White Matter Brain Changes In Post-Chemotherapy Breast Cancer Patients
Overview
In this study, the objective was to evaluate white matter microstructural changes in older breast cancer survivors 5-15 years post-chemotherapy treatment. The participants included breast cancer survivors aged 65 or older who underwent chemotherapy (C+) and those who did not (C-), along with age- and sex-matched healthy controls (HC). The study spanned two time points, TP1 and TP2, with a two-year follow-up.
All participants underwent brain MRI with diffusion tensor images and neuropsychological testing using the NIH Toolbox Cognition Battery. The analysis employed tract-based spatial statistics (TBSS) to assess white matter microstructural changes based on the fractional anisotropy (FA) parameter.
Results revealed significant longitudinal alterations in FA within the C+ group over time. The C+ group exhibited diminished FA in the body and genu of the corpus callosum, anterior corona radiate, and external capsule in both whole brain and region of interest (ROI) based analyses after family-wise error (FWE) correction (p < 0.05). However, there were no significant group differences between C+ and C- groups at TP1. Additionally, at TP1, a positive correlation (R=0.58, p=0.04) was observed between the FA value of the anterior corona radiata and the crystallized composite score in the C+ group.
The study suggests that brain white matter microstructural alterations may be the underlying neural correlates of cognitive changes in older breast cancer survivors who underwent chemotherapy treatment years ago.
Introduction
Cancer-related cognitive impairment (CRCI) poses a growing challenge for cancer survivors, particularly those in the older age bracket. The advent of advanced cancer treatments, such as targeted therapies, immunotherapy, and endocrine therapy, has substantially increased survival rates for breast cancer patients. Nevertheless, the emergence of CRCI significantly affects the quality of life for cancer survivors. Older individuals, especially those who have undergone chemotherapy, often grapple with persistent cognitive issues, notably in attention, processing speed, working memory, and executive function, even several years post-treatment.
Despite the acknowledged vulnerability of older cancer survivors to cognitive impairment, there exists a notable dearth of research focusing on the prolonged consequences of chemotherapy in this demographic. Neuroimaging techniques, particularly the use of diffusion tensor imaging (DTI) for examining brain white matter, offer a valuable avenue to explore the neural underpinnings of CRCI. Previous studies have reported a decrease in white matter microstructural integrity in specific regions of the brain in breast cancer patients shortly after undergoing chemotherapy.
The current prospective longitudinal study seeks to address this research gap by enrolling older, long-term breast cancer survivors, both with and without chemotherapy history, alongside an age- and sex-matched healthy control group. Over a two-year period, participants are closely monitored to investigate enduring changes in white matter microstructure occurring 5-15 years post-chemotherapy. Rigorous analysis of brain DTI data is employed to scrutinize white matter alterations through fractional anisotropy (FA) values. Additionally, cognitive performance is assessed using neuropsychological testing scores.
The underlying hypothesis driving this study posits that the group treated with chemotherapy will exhibit diminished FA values, and these reductions will be correlated with lower neuropsychological scores. This comprehensive approach, integrating neuroimaging and cognitive assessments, aims to offer a nuanced understanding of the intricate relationship between chemotherapy, white matter integrity, and cognitive function in older breast cancer survivors.
This research endeavors to shed light on the long-term consequences of chemotherapy on the white matter microstructure in older breast cancer survivors, contributing valuable insights into the intersection of cancer treatment, neurological changes, and cognitive well-being in this specific demographic.
Methods
In the course of this study, a meticulous enrollment process targeted older breast cancer survivors aged 65 years or above who had undergone chemotherapy (C+) 5-15 years before enrollment. This cohort was juxtaposed against age- and sex-matched breast cancer survivors without chemotherapy (C-) and a control group of healthy individuals (HC) at the initial time point (TP1).
The research spanned up to 2 years, monitoring participants through a subsequent time point (TP2). Exclusion criteria were stringent, encompassing a history of psychiatric disease, alternative cancer diagnoses or treatments, neurodegenerative disorders, metastatic disease, or stroke. Notably, all participants were right-handed.
The cognitive evaluation was conducted using the NIH Toolbox Cognition Battery, a comprehensive tool generating scores across various cognitive domains. To analyze the cognitive data, a generalized linear model (GLM) was employed, factoring in repeated measurements within subjects and accounting for group and time point as categorical fixed effects.
The GLM executed three key tests, elucidating differences in neuropsychological (NP) scores between groups at TP1, discerning significant longitudinal variations within groups, and examining the interaction effect between group and time.
It is noteworthy that this cognitive testing constituted a subset of a larger trial, titled “Cognition in older breast cancer survivors: treatment exposure, APOE, and smoking history”.
