Blood biomarkers for neuroaxonal injury and astrocytic activation in chemotherapy-induced peripheral neuropathy
DOI:
https://doi.org/10.2340/1651-226X.2024.39895Keywords:
chemotherapy, neurofilament, biomarkers, neuropathyAbstract
Background and purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome side effect in patients exposed to taxanes in the treatment of cancer and may affect quality of life dramatically. Here we assessed whether serum levels of neurofilament light (NfL) and tau (two neuroaxonal injury biomarkers) and glial fibrillary acidic protein (GFAP, a biomarker for astrocytic activation) correlate with the development of CIPN in the adjuvant setting of early breast cancer.
Materials and methods: Using ultrasensitive single molecule array technology, serum levels of NfL, GFAP, and tau were measured before and every 3 weeks in 10 women receiving adjuvant EC (epirubicin 90 mg/m² and cyclophosphamide 600 mg/m²) every 3 weeks × 3, followed by weekly paclitaxel 80 mg/m² × 9–12 weeks after surgery due to early breast cancer. CIPN was graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) and the questionnaire EORTC QLQ CIPN-20.
Results: Serum levels of GFAP increased successively during cycles of EC. NfL increased instead in response to the treatment of paclitaxel. NfL and GFAP continued to rise throughout exposure of cumulatively higher doses of paclitaxel and were reduced 3 months after the end of chemotherapy. Serums levels of tau were marginally affected by exposure to chemotherapy. Women with worse symptoms of CIPN had higher concentrations of NfL than women with mild symptoms of CIPN.
Interpretation: NfL and GFAP are promising biomarkers to identify women at risk of developing CIPN. Larger prospective studies are now needed.
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Cavaletti G, Marmaroli P: Chemotherapy-induced peripheral neurotoxicity. Curr Opin Neurol. 201528(5):500–7.
https://doi.org/10.1097/WCO.0000000000000234 DOI: https://doi.org/10.1097/WCO.0000000000000234
Bao T, Basal C, Seluzicki C, Li SQ, Seidman AD, Mao JJ. Long-term chemotherapy-induced peripheral neuropathy among breast cancer survivors: prevalence, risk factors, and fall risk. Breast Cancer Res Treat. 2016;159(2):327–33.
https://doi.org/10.1007/s10549-016-3939-0 DOI: https://doi.org/10.1007/s10549-016-3939-0
Engvall K, Gréen H, Fredrikson M, Lagerlund M, Lewin F, Åvall-Lundqvist E. Impact of persistent peripheral neuropathy on health-related quality of life among early-stage breast cancer survivors: a population-based cross-sectional study. Breast Cancer Res Treat. 2022;195(3):379–91.
https://doi.org/10.1007/s10549-022-06670-9 DOI: https://doi.org/10.1007/s10549-022-06670-9
Speck RM, Sammel MD, Farrar JT, Hennessy S, Mao JJ, Stineman MG, et al. Impact of chemotherapy-induced peripheral neuropathy on treatment delivery in nonmetastatic breast cancer. J Oncol Pract. 2013;9(5):e234–40.
https://doi.org/10.1200/JOP.2012.000863 DOI: https://doi.org/10.1200/JOP.2012.000863
Rivera E, Cianfrocca M. Overview of neuropathy associated with taxanes for the treatment of metastatic breast cancer. Cancer Chemother Pharmacol. 2015;75(4):659–70.
https://doi.org/10.1007/s00280-014-2607-5 DOI: https://doi.org/10.1007/s00280-014-2607-5
Gafson AR, Barthélemy NR, Bomont P, Carare RO, Durham HD, Julien JP, et al. Neurofilaments: neurobiological foundations for biomarker applications. Brain. 2020;143(7):1975–98.
https://doi.org/10.1093/brain/awaa098 DOI: https://doi.org/10.1093/brain/awaa098
Petzold A. The 2022 Lady Estelle Wolfson lectureship on neurofilaments. J Neurochem. 2022;163(3):179–219.
https://doi.org/10.1111/jnc.15682 DOI: https://doi.org/10.1111/jnc.15682
Yuan A, Rao MV, Veeranna, Nixon RA. Neurofilaments at a glance. J Cell Sci. 2012;125(Pt 14):3257–63.
https://doi.org/10.1242/jcs.104729 DOI: https://doi.org/10.1242/jcs.104729
Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association between longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 2019;76(7):791–9.
https://doi.org/10.1001/jamaneurol.2019.0765 DOI: https://doi.org/10.1001/jamaneurol.2019.0765
Disanto G, Barro C, Benkert P, Naegelin Y, Schädelin S, Giardiello A, et al. Swiss Multiple Sclerosis Cohort Study Group. Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis. Ann Neurol. 2017;81(6):857–70.
https://doi.org/10.1002/ana.24954 DOI: https://doi.org/10.1002/ana.24954
Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018;14(10):577–89.
https://doi.org/10.1038/s41582-018-0058-z DOI: https://doi.org/10.1038/s41582-018-0058-z
Millere E, Rots D, Simrén J, Ashton NJ, Kupats E, Micule I, et al. Plasma neurofilament light chain as a potential biomarker in Charcot-Marie-Tooth disease. Eur J Neurol. 2021;28(3):974–981.
https://doi.org/10.1111/ene.14689 DOI: https://doi.org/10.1111/ene.14689
Sandelius Å, Zetterberg H, Blennow K, Adiutori R, Malaspina A, Laura M ,et al. Plasma neurofilament light chain concentration in the inherited peripheral neuropathies. Neurology. 2018;90(6):e518–24.
