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The effect of using adjuvant aromatase inhibitors on cognitive functions in postmenopausal women with hormone receptor-positive breast cancer


1 Department of Internal Medicine, Akdeniz University Faculty of Medicine, Antalya, Turkey
2 Department of Medical Oncology, Akdeniz University Faculty of Medicine, Antalya, Turkey

Date of Submission19-Apr-2021
Date of Acceptance22-Apr-2021
Date of Web Publication15-Feb-2022

Correspondence Address:
Yusuf Ilhan,
Department of Medical Oncology, Akdeniz University, Faculty of Medicine, 07070 Konyaaltı, Antalya
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_632_21

 > Abstract 


Introduction: Breast cancer is the most frequently diagnosed cancer in women worldwide. Aromatase inhibitors (AIs) are effective treatment options for both early-stage and advanced hormone receptor-positive breast cancer. Because of AIs are used long term in adjuvant therapy, side effects are also very important. It is considered that AIs may affect cognitive functions by decreasing the level of estrogen in the brain. The purpose of our study is that evaluate the relationship between duration of treatment and cognitive functions in patients with breast cancer who use AIs in adjuvant therapy.
Methods: Two-hundred patients diagnosed with breast cancer who were treated with AIs as adjuvant treatment were included. The patients were surveyed for demographic characteristics. Montreal Cognitive Assessment (MoCA) and Standardized Mini-Mental State Examination (SMMT) tests were performed to evaluate patients' cognitive functions. The total scores of the tests and the orientation, short-time memory, visuospatial functions, attention, language, executive functions which are the MoCA subscales were evaluated separately. Patients were grouped as 0–6, 6–12, 12–24, 24–36, 36, and more months according to the duration of AIs using time.
Results: The total MoCA and SMMT scores were affected by factors such as age, education level, and employment status. There was no relationship between duration of treatment and cognitive functions in patients with breast cancer who use AIs in adjuvant therapy (P > 0.05). In addition, no statistically relationship was found in the evaluation of MoCA subscales (P > 0.05).
Discussion: Prolonged adjuvant treatment with AIs does not affect cognitive functions in hormone receptor-positive breast cancer patients.

Keywords: Aromatase inhibitors, breast cancer, cognitive functions



How to cite this URL:
Ilhan RG, Ilhan Y, Goksu SS, Tatli AM, Coskun HS. The effect of using adjuvant aromatase inhibitors on cognitive functions in postmenopausal women with hormone receptor-positive breast cancer. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 8]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=337714




 > Introduction Top


Breast cancer is the most frequently diagnosed cancer in women worldwide.[1] Most postmenopausal women with early-stage breast cancer have estrogen receptor-positive disease and are treated with at least 5 years of adjuvant endocrine therapy. Both aromatase inhibitors (AIs) and tamoxifen are effective treatment options for early-stage hormone receptor-positive breast cancer.[2] It has been shown in some randomized trials and meta-analyses that AIs are more effective than tamoxifen. AIs reduce breast cancer recurrence risk more than tamoxifen, particularly during the first 5 years. Furthermore, 10-year breast cancer mortality was lower with AIs than tamoxifen.[3] Thus, AIs such as anastrozole, exemestane, and letrozole often use effectively as adjuvant therapy in postmenopausal women. Although generally well-tolerated, they have some adverse effects. The most common side effects reported with AIs are increasing menopausal symptoms and musculoskeletal complaints due to low estrogen levels. Other important side effects are osteoporosis and increased incidence of coronary artery disease.[4] Because of AIs are used long term in adjuvant treatment, long-term side effects are very important.

Some side effects of AIs are well characterized, but others, such as their potential effects on cognitive functions are not well understood. There are a few studies in the literature investigating cognitive functions for the use of AIs in breast cancer patients. Preclinical and a little clinic data indicate that estrogens exert neurotrophic and neuroprotective actions in the brain. Moreover, estrogen receptors have been documented in various parts of the brain. Estrogen appears to play an important role in cognitive function and memory.[2],[5] We know that AIs reduce circulating estrogen to very low levels. For this reason, there has been concern that these agents may decline cognitive functions. In some studies, it has been observed that cognitive functions decrease with different AIs.[6],[7] Contrary to these findings in some other studies, using AIs doesn't have any effect on cognitive functions.[8],[9] This situation is still highly controversial and unclear. Also, the relationship between the duration of treatment and decline in cognitive functions is not known. We hypothesized that there may be a relationship between the duration of AI treatment and decline in cognitive functions.

