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Menopause: The Journal of The North American Menopause Society

Vol. 22, No. 1, pp. 17/25


DOI: 10.1097/gme.0000000000000271
* 2014 by The North American Menopause Society

Cognitive functioning during long-term tamoxifen treatment in


postmenopausal women with breast cancer
Florien W. Boele, MSc,1 Christina M.T. Schilder, PhD,2 Mari-Lou de Roode, MSc,3
Jan Berend Deijen, PhD,4 and Sanne B. Schagen, PhD3

Abstract
Objective: Endocrine therapy is widely usedVoften for many yearsVin women with breast cancer. Yet little is
known about cognitive functioning after long-term use of tamoxifen. We examine cognitive sequelae, approximately
3 years after diagnosis, in postmenopausal women with breast cancer who were treated with adjuvant tamoxifen.
Methods: Data from participants who underwent surgical operation with or without radiotherapy, participants
who received adjuvant tamoxifen, and healthy controls were collected. Neuropsychological tests were administered,
and participants completed questionnaires on health-related quality of life (Quality of Life Questionnaire Core 30
and Breast CancerYSpecific Quality-of-Life Questionnaire), menopausal symptoms (Functional Assessment of
Cancer TherapyVBreast endocrine symptom subscale), and anxiety and depression (Hopkins Symptom Checklist).
Results: In total, 107 women participated (adjuvant tamoxifen group, n = 20; surgical operation/radiotherapy
group, n = 43; healthy control group, n = 44). Women in the adjuvant tamoxifen group had received tamoxifen for a
mean (SD) of 31.5 (18.6) months (range, 15-79 mo) and performed worse on verbal memory than the surgical
operation/radiotherapy group (P G 0.05) and the healthy control group (P G 0.05). Participants in the adjuvant
tamoxifen group performed worse on measures of fluency than healthy controls (P G 0.05). Furthermore, women in
the adjuvant tamoxifen group reported worse cognitive functioning (P G 0.05) than women in the surgical operation/
radiotherapy group or the healthy control group.
Conclusions: Our results provide insights into cognitive functioning in women who receive long-term adjuvant
tamoxifen treatment. By adding the surgical operation/radiotherapy group, we could control for the mental and
physical influences of the diagnosis and treatment of breast cancer. Cognitive domains that rely on verbal abilities
(verbal memory and fluency) seem to be at risk for deterioration after treatment with tamoxifen.
Key Words: Tamoxifen Y Cognition Y Postmenopausal Y Breast cancer.

W
ith increased survival, cognitive functioning after inhibitors (AIs), which block the synthesis of estrogen, thus
breast cancer therapy becomes of greater importance lowering estrogen levels. These endocrine therapies may be
to the well-being of women. In postmenopausal provided in a switch schedule (initially SERMs for a number of
women, approximately 75% of breast tumors are hormone- years followed by an AI up to a total of 5-7 y of endocrine
sensitive.1 In this group of women, endocrine therapy is widely therapy).2,3 Common adverse effects of endocrine therapy,
used and often prescribed for many years. such as hot flashes and mood disturbances, are related to
Endocrine therapy aims to inhibit the growth of estrogen re- estrogen deprivation.4 Increasing evidence suggests that
ceptor (ER)Ypositive tumors by inhibiting or blocking estrogen. estrogens play a role in cognitive functioning.5 Although the
This can be achieved by administering either selective ER mechanisms of action of estrogens on the brain are not entirely
modulators (SERMs), which allow selective inhibition or stim- understood, neuroscientific studies indicate that estrogens exert
ulation of estrogen-like action in various tissues, or aromatase neurotrophic and neuroprotective actions.6 Estrogens seem to
favor differentiation and survival by acting through ERs,7 but
Received January 24, 2014; revised and accepted April 10, 2014. estrogens also act through membrane receptors to influence
From the 1Department of Medical Psychology, VU University Medical the functioning of the brain.8 These ERs are present in struc-
Center, Amsterdam, the Netherlands; 2Department of Medical Psychol- tures that are important for cognitive functioning, such as the
ogy, Medical Center Haaglanden, the Hague, the Netherlands; 3Division
of Psychosocial Research and Epidemiology, Netherlands Cancer Insti- frontal lobe and the hippocampus.9 Therefore, it is biologically
tute, Amsterdam, the Netherlands; and 4Department of Clinical Neuro- plausible that endocrine therapy could affect cognitive func-
psychology, VU University, Amsterdam, the Netherlands. tioning. Moreover, because estrogen is known to interact with
Funding/support: None. the cholinergic system,10 it seems probable that cognitive func-
Financial disclosure/conflicts of interest: None reported. tions such as attention, verbal learning, and memory may be
Address correspondence to: Florien Willemijn Boele, MSc, Department particularly vulnerable.
of Medical Psychology, VU University Medical Center, D-345, Van
der Boechorststraat 7, Amsterdam 1081 BT, the Netherlands. E-mail: Although much is already known about the cognitive effects
f.boele@vumc.nl of chemotherapy,11 many women with breast cancer receive

