Imaging, Diagnosis, Prognosis Regional Brain Activation during Verbal Declarative Memory in Metastatic Breast Cancer

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 declarativememory tasks comparedwith 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 cingulate gyrus in women with breast cancer compared with controls (5, 6). Additionally, reduced corpus callosum genu white matter pathway integrity (i.e., fractional anisotropy) was noted in a small sample of women with breast cancer compared with controls and was correlated with lower processing speed (7). A case study of monozygotic twins discordant for breast cancer indicated increased white matter hyperintensities and altered frontal-parietal functional brain activation in the twin with breast cancer (8). This case study represents the only functional magnetic resonance imaging (fMRI) study conducted to date. fMRI allows in vivo assessment of brain function by detecting blood flow differences and is widely used to study brain-behavior relationships in children and adults (9–12). Group fMRI studies could significantly advance our understanding regarding the Authors' Affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California Received 5/14/09; revised 6/29/09; accepted 7/31/09; published OnlineFirst 10/20/09. Grant support: National Institute of Aging/National Cancer Institute Program Project grant AG18784 (D. Spiegel), the Randolph H. Chase, M.D., Fund II (D. Spiegel), The Jay and Rose Phillips Family Foundation (D. Spiegel), and the National Institutes of Health Director's New Innovator Award 1DP2OD004445-01 (S.R. Kesler). The costs of publication of this article were defrayed in part by the payment of page charges. This articlemust therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Shelli R. Kesler, Stanford University School of Medicine, 401 Quarry Road, CIBSR MC5795, Stanford, CA 94305-5795. Phone: 650-723-0058; Fax: 650-433-5402; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1227 6665 Clin Cancer Res 2009;15(21) November 1, 2009 www.aacrjournals.org Research. on April 14, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst October 20, 2009; DOI: 10.1158/1078-0432.CCR-09-1227