In this study, we aimed to evaluate the relationship between duration of treatment and cognitive functions in the large patient population with breast cancer that uses AIs in adjuvant therapy.


 > Materials And Methods Top


Patients

We designed a cross-sectional study including 200 patients who were diagnosed with hormone-positive breast cancer and use AIs (anastrozole, exemestane, or letrozole) as adjuvant treatment. All of the patients were postmenopausal. Patients with metastatic disease, patients with central nervous system pathology, patients with alcohol or substance abuse, illiterate patients, and patients whose native language was not Turkish were excluded from the study. Patients who used AI after adjuvant chemotherapy were also included. This study was approved by the Akdeniz University Faculty of Medicine Clinical Research Ethics Committee and was conducted in accordance with the declaration of Helsinki.

Assessments

Demographic and clinical data were obtained through the hospital database. The patients were also surveyed for their demographic characteristics with a questionnaire form. Turkish Version of the Montreal Cognitive Assessment (MoCA) and Standardized Mini-Mental State Examination (SMMT) tests were performed to patients by the same investigator to evaluate their cognitive functions. The total scores of the tests and the orientation, naming, short-time memory, visuospatial functions-executive functions, attention, abstract thinking, language which are the MoCA subscales were evaluated separately. In the Turkish population, the normal range of the MoCA and SMMT tests are 21–30 points and 24–30 points, respectively.[10],[11] Patients were grouped as 0–6, 6–12, 12–24, 24–36, 36, and more months according to the duration of AIs using time.

Statistical analysis

Statistical analyses were made with IBM SPSS 23.0 package program (IBM Corp., Armonk, NY, USA). Descriptive statistics were presented as n (%) and mean ± Standard deviation (min-max) and median (min-max) values. In the analysis of the difference between the scores of the two groups, the Mann-Whitney U test was used when data did not conform to normal distribution; and Student's t-test was used in a normally distributed population. The Kruskal–Wallis test was used for nonparametric comparison of the scores of three or more groups, and the Bonferroni–Dunn test was used as a post hoc test for significant cases. ANOVA test was used in the comparison of three or more groups in the case of normal distribution assumption. Tukey's HSD test and Dunnett's T3 tests were used for paired comparisons. Spearman correlation test was used for relationships between ordinal or continuous variables not conforming to a normal distribution, and Pearson correlation test was used for continuous variables conforming to normal distribution. Multivariate linear regression analysis with variables P < 0.1 in univariate analysis was performed to determine independent factors affecting the Mini-Mental score and MOCA total score in patients. P <0.05 were considered as statistically significant.


 > Results Top


There were 200 patients who used AIs in the adjuvant treatment. The mean age of patients was 61.3 ± 7.8 (min: 44; max: 87) years. The median follow-up time was 55.5 months. The median duration of AIs treatment was 36.5 months. The demographic and clinical characteristics of the 200 patients were given detailed in [Table 1].
Table 1: The demographic and clinical characteristics of patients

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The mean MoCA score and SMMT score were 20.1 and 24.8 points, respectively. There was no relationship between duration of treatment and MoCA and SMMT scores which indicates cognitive functions (P > 0.05). In addition, no statistically relationship was found in the evaluation of MoCA subscales (P > 0.05). The orientation, naming, short-time memory, visuospatial functions-executive functions, attention, abstract thinking, language which are the MoCA subscales, mean points were 5.9, 2.3, 1.9, 3.4, 3.6, 1.1, and 1.9 respectively. The duration of treatment with AIs and MoCA and SMMT scores of the patients were given detailed in [Table 2].
Table 2: Relationship between the duration of treatment with aromatase inhibitors and Montreal Cognitive Assessment and standardized mini-mental state examination scores

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As expected, the total MoCA and SMMT scores were affected by factors such as age, education level, and employment status. Although it was observed that the average MoCA scores of singles were higher than married patients, this difference was not statistically significant (P = 0.053). MoCA and SMMT scores were significantly associated with education level (P < 0.001). There was also a significant association between the cognitive functions and average monthly income (P = 0.005). These significant differences were also demonstrated by the comparison of SMMT scores and the results were consistent.