Menopause, Vol. 22, No. 1, 2015 17

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BOELE ET AL

either a combination of chemotherapy and endocrine therapy trozole appearing to have a negative effect on cognition com-
or adjuvant endocrine therapy alone.12 Relatively little pre- pared with tamoxifen.18,19 This was most clearly pronounced
clinical or clinical research has been performed to find out in processing speed, verbal memory,19 and visual memory.18
the specific effects of adjuvant endocrine therapy on cogni- Three years after treatment, however, one study reported that
tive functioning in women with breast cancer.12,13 Human women who received a SERM or an AI did not perform dif-
studies focusing on this topic show inconsistent associations ferently on neurocognitive tests from women who were never
between endocrine therapy and cognitive deficits in women treated with endocrine therapy.20 However, another study that
with breast cancer14 (see Table 1 for an overview). Compared with compared the cognitive effects of tamoxifen and exemestane
healthy controls, women receiving either tamoxifen (a SERM), (an AI) showed that women using tamoxifen performed worse
anastrozole (an AI), or both performed worse on measures on measures of verbal memory and executive functioning than
of immediate verbal episodic memory and complex visuomotor healthy controls, whereas exemestane users did not perform
attention15 or speeded higher brain functions (letter fluency, significantly worse on any cognitive measurement.21 Compar-
complex visuomotor attention, and speeded manual dexterity).16 ison of cognitive functioning in women with breast cancer after
Although anastrozole does not seem to have negative cognitive 5 years of tamoxifen or letrozole (an AI) yields similar results
effects on postmenopausal women at high risk for developing as the SERM seemed to have more negative effects on cogni-
breast cancer,17 the opposite has also been found, with anas- tion than the AI.22 One year after treatment completion, these

TABLE 1. Overview of studies on the cognitive effects of endocrine therapy


Duration of
tamoxifen
Study Study design Study population Control group Menopause status treatment
18
Bender et al Cross-sectional 16 Women with early-stage Women with early-stage Postmenopausal 23.8 mo,
(2007) breast cancer who breast cancer who on average
received adjuvant received adjuvant
tamoxifen anastrozole (n = 15)
Breckenridge Cross-sectional 77 Women with past or Women with breast Premenopausal and Not specified
et al20 (2012) current treatment with cancer who had no postmenopausal
tamoxifen or aromatase history of endocrine
inhibitors treatment (n = 56)
Collins et al19 Longitudinal; 31 Women receiving (1) Women with breast Postmenopausal 20 wk, on
(2009) baseline tamoxifen cancer who are average, at T2
assessment (T1) receiving anastrozole
and 5-6 mo later (T2) (n = 14)
(2) Healthy
controls (n = 28)
Jenkins et al15 Cross-sectional 94 Women receiving Healthy controls Postmenopausal Not specified;
(2004) analysis within anastrozole or tamoxifen (n = 35) 36 mo, on
the ATAC trial alone or in combination average, in
the ATAC
trial (range,
12-60 mo)
Jenkins et al17 Longitudinal 111 Women at high risk for Women at high risk Postmenopausal NA
(2008) analysis within a breast cancer who are for breast cancer
double-blind receiving anastrozole who are receiving
placebo-controlled placebo (n = 116)
trial (IBIS II)
Lejbak et al16 Cross-sectional 28 Women receiving Healthy controls Postmenopausal Minimum of
(2010) tamoxifen or anastrozole (n = 37) 1 y (range,
12-56 mo)
Phillips et al22 Cross-sectional 55 Women receiving Women with breast Postmenopausal Within year 5
(2010) analyses within tamoxifen or cancer who are of endocrine
a prospective letrozole (2 y) receiving letrozole treatment
randomized study followed by or tamoxifen (2 y)
(BIG 1-98 trial) tamoxifen (3 y) followed by letrozole
(3 y) (n = 65)
21
Schilder et al Longitudinal analyses 80 Women with breast (1) Women with Postmenopausal Up to 1 y
(2010) within a prospective cancer who have breast cancer who
randomized study received tamoxifen are receiving
(TEAM trial) for 2.5-3 y then exemestane (n = 99)
exemestane for 2-2.5 y (2) Healthy controls
(n = 120)
ATAC, Arimidex, Tamoxifen, Alone or in Combination; IBIS II, International Breast Cancer Intervention Study II; NA, not applicable; BIG 1-98, Breast
International Group 1-98; TEAM, Tamoxifen Exemestane Adjuvant Multinational.

