The findings of this study have important implications for the effects of primary BC on brain function. Survivors of BC demonstrated significantly reduced left middle dorsolateral prefrontal cortex and left medial frontal activation compared with controls, irrespective of treatment history. However, women in the chemotherapy group showed significantly poorer outcome, including additional reductions in left caudal lateral prefrontal function and decreased executive function compared with women not treated with chemotherapy and healthy controls.
Although previous studies3,8,11
have shown prefrontal deficits during other executive function tasks and behavioral impairment in chemotherapy-treated women,23
the present study contributes findings that are unique, to our knowledge, regarding neurophysiologic and behavioral outcome in BC. Specifically, reduced BA 8 activation was significantly correlated with increased self-reported executive dysfunction in the chemotherapy group, who rated themselves as having more executive deficits. An association between brain function and self-reported executive function was noted for healthy controls involving a different prefrontal region (BA 10/46), although this group rated themselves, on average, as having normal executive function skills. Discordance often is observed between objective and subjective outcome measures in BC, likely due to the often subtle nature of cognitive changes in this group23
and the limited sensitivity and ecological validity of most objective measures.24
The present findings suggest a potential neurobiological marker of subjective or subclinical executive impairment in chemotherapy-treated BC survivors related to real-world difficulties.
Reduced BA 8 activation was unique to the chemotherapy group and may suggest potential neurotoxic brain injury. Animal studies25–28
suggest that chemotherapy regimens are toxic to progenitor cells in the brain, increasing cell death and suppressing cell proliferation. A previous study8
demonstrated an association between certain chemotherapies and prefrontal dysfunction. However, too much variability was reported in chemotherapy regimens among the present sample to address the relationship between treatment protocol and brain function. The BC groups also differed significantly in terms of cancer stage or severity at diagnosis. However, only the chemotherapy group showed an association between disease stage and BA 8 activation. A post hoc comparison of BA 8 activation between the BC groups controlling for disease stage reduced the significance of the finding (F
=.21). However, stage was not a significant covariate (F
=.61) and likely only removed the effect of interest (ie, the group) from the analysis, given that adjuvant chemotherapy and disease stage are highly interrelated. Specifically, treatment regimen and intensity often are influenced by cancer stage, and patients with a higher stage at diagnosis are more likely to receive adjuvant chemotherapy.29
These findings highlight the importance of continued investigation of the relationship between chemotherapy and brain function in BC.
The BA 8 region is involved in switching attention to alternative competing responses based on learned conditional rules.30
It is demonstrated herein that increased activation of the BA 8 region was associated with faster completion time on the WCST:CV4 in healthy women. Thus, individuals with abnormalities in this area would be expected to have difficulties in flexibly shifting between response options and/or to experience slower processing speed during rule-governed tasks. Consistently, women in the chemotherapy group showed more perseverative errors than healthy controls, indicating that they tended to persist in responding to an incorrect rule. Also, the chemotherapy group took significantly longer to complete the WCST:CV4 test compared with the other groups. Even though the chemotherapy-treated women took more time on this task, they still made more errors. Thus, slowing down may not be an adequate compensatory strategy for these women. Taking more time may have been helpful for the no-chemotherapy group. These women showed a uniquely significant correlation between increased WCST:CV4 completion time and lower number of perseverative errors in the context of performance on the WCST:CV4 comparable to that of controls. These findings may suggest that factors specific to the chemotherapy group may have decreased these women’s ability to compensate for certain executive function impairments through simple behavioral adjustments. This may reflect stage of illness, in which slowing down is a first compensatory approach that no longer works when the disease has advanced to the point that increasing prefrontal damage has been incurred.
Decreased BA 10/46 and BA 6 function in both BC groups point to non–chemotherapy-related factors, such as abnormal endocrine function. Tamoxifen and menopause both result in estrogen deficiency, which can impair brain and cognitive function.31
Although these variables were not related to outcome or brain activation within the BC groups and groups were matched for menopausal status, individual variation in estrogen levels still may exist. Two previous studies32,33
have indicated negative effects of tamoxifen on cognitive status and brain function in BC survivors and suggest that women treated with chemotherapy and tamoxifen are at highest risk for cognitive and neurobiological deficits.4
The behavioral effects of decreased BA 10/46 and BA 6 activation in survivors of BC are unclear because no significant correlations were observed between activation in these regions and measures of subjective or objective executive function. Also, only the chemotherapy-treated group demonstrated significant differences in executive function performance. Brodmann area 10/46 is responsible for working memory, cognitive control, and monitoring.30
Brodmann area 6 has been associated with rule-based motor responses,30,34
and maintenance of working memory processes.36
Thus, a more comprehensive battery of executive function measures may be required to elucidate the relationships between BA 10/46 and BA 6 dysfunction and cognitive outcome in BC.
Cognitive reserve and age also may influence executive function outcome in chemotherapy-treated BC survivors. Individuals with greater cognitive reserve, stemming from genetic and environmental enrichment factors, tend to be less vulnerable to the effects of neurological disease, injury, and senescence.37
The chemotherapy group showed a significant relationship between higher educational level (a proxy of cognitive reserve) and decreased number of perseverative errors. Also, older women in the chemotherapy group tended to show increased perseverative errors, but aging was not associated with executive function in the other 2 groups. A previous study9
demonstrated an effect of cognitive reserve and age on processing speed in chemotherapy-treated women. These findings suggest that chemotherapy-treated women may be more vulnerable to the effects of lower environmental enrichment and aging on executive function.
Limitations of this study include its cross-sectional design. Longitudinal studies are necessary to more specifically address the effects of chemotherapy on brain and cognitive outcome. As noted herein, the selection of objective and subjective tests and indices was limited. This approach was taken to focus on the most reliable and salient measures and to reduce the number of statistical tests performed in a relatively small sample. The relatively small sample size may limit the interpretability of the results. For example, a moderate effect size was observed (P=.09, effect size=0.66) for a difference in BA 10/46 activation between the chemotherapy and no-chemotherapy groups. Power was calculated to be 86% or higher for pairwise omnibus statistics, and effect sizes ranged from 0.66 to 1.20, but larger sample sizes are needed to detect any smaller effects that may exist. Also, as with most such studies of BC, the inherent heterogeneity of this sample in terms of disease and treatment factors may limit the generalizability of these results to other patients.
This study provides further evidence that primary BC may cause measurable brain injury. Women treated with chemotherapy may show additional prefrontal deficits and have difficulty compensating for neurobiological changes such that they also show impaired executive function. The left caudal lateral prefrontal region may be particularly vulnerable to the effects of chemotherapy and/or disease severity and may represent a novel biomarker of subjective or subclinical executive dysfunction in chemotherapy-treated women.