A prospective study of grey matter and cognitive function alterations in chemotherapy-treated breast cancer patients

Lepage, Christian; Smith, Andra; Moreau, Jeremy T; Barlow-Krelina, Emily; Wallis, Nancy; Collins, Barbara; MacKenzie, Joyce; Scherling, Carole

doi:10.1186/2193-1801-3-444

Cited by 86 publications

(89 citation statements)

References 63 publications

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“…As hypothesized, we found that breast cancer survivors receiving adjuvant chemotherapy and estrogen blockade therapy exhibit more inward deformation of the hippocampus, with significant inward deformation in the right hippocampus relative to controls. This finding is consistent with previous studies that found right hippocampal grey matter reductions (Lepage et al, 2014), however, it is in contrast to several studies that found the left hippocampus and para-hippocampus to be affected to a greater extent (S. Kesler et al, 2013, Inagaki et al, 2007). Still, another group has reported that left and right hippocampi are affected equally by breast cancer (Bergouignan et al, 2011).…”

Section: Discussionsupporting

confidence: 92%

Subtle hippocampal deformities in breast cancer survivors with reduced episodic memory and self-reported cognitive concerns

Apple

Ryals

Alpert

et al. 2017

NeuroImage: Clinical

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Cancer survivors have lingering cognitive problems, however the anatomical basis for these problems has yet to be fully elucidated. Clinical studies as well as animal models of chemotherapy have pinpointed cell and volume loss to the hippocampus, however, few studies have performed shape analysis of the hippocampus on cancer survivors. This study used high-dimensional deformation mapping analysis to test whether localized hippocampal deformation differs in breast cancer survivors who received adjuvant chemotherapy coupled with hormone blockade therapy, and if deformation was related to subjective self-reported concerns and cognitive performance. 3 T MRI images were acquired from 16 pre-menopausal breast cancer survivors and 18 healthy controls without a history of cancer. Breast cancer survivors had undergone chemotherapy within the eighteen months prior to the study, and were receiving estrogen-blockade therapy at the time of the study. Automated high-dimensional deformation mapping was used to compare localized hippocampal deformation differences between groups. Self-reported subjective concerns were assessed using Neuro-QOL Cognitive Function assessment, whereas cognitive performance was evaluated using the NIH Toolbox Cognition Battery. Relative to healthy controls, cancer survivors showed significantly more inward hippocampal deformation, worse self-reported cognitive functioning, and inferior episodic memory test score. This study is the first of its kind to examine the relationship between hippocampal deformity and cognitive impairment in cancer survivors.

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Section: Discussionsupporting

confidence: 92%

Subtle hippocampal deformities in breast cancer survivors with reduced episodic memory and self-reported cognitive concerns

Apple

Ryals

Alpert

et al. 2017

NeuroImage: Clinical

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“…Our findings are consistent with those of previous studies that also demonstrated abnormalities in the precuneus, hippocampus, frontal, and parietal regions following exclusively or primarily AN-THR-based treatment regimens. 12,19,41,44 These are “hub” regions—areas that participate in a large number of functional interactions. 45 This centrality to brain network organization is associated with significantly high metabolic demands.…”

Section: Discussionmentioning

confidence: 99%

“…18 Clinical studies have demonstrated significant cognitive impairments and brain changes in patients with breast cancer treated exclusively with ANTHR-containing regimens 19 as well as in cohorts in which most were treated with ANTHRs. 3,12,14 To date, no studies have directly compared ANTHRs with other agents. Therefore, we retrospectively examined the differential effects of ANTHR and non-ANTHR chemotherapies on cognitive status and brain network connectivity in long-term breast cancer survivors.…”

