Original Article the Dorsolateral Prefrontal Cortex Is Selectively

Am J Cancer Res 2019;9(8):1776-1785 www.ajcr.us /ISSN:2156-6976/ajcr0098769

Original Article The dorsolateral prefrontal cortex is selectively involved in chemotherapy-related cognitive impairment in breast cancer patients with different hormone receptor expression

Haijun Chen1*, Ke Ding1*, Jingjing Zhao1*, Herta H Chao2,3, Chiang-Shan R Li4, Huaidong Cheng1*

1Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, Anhui, China; 2Cancer Center, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Departments of 3Internal Medicine, 4Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA. *Equal contributors. Received June 21, 2019; Accepted June 30, 2019; Epub August 1, 2019; Published August 15, 2019

Abstract: To investigate chemotherapy-related cognitive impairment (CRCI) in breast cancer patients with different hormone receptor (HR) expression and its neural mechanisms, forty BC patient were enrolled in this study and were divided into two groups. HR+ group was composed of twenty-one patients with Estrogen Receptor (ER)+/ Progesterone Receptor (PR) +, HR- group included nineteen patients with ER-/PR-. A battery of neuropsychological tests and resting-state functional magnetic resonance imaging (rs-fMRI) examinations were administered to all subjects. The functional connectivity of the dorsolateral prefrontal cortex (DLPFC) of the patients was calculated from the resting-state fMRI data, and the correlation between the DLPFC’s connectivity and the neuropsychological test was analyzed. The functional connectivity (FC) of the left dorsolateral prefrontal cortex (DLPFC) with the left precuneus (PCU), the right DLPFC with the right precuneus and the right superior frontal gyrus (SFG) of the HR- group were significantly increased compared to the HR+ group. Meanwhile, a significant positive correlation was found between the post-chemotherapy prospective memory (PM) score and the functional connectivity of the left DLPFC with the left precuneus in the HR- group. These findings suggest that different hormone receptor expression in patients with breast cancer may be associated with CRCI and provide evidence that the DLPFC functional connectivity (FC) strength may be selectively involved in CRCI in HR- group breast cancer patients, especially in regard to the subjective prospective memory.

Keywords: Breast cancer, chemotherapy, cognitive impairment, functional connectivity

