Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) affects at least 50% of patients (pts) who undergo systemic therapy. CIPN not only impacts quality of life but also adversely affects survival by frequently causing dose reductions, delays, or premature cessation of therapy. While the best strategy for preventing CIPN symptoms is currently cryotherapy, the exact mechanism remains elusive. It is hypothesized that cryotherapy prevents toxicity by modulating the neuroinflammatory process. Therefore, we posited that by systematically profiling the neuroinflammatory microenvironment in sera of patients enrolled in a completed prospective CIPN trial, the mechanisms of CIPN and those patients who are at highest risk for its development could be identified. Methods: This cohort consists of 14 pts with metastatic breast cancer enrolled in a phase 2 study of ixabepilone in which the primary endpoint of the original trial was to define the effect of ixabepilone on the development of CIPN and on the ultrastructure of neurons evaluated by electron microscopy of serial skin biopsies. Pts enrolled in this trial underwent an extensive clinical neurologic evaluation every 3 weeks using the Total Neuropathy Score-clinical (TNSc), a validated tool that utilizes both physical exam and patient report, to assess CIPN. In this study, severe CIPN was defined as the presence of a TNSc score of 10 or greater, a score increase of 4 or more points from baseline, or peripheral neuropathy that led to dose reduction, delay, or cessation of therapy. Using these criteria, 5 patients with severe CIPN and 3 patients without severe CIPN had sufficient serum sample available for analysis from the completed trial. Serum samples were collected at baseline and over time throughout the study, 18 timepoints among the patients with severe CIPN and 10 timepoints among the patients without severe CIPN were evaluated. Next, neuroinflammatory biomarker concentrations of the banked patient serum samples were measured with the Luminex 48-plex assay and custom discovery panels, allowing for the levels of 80 cytokines, chemokines, and growth factors to be measured in duplicate. Diluent and serum were combined in a well, incubated with mixed micro-beads, and then re-incubated with detection antibody and later streptavidin-phycoerythrin. The labeled micro-beads were then re-suspended in sheath fluid and analyzed by the Luminex 100 system. The instrument readout of mean fluorescent intensity (MFI) was converted to pg/ml based on MFI values of standards run alongside the samples in the assay. Results: Seven cytokines were significantly differentially expressed between the two groups. The MFI of the chemokine CCL24 was decreased over 3.2-fold in the group with severe CIPN compared to the group without severe CIPN (p0.0001). CXCL2 (p0.01) and IL-12 (p0.05) were also significantly decreased in the severe CIPN group. Four biomarkers were elevated in the group with severe CIPN compared to those without severe CIPN: CCL8 (p0.05), CCL18 (p0.05), CCL23 (p0.05), and PDGF-AA (p0.05). Conclusions: Together, these seven biomarkers reveal a novel neuroinflammatory signature of CIPN. Elevated serum levels of CCL18 and PDGF-AA in patients with severe CIPN are suggestive of chemotherapy-induced pro-fibrotic macrophage activation, which has been shown to exacerbate neuropathy. While CCL8 and CCL23 have been reported in the literature in relation to peripheral neuropathy, this study marks the first report identifying CCL24 in this context. Decreased expression of CCL24 may be associated with a negative feedback regulatory mechanism, in which increased occupancy of CCR3, the receptor for CCL24, by additional endogenous ligands leads to downregulation of CCL24 over time. These results will be validated in a forthcoming prospective trial. Citation Format: I. S. Marchal, E. P. Kuhn, J. M. Mikecz, P. A. Pioli, L. T. Vahdat. Defining a Neuroinflammatory Signature of Chemotherapy-Induced Peripheral Neuropathy abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-01-17.
Marchal et al. (Tue,) studied this question.