18 Menopause, Vol. 22, No. 1, 2015 * 2014 The North American Menopause Society

Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
COGNITION IN BREAST CANCER PATIENTS ON SERMS

women exhibited a significant improvement in cognitive func- METHODS


tioning,23 suggesting that these negative effects may be re- Participants
versible in nature. Eligible participantsVwomen who had undergone surgical
A possible explanation for the inconsistent findings from operation with or without radiotherapy and adjuvant tamoxifen
these studies is that they differed in the timing of cognitive (AT group) or women who had undergone only surgical oper-
testing (during use of endocrine therapy,15,16,19,21,22 after treat- ation with or without radiotherapy (SR group)Vwere selected
ment,23 or mixed20), age of the participants, and hormone by inspecting the medical records of women who were treated
status of the participants (postmenopausal16,19,21<23 or both pre- for breast cancer in the Netherlands Cancer Institute (Amsterdam,
menopausal and postmenopausal20). In addition, two studies the Netherlands). With the consent of their surgeon, we invited
did not make a distinction between SERMs and AIs15,20 despite these women (by letter) to participate in this study. Data from a
these pharmaceuticals having different working mechanisms group of healthy controls had been collected previously during
that may affect cognitive performance differently. our study on the cognitive effects of endocrine therapy.21 These
A major limitation of the studies described above is that, in controls were friends or family members of participants. From
most studies, only the study groups and a group of healthy this large group, a subset of healthy controls (healthy control group
controls were compared. This does not enable them to control [HC group]), matched to both the AT group and the SR group for
for the influence of the diagnosis of cancer and subsequent age and educational level, was selected. The following inclusion
anxiety, depression, or fatigue on cognitive functioning. Fur- criteria had to be met by all participants in the breast cancer
thermore, the cognitive effects of endocrine therapy after long- groups: histologically or cytologically confirmed breast cancer,
term use are still mostly unknown. In the present cross-sectional previous treatment with curative intent, and postmenopause
study, we compare the cognitive performance of postmeno- status. In addition, participants in the AT group had to be on
pausal women with breast cancer who underwent surgical tamoxifen treatment currently and to have received tamoxifen
operation and/or radiotherapy with the cognitive performance for at least 12 months without a switch in endocrine therapy.
of women who also received adjuvant endocrine therapy Women were excluded if they (1) had received adjuvant chemo-
(tamoxifen) and a group of healthy matched individuals. This therapy; (2) had been diagnosed as having a psychiatric illness
enables us to tell apart the effects of tamoxifen treatment and or a central nervous system disease whose effect on cognitive
the effects of being diagnosed as having breast cancer, followed functioning is known; (3) were not fluent in Dutch; and (4)
by surgical operation and/or radiotherapy. Approximately 3 years had signs of dementia according to a dementia screening tool
after the diagnosis of breast cancer, cognitive performance was (7-min screen24). For healthy controls, the exclusion criteria
evaluated to examine the long-term (91 y) consequences of were the same plus no history of breast cancer. All participants
the treatments. In line with the existing literature, we hypo- signed a written informed consent form and were not compen-
thesized that the adjuvant tamoxifen group (AT group) would sated for participation.
perform worse than the surgical operation/radiotherapy group
(SR group) and the healthy controls on measures of verbal Outcome measures
memory and executive functioning. In addition, we investi- Cognitive functioning was assessed using a battery of neu-
gated how cognitive functioning and self-reported measures ropsychological tests25<33 (Table 2). In addition to the tests re-
of various aspects of well-being were associated. ported in Table 2, a measure of premorbid intelligence was

