Changes in leukoencephalopathy and serum neurofilament after (neo)adjuvant chemotherapy for breast cancer.

BACKGROUND: Previous case studies have provided evidence for chemotherapy-induced leukoencephalopathy in patients with breast cancer. However, prospective research is lacking. Hence, we investigated leukoencephalopathy before and after chemotherapy and its association with a serum neuroaxonal damage marker. METHODS: This prospective cohort study included 40 patients receiving chemotherapy for breast cancer, and two age- and education-matched control groups, recruited between 2018 and 2021 (31-64 years of age). The latter control groups consisted of 39 chemotherapy-naïve patients and 40 healthy women. Fluid-attenuated inversion-recovery magnetic resonance imaging was used for lesion volumetry (total, juxtacortical, periventricular, infratentorial, and deep white matter) and blood serum to measure neurofilament light chain (NfL) levels. Acquisition took place pre-chemotherapy and three months and one-year post-chemotherapy, or at corresponding intervals. Within/between group differences were compared using robust mixed-effects modeling, and associations between total lesion volume and serum-NfL with linear regression. RESULTS: Stronger increases in deep white matter lesion volumes were observed shortly post-chemotherapy, compared with healthy women (ßstandardized=0.09, pFDR<0.001). Increases in total lesion volume could mainly be attributed to enlargement of existing lesions (mean±SD, 0.12±0.16 mL), rather than development of new lesions (0.02±0.02 mL). A stronger increase in serum-NfL concentration was observed shortly post-chemotherapy compared with both control groups (ß>0.70, p<0.004), neither of which showed any changes over time, whereas a decrease was observed compared with healthy women one-year post-chemotherapy (ß=-0.54, p = 0.002). Serum-NfL concentrations were associated with lesion volume one-year post-chemotherapy (or at matched timepoint; ß=0.36, p = 0.010), whereas baseline or short-term post-therapy levels or changes were not. CONCLUSION: These results underscore the possibility of chemotherapy-induced leukoencephalopathy months post-treatment, as well as the added value of serum-NfL as a prognostic marker for peripheral/central neurotoxicity. TRANSLATIONAL RELEVANCE: Previous case studies have provided evidence of chemotherapy-induced leukoencephalopathy in patients with breast cancer. However, prospective studies to estimate longitudinal changes are currently missing. In this study, we used longitudinal fluid-attenuated inversion-recovery magnetic resonance imaging to assess white matter lesion volumes in patients treated for non-metastatic breast cancer and healthy women. Our findings demonstrate that chemotherapy-treated patients exhibit stronger increases in lesion volumes compared with healthy women, specifically in deep white matter, at three months post-chemotherapy. Increases could mainly be attributed to enlargement of existing lesions, rather than development of new lesions. Last, serum concentrations of neurofilament light chain, a neuroaxonal damage marker, increased shortly after chemotherapy and long-term post-chemotherapy levels were associated with lesion volumes. These findings highlight the potential of this non-invasive serum marker as a prognostic marker for peripheral and/or central neurotoxicity. Implementation in clinical practice could aid in therapeutic decisions, assessing disease activity, or monitoring treatment response.