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confidence: 99%

Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors

2016

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IMPORTANCE Chemotherapy exposure is a known risk factor for cancer-related cognitive impairments. Anthracycline-based regimens are commonly used chemotherapies that have been shown to be associated with cognitive impairment and brain changes in clinical studies. OBJECTIVE To directly compare the effects of anthracycline and nonanthracycline regimens on cognitive status and functional brain connectivity. DESIGN, SETTING, AND PARTICIPANTS In this observational study, we retrospectively examined cognitive and resting state functional magnetic resonance imaging data acquired from 62 primary breast cancer survivors (mean [SD] age, 54.7 [8.5] years) who were more than 2 years off-therapy, on average. Twenty of these women received anthracycline-based chemotherapy as part of their primary treatment, 19 received nonanthracycline regimens, and 23 did not receive any chemotherapy. Participants were enrolled at a single academic institution (Stanford University) from 2008 to 2014, and the study analyses were performed at this time. MAIN OUTCOMES AND MEASURES Cognitive status was measured using standardized neuropsychological tests, and functional brain connectivity was evaluated using resting state functional magnetic resonance imaging with a focus on the brain’s default mode network. RESULTS The anthracycline group demonstrated significantly lower verbal memory performance including immediate recall (F = 3.73; P = .03) and delayed recall (F = 11.11; P < .001) as well as lower left precuneus connectivity (F = 7.48; P = .001) compared with the other 2 groups. Patient-reported outcomes related to cognitive dysfunction (F = 7.27; P = .002) and psychological distress (F = 5.64; P = .006) were similarly elevated in both chemotherapy groups compared with the non–chemotherapy-treated controls. CONCLUSIONS AND RELEVANCE These results suggest that anthracyclines may have greater negative effects than nonanthracycline regimens on particular cognitive domains and brain network connections. Both anthracycline and nonanthracycline regimens may have nonspecific effects on other cognitive domains as well as certain patient reported outcomes. Further research is needed to identify potential methods for protecting the brain against the effects of various chemotherapeutic agents.

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“…Several cross‐sectional and longitudinal studies have demonstrated abnormalities in brain structure and function, particularly in chemotherapy‐treated patients and survivors (D'Agata et al., 2013; Deprez et al., 2014; Jung et al., 2016; Kesler & Blayney, 2015; Lepage et al., 2014; Nudelman et al., 2014; Simo et al., 2015; Stouten‐Kemperman et al., 2014). However, many patients demonstrate differences in brain structure and function prior to chemotherapy suggesting that cancer pathogenesis, surgery/anesthesia, disease burden, host‐related, and/or other factors may contribute to early brain changes (Cimprich et al., 2010; McDonald, Conroy, Ahles, West, & Saykin, 2012; Menning et al., 2015; Sato et al., 2015; Scherling, Collins, Mackenzie, Bielajew, & Smith, 2012; Scherling, Collins, Mackenzie, Lepage, et al., 2012).…”

Section: Introductionmentioning

confidence: 99%

Disrupted brain network functional dynamics and hyper‐correlation of structural and functional connectome topology in patients with breast cancer prior to treatment

et al. 2017

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IntroductionSeveral previous studies have demonstrated that cancer chemotherapy is associated with brain injury and cognitive dysfunction. However, evidence suggests that cancer pathogenesis alone may play a role, even in non‐CNS cancers.MethodsUsing a multimodal neuroimaging approach, we measured structural and functional connectome topology as well as functional network dynamics in newly diagnosed patients with breast cancer. Our study involved a novel, pretreatment assessment that occurred prior to the initiation of any cancer therapies, including surgery with anesthesia. We enrolled 74 patients with breast cancer age 29–65 and 50 frequency‐matched healthy female controls who underwent anatomic and resting‐state functional MRI as well as cognitive testing.ResultsCompared to controls, patients with breast cancer demonstrated significantly lower functional network dynamics (p = .046) and cognitive functioning (p < .02, corrected). The breast cancer group also showed subtle alterations in structural local clustering and functional local clustering (p < .05, uncorrected) as well as significantly increased correlation between structural global clustering and functional global clustering compared to controls (p = .03). This hyper‐correlation between structural and functional topologies was significantly associated with cognitive dysfunction (p = .005).ConclusionsOur findings could not be accounted for by psychological distress and suggest that non‐CNS cancer may directly and/or indirectly affect the brain via mechanisms such as tumor‐induced neurogenesis, inflammation, and/or vascular changes, for example. Our results also have broader implications concerning the importance of the balance between structural and functional connectome properties as a potential biomarker of general neurologic deficit.

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A prospective study of grey matter and cognitive function alterations in chemotherapy-treated breast cancer patients

Cited by 86 publications

References 63 publications

Subtle hippocampal deformities in breast cancer survivors with reduced episodic memory and self-reported cognitive concerns

Subtle hippocampal deformities in breast cancer survivors with reduced episodic memory and self-reported cognitive concerns

Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors

Disrupted brain network functional dynamics and hyper‐correlation of structural and functional connectome topology in patients with breast cancer prior to treatment

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