TABLE 2. Cognitive domains and their content plus z-scores corrected for age and estimated premorbid IQ
AT group SR group HC group
Domain Content (n = 20) (n = 43) (n = 44) P ¯G2
a
Verbal memory Rey auditory verbal learning test j0.493 (0.66) j0.006 (0.63) j0.001 (0.81) 0.009 0.090
(total score, delayed recall)20
Visual association test (total score)21
Visual memory Visual memory subtest (WMS; 0.136 (0.80) j0.247 (1.09) 0.000 (0.95) 0.339 0.022
immediate recall, delayed recall)22
Working memory Letter-number sequencing (WAIS III)23 j0.144 (0.82) 0.083 (1.06) 0.001 (1.00) 0.965 0.001
Executive functioning Stroop (card 3),24 trailmaking (part B)25 j0.099 (0.92) 0.067 (0.93) 0.000 (0.88) 0.444 0.016
Processing speed Stroop (cards 1 and 2),24 trailmaking j0.055 (0.65) j0.009 (0.82) 0.000 (0.79) 0.554 0.012
(part A)25
Reaction speed Fepsy reaction times (dominant hand, 0.238 (0.79) j0.123 (1.07) 0.000 (0.91) 0.529 0.013
nondominant hand)26
Fluency Category fluency (animals, professions),27 j0.414 (0.78) j0.308 (0.70) 0.000 (0.88) 0.012 a
0.085
letter fluency (D, A, T)28
Motor functioning Fepsy tapping (dominant hand, 0.288 (0.70) 0.144 (0.84) 0.000 (0.96) 0.667 0.007
nondominant hand)26
Data are presented as mean (SD).
AT, adjuvant tamoxifen; SR, surgical operation/radiotherapy; HC, healthy control; WMS, Wechsler Memory Scale; WAIS III, Wechsler Adult Intelligence
Scale III.
a
P G 0.05.

Menopause, Vol. 22, No. 1, 2015 19

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BOELE ET AL

administered (Dutch Adult Reading Test32) so that we could the three groups were compared using univariate analysis of
correct for this in the analyses. All tests are widely used in variance (ANOVA) and W2 test. ANOVA and W2 test were
clinical practice and were selected because of their reliability also used to examine between-group differences in self-reported
and validity, availability of normative data, and their suit- cognitive complaints, QLQ-C30 and Breast CancerYSpecific
ability for older age groups. Neuropsychological assessments Quality-of-Life Questionnaire scales, anxiety and depression,
were performed by a trained test assistant or by students who and menopausal symptoms.
were in the final phase of the master’s program in clinical Neuropsychological test scores were transformed into z-scores
neuropsychology (F.W.B. and M.-L.d.R.), who were super- using the means (SDs) of healthy controls, and cognitive do-
vised by a board-certified neuropsychologist (C.M.T.S.). mains (Table 2) were created for the purpose of data reduction.
The European Organization for Research and Treatment of Higher scores indicate better performance in all domains. Mul-
Cancer Quality of Life Questionnaire Core 30 (QLQ-C30)34 tivariate ANOVA (MANOVA) across cognitive domains was
was used to assess health-related quality of life (HRQOL). The performed to compare cognitive functioning between groups.
questionnaire can be divided into five function scales (physical, Follow-up ANOVA was conducted to determine the differences
role, cognitive, emotional, and social functioning), nine symp- between the groups. Although differences in age and estimated
tom scales (fatigue, pain, nausea and vomiting, dyspnea, insom- premorbid IQ were not statistically significant, both MANOVA
nia, appetite loss, constipation, diarrhea, and financial impact), and ANOVA were corrected for age and estimated premorbid
and a scale for overall quality of life. Items were rated on a IQ because these are strong predictors of neuropsychological
four-point scale. Higher scores on the functional scales indi- test performance. A two-sided P value less than 0.05 was con-
cate better functioning, whereas higher scores on the symp- sidered to be significant. Effect sizes were calculated as ¯G2.
tom scales indicate more impediments of symptoms. To examine the associations between cognitive functioning
A shortened 18-item version of the European Organization and self-reported measures of cognitive functioning, fatigue,
for Research and Treatment of Cancer Breast CancerYSpecific pain, sleep disturbances, global HRQOL, anxiety, depression,
Quality-of-Life Questionnaire35 was used to assess the impact and menopausal symptoms, we calculated Pearson’s correla-
of breast cancer and its treatment on women’s well-being. The tions for the three groups combined. Corrections were sepa-
shortened questionnaire consists of a functioning scale (body rately applied for the eight cognitive outcome measures and
image, sexuality, and future perspective) and single items to the eight self-reported outcomes (dividing 0.05 by 8) to ad-
investigate arm and breast symptoms. All items were rated on just for multiple testing. Here, two-sided P values less than
a four-point scale. Higher scores on the functional scale indi- 0.0063 were required for statistical significance.
cate better functioning, whereas higher scores on the symptom
scale indicate more symptoms being present.
The 18-item Functional Assessment of Cancer TherapyV RESULTS
Breast endocrine symptom subscale36 was used to assess meno- Participant characteristics
pausal symptoms. Women rated the items on a five-point scale. Fifty-one women diagnosed as having breast cancer between
Higher scores indicate better functioning. 2003 and 2009 were invited to participate in the AT group.
To measure symptoms of depression and anxiety, we used Twenty women (39.2%) declined to participate, whereas others
the 25-item Hopkins Symptom Checklist.37 The questionnaire could not be contacted or resided abroad (n = 11; 21.6%). Those
is divided into two subscales (Banxiety[ and Bdepression[) and who declined participation stated that they expected participa-
a Btotal[ scale. Items were rated on a four-point scale. Higher tion to be too burdensome (n = 11) or that they were too busy
scores indicate more impediments of symptoms. The cutoff point (n = 9). Twenty women (39.2%) were included in the AT group,
for Bpossibly depressive cases[ was set at a mean item score 13 (65%) of whom had also undergone radiotherapy and
equal to or greater than 1.55.37 19 (95%) of whom had also undergone surgical operation.
For the SR group, 74 women diagnosed between 2007 and
Procedure
2008 were invited to participate. Thirteen women (17.6%) de-
Assessments took place either at the participant’s home or
clined to participate. Others could not be contacted (n = 5;
at the Netherlands Cancer Institute. All participants provided
6.8%), had health issues (n = 5; 6.8%), or reported other (or no)
detailed information about their background and medical his-
reasons for nonparticipation (n = 8; 10.8%). Those who declined
tory during a structured interview. In approximately 2 hours,
participation stated that they expected participation to be too
the questionnaires and neuropsychological tests were admin-
burdensome (n = 5), were too busy (n = 5), or were not in-
istered in fixed order.
terested (n = 3). In total, 43 women (58.1%) were included in
Statistical analysis the SR group.
All statistical analyses were performed with the Statistical For the HC group, 44 women were selected to match the
Package for Social Science version 17.0. Standard scoring breast cancer groups for age and educational level. We do not
rules were used to convert the data from the questionnaires. have full information on the participation rates of healthy con-
The demographic characteristics (age, estimated IQ, educa- trols because these women were first invited to participate by
tional level, marital status, presence or absence of children, participants and could only afterward be contacted by the re-
time since diagnosis, and antitumor treatment received) of searchers. Table 3 shows the background characteristics of

