Cognitive effects of hormonal therapy in early stage breast cancer patients: a prospective study

Psycho-OncologyPsycho-Oncology 18: 811–821 (2009)Published online 10 December 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pon.1453

Cognitive effects of hormonal therapy in early stagebreast cancer patients: a prospective study

Barbara Collins1�, Joyce Mackenzie1, Angela Stewart2, Catherine Bielajew2 and Shailendra Verma3

1The Ottawa Hospital—Civic Campus, Ottawa, Ont., Canada2University of Ottawa, School of Psychology, Ottawa, Ont., Canada3The Ottawa Hospital Regional Cancer Centre, Ottawa, Ont., Canada

Abstract

Objective: The primary purpose of this study was to evaluate the cognitive effects of adjuvant

hormonal therapies in breast cancer patients.

Participants and Methods: Post-menopausal breast cancer patients scheduled to receive

tamoxifen (n5 31) or anastrozole (n5 14) completed neuropsychological testing around the

time of commencement of treatment (T1), and again 5–6 months later (T2). A sample of

healthy female volunteers (n5 28) was tested at comparable intervals. A standardized

regression-based approach was used to assess cognitive change. This method uses test/retest

scores of the healthy control group to generate an equation that predicts T2 scores from

T1 scores. The difference between the predicted and obtained T2 scores divided by the

standard error of the estimate produces a deviation score that reflects the discrepancy

from the T1–T2 difference scores that would be expected on the basis of practice and error

alone.

Results: Analysis of individual deviation scores revealed that both the patients taking

tamoxifen and those taking anastrozole were more likely than healthy controls to show reliable

cognitive decline from T1 to T2 (39, 64, and 7%, respectively). Processing speed and verbal

memory were the cognitive domains most affected.

Conclusion: These data suggest that hormonal therapies exert a subtle negative influence on

cognition in breast cancer patients. Further analyses indicated that this effect was not fully

accounted for by demographic factors or fatigue. Methodological limitations of the current

study are addressed, along with recommendations for future studies in this area.

Copyright r 2008 John Wiley & Sons, Ltd.

Keywords: breast cancer; adjuvant hormonal therapy; cognition; tamoxifen; anastrozole

Introduction

The overall 5-year survival rate in breast cancerpatients now approaches 90% [1] due, in large part,to advances in adjuvant treatment. However, thesame adjuvant treatments that prolong survival canhave long-term adverse effects that detract fromquality of life.Many breast cancer patients complain of cogni-

tive changes during and after cancer treatment,which can interfere with social, educational, andoccupational function [2]. These complaints havebeen corroborated by numerous studies demon-strating neuropsychological disturbances inpatients exposed to adjuvant treatments [3–19].Patients and researchers alike have tended toattribute these cognitive changes to chemotherapy;in fact, in patient circles, this phenomenon isreferred to as chemo fog or chemo brain. However,some 60% of breast cancers are estrogen receptor

positive (such that exposure to estrogen promotestheir development and growth) [20], and soadjuvant treatment more often than not includesanti-estrogen (hormonal) therapy, with or withoutchemotherapy. Taken for 5 years, these agentsreduce the annual breast cancer death rate by 30%or more [21]. There is convincing evidence thatestrogen has both organizational and activationaleffects in the brain [22–25] and exerts a variety ofneurotropic and neuroprotective influences[22,24,26–28]. This begs the question of the roleof hormonal therapies in the cognitive perturba-tions reported by and observed in breast cancerpatients.

Paganini-Hill & Clark [29] were among the firstto report that adjuvant hormonal treatment mightexert negative effects on cognitive function inbreast cancer patients. They found that patientswho had used tamoxifen for 5 years were morelikely than never-users to report having seen their

* Correspondence to: TheOttawa Hospital, CivicCampus, 1053 Carling Ave.,Room A603, Ottawa, Ont.,Canada K1Y 4E9. E-mail:[email protected]

Received: 22 April 2008

Revised: 5 August 2008

Accepted: 8 August 2008

Copyright r 2008 John Wiley & Sons, Ltd.

