A systemic literature review of neuroimaging studies in women with breast cancer treated with adjuvant chemotherapy

Introduction

The results of neuropsychological examinations carried out over the last two decades indicate the occurrence of cognitive impairments in patients with breast cancer who received chemotherapy [1]. A recent metaanalysis [2] showed a decrease in capacity of attention and selective attention as well as in immediate and delayed verbal recall in patients treated with chemotherapy compared to healthy persons. Changes observed during neuropsychological testing are corroborated by the results of neuroimaging studies carried out in the recent years [3–18].
The aim of this paper is to analyse the results of the neuroimaging studies conducted to date, assessing the cerebral alterations of women with breast cancer treated with chemotherapy.
The paper first focuses on the mechanisms underlying the cognitive decline, then describes the results of the studies on the structural and functional changes in the brain, and finally reports on the compensatory mechanisms observed in chemotherapy-treated women with breast cancer.

Mechanisms of chemotherapy-induced cognitive impairments

The mechanisms of cognitive impairment after chemotherapy (CTx) are still not fully understood [19, 20]. The potential role of various factors is indicated, related both to individual characteristics (host-related, soil characteristics) and the neoplastic disease itself (disease-related, seed characteristics) [21].
Research results imply a direct neurotoxic effect of cytostatic agents, which cross the blood-brain barrier causing, for exzample damage to neurons or glial cells, changes in neurotransmitter levels [22–26], and microvascular damage related to ischemia and brain damage, such as decreased vascular density in the hippocampus after the use of methotrexate [19, 27]. The indirect mechanisms are associated with the deregulation of the immune system and/or release cytokines [22, 28, 29], hormonal changes, e.g., decreased levels of oestrogen and progesterone due to premature menopause [30, 31], or DNA damage due to the effect of oxidative stress and accelerated telomere shortening [22, 28]. Moreover, the significance of individual factors associated with age, vascular risk factors, or the pre-cancer level of cognitive functioning and the amount of cognitive reserves, is also pointed out [31].
The results of more recent studies indicate that some patients may exhibit genetic predisposition to cognitive impairments [20, 31]. A relationship has been shown between the allele 4 of apolipoprotein E (APOE) gene and the deterioration of cognitive functioning in patients previously treated for breast cancer or lymphoma [26]. It was also found that persons with the catechol-O-methyltransferase (COMT)-Val genotype are more susceptible to the negative effects of CTx on cognitive functioning [32]. Genetic polymorphism may be related to the effectiveness of the blood-brain barrier (e.g. different expression of the multidrug resistance gene encoding P-glycoprotein, MDR1), the functioning of cytokines (e.g. polymorphism of the interleukin 6 cytokine gene), neurotransmitters (e.g. the polymorphism of COMT gene), and DNA repair mechanisms (e.g. the polymorphism of the X-ray repair cross complementing protein gene, XRCC1) [22, 33].

Methods

A comprehensive literature search was conducted using the PubMed database. The following search terms and their derivatives were used: cognition, neuroimaging, fMRI, PET, MRI, chemotherapy, breast cancer. Studies had to assess brain functioning with neuroimaging methods, be published in a peer-reviewed journal, and be available as full text in English language. No time period was specified.

Results

Forty-one studies fulfilled the inclusion criteria and were selected for further analysis. Changes in the central nervous system of women with breast cancer (BC) treated with CTx were assessed in 15 studies using an MRI [6, 10–13, 34–43] and in 24 studies using functional neuroimaging methods [3, 5, 7–9, 14–18, 44–57]. In two studies both structural and functional changes were assessed [4, 58]. The characteristics of structural and functional studies in breast cancer patients are presented in Tables 1–4.

Structural changes in the central nervous system of women with breast cancer treated with chemotherapy

In ten studies researchers used Voxel-Based Morphometry (VBM) [4, 6, 12, 37–42, 58] to compare the volume of brain areas and the density of grey and white matter [59]. In five studies Diffusion-Tensor Imaging (DTI) [11, 35, 36, 38, 43] was used to measure the microstructural integrity of white matter using fractional anisotropy (FA) and structural connectivity of the brain [60] was applied. In one study semi-automatic segmentation procedure was used [34] and in three automatic seqmentation procedure were used [10, 13, 39]. Most of the studies were conducted in cross-sectional design: 10 in breast cancer survivors treated with CTx [4, 6, 10, 13, 34, 35, 38–40, 43] and 2 in breast cancer patients prior to CTx [41, 58]; 5 studies were conducted with longitudinal design [11, 36, 37, 61, 62]. The results obtained from breast cancer patients treated with CTx were compared to breast cancer patient without CTx [34, 38, 55], healthy controls [4, 10, 13, 35, 40, 41, 62], non-cancer reference subjects [39, 43], or breast cancer patients without CTx and healthy controls [6, 36, 37, 58, 61]. In four studies breast cancer patients were treated with the same schema of CTx [38, 39, 43, 58] and in the other studies different schemas were applied [4, 6, 10–13, 34–37, 40, 42]. A summary of the structural cerebral changes described in analyzed studies is presented in Table 1.
The evaluation of the anatomical properties of the brain using MRI yields information on the structural changes occurring over time and makes it possible to discern the differences between groups. As already mentioned in the discussion of some of the studies, supplementing the research using MRI with functional imaging techniques is a method to obtain fuller descriptions of chemotherapy-related cognitive impairment (CRCI) [63].

