Purpose: To determine the neurofunctional basis of verbal memory dysfunction in women with metastatic breast cancer. This objective was based on previous research suggesting memory and other cognitive deficits in this population. We attempted to determine if verbal memory impairments were related to the most commonly studied disease parameters including adjuvant chemotherapy and chronic stress-related disruption of limbic system structures. Experimental Design: We used functional magnetic resonance imaging to test our hypothesis that women with breast cancer would show significantly lower brain activation during verbal declarative memory tasks compared with age and education-matched healthy female controls. We also assessed several stress-related variables including diurnal cortisol levels to test our hypothesis that women with breast cancer would show higher stress and this would contribute to brain activation deficits during memory tasks. Results: Women with breast cancer had significantly lower prefrontal cortex activation during the memory encoding condition compared with controls. However, the breast cancer group showed significantly greater activation than controls during the recall condition in multiple, diffuse brain regions. There were no significant differences between the groups in stress-related variables. Women who were treated with cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy showed lower prefrontal cortex activation during memory encoding. Conclusions: These results suggest that women with metastatic breast cancer may be at risk for verbal memory impairments as a result of altered functional brain activation profiles. These findings may be associated with chemotherapy type and/or other aspects of the breast cancer disease process. (Clin Cancer Res 2009;15(21):6665-73) Women with breast cancer may have an increased risk for long-term cognitive-behavioral impairments including those of executive function and memory, likely due to neurotoxic side effects of chemotherapy (1-3). The incidence of these impairments is uncertain but has been reported to range from 28% to 75% among breast cancer patients receiving cyclophosphamide, methotrexate, and 5-fluorouracil (CMF; ref. 4). Cognitivebehavioral impairments significantly extend disease-related disability, affecting home, educational, and occupational activities. Additionally, the high prevalence of breast cancer and increasing survival rates contribute to a large and growing cohort of cognitively affected individuals (3). Currently, there are no specific treatments for these cognitive impairments and no preventive interventions are available.Neuroimaging studies provide insight regarding the neurobiological mechanisms underlying cognitive impairment in various populations. To date, there have been only four such studies conducted in breast cancer to our knowledge. These reports indicate altered cerebral metabolism and decreased volume in executive function regions, including prefrontal cortex, basal ganglia, and the cingul...

Breast cancer survivors are at increased risk for cognitive dysfunction, which reduces quality of life. Neuroimaging studies provide critical insights regarding the mechanisms underlying these cognitive deficits as well as potential biologic targets for interventions. We measured several metabolite concentrations using 1H magnetic resonance spectroscopy as well as cognitive performance in 19 female breast cancer survivors and 17 age-matched female controls. Women with breast cancer were all treated with chemotherapy. Results indicated significantly increased choline (Cho) and myo-inositol (mI) with correspondingly decreased N-acetylaspartate (NAA)/Cho and NAA/mI ratios in the breast cancer group compared to controls. The breast cancer group reported reduced executive function and memory, and subjective memory ability was correlated with mI and Cho levels in both groups. These findings provide preliminary evidence of an altered metabolic profile that increases our understanding of neurobiologic status post-breast cancer and chemotherapy.

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