physician for memory problems, and that currenttamoxifen users had lower mean complexity scoresthan non-users on a narrative writing task. Therehave since been other indications that tamoxifenmay have adverse cognitive effects. In their meta-analysis of studies of cognitive function in breastcancer patients, Falleti et al. [30] found that thegeneral effect size at the study level was directlyrelated to the proportion of the chemotherapysample taking tamoxifen at the time of assessment,and both Bender et al. [4] and Castellon et al. [6]found that breast cancer patients who receivedchemotherapy plus tamoxifen exhibited greatercognitive compromise than did women who re-ceived chemotherapy alone. Eberling et al. [31]reported that tamoxifen-treated post-menopausalbreast cancer patients had significantly lowersemantic memory scores, smaller right hippocampi,and widespread hypometabolism in the inferiorand dorsal lateral frontal lobes on PET scanningrelative to healthy women. Preliminary evidencefrom the ATAC trial, a double blind randomizedcontrolled comparison of anastrozole andtamoxifen alone or in combination in the treat-ment of early breast cancer, indicates cognitivecompromise in patients receiving hormonal treat-ments compared to non-cancer control subjects[32,33].In our recent prospective study in breast cancer

patients [7], we found that the women who receivedchemotherapy and hormonal treatment scoredsignificantly lower than the women who receivedchemotherapy alone on separate compositemeasures of processing speed and verbal memory.This finding is consistent with previous reportsthat estrogen levels and HRT are specificallyassociated with verbal learning and memoryfunctions in healthy post-menopausal women[27,34–38], and with preliminary results fromthe ATAC trial indicating that adjuvanthormonal therapies in breast cancer patientsprimarily affect verbal memory and processingspeed [32,33].At the same time, several other studies in breast

cancer patients have failed to find any effectof hormonal therapy on cognitive function[3,10–11,15,39], and the state of knowledge in thisarea is best described as very uncertain. Giventhe long-term nature of adjuvant hormonal therapyin breast cancer patients (up to 5 years), theincreasing use of agents (such as aromataseinhibitors) that can deplete estrogen by 95% ormore, and the fact that cognitive function hasimportant implications for quality of life, it isessential that we advance our understanding of thecognitive impact of these hormonal therapies.Toward this end, we examined change in neurop-sychological function in early-stage ER-positivebreast cancer patients over a 5- to 6-month periodof hormonal treatment.

Method

This study was an unplanned extension of anearlier study concerning the cognitive effects ofchemotherapy [7,14].

Participants

The current analyses included three groups ofwomen. Two of these groups comprised early stageER-positive breast cancer patients who wererecruited at the Ottawa Hospital Cancer Centerin Canada between February 2002 and March 2005to serve as control subjects in our initial che-motherapy study. These women were treated witheither tamoxifen (n5 31) or anastrozole (n5 14)without adjuvant chemotherapy. The study wasintroduced to these patients by their treatingoncologist and we consecutively enrolled allpatients who met pre-screening criteria and whoconsented to participate. For the current analyses,a group of healthy women (n5 28) served ascontrols. They were primarily recruited by meansof a newspaper advertisement that appeared insummer 2005.For all groups, we included only post-menopau-

sal women between the ages of 50 and 65 in orderto reduce variability in cognitive function asso-ciated with age [40] and circulating estrogen levels[31], and because adjuvant endocrine therapy isgiven primarily to post-menopausal women. Parti-cipants were required to have a minimum grade-8education and to be fluent in English, and wereexcluded if they had a previous history of cancer orchemotherapy, or unstable psychiatric, neurologi-cal, or substance use disorders that might affectcognition. Additional exclusion criteria for thepatient groups were advanced disease (distantmetastasis) and exposure to neo-adjuvant therapy.The study was approved by the ethics board of TheOttawa Hospital, and written informed consentwas obtained from all participants.

Assessment

Within the patient groups, baseline assessment (T1)comprising clinical history, neuropsychologicaltesting, and completion of a mood-rating scalewas conducted after surgery, closely coincidingwith initiation of hormonal therapy in most cases.A second assessment (T2) was conducted 5–6months after T1 in all groups. Almost three-quarters of the patients received radiation betweenT1 and T2. See Table 1 for timing and duration oftreatment relative to testing. Women were given thechoice of being assessed at the hospital or in theirhomes. Most opted to be seen at home. Assess-ments were conducted by psychometrists with aminimum of master’s level training in clinical

Copyright r 2008 John Wiley & Sons, Ltd. Psycho-Oncology 18: 811–821 (2009)

DOI. 10.1002/pon

812 B. Collins et al.

psychology under the supervision of a licensedneuropsychologist.We used a battery of 18 neuropsychological

tests, yielding 23 measures and covering all majorrecognized cognitive domains. The neuropsycholo-gical tests, organized according to the cognitivedomain they represent, are described in Table 2.Tests were administered in the same order atall testing sessions. In addition, we used theQuick Test [52], a measure of receptive vocabulary,to estimate pre-morbid intellectual function,and the Profile of Mood States (POMS) [53]to assess depressive symptoms, anxiety, andfatigue.

