Altered brain functional networks in patients with breast cancer after neoadjuvant chemotherapy Running title: Disrupted Network in Breast Cancer After Chemotherapy

Abstract Background In this study, we prospectively investigated changes in the brain connectome at multiple time points in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NAC). Methods Fifty-five participants with a diagnosis of BC underwent clinical assessments and fMRI at three timepoints, including before NAC (tp1), after the first cycle of NAC (tp2), and the end of the NAC regimen (tp3). Two matched healthy controls (HCs) groups received the same assessments at matching time points were also enrolled. Brain functional networks were constructed and analyzed using graph theory approaches to quantify the effect of NAC on brain cognitive dysfunction. We analyzed changes in brain connectome metrics both in HC and patient group and explored the relationship between these changes and clinical scales. Patient-subgroups were created by clinical subtype, chemotherapy regimen and menopausal status, and longitudinal subgroup analysis was performed. Results There were no longitudinal differences within the two HC groups, and no differences between the two HC groups and patient group at tp1. BC patients who underwent NAC showed significantly increased global efficiency (p = 0.032), decreased characteristic path length (p = 0.020), and altered nodal centralities mainly in the frontal-limbic system and cerebellar cortex. There were few changes between the two chemotherapy sessions. Changes in the topological parameters were correlated with changes in clinical scales but did not differ between subgroups. Conclusions Our findings demonstrated that NAC might affect brain functional connectivity in BC patients, especially in the early stage.