Changes in Brain Functional and Effective Connectivity After Treatment for Breast Cancer and Implications for Intervention Targets.

Background: Patients with breast cancer frequently report cognitive impairment both during and after completion of therapy. Evidence suggests that cancer-related cognitive impairments are related to widespread neural network dysfunction. The default mode network (DMN) is a large conserved network that plays a critical role in integrating the functions of various neural systems. Disruption of the network may play a key role in the development of cognitive impairment.
Methods: We compared neuroimaging and neurocognitive data from 43 newly diagnosed primary breast cancer patients (mean age = 48, standard deviation [SD] = 8.9 years) and 50 frequency-matched healthy female controls (mean age = 50, SD = 10 years) before treatment and 1 year after treatment completion. Functional and effective connectivity measures of the DMN were obtained using graph theory and Bayesian network analysis methods, respectively.
Results: Compared with healthy females, the breast cancer group displayed higher global efficiency and path length post-treatment (p < 0.03, corrected). Breast cancer survivors showed significantly lower performance on measures of verbal memory, attention, and verbal fluency (p < 0.05) at both time points. Within the DMN, local brain network organization, as measured by edge-betweenness centralities, was significantly altered in the breast cancer group compared with controls at both time points (p < 0.0001, corrected), with several connections showing a significant group-by-time effect (p < 0.003, corrected). Effective connectivity demonstrated significantly altered patterns of neuronal coupling in patients with breast cancer (p < 0.05). Significant correlations were seen between hormone blockade therapy, radiation therapy, chemotherapy cycles, memory, and verbal fluency test and edge-betweenness centralities. Discussion: This pattern of altered network organization in the default mode is believed to result in reduced network efficiency and disrupted communication. Subregions of the DMN, the orbital prefrontal cortex and posterior memory network, appear to be at the center of this disruption and this could inform future interventions. Impact statement This prospective study is the first to investigate how post-treatment changes in functional and effective connectivity in the regions of default mode network are related to cancer therapy and measures of memory and verbal learning in breast cancer patients. We demonstrate that the interactions between treatment, brain connectivity, and neurocognitive outcomes coalesce around a subgroup of brain structures in the orbital frontal and parietal lobe. This would suggest that interventions that target these regions may improve neurocognitive outcomes in breast cancer survivors.