Functional changes in the central nervous system of women with breast cancer treated with chemotherapy

The functional studies were carried out using fMRI [4, 5, 7, 8, 14–16, 18, 48–55, 57, 58, 64], EEG [44, 45, 65], resting state fMRI [3, 17], PET [9] and Pulsed Arterial Spin Labelling MRI Perfusion [56]. During fMRI cognitive processes were assessed using verbal and visual working memory tasks [4, 8, 18, 46, 48, 49, 52–54], visual memory task [5, 57], verbal memory task [9, 14–16], attention [53] and executive functioning [5, 7, 41, 55, 57]. Most studies were conducted in cross-sectional design: 14 in breast cancer survivors treated with CTx [3–5, 7, 9, 14, 16, 17, 44–46, 51, 57, 65] and 4 in breast cancer patient prior to CTx [48–50, 58]; 8 studies were conducted in longitudinal design [8, 15, 18, 52–56]. The results obtained by breast cancer patients treated with CTx were compared with breast cancer patients without CTx [7, 8, 16, 18, 38, 44, 45, 54–56], with breast cancer patients treated with different schemas of CTx [9, 16, 45, 57, 65], with patients treated with radiotherapy [57], with healthy controls [3, 4, 8, 14, 15, 18, 46, 48, 52, 57], or non-cancer reference subjects [49, 50] or with breast cancer patients without CTx and healthy controls [7–9, 18, 51, 54–56]. In three studies breast cancer patients were treated with the same schema of CTx [44, 45, 65], and in the others studies different schemas were applied [3, 4, 7, 8, 14–18, 45–48, 50–57].
Summary of functional changes described in the analysed studies (Table 2).

Compensatory mechanisms

An interesting study to observe the mechanism underlying the process of coping with cognitive demand was performed on 60-year-old homozygous twin sisters [46]. One of the sisters was previously (22 months earlier) treated for breast cancer that AC+T adjuvant chemotherapy (four cycles of AC followed by four cycles of T – docetaxel), and received hormonal therapy (tamoxifen) during the study. While diseases and therapies which could negatively affect cognitive functioning were excluded in both sisters, they were found to have the allele 4 of apolipoprotein E, associated with the occurrence of cognitive deficits [26]. Cognitive functioning was evaluated using standard neuropsychological tests, a self-assessment questionnaire, and functional magnetic resonance imaging (fMRI). It was found that the twin treated with CTx reported much greater problems with cognitive functioning. Nevertheless, the results of the performed neuropsychological tests lay within the norm and differed minimally from those of the healthy sister. The fMRI results showed white matter hyperintensities in both sisters, which are also observed among the carriers of the allele 4 of apolipoprotein E [66, 67]. No coherent pattern of the differences in the volumes of selected brain areas (including the hippocampus, amygdala, frontal part of the hippocampal gyrus cortex, and corpus callosum) were found between sisters. Nonetheless, interesting results were obtained in an fMRI examination during the performance of a task evaluating working memory using the n-back paradigm. It was shown that the more the task was taxing to the working memory, the greater was the scope of activation of brain areas (bilateral stimulation of frontal and parietal areas) in the sister treated with CTx compared to the healthy one. However, no significant differences in the task performance level were observed [64].
The obtained results indicate that in order to enable the adequate performance level of a task by the twin treated with CTx, it was necessary to activate a greater area of neural networks, which most likely requires greater mental effort, reflected in the greater number of complaints about cognitive functioning [64, 68]. It may be supposed that, if the task were made increasingly more taxing, at a certain level of difficulty the compensation for the deficits would be insufficient and the test results would become poorer [68]. The activation of larger areas of the brain in order to maintain the appropriate performance level in cognitive tasks was also confirmed by numerous studies on people aging normally [69–71].
The activation of compensatory mechanisms was also confirmed in a more recent longitudinal study carried out by McDonald, Conroy, Ahles, West, and Saykin [8], which assessed working memory using the n-back paradigm and brain activation using fMRI in women with breast cancer and in healthy ones. The measurements were taken three times: before chemotherapy, and one month, and one year after treatment. The performance level of n-back tasks did not differ significantly between groups; however, changes in activation patterns were observed in all three measurements, both during greater and lesser working memory-loaded tasks. Moreover, greater activation of prefrontal areas was found in the examinations before and one year after the treatment.
Thanks to compensatory neuroplasticity, the cognitive functioning of people treated with chemotherapy can be maintained on an unchanged or only slightly deteriorated level compared to their premorbid abilities. The studies on the levels of brain activation carried out with fMRI revealed that additional brain areas become involved in the performance of lower difficulty tasks, allowing their performance to remain within the norm. A deterioration in functioning becomes visible when the increasing difficulty exceeds the efficiency of compensatory mechanisms [68].

Conclusions

Based on the studies carried out using neuroimaging methods, it is possible to describe the cognitive deficits caused by adjuvant chemotherapy [72]. Specific, albeit small, structural changes and functional changes within the central nervous system are associated with the minor specific impairments of cognitive functions described in literature [72].
The changes in the activity of various cerebral regions in patients treated with chemotherapy indicate that the brain functions in an altered way, by activating new areas or creating new neural connections to reach the same cognitive efficiency. A greater expenditure of energy on mental activities can lead to increased fatigue and be associated with the deterioration in cognitive effectiveness and quality of life suffered by the patients [63]. Even though neuroimaging methods are not free from limitations, using them in CRCI studies in combination with self-descriptive and neuropsychological methods may yield a broader image of the described phenomenon [72].

The authors declare no conflict of interest.

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Address for correspondence

Paulina Andryszak
Institute of Psychology
Kazimierz Wielki University in Bydgoszcz
Staffa 1
85-867 Bydgoszcz, Poland
e-mail: pandryszak@gmail.com

Submitted: 13.12.2015
Accepted: 30.09.2016