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COGNITION IN BREAST CANCER PATIENTS ON SERMS

TABLE 3. Demographic characteristics of the three groups


Adjuvant tamoxifen Surgical operation/radiotherapy Healthy control
group (n = 20) group (n = 43) group (n = 44) P
Age, mean (SD), y 61.60 (6.14) 62.16 (7.99) 62.02 (6.32) 0.957
Age at menopause, mean (SD), y 48.71 (3.98) 48.77 (4.41) 47.70 (7.25) 0.657
Estimated premorbid IQ, mean (SD) 105.95 (14.79)a 104.67 (9.81) 103.25 (14.64) 0.729
Level of education, n (%) 0.401
Low 1 (5.0) 6 (14.0) 6 (13.6)
Middle 9 (45.0) 20 (46.5) 26 (59.1)
High 10 (50.0) 17 (39.5) 12 (27.3)
Marital status, n (%) 0.017b
Single 3 (15.0) 2 (4.6) 3 (6.8)
Married/living together 11 (55.0) 23 (53.5) 33 (75.0)
Divorced 0 (0.0) 10 (23.3) 1 (2.3)
Widow 5 (25.0) 8 (18.6) 6 (13.6)
In a relationship, not living together 1 (5.0) 0 (0.0) 1 (2.3)
Children, n (%) 0.105
Yes 14 (70.0) 36 (83.7) 40 (90.9)
No 6 (30.0) 7 (16.3) 4 (9.1)
Comorbidities, n (%)
Contusion or whiplash (ever) 0.291
Yes 1 (5) 7 (16.3) 9 (20.5)
No 19 (95) 36 (83.7) 35 (79.5)
Cerebrovascular accident (ever) 1.000
Yes 0 (0) 0 (0) 0 (0)
No 20 (100) 43 (100) 44 (100)
Transient ischemic attack (ever) 0.353
Yes 1 (5) 0 (0) 2 (4.5)
No 19 (95) 43 (100) 42 (95.5)
Diabetes mellitus 0.147
Yes 2 (10) 0 (0) 3 (6.8)
No 18 (90) 43 (100) 41 (93.2)
High blood pressure 0.238
Yes 3 (15) 11 (25.6) 14 (31.8)
No 17 (85) 32 (74.4) 30 (68.2)
Other chronic illnessc 0.107
Yes 8 (40) 20 (46.5) 11 (25)
No 12 (60) 23 (53.5) 33 (75)
Time since diagnosis, mean (SD) [range], mo 38.8 (22.9) [18-84] 33.2 (3.2) [28-39] NA 0.119
Antitumor treatment
Tamoxifen, mean (SD) [range], mo 31.5 (18.6) [15-79] NA NA NA
Radiotherapy, n (%) 13 (65) 28 (65.1) NA 0.604
Surgical operation, n (%) 19 (95) 43 (100) NA 0.317
Ever use of hormone therapy (estrogen/progesterone), n (%) 3 (15)d 8 (18.6) 11 (25) 0.603
NA, not applicable.
a
Data from one participant missing.
b
P G 0.05.
c
Chronic illnesses reported: thyroid deficiency (n = 11), high cholesterol (n = 4), arthrosis (n = 5), osteoporosis (n = 3), arthritis (n = 1), asthma/bronchitis/atypical
lung bacteria (n = 4), Crohn’s disease (n = 2), decreased kidney function (n = 1), arrhythmia (n = 1), mood disorder (n = 3), multiple sclerosis (n = 1),
polyneuropathy (without medication; n = 1), presumed cataract (n = 1), carpal tunnel syndrome (n = 1), and rosatia (n = 1).
d
Data from three participants missing.