Introduction that CRCI is widespread, involving memory, executive function, information processing sp- It has been reported in many recent studies eed and other aspects, and there is no signifi- that breast cancer (BC) patients frequently cant change in the early stage and it is not easy experience cognitive impairment following che- to be detected [7]. Pinto et al. found that the motherapy [1, 2]. Chemotherapy-related cogni- improvement of breast cancer treatment tech- tive impairment (CRCI) is the decline of memo- nology led to an increase in the number of long- ry, learning ability, attention, reasoning ability, term survival of breast cancer patients, and executive function, information processing sp- cognitive changes such as memory disorder, eed and visual space function that occurs in insomnia and depression were the most impor- cancer patients during or after chemotherapy tant factors affecting the quality of life after [3-5]. The study showed that breast cancer chemotherapy [8-10]. However, the specific patients were affected by CRCI for a long period mechanisms underlying chemotherapy-related of time after standard treatment and 45.2% of cognitive impairment (CRCI) are still not well breast cancer patients showed changes in cog- understood. nitive function after treatment, while only 10% of healthy control group showed changes in However, neuroimaging studies have found th- cognitive function [6]. The research believes at changes in brain structure and function in DLPFC functional connectivity in breast cancer patients breast cancer patients were associated with ch- the field of breast cancer research. Due to emotherapy-related cognitive impairment [11- molecular genetic changes, there is a high de- 13]. Structural changes in both gray matter gree of heterogeneity at the molecular level, (GM) and white matter (WM) are evident in br- which leads to a great difference in the progno- east cancer patients after chemotherapy [14]. sis and response to treatment of breast cancer. The gray matter structure of corresponding br- Several studies have shown heterogeneity with- ain regions was changed and the damage of in CRCI among breast cancer survivors [23, axons and demyelinating lesion of local white 24]. However, the specific mechanisms driving matter in breast cancer patients are related to the heterogeneity of CRCI in breast cancer the damage of cognitive function [15-18]. The patients is not obvious. A study indicated that neurotoxicity of chemotherapy affects both the the different hormone receptor expression in structure and function of the brain, especially BC patients may be related to the heterogene- the frontal lobe and the cognition processes ity of CRCI [25]. The prognosis is different for [19]. In recent years, the improvement of rs- BC patients with different hormone receptor fMRI technology provides a relatively more expression, but the relationship between the direct and objective means for us to study brain occurrence of CRCI in breast cancer and the network changes. Of course, this technique expression of hormone receptors remains un- was also applied in the research of traditional clear. Currently, few neuroimaging studies have central nervous system diseases, and soon investigated how alterations in the resting state some scholars applied it to explore the brain functional connectivity within specific brain network generation mechanism of CRCI in br- regions are related to cognitive function in BC east cancer. Bruno studied the network of patients with different hormone receptor ex- breast cancer patients after chemotherapy, pression. Therefore, the current study aims to and found that the brain network in the frontal explore the alterations of functional connectiv- lobe, temporal lobe and striatum area showed obvious abnormalities, and its clustering coef- ity in BC patients with different hormone recep- ficient was significantly lower than that of tor expression by using resting-state fMRI. The healthy people. The conclusion was that the dorsolateral prefrontal cortex (DLPFC), which is increase of the shortest path and the decrease in the middle frontal gyrus, is involved func- of the clustering coefficient in the frontal lobe, tions including working memory, prospective temporal lobe and other regions of breast can- memory and executive function [26]. We chose cer patients after chemotherapy suggested the DLPFC as the seed region and computed its that the abnormal brain network in the frontal functional connectivity with the whole brain at lobe and temporal lobe, which are related to resting-state and then analyzed the relation- cognitive function, may be one of the important ship between the functional connectivity of the mechanisms of the occurrence of CRCI in DLPFC network and neuropsychological perfor- breast cancer [20]. Similarly, Kesler pointed mance of BC patients with different hormone that patients may suffer damage of DMN after receptor expression. chemotherapy, which will further affect brain function and cause decline in learning, memory Materials and methods and other cognitive abilities [21]. Miao used anterior cingulate cortex (ACC) as the seed Participants point and found that functional connectivity of Forty patients with breast cancer, before and left superior frontal gyrus, left medial frontal after chemotherapy, were enrolled in this study gyrus, left middle temporal gyrus, and right superior frontal gyrus had significantly de- in the Department of Oncology of the Affiliated creased in breast cancer patients after chemo- Second Hospital of Anhui Medical University therapy, and the decreased connectivity of from September 2016 to February 2018. The these areas was significantly correlated with patients were divided into two groups. The HR+ cognitive dysfunction, especially the executive group was composed of twenty-one patients function [22]. with ER+/PR+ status, and the HR- group included nineteen patients with ER-/PR- status. The Molecular classification of breast cancer has study was approved by the Research Ethics become one of the most important direction in Committee of the Affiliated Second Hospital of

