Recent advances in breast cancer treatment have improved the long-term survival rate in cancer patients. The success in primary breast cancer treatment marks the importance of the post-treatment care. Cancer-related trauma after chemotherapy have been widely reported by breast cancer survivors. Previous study showed the decreased gray matter volume one month after chemotherapy completion, especially in frontal regions which is known for cognitive function [1]. Another study indicated that there is reduction in cerebellar regions and right thalamus after the chemotherapy [2]. However, several studies focused on the change of brain volume, but did not mention about the change of brain shape. Thus, in the study we aim to find out the differences of both brain volume and shape between chemotherapy-treated breast cancer patients and healthy subjects based on voxel-based morphometry (VBM) and vertex-wise shape analysis, respectively.

The study included 12 breast cancer (BC) survivors exposed to chemotherapy (age = 43 ± 12 y/o) and 12 normal control (NC) women (age = 43 ± 11 y/o). All of them were arranged for a MRI brain examination on a 1.5T imaging system (Area, Siemens, Germany). T1 weighted images were acquired using MPRAGE sequence for VBM and vertex-wise shape analysis. The imaging parameter were TR/TE/TI = 2800/3.98/930 ms, FOV = 256 x 256 mm², matrix size = 256 x 256, slice thickness = 1 mm, voxel size 1 x 1 x 1 mm³, and scan time = 6.5 min.

VBM was used to evaluate the alternation in brain structure, including gray and white matter. Each brain was first normalized to International Consortium for Brain Mapping (ICBM) space template, East Asian brains. We then used Statistical Parametric Mapping (SPM) to segment gray and white matter, and MRIcro software was used to check the normalization and segmentation results. After the examination, two-sample t-test was performed to the segmented brains finding the differences between chemotherapy-treated breast cancer patients and NC. Finally, suitable p-value (typically less than 0.05) and cluster size were set to observe the differences between two groups.

In the vertex-wise shape analysis, FMRIB software library (FSL) was applied to segment the brain into several specific structures, including brain stem, amygdala, accumbens, caudate, hippocampus, putamen, pallidum and thalamus. After that, FSL was performed to produce a matrix to take a comparison of brain shape between chemotherapy-treated breast cancer patients and NC.

In the VBM analysis, we found larger gray matter volume of amygdala (Fig. 1a) and larger white matter volume of thalamus (Fig. 1b) in the chemotherapy-treated breast cancer patients compared to NC. In the other hand, reduced gray matter volume of thalamus, particularly in right thalamus (Fig. 1c), and reduced white matter volume of cerebellum (Fig. 1d) were found in the breast cancer patients after chemotherapy compared to NC. All the results above reached statistical significant differences (p < 0.05). It indicated the breast cancer who received adjuvant chemotherapy will result in smaller volumes in right thalamus and cerebellum. Several studies demonstrated that lower volume of both gray and white matter were found after receiving chemotherapy [3-5]. Even nine years later, the chemotherapy-treated patients still have the problem of structural alternations in brain [5]. However, it is true that frontal region is in charge of the cognitive function and executive process [1], but there was no alternation of frontal regions in our study. What really interest us was our most obvious results, i.e. cerebellum, have been reported that it correlated with the frontal regions, therefore cerebellum and frontal region shared the same function of cognition [6].

In the results of vertex-wise shape analysis, brain shape changes of breast cancer patients after chemotherapy compared to NC in left amygdala (Fig. 2a), bilateral thalamus (Fig. 2b) and bilateral hippocampus (Fig. 2c) were found. Although altered hippocampus was not found in our VBM analysis, we do observe a big shape difference of bilateral hippocampus in our vertex-wise shape analysis (Fig. 2c). Smaller hippocampus volume was also found in the breast cancer patients exposed chemotherapy in several VBM analyses [4, 7].

In our results, reduced gray matter volume of right thalamus and white matter volume of cerebellum, and altered shape of left amygdala, bilateral thalamus, and bilateral hippocampus was found in the chemotherapy-treated breast cancer patients compared to NC. The results may provide the evidence of brain structural alteration in women with breast cancer and highlight the importance of the breast cancer-related trauma and chemotherapy. Because of the side-effects of chemotherapy, several notable changes in brain volume and shape were found, it provided more information in deciding what kind of therapy should be used in the future.