all participants. For most of the demographic and clinical Self-reported cognitive functioning
variables, no significant differences were found between MANOVA revealed a significant difference in the cogni-
the groups. tive functioning scale of the QLQ-C30 (P G 0.05; Table 4).
Post hoc tests revealed that the AT group reported worse levels
of cognitive functioning than both the SR group (P G 0.05) and
Cognitive functioning
healthy controls (P G 0.05).
Differences in cognitive functioning were found for the ver-
bal memory domain (P G 0.05) and the fluency domain (P G 0.05;
Table 2). Subsequent analyses revealed that women in the AT HRQOL, anxiety and depression, impact of breast cancer,
group performed worse on the verbal memory domain than and menopausal symptoms
women in the SR group (P G 0.05) and participants in the HC Table 4 shows between-group comparisons for HRQOL,
group (P G 0.05). For the fluency domain, the AT group only anxiety and depression, impact of breast cancer on women’s
performed significantly worse than the HC group (P G 0.05). well-being, and menopausal symptoms. The groups did not
No other statistically significant differences were found. differ on most measures such as fatigue, pain, anxiety, and

Menopause, Vol. 22, No. 1, 2015 21

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BOELE ET AL

TABLE 4. Scores on the QLQ-C30 and BR23 scales, scores on the HSCL depression and anxiety scales, and total FACT-B ES score
Surgical operation/
Adjuvant tamoxifen group (n = 20) radiotherapy group (n = 43) Healthy control group (n = 44) P
QLQ-C30
Functional scales
Physical functioning 89.67 (9.30) 86.05 (14.61) 87.42 (15.10) 0.633
Role functioning 89.17 (18.16) 90.31 (20.00) 87.88 (21.68) 0.857
Cognitive functioning 75.00 (26.77) 88.37 (15.66) 90.15 (14.07) 0.006a
Emotional functioning 76.67 (25.16) 81.98 (20.00) 84.85 (18.79) 0.340
Social functioning 88.33 (20.30) 89.53 (22.43) 90.91 (17.41) 0.884
Global HRQOL 87.08 (13.91) 82.17 (16.02) 84.09 (15.23) 0.495
Symptom scales
Fatigue 26.67 (20.20) 23.51 (18.66) 17.42 (14.05) 0.094
Nausea and vomiting 3.33 (6.84) 1.94 (6.52) 3.03 (8.26) 0.707
Pain 19.17 (21.81) 17.83 (23.40) 21.21 (27.22) 0.816
Dyspnea 5.00 (12.21) 12.40 (19.27) 6.82 (13.60) 0.139
Sleep disturbance 30.00 (30.40) 26.36 (26.78) 20.45 (28.95) 0.404
Appetite loss 1.67 (7.45) 3.10 (9.80) 2.27 (8.50) 0.818
Constipation 11.67 (19.57) 2.32 (8.59) 6.06 (14.86) 0.047a
Diarrhea 3.33 (10.26) 2.33 (8.59) 1.52 (7.02) 0.714
Financial impact 1.67 (7.45) 5.43 (16.15) 1.52 (7.02) 0.248
BR23
Body image 86.25 (17.79) 16.11 (21.77) NA 0.858
Arm symptoms 16.11 (21.77) 12.40 (16.66) NA 0.460
Breast symptoms 17.92 (21.51) 15.31 (13.96) NA 0.566
HSCL
Anxiety 11.17 (10.39) 13.57 (11.74) 9.92 (10.55) 0.303
Depression 12.89 (8.40) 15.46 (15.82) 11.92 (10.97) 0.425
Total (cutoff at 91.55) 1.34 (0.24) 1.44 (0.39) 1.33 (0.30) 0.310
FACT-B ES 59.21 (8.98) 61.52 (5.94) 62.28 (7.05) 0.271
Data are presented as mean (SD).
P values for multivariate analysis of variance are given.
QLQ-C30, Quality of Life Questionnaire Core 30; BR23, Breast CancerYSpecific Quality-of-Life Questionnaire; HSCL, Hopkins Symptom Checklist; FACT-B
ES, Functional Assessment of Cancer TherapyVBreast endocrine symptom subscale; HRQOL, health-related quality of life.
a
P G 0.05.