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Anhui Medical University, and all subjects pro- names, schools, daily necessities, fruits, vege- vided their informed consent. tables, animals, vehicles, and last names, and one point will be given for each answer. The inclusion criteria for the participants were as follows: (1) Postoperative pathological tis- The DST (digit span test) assessed participants’ sue and immune-histochemical diagnosis of short-term memory and concentration, includ- breast cancer patients; (2) Standard-dose che- ing digits forward or backward. When perform- motherapy treatment with doxorubicin (40 mg/ ing a number breadth order test, subjects are m2) and paclitaxel (175 mg/m2) for each che- asked to repeat the number read by the opera- motherapy cycle for 6 cycles; (3) Mini-Mental tor. For example, the researchers read out five State Examination (MMSE) score ≥24; (4) Ka- numbers: 11, 12, 13, 14, 15. The subjects rnofsky Performance Scale (KPS) score ≥80; repeated 11, 12, 13, 14, 15. The score for the (5) No impairment in vision, hearing or lan- last retelling of the correct string is 8. To do the guage. Patients with breast cancer were exclud- number span backwards test, subjects were ed if the following conditions were present: (1) asked to repeat the number the researchers treatment with hormone- or radiation-thera- had read backwards. For example, the research- py; (2) anxiety, depression, delusion and other ers read out five numbers: 11, 12, 13, 14, 15, mental symptoms; (3) a history of alcohol or and the subjects returned the five numbers: drug dependence; (4) distant metastasis and 15, 14, 13, 12, 11. According to the order set advanced cachexia (5) other physical and men- by the scale, digits backward was carried out, tal disorders that can lead to cognitive im- and the score was the corresponding score of pairment. the last backward correct string, with the high- est score being 8 points. Neuropsychological background tests Prospective memory (PM) and retrospective A series of neuropsychological background memory (RM) questionnaires tests were administered within one week before chemotherapy and within one month after che- The PM/RM questionnaires (PRMQ) consisted motherapy to assess the general cognitive of 16 items, 8 testing for PM disorders, and 8 function, working memory and executive func- for RM disorders. Patients were required to rate tions in patients with breast cancer. The neuro- the degree of their memory failure on a 4-point psychological assessment was performed on Likert scale for each item: 4: very often, 3: the same day as the MRI examination. sometimes, 2: rarely, 1: never. Total scores for RM or PM ranged from 8 to 32, with higher The MMSE (mini-mental state examination) scores indicating greater memory impairment. was to assess the general cognitive, including All the tests were conducted in a quiet room memory, orientation, executive function, visual without interference and were completed in 10 and spatial ability. The scale consists of 30 minutes. questions, one point for each question, and one point for correct answer, no point are aw- Image acquisition arded for wrong answer or unknown answer. The total score reflects the general cognitive The image data was obtained by a Siemens function. The higher the score, the better the Verio 3.0 Tesla scanner (Siemens, Erlangen, cognitive function; the lower the score, the Germany) with 16-channel head coil at the worse the cognitive function. Affiliated Second Hospital of An Hui Medical University. The whole MRI scan was about 15 The VFT (verbal fluency test) widely used for min. The resting-state functional connectivity spontaneous speech generation, in which sub- fMRI (R-fMRI) images were obtained by a gradi- jects are asked to generate a word in response ent-recalled echo-planar imaging (GRE-EPI) to a prompt, reflecting the ability of patients to pulse sequence. The R-fMRI data was obtained retrieve key words related to the content of the as following parameters: TR = 2000 ms, TE = prompt from their own long-term memory. VFT 25 ms, FA = 90°, acquisition matrix = 64 × 64, requires subjects to list as many examples as FOV = 240 × 240 mm, thickness = 4.0 mm, gap possible within a specified time (1 min). The = 0 mm, NEX = 1.0, number of slices = 36, time commonly used ranges include country, place points = 240. The T1-weighted 3D Spoiled