Data analysis

The Statistical Package for the Social Sciences(version 15.0) was used for all data analyses. Alphawas set at 0.05 for all statistical tests.As it has been repeatedly shown that only a

subgroup of patients experience cognitive effects ofcancer therapy, we used a standardized regression-based (SRB) approach to identify cognitive changeat the individual level [54,55]. First, the test/retestscores of the women in the healthy control groupwere used to develop a regression equationpredicting T2 scores from T1 scores. Using thisequation, a score was predicted for each subject onevery neuropsychological measure. Age, education,and T1 Quick Test score, as well as change from T1to T2 on POMS depression, tension–anxiety, andfatigue scores, were included as covariates inpredicting T2 scores where indicated (i.e. if theypredicted T1–T2 change in that same neuropsy-chological measure in a preliminary stepwiseregression including all of the candidate covariatesand pooling participants from all groups). An SRBscore was then obtained for each subject on each

neuropsychological variable by subtracting herpredicted T2 score from her actual T2 score on agiven cognitive measure, and dividing by thestandard error of estimate of the model in thecontrol group. The resultant SRB scores reflect theextent to which the observed change on eachneuropsychological measure deviated from thechange that would be expected on the basis ofpractice and error alone. The SRB scores areexpressed in standard deviation units and reflectthe direction and magnitude of deviation.Although other methods of assessing individualchange over time have been employed in thisresearch domain (such as reliable change indexes),the SRB approach is preferred in that it allows theinclusion of moderator variables, accounts forregression-to-the-mean, and permits comparisonsacross measures [56].It should be noted that, even if an individual’s

raw score on a given test actually improved fromT1 to T2, the SRB score would be negative if theretest score did not improve to the extent predicted.We considered an individual subject to have shownreliable overall cognitive decline if she had two ormore SRB scores of �2.0 or less, and to haveshown reliable cognitive improvement if she hadtwo or more SRB scores of 12.0 or greater. Thesedefinitions of cognitive decline and improvementare admittedly somewhat arbitrary. However, thestringency of these criteria, while profoundlyaffecting the observed rate of decline within a givengroup [57], is not as critical when the frequency ofdecline is being statistically compared with that inan appropriate control group. Chi-square was usedto determine group differences in frequency ofreliable cognitive decline and improvement.Domain-specific cognitive summary scores were

computed by averaging SRB scores for all variableswithin a given cognitive domain (see Table 2 for

Table 1. Demographic and clinical characteristics of healthy group (n 5 28), tamoxifen group (n 5 31), and anastrozole group(n 5 14), significance of ANOVAs, and significant pairwise post hoc comparisonsa

Characteristic Healthy Tamoxifen Anastrozole Test statistic Sig Significant post

hoc comparisons

Age M 5 59.32 SD 5 4.23 M 5 57.52 SD 5 4.02 M 5 57.86 SD 5 4.42 F 5 1.46 0.24

Educationb M 5 15.93 SD 5 2.54 M 5 14.29 SD 5 2.83 M 5 13.00 SD 5 2.91 F 5 5.87 0.00 H–A

Disease Stage (I/II)c N/A 27/4 13/1 w2 5 0.32 0.57

Quick testd (AT BASELINE) M 5 46.00 SD 5 2.45 M 5 44.61 SD 5 3.18 M 5 42.57 SD 5 3.11 F 5 6.56 0.00 H–A

Percentage of sample on

hormonal treatment at T1

N/A 45% 36% w2 5 0.35 0.55

Percentage of sample receiving

radiation between T1 and T2

N/A 74% 71% w2 5 0.04 0.85

Time on hormonal treatment

at T2 (in days)

N/A M 5 140.61 SD 5 45.71 M 5 130.14 SD 5 59.25 t 5 0.65 0.52

T1–T2 interval (in days) M 5 151.89 SD 5 30.07 M 5 158.84 SD 5 31.81 M 5 160.71 SD 5 32.10 F 5 0.52 0.60

M, mean; SD, standard deviation.aBonferroni test used with homogeneity of variance; Tamhane’s test used with heterogeneity of variance. Sig, significance level of test statistic; H–A, healthy vs anastrozole.bNumber of years in educational program leading to a diploma or degree.cNumber with stage I disease/number with stage II disease.dQuick Test raw score of 44 corresponds to an IQ of 104.