depression (all P 9 0.05). A difference was observed on dergoing adjuvant tamoxifen treatment seem to score worse
the constipation scale (P G 0.05). on measures of verbal memory than women with breast can-
cer who were only treated with surgical operation and/or radio-
Associations between cognitive functioning, self-reported therapy and healthy controls. These findings could be indicative
cognitive functioning, global HRQOL, fatigue, pain, of an association between long-term use of tamoxifen and a
sleep disturbances, anxiety and depression, and decrease in verbal memory abilities. Although we did not find
menopausal symptoms differences in the performance on tests considered to be part
In the cognitive domains, significant positive correlations of the executive functioning domain, breast cancer patients
of moderate strength were found between processing speed on tamoxifen scored worse than healthy controls on measures
and global HRQOL (r = 0.30, P G 0.05) and between reaction of verbal fluency, which are often considered to be part of
speed and global HRQOL (r = 0.39, P G 0.05), indicating that executive functioning. The association between verbal flu-
higher scores on the processing speed and reaction speed do- ency and tamoxifen use per se seems less straightforward in
mains are associated with better self-reported global HRQOL. our sample because participants in the AT group had worse
Negative associations of moderate strength were found between fluency scores than healthy controls, but not when compared
processing speed and anxiety (r = j0.31, P G 0.05), and both with cancer controls (SR group).
processing speed and executive functioning were negatively As previous studies showed similar results,15,21 the present
associated with depression (r = j0.30, P G 0.05 and r = j0.30, results add further support to the notion that estrogen espe-
P G 0.05, respectively). Worse performance on the processing cially influences verbal learning and memory. In addition, the
speed and executive functioning domains was related to more literature shows that both premenopausal and postmenopausal
complaints of depression and anxiety. No other significant cor- women with breast cancer who were treated with chemother-
relations were found between the cognitive domains and the apy performed worse on measures of processing speed and
self-reported measures (Table 5). verbal ability than women with breast cancer who were not
treated with chemotherapy and healthy controls.38 Most of
DISCUSSION the women in the chemotherapy group had also received ta-
Consistent with our hypothesis, the present study indicates moxifen, suggesting a combined effect of chemotherapy and
that postmenopausal women with breast cancer who are un- tamoxifenVa notion supported by earlier studies.39,40 However,

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COGNITION IN BREAST CANCER PATIENTS ON SERMS

TABLE 5. Associations between scores on the cognitive domains and self-reported measures of cognitive functioning, quality of life, fatigue,
pain, sleep disturbances, anxiety, depression, and menopausal symptoms
Global quality Self-reported Sleep Menopausal
of life cognitive functioning Fatigue Pain disturbances Anxiety Depression symptoms
Verbal memory
r 0.141 0.012 j0.138 j0.070 j0.145 0.009 j0.141 j0.093
P 0.146 0.905 0.156 0.471 0.136 0.926 0.147 0.343
Visual memory
r 0.151 j0.031 j0.098 j0.200 j0.167 j0.072 j0.249 0.021
P 0.120 0.751 0.371 0.086 0.086 0.460 0.010 0.832
Working memory
r 0.177 0.078 0.017 j0.160 0.059 j0.178 j0.093 0.104
P 0.068 0.424 0.861 0.099 0.547 0.067 0.340 0.287
Executive functioning
r 0.255 j0.037 j0.079 j0.251 j0.034 j0.156 j0.299 0.037
P 0.008 0.706 0.422 0.027 0.726 0.109 0.002a 0.705
Processing speed
r 0.304 0.173 j0.123 j0.145 j0.092 j0.313 j0.296 j0.013
P 0.001a 0.075 0.205 0.136 0.344 0.001a 0.002a 0.896
Reaction speed
r 0.386 0.007 j0.253 j0.249 0.023 j0.085 j0.176 0.155
P G0.001a 0.939 0.009 0.010 0.816 0.383 0.069 0.110
Fluency
r 0.175 0.114 j0.121 j0.093 j0.010 j0.145 j0.227 0.089
P 0.073 0.243 0.218 0.340 0.915 0.139 0.019 0.362
Motor functioning
r 0.216 j0.022 j0.074 0.077 0.045 j0.042 j0.219 j0.079
P 0.026 0.818 0.449 0.432 0.644 0.668 0.024 0.421
a
P G 0.0063.