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Gradient Recalled Echo (3D-SPGR) images assessed using independent samples t-tests. were obtained with the following parameter set- In addition, the categorical variables such as tings: repetition time (TR) = 1900 ms, echo pathological pattern and stage of tumor in the time (TE) = 2.48 ms, flip angle (FA) = 9°, acqui- groups were assessed by the chi-square (χ2) sition matrix = 256 × 256, field of view (FOV) = test. All statistical tests were two-tailed with 240 × 240 mm, thickness = 1.0 mm, gap = 0 the level of significance set at P < 0.05. mm, number of slices = 176, number of excita- tions (NEX) = 1.0. During the data scans, all Analysis of resting-state functional connectivi- participants were instructed to keep their eyes ty: We used an anatomical region-of-interest closed and to avoid falling asleep or getting dis- (ROI) method to extract the bilateral DLPFC as tracted during the scanning. the seed region. Data from the bilateral DLPFC regions over time were extracted from function- Image preprocessing al EPI images of each subject. The mean time course of the signal in each DLPFC region was The fMRI data were preprocessed by using a used as the seed time course, and cross-corre- SPM12 toolkit (http://www.fil.ion.ucl.ac.uk/ lation was used to correlate the time course of spm) and MATLAB version 8.0 (The Math all brain voxels. Then, the Pearson correlation Works, Inc., Natick, MA, USA). First, the first ten coefficient (r) was subjected to a Fisher z trans- volumes of the scanning session were discard- form to obtain variables approximating a nor- ed for T1 equilibration effects. The remaining mal distribution [m = 0.5 ln (1 + r)/(1-r)]. Finally, 230 volumes were corrected for slice timing, the data were spatially normalized to MNI realigned, and subsequently spatially normal- space, resampled to 3 mm isotropic voxels, and ized to the standard Montreal Neurological smoothed with a Gaussian kernel (6-mm full Institute (MNI) EPI template using the default width at half maximum). settings. All the normalized images were resliced by 3.0 × 3.0 × 3.0 mm3 voxels. To fur- Partial correlation analysis: To explore whether ther reduce the effects of confounding factors, the DLPFC functional connectivity alterations six motion parameters, the global mean signal, were associated with the cognitive performanc- white matter (WM) signal, and cerebrospinal es of the breast cancer patients. The correla- fluid (CSF) signal were removed from the data tion between the change of neuropsychological through linear regression. The head motion in test and the change of DLPFC functional con- each direction over 2 mm or rotation angle nectivity in breast cancer patients was ana- exceed 2° were excluded. We also calculated lyzed. The correlation analyses were also con- the framewise displacement (FD), which re- ducted separately in the HR+ and HR- group flects the mismatch of volume to volume head breast cancer patients. position [27, 28]. There was no significant difference in the FD among groups (P > 0.05), and Results the mean FD was also applied as a covariate in the imaging analyses. Moreover, a bandpass Demographic characteristic and clinical data filter was applied to maintain low-frequency fluctuations within a frequency range of 0.015- As illustrated in Table 1, there were no signifi- 0.1 Hz. Lastly, the images were smoothed by a cant differences in the demographic informa- 6 mm full width at half maximum Gaussian ker- tion, including the age, the level of education, nel. After preprocessing, the individual data and the menstrual status, as well as in clinical were used for further connectivity analyses. information such as the Karnofsky performance status (KPS), pathological pattern and Statistical analysis tumor stage between the HR+ and HR- groups (P > 0.05). Demographic and neuropsychological data: The Statistical Package for Social Sciences Neuropsychological assessment and memory (SPSS) 16.0 was used for all statistical analy- questionnaire results ses. Differences in questionnaire scores that were obtained before and after chemotherapy Table 2 shows the performance of the breast were analyzed by means of paired-samples cancer patients before and after chemotherapy t-tests. Comparisons between groups were on the neuropsychological tests and memory