In terms of neuroimaging, a Verio 3 T scanner and the FMRIB Software Library (FSL) were utilized for DTI data acquisition and processing. TBSS analysis was applied, focusing on white matter integrity. Whole brain and region of interest (ROI) analyses were conducted, employing the JHU white matter template for the latter. The research identified specific white matter tracts, including the left anterior corona radiata, body of the corpus callosum, genu of the corpus callosum, and left external capsule, showing significant longitudinal changes.
This multifaceted study contributes significantly to the understanding of cognitive and white matter microstructural alterations in older breast cancer survivors who had undergone chemotherapy. By amalgamating cognitive assessments, advanced neuroimaging techniques, and rigorous statistical analyses, the research provides a nuanced exploration of the intricate relationships between chemotherapy exposure, cognitive function, and white matter integrity in the context of breast cancer recovery for older individuals.
Statistical Analysis
Statistical analyses were rigorous, encompassing t-tests, linear mixed models, and ANOVA for whole brain and ROI levels. Family-wise error correction was applied to ensure the robustness of statistical significance. Additionally, correlation analyses delved into the associations between mean ROI values and composite cognitive scores at TP1, as well as the correlations between fractional anisotropy (FA) changes and changes in composite scores.
Results
Despite the initial cohort comprising 60 participants at TP1, evenly distributed among the C+, C−, and HC groups, the study encountered significant attrition. The final cohort with both TP1 and TP2 data included only 12 subjects in each group, as a result of various factors such as the emergence of new memory problems, new cancer diagnoses, participants refusing to continue, loss of follow-up, and unfortunately, mortality. This attrition highlighted the real-world challenges and complexities associated with long-term longitudinal studies in older populations, particularly those with a history of cancer.
Demographic analysis at the outset revealed no significant differences in age, education, or race among the three groups, ensuring a baseline comparability for subsequent analyses. The chemotherapy regimens in the C+ group were diverse, with the majority receiving TC (docetaxel and cyclophosphamide). This diversity in treatment regimens reflects the heterogeneous nature of cancer treatment in real-world clinical settings.
The neuroimaging analysis, particularly voxel-wise whole-brain TBSS at TP1, did not show significant differences in fractional anisotropy (FA) values between the groups, emphasizing the importance of longitudinal assessments to capture changes over time. Longitudinal analysis within the C+ group revealed notable decreases in FA values in specific white matter regions, providing valuable insights into the chronic impact of chemotherapy on white matter microstructure in older breast cancer survivors.
The subsequent region of interest (ROI) analysis focused on the regions identified from the whole-brain analysis. This in-depth exploration demonstrated significant decreases in FA values over time in the C+ group, particularly in the left anterior corona radiata, body of the corpus callosum, genu of the corpus callosum, and left external capsule. The utilization of non-parametric tests further validated these findings, enhancing the robustness of the results.
Cognitive testing at TP1 uncovered lower crystallized composite scores and oral reading recognition scores in the C+ group compared to the C− group, highlighting early cognitive differences associated with chemotherapy. Longitudinal analysis within the C+ group demonstrated significant declines in multiple cognitive domains over time, providing evidence of persistent cognitive effects in older breast cancer survivors who had undergone chemotherapy.
The correlation analysis revealed a significant positive correlation between the crystallized composite score and FA values in the left anterior corona radiata at TP1 within the C+ group. This correlation underscores the intricate relationship between white matter microstructure and cognitive performance in the context of chemotherapy-treated breast cancer survivors.
Despite the challenges posed by attrition, this study presents a comprehensive examination of the longitudinal changes in white matter microstructure and cognitive performance in older breast cancer survivors who underwent chemotherapy. The findings contribute to our understanding of the enduring impact of chemotherapy on both structural and cognitive aspects of the brain in this specific population, emphasizing the need for tailored interventions and support for long-term survivors.
Conclusion
Our investigation revealed a notable decline in the structural integrity of white matter in older breast cancer survivors who underwent chemotherapy 5–15 years ago. This finding underscores the enduring impact of chemotherapy on the microstructure of white matter in long-term survivors. Furthermore, our study identified a significant correlation between the observed white matter alterations and cognitive function. This correlation suggests that the identified changes in white matter integrity may potentially function as a neural correlate for Cancer-Related Cognitive Impairment (CRCI) in older individuals who have survived breast cancer over the long term. These results highlight the intricate relationship between white matter health and cognitive outcomes in the context of cancer survivorship, emphasizing the need for continued research and potential interventions to address cognitive challenges in this specific population.
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