It was determined that the MoCA scores of the patients did not differ significantly according to the presence of diabetes mellitus, presence of coronary arterial disease, antidepressant using, cancer stage, history of chemotherapy, and history of radiotherapy. Contrary to these findings, the MoCA score was found 19.0 ± 5 points in the hypertension group. In the patient group without hypertension, it was 21 ± 4.3 points. Hence, a causal relationship between the presence of hypertension and cognitive decline was shown in our study (P = 0.004). The relationship between the MoCA total scores with the demographic and clinical characteristics of the patients was shown in [Table 3].
Table 3: The relationship between the Montreal Cognitive Assessment total scores with the demographic and clinical characteristics of the patients

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A statistically strong correlation was found between the total MoCA and SMMT scores (P < 0.001). This strong correlation was also shown between the MoCA subscales such as attention, language, visuospatial functions-executive functions, and SMMT scores.


 > Discussion Top


In our study, there was no relationship between the duration of treatment with AIs and cognitive functions (P > 0.05). In addition, no statistically relationship was found in the evaluation of MoCA subscales such as orientation, naming, short-time memory, visuospatial functions-executive functions, attention, abstract thinking, and language (P > 0.05). The data shows us that there is no apparent cumulative detrimental effect of AIs on cognitive function.

We know that AIs reduce circulating estrogen to very low levels. There are many preclinic data and animal models that evaluating the relationship between estrogen and cognitive functions. Estrogen receptors are found in many areas of the brain, especially the hippocampus, prefrontal cortex, and amygdala which are important in cognitive functions.[2],[12] The contribution of estrogen to the development of cognitive functions has been explained by several hypotheses. Brain-derived neurotrophic factor is a growth factor that increases dendritic spines and enhances memory function. Estrogens increase BDNF levels in the hippocampus thus help development of memory.[13] Similarly, it has been shown that estrogen has an effect on vascular endothelial growth factor and insulin-like growth factor-1 which are important for developing cognitive functions.[14] Animal studies were also shown that inhibition of the aromatase enzyme impairs cognitive functions. For example in one study, using a Y-maze test for short-term spatial reference memory, it was found that both male and female mices with genetic damage of the aromatase enzyme performed significantly worse than wild-type control mices.[15] For these reasons, the relationship between AIs and cognitive function has been an important subject of clinical research.

Despite the widespread use of AIs in the treatment of breast cancer, there are only a few studies on this subject. Furthermore, the results are conflicting. The first pilot study investigating the relationship between endocrine treatment and cognitive functions was made by Jenkins et al. In this study, 94 breast cancer patients who received hormonal therapy (anastrozole or tamoxifen or their combination) and 34 healthy postmenopausal women with similar demographic characteristics were compared. Verbal memory and processing speed were worse than untreated controls. However, it is not clear whether this difference was due to tamoxifen or anastrozole.[16] The International Breast Intervention Study (IBIS II) was a randomized trial which compared anastrozole with placebo in the prevention of breast cancer. In this study, cognitive functions of patients were also evaluated at the initiation of treatment, 6 and 24 months (n = 151). It was reported from the IBIS II trial that there was no significant difference between the anastrozole and placebo in all cognitive function tests.[8] The Tamoxifen and Exemestane Adjuvant Multinational trial (TEAM) was a phase 3 trial comparing exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane) in adjuvant treatment for early-stage breast cancer.[17] A neuropsychological side study was designed with the participants of TEAM study. In this study, there were 80 tamoxifen users, 99 exemestane users, and 120 healthy controls consisting of healthy female having approximately the same age as the participating TEAM patients. In comparison with the control group, there was no statistically significant effect of exemestane on cognitive functions; but tamoxifen was associated with worse verbal memory and executive function.[9] The IBIS and TEAM studies showed that there was no effect of AIs on cognitive function when compared with placebo. In our current study, it was shown with 200 patients that there was no relationship between duration of treatment and MoCA and SMMT scores which indicates cognitive functions (P > 0.05). No statistically relationship was found between the duration of AIs using and MoCA subscales (P > 0.05). Although IBIS and TEAM trials were randomized controlled studies, data from these two studies do not provide information about the cognitive effects of more than 2 years of AIs therapy. Despite our study was a cross-sectional study, more than half of our patients had received treatment for more than 3 years, so we had the chance to evaluate the long-term effects of AIs on cognitive functions. There was no difference between the 0–6-month treatment group and more than 36-month group.