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Table 1. Comparison of demographic characteristics and clinical Functional connectivity data of breast cancer between the HR+ group and the HR- group There was a significant diff- HR+ (n=21) HR- (n=19) t/χ2 P erence in the functional con- Age (years) 52.29±7.27 48.47±7.62 1.618 0.114 nectivity in the bilateral DL- Education (years) 7.76±3.67 8.16±3.29 -0.358 0.722 PFC network in the BC pa- KPS 89.52±5.90 87.89±5.35 0.911 0.368 tients after chemotherapy Pathological pattern (cases) (Figure 1 and Table 4). Com- Invasive ductal carcinoma 16 13 0.302 0.583 pared to before chemothera- Invasive lobular carcinoma 5 6 py, there was a significant in- Stage (cases) crease in the functional con- I 4 5 0.311 0.856 nectivity in the BC patients II 10 8 after chemotherapy in the fo- III 7 6 llowing areas: the left DLPFC Menstrual status with the left precuneus (t = -2.789, P < 0.01), the right Premenopausal 8 10 0.852 0.356 DLPFC with the right precu- Postmenopausal 13 9 neus (t = -3.086, P < 0.01), Notes: Data are presented as mean ± SD. Abbreviations: SD, standard deviation; KPS, Karnofsky performance status; HR+, breast cancer patients with ER+/PR+ and the right superior frontal status; HR-, breast cancer patients with ER-/PR- status. gyrus (t = -3.442, P < 0.01). In addition, the functional connectivity of the left DLPFC Table 2. Comparison of neuropsychological tests and memory per- with left precuneus (t = formance in patients with breast cancer before and after chemo- -2.247, P < 0.05), the right therapy DLPFC with the right precu- Parameters CB (n=40) CA (n=40) t P neus (t = -2.034, P < 0.05), MMSE 29.10±0.87 25.03±2.37 9.781 0 and the right superior frontal VFT 11.55±2.29 6.30±1.47 12.774 0 gyrus (t = -2.337, P < 0.05) in DST 6.38±0.87 4.78±1.21 7.495 0 the HR- group were signifi- PM 10.90±1.74 20.18±4.01 -14.153 0 cantly increased in comparison with those in the HR+ RM 10.15±1.56 19.65±2.67 -20.782 0 group (Figure 2). Notes: Data are presented as mean ± SD. Abbreviations: SD, standard deviation; MMSE, mini-mental state examination; DST, digit span test; VFT, verbal fluency test; PM, prospective memory; RM, retrospective memory; CB, breast cancer patients Correlation before chemotherapy; CA, breast cancer patients after chemotherapy. A significant positive correlation was observed between questionnaires. There were significant differ- the FC of the left DLPFC-left precuneus and the ences in the total scores on the MMSE (t = PM score in the HR- group breast cancer pa- 9.781, P < 0.01), VFT (t = 12.774, P < 0.01), tients after chemotherapy (r = 0.444, P = 0.02) DST (t = 7.495, P < 0.01), PM (t = -14.153, P < (Figure 3). No significant correlation was ob- 0.01), and RM (t = -20.782, P < 0.01). In Table served between the other neuropsychological 3, it suggested that the general cognitive func- performances and the FC alteration. tion on MMSE (t = 3.381; P < 0.01), VFT (t =3.205; P < 0.01), DST (t = 2.101; P < 0.05), Discussion PM (t = -2.207; P < 0.05) and RM (t = -4.006; P < 0.01) had significant differences between the In the present study, we found that BC patients HR+ group and the HR- group breast cancer with different hormone receptor expression patients after chemotherapy. have different levels of CRCI. Specifically, BC patients with an ER-/PR-status have poorer However, there were no significant differences scores on memory and the DS tests than on the neuropsychological tests and memory patients with an ER+/PR+ status. In addition, questionnaires between the HR+ group and the BC patients in the HR- group had more serious HR- group breast cancer patients before ch- chemotherapy-induced PM and RM impairment emotherapy. than patients in the HR+ group. This is consis-

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Table 3. Comparison of neuropsychological tests and memory questionnaires between the HR+ group and the HR- group breast cancer patients before and after chemotherapy Before After Parameters HR+ (n=21) HR- (n=19) t P HR+ (n=21) HR- (n=19) t P MMSE 29.14±0.91 29.05±0.85 0.323 0.748 26.10±1.92 23.84±2.29 3.381 0.002 VFT 11.76±2.76 11.32±1.67 0.626 0.536 6.95±0.86 5.58±1.68 3.205 0.004 DST 6.29±0.85 6.47±0.90 -0.679 0.501 5.14±0.98 4.37±1.34 2.101 0.042 PM 10.86±1.85 10.95±1.65 -0.162 0.872 18.90±3.97 21.58±3.66 -2.207 0.033 RM 10.14±1.59 10.16±1.57 -0.030 0.976 18.29±2.22 21.16±2.32 -4.006 0.000 Notes: Data are presented as mean ± SD. Abbreviations: SD, standard deviation; MMSE, mini-mental state examination; DST, digit span test; VFT, verbal fluency test; PM, prospective memory; RM, retrospective memory; HR+, breast cancer patients with ER+/PR+ status; HR-, breast cancer patients with ER-/PR- status.

