Neurofilament proteins as a potential biomarker in chemotherapy-induced polyneuropathy
Petra Huehnchen, … , Matthias Endres, Wolfgang Boehmerle
Petra Huehnchen, … , Matthias Endres, Wolfgang Boehmerle
Published February 8, 2022
Citation Information: JCI Insight. 2022;7(6):e154395. https://doi.org/10.1172/jci.insight.154395.
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Clinical Research and Public Health Neuroscience

Neurofilament proteins as a potential biomarker in chemotherapy-induced polyneuropathy

Abstract

BACKGROUND Paclitaxel chemotherapy frequently induces dose-limiting sensory axonal polyneuropathy. Given that sensory symptoms are challenging to assess objectively in clinical practice, an easily accessible biomarker for chemotherapy-induced polyneuropathy (CIPN) holds the potential to improve early diagnosis. Here, we describe neurofilament light chain (NFL), a marker for neuroaxonal damage, as a translational surrogate marker for CIPN.METHODS NFL concentrations were measured in an in vitro model of CIPN, exposing induced pluripotent stem cell–derived sensory neurons (iPSC-DSNs) to paclitaxel. Patients with breast or ovarian cancer undergoing paclitaxel chemotherapy, breast cancer control patients without chemotherapy, and healthy controls were recruited in a cohort study and examined before chemotherapy (V1) and after 28 weeks (V2, after chemotherapy). CIPN was assessed by the validated Total Neuropathy Score reduced (TNSr), which combines patient-reported symptoms with data from clinical examinations. Serum NFL (NFLs) concentrations were measured at both visits with single-molecule array technology.RESULTS NFL was released from iPSC-DSNs upon paclitaxel incubation in a dose- and time-dependent manner and was inversely correlated with iPSC-DSN viability. NFLs strongly increased in paclitaxel-treated patients with CIPN, but not in patients receiving chemotherapy without CIPN or controls, resulting in an 86% sensitivity and 87% specificity. An NFLs increase of +36 pg/mL from baseline was associated with a predicted CIPN probability of more than 0.5.CONCLUSION NFLs was correlated with CIPN development and severity, which may guide neurotoxic chemotherapy in the future.TRIAL REGISTRATION ClinicalTrials.gov NCT02753036.FUNDING Deutsche Forschungsgemeinschaft (EXC 257 NeuroCure), BMBF (Center for Stroke Research Berlin, 01 EO 0801), Animalfree Research, EU Horizon 2020 Innovative Medicines Initiative 2 Joint Undertaking (TransBioLine, 821283), Charité 3R — Replace — Reduce — Refine.

Authors

Petra Huehnchen, Christian Schinke, Nikola Bangemann, Adam D. Dordevic, Johannes Kern, Smilla K. Maierhof, Lois Hew, Luca Nolte, Peter Körtvelyessy, Jens C. Göpfert, Klemens Ruprecht, Christopher J. Somps, Jens-Uwe Blohmer, Jalid Sehouli, Matthias Endres, Wolfgang Boehmerle

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Figure 6

Predicted probability of CIPN diagnosis dependent on NFLs concentrations.

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Predicted probability of CIPN diagnosis dependent on NFLs concentrations...
(A) ROC analysis revealed an 86% sensitivity and 87% specificity for the parameter ΔNFLs greater than 7.05 pg/mL to detect CIPN. (B) A likelihood of more than 0.5 for a patient to have CIPN was given at an increase in NFLs by +36 pg/mL (area filling indicates 95% CI). (C) Not taking baseline NFLs values into account, a probability of more than 0.5 for a CIPN diagnosis was predicted at NFLs concentrations of 49 pg/mL at V2 (area filling indicates 95% CI). (D) Baseline NFLs concentrations were not different among controls, chemotherapy-treated patients without CIPN, and patients with CIPN. (E) Baseline NFLs values did not correlate with change in TNSr (area filling indicates 95% CI). Statistical analysis: (A) ROC analysis; (B and C) logistic regression; (D and E) Kruskal-Wallis test. Study participants: (A–C and E) n = 6 (healthy), n = 24 (control), n = 30 (chemo); (D) n = 30 (control), n = 12 (no CIPN), n = 17 (CIPN).