as these studies were not adequately powered to investigate the cancer on women’s well-being, and menopausal symptoms.
cognitive effects of endocrine therapy specifically, the results of Because we included the SR group to control for the influence
these studies should be interpreted with caution. of the diagnosis of cancer and subsequent anxiety, depression, or
Interestingly, in the Cognition in the Study of Tamoxifen fatigue on cognitive functioning, some degree of difference from
and Raloxifene (CoSTAR) trial, tamoxifenVcompared with the healthy participants could be expected. An explanation for
raloxifene (a SERM)Vdid not have negative cognitive effects this lack of difference is that we included participants with a
on healthy women older than 65 years who were at increased long interval between the initial diagnosis and primary local
risk for breast cancer.41 This may suggest that women with breast treatment, providing the women time to psychologically pro-
cancer who are treated with adjuvant therapy are at increased risk cess their situation. However, as 6.8% of women invited for
for decline in cognitive functioning. However, our participants the SR group and 21.6% of women invited for the AT group
with breast cancer were, on average, younger (mean, 62 vs 70 y) declined participation because they expected participation to
and had probably been postmenopausal for a shorter period be too burdensome, a response bias cannot be excluded.
than participants in the CoSTAR trial. Moreover, lifetime Subsequently, we examined possible associations between
exposure to estrogens may differ between study samples. The self-perceived and tested cognitive functioning and several
lack of placebo conditions in the CoSTAR trial, combined cancer-related self-reported outcomes such as fatigue, pain,
with an incomplete baseline assessment of cognition, makes and distress of the three groups combined. Positive associa-
comparison even harder. Because SERMs act differently in the tions of moderate strength were found between the processing
presence or absence of estrogens,12 obtaining as much inform- speed and reaction speed domains and global HRQOL, indi-
ation as possible on the endocrine profile of participants in cating that higher scores on these domains are related to better
tamoxifen trials could help interpret the seemingly contradicting overall quality of life. Fewer symptoms of anxiety and depres-
study outcomes. sion are also related to better processing speed scores, as well
More self-perceived difficulty in cognitive functioning, as as better executive functioning in the case of less depressive
measured by a QLQ-C30 scale, are reported by women treated symptoms. Processing speed and reaction speed are in particular
with adjuvant tamoxifen than by either women treated only domains that are easily influenced by motivation, as the scores
with surgical operation and/or radiotherapy or healthy par- rely on the time taken to complete the task. One can argue that
ticipants. This was not directly reflected by an association participants who feel worse mentally might also put in less
with any of the cognitive domain scores. Previous studies have effort on these cognitive assessments. Our study groups were
already observed that self-reported complaints do not neces- not statistically different in global HRQOL, anxiety, and depres-
sarily match with measurable cognitive deficits,42,43 a statement sion. Thus, our results for differences in cognitive functioning
that is supported by our findings. are probably only minimally influenced by these factors. These
We found no statistically significant between-group dif- findings suggest that it is important to continue assessing
ferences in HRQOL, anxiety and depression, impact of breast mental health when interpreting the results of cognitive tests.

Menopause, Vol. 22, No. 1, 2015 23

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BOELE ET AL

The present study has its limitations. To examine cognitive knowledge on the long-term cognitive effects of endocrine treat-
functioning after solely long-term use of tamoxifen, we were ments and the causal relationships between cognitive sequelae
quite strict with our inclusion criteria for the AT group. This of endocrine treatments, we highly recommend that future
resulted in a relatively small AT group of 20 women. In ad- studies incorporate a longitudinal study design.
dition, because we used a cross-sectional research design, we
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