Figure 1. The resting state analysis of functional connectivity of bilateral DLPFC networks in breast cancer patients before and after chemotherapy. (Warm color represents the increase of FC value after chemotherapy, while cool color represents the decrease of FC value. After 3 d clustsim correction, P=0.005, α=0.05, cluster size >35).

Table 4. Analysis results of functional connectivity of bilateral DLPFC networks in breast cancer patients after chemotherapy MNI Coordinate (RAI) Brain region BA Cluster size Peak (Z value) t P X Y Z Left DLPFC FC networks Left Precuneus 7 39 -12 -57 72 3.35 -2.789 0.007 Right DLPFC FC networks Right SFG 8 66 27 30 51 3.35 -3.442 0.001 Right Precuneus 7 36 3 -57 69 3.73 -3.086 0.003 Abbreviations: MNI, Montreal Neurological Institute; BA, Brodmann area; DLPFC, dorsolateral prefrontal cortex; FC, functional connectivity; SFG, superior frontal gyrus. tent with a previous study that showed that the within the HR- group also indicated that the expression of different hormone receptors may altered functional connectivity between the left be related to the heterogeneity of CRCI in DLPFC and left PCU was significantly correlat- breast cancer [25]. ed with the prospective memory (PM) in HR- group. In this study, we found that breast cancer patients with different hormone receptor expres- There is evidence that estrogen and progester- sion receiving chemotherapy displayed change one play an important role in the regulation of of functional connectivity in the bilateral DLPFC cognition [29]. In clinical, estrogen is useful in networks, and that the correlation analysis the treatment of menopause and age-related 1781 Am J Cancer Res 2019;9(8):1776-1785 DLPFC functional connectivity in breast cancer patients

patients in the HR- group after chemotherapy (scores), and the y-axis represents the functional connectivity strength. The thresh- old was set to P<0.05 (corrected using the Monte Carlo method). DLPFC, dorsolateral prefrontal cortex; FC, functional connectivity; PM, prospective memory.

cognitive decline [30]. Estro- gen works by binding to estrogen receptors and plays a key role in cognitive function, especially in memory. Proges- terone is involved in regulating the expression of nerve nutri- ents and promoting cell survival. When progesterone bin- ds to its receptor, it can acti- vate signal transduction path- ways and trigger relevant cel- lular events, which is the key to neural protection [31]. It can be seen that PRs can mediate the neuroprotective Figure 2. Brain regions showing significant differences in the bilateral DLPFC effect of progesterone in the functional connectivity networks between the HR+ group and the HR- group central nervous system, espe- breast cancer after chemotherapy are illustrated in (A) (Left Precuneus), (B) cially the release of brain- (Right SFG) and (C) (Right Precuneus). The numerical representation of sig- derived neurotrophic factor, nificant differences in the bilateral DLPFC networks is described in the histo- grams. The color bar presents Z scores. Abbreviations: L.DLPFC, left dorso- which is widely and richly ex- lateral prefrontal cortex; L.PCU, left precuneus; R.DLPFC, right dorsolateral pressed in the brain [32]. Br- prefrontal cortex; R.SFG, right superior frontal gyrus; R.PCU, right precuneus. ain-derived neurotrophic fac- BC-HR+, breast cancer patients with ER+/PR+ status; BC-HR-, breast cancer tors play an important role in patients with ER-/PR- status. neuronal homeostasis, plasticity, and memory consolida- tion and recovery [33]. The study also found that estrogen not only has nutritional and neuroprotective effects, but also can enhance memory and language ability [34, 35]. Our results suggest that cognitive impairment is more significant in breast cancer patients with negative hormone receptor expression than in breast cancer patients with positive receptor expression after chemotherapy, which may be related to the role of estrogen and progesterone in regulating cognitive function.

