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Background: The underlying brain mechanisms of altered cognitive function associated with adjuvant chemotherapy for breast cancer, commonly designated “chemobrain”, have yet to be determined. Recent research indicates that compromised cognitive function may already exist prior to treatment, adding to the complexity of determining the true impact of adjuvant chemotherapy on brain function. We examined whether two common symptoms associated with breast cancer diagnosis, worry and fatigue, might influence neurocognitive responses during functional magnetic resonance imaging (fMRI) before adjuvant therapy. Methods: Seventy five women (29–75 years) awaiting either adjuvant chemotherapy (n=25) or radiation therapy (n=25) for localized breast cancer and age-matched controls without breast cancer (n=25) were enrolled. Participants performed a verbal working memory task (VWMT) with varying levels of demand for cognitive control during fMRI scanning and provided self-reports of worry and fatigue after scanning. Imaging data were analyzed using the general linear model implemented in SPM5; comparative statistics were used to determine group differences in self-report and behavioral measures. Results: In general, the pre-chemotherapy group showed compromised cognitive functioning relative to the other groups. Specifically, they reported higher worry than the pre-radiation therapy (p=.036) and control (p=.047) groups. The pre-chemotherapy group also identified greater fatigue than controls (p=.04); the pre-radiation group reported a fatigue level between the other two groups. In the VWMT, the pre-chemotherapy group was less accurate than controls (p=.05), while the mean accuracy for the pre-radiation group again fell between these two groups. fMRI results showed that the control group selectively increased recruitment of executive control brain regions including the left inferior frontal gyrus (LIFG) and the anterior cingulate cortex (ACC) in response to high vs. low demand conditions. However, recruitment of LIGF and ACC by the control group was greater than that by both the pre-chemotherapy (p=.01 and p=.003 respectively) and the pre-radiation groups (p=.027 and p=.02 respectively). Overall, higher fatigue was correlated with failure to increase recruitment of the LIFG and ACC in high vs. low demand conditions (p=.002 and p=.078 respectively). Greater worry was correlated with failure to suppress task-irrelevant activation of default network regions, particularly the posterior cingulate cortex, in high vs. low demand conditions, and with lower accuracy in the VWMT (p=.01). Thus, fatigue and worry made independent contributions to altered neurocognitive responses prior to any adjuvant treatment. Discussion: These findings suggest that women awaiting adjuvant chemotherapy are vulnerable to compromised cognitive functioning, specifically in the domains of attention and working memory, related to higher worry and fatigue. Worry and fatigue may contribute to the cognitive impact often attributed to adjuvant chemotherapy. Therapeutic interventions to counteract worry and fatigue hold potential for optimizing cognitive function prior to adjuvant treatment for breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD04-08.

Background: Our previous research showed evidence of compromised cognitive function prior to adjuvant chemotherapy for breast cancer, with fatigue as a contributory factor. Fatigue is a common symptom reported by women treated for breast cancer, yet its association with neurocognitive function has not been systematically examined. In this prospective study, we examined possible alterations in neurocognitive responses, namely, working memory, from pre- to post- adjuvant treatment during functional magnetic resonance imaging (fMRI) and further investigated whether early fatigue might be linked to cognitive alterations over time. Methods: Women treated with either adjuvant chemotherapy (anthracyline-based combination regimen, n=29) or radiotherapy (n = 37) for localized breast cancer (Stages 0-IIIa) and age-matched healthy controls (n = 32) were enrolled. Participants performed a verbal working memory task (VWMT) with varying levels of demand for cognitive control during fMRI scanning and provided self-reports of fatigue (FACT-F) at two time points coincident with pre- and one-month post chemotherapy assessments. Imaging data were analyzed with general linear models using SPM5; comparative statistics were used to determine group differences, and correlational analyses addressed relationships of fatigue and neurocognitive measures. Findings: The chemotherapy group reported significantly greater severity of fatigue (p < .05) and performed less accurately on the VWMT both pre- and one-month post-treatment than the other groups. Greater fatigue was correlated with poorer performance on the VWMT at both time points across groups, with stronger correlation post-treatment (r = −.22, p = .03). A 2 time-point (pre- vs. post-treatment) × 2 group (chemotherapy vs. controls) × 2 demand-level contrasts (high minus low vs. medium minus low) analytic model showed a significant group × time interaction (p < .05), mainly due to lower pre-treatment activation in an area of the prefrontal cortex supporting working memory, the anatomical left inferior frontal gyrus (LiFG), at higher task demand in the chemotherapy group. The radiotherapy group scored between the other two groups with intermediate activation of those contrasts. Of interest, lower pre-treatment activation in the LiFG in the high-low demand contrast predicted severity of fatigue across all participants at the post-treatment assessment (r = −.27, p < .01), linking early compromise in neurocognitive performance with greater fatigue over time. Discussion: Neurocognitive alterations during a working memory task and greater fatigue were evident before any adjuvant chemotherapy for breast cancer. Notably, functional alterations in working memory processes were evident with fMRI before adjuvant chemotherapy and predicted severity of post-treatment fatigue. Importantly, across all participants, greater fatigue over time was correlated with reduced cognitive performance. Taken together, these findings indicate that pre-treatment neurocognitive compromise and fatigue are key contributors to the cognitive impact often attributed solely to chemotherapy. Early therapeutic interventions targeting fatigue may improve cognitive function and reduce the distress of “chemo brain” throughout the course of adjuvant treatment. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-3.