ευαισθησία 46.2%, ειδικότητα 84.8%). Η ανάλυση με λογιστική παλινδρόμηση έδειξε ότι η ηλικία > 50 ετών και η τιμή sNfL > 85 pg/mL την εβδομάδα 3 αποτελούν ανεξάρτητους προγνωστικούς παράγοντες ανάπτυξης ΠΝ βαθμού 2-3 την εβδομάδα 12 με ευαισθησία 46%, ειδικότητα 91% και θετική και αρνητική προγνωστική αξία 75% και 67%, αντίστοιχα. Συμπεράσματα: Τα sNfL φαίνεται να αποτελούν ισχυρό προγνωστικό βιοδείκτη νευρο-αξονικής βλάβης, ενώ η πρώιμη αύξηση των επιπέδων τους μετά από 3 κύκλους εβδομαδιαίας χημειοθεραπείας κατέχει σημαντική προβλεπτική αξία για την τελική έκβαση της περιφερικής νευροπάθειας σχετιζόμενης με πακλιταξέλη

Serum neurofilament light chain levels as biomarker of paclitaxel-induced cognitive impairment in patients with breast cancer: a prospective study

Objective: To prospectively assess the utility of serum neurofilament light chain (sNfL) levels in identifying the risk to develop chemotherapy-induced cognitive impairment (CICI) in cancer patients. We also examined if sNfL can be identified as an early biomarker of CICI development. Methods: We longitudinally measured sNfL levels in 20 female patients with breast cancer, scheduled to receive the 12 weekly paclitaxel-based regimen. An equal number of age-matched female heathy subjects was incuded as control group. CICI was graded by means of the Montreal Cognitive Assessment scale (MOCA); peripheral neurotoxicity (PN) was graded using the neurosensory Common Criteria for Adverse Events (CTCAE)v5.0, while sNfL levels were quantified using a high-sensitive technique (Quanterix, Simoa) before the administration of chemotherapy (T0), after 3 courses (T1), and at the end of chemotherapy (T2). Results: Pre-treatment sNfL levels were comparable in patients and controls (p = 0.103). At T2, 5/20 patients (mean age 61.4 ± 5.0 years) developed CICI. These 5 patients also had clinically-significant PN. Patients with and without CICI had comparable sNfL values at T2 (p = 0.1). In addition, at T2, sNfL levels did not correlate significantly with MOCA score in CICI patients (p = 0.604). The difference of sNfL levels between T1 and T0 failed to predict independently the occurrence of CICI at T2. Conclusion: Our findings do not support the utility of measuring sNfL levels as a biomarker of CICI. Grade 2-3 PN most strongly confounded our outcomes. Considering the small sample size, which might have prevented the results from being extrapolated, further testing in larger studies is warranted

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

Our aim was to assess the significance of measuring serum neurofilament light chain (sNfL) levels as 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 wth TNSc grade 2-3 PIPN had significantly increased sNfL levels at week-12, compared to those with grade 0-1. 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. Early increase of this biomarker after a 3 weekly chemotherapy course can be a predictive marker of final PIPN severity. This article is protected by copyright. All rights reserved