The DLPFC is believed to play a key role in the working memory, prospective memory and ex- Figure 3. Scatter plot of the DLPFC functional con- ecutive function, and damage to this region will nectivity and the PM Test. A significant positive cor- cause executive dysfunction syndrome [36]. A relation was found between the PM scores and the significant positive correlation was observed functional connectivity of the left DLPFC with the left precuneus in the HR- group (r=0.444, P=0.02). The between the functional connectivity strength of x-axis represents the PM test of the breast cancer the left DLPFC and the left PCU and the pro-

1782 Am J Cancer Res 2019;9(8):1776-1785 DLPFC functional connectivity in breast cancer patients spective memory (PM) in the HR- group. The Conclusion increased functional connectivity between the left DLPFC and the left PCU might account for The present research combined neuropsycho- the prospective memory impairment. The PCU logical tests with fMRI examination and sug- is an area located in the posterior portion of the gests that BC patients with different hormone parietal lobe, which is reported to be involved receptor expression may present with differ- with attentional tracking and visual-spatial ences in CRCI, and the DLPFC may be selec- imagery [37]. Memory impairment is the most tively involved in the heterogeneity of CRCI in prominent aspect of CRCI, which has attracted BC patients with different hormone receptor increasing recognition as an identifiable cogni- expression, especially in the prospective me- tive change [38, 39]. Prospective memory is mory. the recall of plans or intentions that need to be Acknowledgements made or carried out in the future and is most closely related to daily activities [40]. Neuro- We acknowledge all breast cancer patients who psychological studies have reported that the participated in this study. Department of On- PM is associated with the prefrontal cortex cology, the Second Affiliated Hospital of Anhui [41]. It has been demonstrated that breast can- Medical University should also be acknowl- cer survivors exhibited increased functional edged for their support with the recruitment of connectivity between the left DLPFC and left study participants. This work was supported by PCU, which had significant relevance to the pro- the National Natural Science Foundation of spective memory, reflecting a certain level of China (No. 81872504; 81372487). memory impairment. This study showed the functional connectivity between the left DLPFC Disclosure of conflict of interest and left precuneus, as well as the right DLPFC with the right precuneus and right superior None. frontal gyrus were increased. Most of research- es suggest that the influence of chemotherapy Address correspondence to: Huaidong Cheng, De- on brain structure and function involves the partment of Oncology, The Second Affiliated Hospital frontal lobe [42, 43]. The function of the frontal of Anhui Medical University, Hefei 230601, Anhui, China. E-mail: [email protected] lobe is related to attention, executive function and learning ability. The frontal lobe is also a References significant brain region in our findings that the functional connectivity of SFG increased after [1] Edelstein K, Bernstein LJ. Cognitive dysfunc- chemotherapy. Typically, increased connectivity tion after chemotherapy for breast cancer. J Int of a neural network is associated with improved Neuropsychol Soc 2014; 20: 351-356. performance and efficiency of that network. [2] Bernstein LJ, McCreath GA, Komeylian Z, Rich Sometimes over-connectivity can be a problem, JB. Cognitive impairment in breast cancer survivors treated with chemotherapy depends on but that is typically because the increased effi- control group type and cognitive domains as- ciency of that network is interfering with a more sessed: a multilevel meta-analysis. Neurosci important component of the network or the Biobehav Rev 2017; 83: 417-428. function of a more important competing net- [3] Chen X, Li J, Ren J, Hu X, Zhu C, Tian Y, Hu P, work. Ma H, Yu F, Wang K. Selective impairment of attention networks in breast cancer patients The current study strongly suggested that BC receiving chemotherapy treatment. Psy- patients with different hormone receptor ex- chooncology 2014; 23: 1165-1171. pression have altered functional connectivity of [4] Le Rhun E, Delbeuck X, Lefeuvre-Plesse C, Kra- DLPFC as well as different levels of CRCI after mar A, Skrobala E, Pasquier F, Bonneterre J. A chemotherapy. However, one limitation of our phase III randomized multicenter trial evaluat- ing cognition in post-menopausal breast can- study should be considered. The number of BC cer patients receiving adjuvant hormonothera- patients was limited. Future investigations py. Breast Cancer Res Treat 2015; 152: could include a larger sample of breast cancer 569-580. patients to verify the reliability and validity of [5] Morean DF, O’Dwyer L, Cherney LR. Therapies the tests. for cognitive deficits associated with chemo-

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