https://doi.org/10.1212/WNL.0000000000004932 DOI: https://doi.org/10.1212/WNL.0000000000004932
Kapoor M, Foiani M, Heslegrave A, Zetterberg H, Lunn MP, Malaspina A et al. Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis. J Peripher Nerv Syst. 2019;24(4):314–9.
https://doi.org/10.1111/jns.12350 DOI: https://doi.org/10.1111/jns.12350
Kapoor M, Carr A, Foiani M, Heslegrave A, Zetterberg H, Malaspina A, et al. Association of plasma neurofilament light chain with disease activity in chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol. 2022;29(11):3347–57.
https://doi.org/10.1111/ene.15496 DOI: https://doi.org/10.1111/ene.15496
Kmezic I, Samuelsson K, Finn A, Upate Z, Blennow K, Zetterberg H, et al. Neurofilament light chain and total tau in the differential diagnosis and prognostic evaluation of acute and chronic inflammatory polyneuropathies. Eur J Neurol. 2022;29(9):2810–22.
https://doi.org/10.1111/ene.15428 DOI: https://doi.org/10.1111/ene.15428
Wang KK, Yang Z, Zhu T, Shi Y, Rubenstein R, Tyndall JA, et al. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn. 2018;18(2):165–80.
https://doi.org/10.1080/14737159.2018.1428089 DOI: https://doi.org/10.1080/14737159.2018.1428089
Pîrşcoveanu DFV, Pirici I, Tudorică V, Bălşeanu TA, Albu VC, Bondari S, et al. Tau protein in neurodegenerative diseases – a review. Rom J Morphol Embryol. 2017;58(4):1141–50.
Meregalli C, Fumagalli G, Alberti P, Canta A, Carozzi VA, Chiorazzi A, et al. Neurofilament light chain as disease biomarker in a rodent model of chemotherapy induced peripheral neuropathy. Exp Neurol. 2018;307:129–32.
https://doi.org/10.1016/j.expneurol.2018.06.005 DOI: https://doi.org/10.1016/j.expneurol.2018.06.005
Meregalli C, Fumagalli G, Alberti P, Canta A, Chiorazzi A, Monza L, et al. Neurofilament light chain: a specific serum biomarker of axonal damage severity in rat models of Chemotherapy-Induced Peripheral Neurotoxicity. Arch Toxicol. 2020;94(7):2517–22.
https://doi.org/10.1007/s00204-020-02755-w DOI: https://doi.org/10.1007/s00204-020-02755-w
Huehnchen P, Schinke C, Bangemann N, Dordevic AD, Kern J, Maierhof SK, et al. Neurofilament proteins as a potential biomarker in chemotherapy-induced polyneuropathy. JCI Insight. 2022;7(6):e154395.
https://doi.org/10.1172/jci.insight.154395 DOI: https://doi.org/10.1172/jci.insight.154395
Karteri S, Bruna J, Argyriou AA, Mariotto S, Velasco R, Alemany M, et al. Prospectively assessing serum neurofilament light chain levels as a biomarker of paclitaxel-induced peripheral neurotoxicity in breast cancer patients. J Peripher Nerv Syst. 2022;27(2):166–74.
https://doi.org/10.1111/jns.12493 DOI: https://doi.org/10.1111/jns.12493
Mortensen C, Steffensen KD, Simonsen E, Herskind K, Madsen JS, Olsen DA, et al. Neurofilament light chain as a biomarker of axonal damage in sensory neurons and paclitaxel-induced peripheral neuropathy in patients with ovarian cancer. Pain. 2023;164(7):1502–11.
https://doi.org/10.1097/j.pain.0000000000002840 DOI: https://doi.org/10.1097/j.pain.0000000000002840
Lavoie Smith EM, Barton DL, Qin R, Steen PD, Aaronson NK, Loprinzi CL. Assessing patient-reported peripheral neuropathy: the reliability and validity of the European Organization for Research and Treatment of Cancer QLQ-CIPN20 Questionnaire. Qual Life Res. 2013;22(10):2787–99.
https://doi.org/10.1007/s11136-013-0379-8 DOI: https://doi.org/10.1007/s11136-013-0379-8
Mo H, Yan X, Zhao F, Teng Y, Sun X, Lv Z, et al. Association of taxane type with patient-reported chemotherapy-induced peripheral neuropathy among patients with breast cancer. JAMA Netw Open. 2022;5(11):e2239788.
https://doi.org/10.1001/jamanetworkopen.2022.39788 DOI: https://doi.org/10.1001/jamanetworkopen.2022.39788
Burgess BL, Cho E, Honigberg L. Neurofilament light as a predictive biomarker of unresolved chemotherapy-induced peripheral neuropathy in subjects receiving paclitaxel and carboplatin. Sci Rep. 2022;12(1):15593.
https://doi.org/10.1038/s41598-022-18716-5 DOI: https://doi.org/10.1038/s41598-022-18716-5
Shimozuma K, Ohashi Y, Takeuchi A, Aranishi T, Morita S, Kuroi K, et al. Feasibility and validity of the Patient Neurotoxicity Questionnaire during taxane chemotherapy in a phase III randomized trial in patients with breast cancer: N-SAS BC 02. Support Care Cancer. 2009;17(12):1483–91.
https://doi.org/10.1007/s00520-009-0613-7 DOI: https://doi.org/10.1007/s00520-009-0613-7
Bergman J, Dring A, Zetterberg H, Blennow K, Norgren N, Gilthorpe J, et al. Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS. Neurol Neuroimmunol Neuroinflamm. 2016;3(5):e271.
https://doi.org/10.1212/NXI.0000000000000271 DOI: https://doi.org/10.1212/NXI.0000000000000271
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Copyright (c) 2023 Jamila Adra, Daniel Giglio, Per Karlsson, Henrik Zetterberg, Zakaria Einbeigi
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