Unlike the studies mentioned above; Bender et al. reported that, postmenopausal women with early-stage breast cancer who received chemotherapy plus anastrozole (n = 114) or anastrozole alone (n = 173) and a control group (n = 110) were compared for their cognitive functions. There was a significant decrease in executive functions and concentration in the AI treatment group.[7] Moreover, in the study of Collins et al., it had shown that AIs impaired cognitive functions, especially verbal memory and processing speed. This was an important prospective study about this subject, but the number of patients was very insufficient (n = 73).[6]

In another randomized study, patients who received adjuvant letrozole and tamoxifen were compared. Overall, cognitive functions were significantly better in patients taking letrozole rather than tamoxifen at 5 years.[9],[18] Considering the effect of postmenopausal adjuvant hormonal therapies on cognitive functions in breast cancer, AIs may be safer than tamoxifen.

Interestingly, despite it was not our main purpose, a causal relationship between the presence of hypertension and cognitive decline was shown in our study (P = 0.004). There are also some studies in the literature that hypertension may decline cognitive functions. In addition, studies showing that using antihypertensives prevents the development of dementia in elderly ages.[19] These findings can be interpreted as hypertension impairs cognitive functions.

One of the strongest aspects of our study is the relatively large number of patients. Secondly, the patients' cognitive functions were evaluated with two separate tests which were done by the same investigator, and a statistically strong correlation was found between the total MoCA and SMMT scores which made us think that the tests were reliable. Lack of a control group without using AIs, the cross-sectional planning, and only once time applying of the tests without baseline assessment are the limitations of our study.

As a result, despite conflicting results in the literature, the data shows that there is no apparent cumulative detrimental effect of AIs on cognitive function in postmenopausal hormone receptor-positive breast cancer patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: Patient-level meta-analysis of the randomised trials. Lancet 2015;386:1341-52.  Back to cited text no. 3
    
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Collins B, Mackenzie J, Stewart A, Bielajew C, Verma S. Cognitive effects of hormonal therapy in early stage breast cancer patients: A prospective study. Psychooncology 2009;18:811-21.  Back to cited text no. 6
    
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Bender CM, Merriman JD, Gentry AL, Ahrendt GM, Berga SL, Brufsky AM, et al. Patterns of change in cognitive function with anastrozole therapy. Cancer 2015;121:2627-36.  Back to cited text no. 7
    
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Jenkins VA, Ambroisine LM, Atkins L, Cuzick J, Howell A, Fallowfield LJ. Effects of anastrozole on cognitive performance in postmenopausal women: A randomised, double-blind chemoprevention trial (IBIS II). Lancet Oncol 2008;9:953-61.  Back to cited text no. 8
    
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Schilder CM, Seynaeve C, Beex LV, Boogerd W, Linn SC, Gundy CM, et al. Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: Results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. J Clin Oncol 2010;28:1294-300.  Back to cited text no. 9
    
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Ozdilek B, Kenangil G. Validation of the turkish version of the montreal cognitive assessment scale (MoCA-TR) in patients with parkinson's disease. Clin Neuropsychol 2014;28:333-43.  Back to cited text no. 10
    
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Ciocca DR, Roig LM. Estrogen receptors in human nontarget tissues: Biological and clinical implications. Endocr Rev 1995;16:35-62.  Back to cited text no. 12
    
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Lunie VM. Interactions between estradiol, BNDF and dentritic spines in promating memory. Neuroscience 2013;239:34-45.  Back to cited text no. 13
    
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Barouk S, Hintz T, Li P, Duffy AM, MacLusky NJ, Scharfman HE. 17β-estradiol ıncreases astrocytic vascular endothelial growth factor (VEGF) in adult female rat hippocampus. Endocrinology 2011;152:1745-51.  Back to cited text no. 14
    
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Martin S, Jones M, Simpson E, van den Buuse M. Impaired spatial reference memory in aromatase-deficient (ArKO) mice. Neuroreport 2003;14:1979-82.  Back to cited text no. 15
    
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Jenkins V, Shilling V, Fallowfield L, Howell A, Hutton S. Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psychooncology 2004;13:61-6.  Back to cited text no. 16
    
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Van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): A randomised phase 3 trial. Lancet 2011;377:321-31.  Back to cited text no. 17
    
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  [Table 1], [Table 2], [Table 3]



 

 
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