Cognitive effects of hormonal therapy 813


DOI. 10.1002/pon

tests and variables in each domain). In the casewhere multiple measures were derived from thesame test, the SRB scores were weighted to ensure

that performance on that one test did notcontribute disproportionately to its respectivesummary score (the average of the variables from

Table 2. Test battery arranged by cognitive domain

Test (by cognitive

domain) Description Variable(s) analyzed

Executive function

Paced Auditory Serial Addi-

tion Task (PASAT) [41]

Subject is presented with a series of 61 single-digit numbers at a fixed pace on a tape

recorder, and instructed to add each pair of consecutive numbers. Rate of presentation of

the numbers increases over 4 consecutive trials. This is a very demanding task, especially for

older adults, and many of the participants discontinued their performance following the first

trial. Therefore, only trial 1 (2.4 s interval) scores were analyzed

Number correct on 2.4 s trial

Trail Making Test B (Trails B)

[42]

A pencil-and-paper test of visuomotor tracking, requiring subjects to alternately connect, in

sequence, numbers, and letters randomly distributed on a page

Completion time in seconds

Wisconsin Card Sorting Test

(WCST) [43]

Requires the subject to sort cards in relation to 4 key cards, alternating sorting strategies

deduced from examiner feedback. This test generates numerous scores. In an effort to keep

our number of variables manageable, we opted to analyze the number of successful sorts

divided by the number of trials, as this captures the most information in a single score

Number of sorts divided by

number of trials

Language function

Boston Naming Test [44] Subject is required to name pictures of well-known objects. This test is known to be

sensitive to anomia

Number correct with or

without category cue

Controlled Oral Word Asso-

ciation Test (FAS) [45]

Scores on this test reflect the total number of words beginning with the letters F, A, and S

generated orally in respective 1-min intervals

Total number correct for all

letters

Motor function

Grooved Pegboard [46] A test of manual speed and dexterity requiring the subject to insert 25 pegs into keyhole

slots, using first the dominant, then the non-dominant, hand

Completion time in seconds,

both hands

Processing speed

Digit-Symbol Coding, WAIS-III

[47]

A timed pencil-and-paper test requiring the subject to copy symbols to correspond with

numbers, according to a key

Number correct in 120 s

Symbol Search, WAIS-III [47] A timed test requiring the subject to scan a group of symbols in search of target symbols Number correct in 120 s less

errors

Trail Making Test A (Trails A)

[42]

A pencil-and-paper test of visuomotor tracking, requiring subjects to connect, in sequence,

numbers randomly distributed on a page

Completion time in seconds

Verbal memory

California Verbal Learning

Test II (CVLT) [48]

Assesses ability to learn a list of 16 words over 5 trials, and to recall the list after a 20-min

delay. Variables analyzed included recall of the list on trial 1 (CVLT trial 1; a measure of

short-term memory), free recall after delay (CVLT Delayed Recall; captures both learning

and retention), and the score on a delayed multiple-choice test (CVLT Delayed Recognition;

allows differentiation between retention and retrieval)

Trial 1 (number correct)

Delayed Recall (number

correct) Delayed Recogni-

tion (true positives1true

negatives)

Logical Memory II, WMS-III

[49]

Subjects try to recall 2 stories presented orally. Delayed Recall was analyzed in order to

capture both initial encoding and retention (Immediate and Delayed Recall were highly

correlated)

Delayed Recall, total score

Visual memory

Rey Visual Learning Test

(RVLT) [50]

A visual analogue of the CVLT that assesses an individual’s ability to learn a series of 15

nonsense designs over 5 trials, and to recall the designs after a 20-min delay. Variables

analyzed were chosen to correspond to those of the CVLT

Trial 1 (number correct)

Delayed Recall (number

correct) Delayed Recogni-

tion (true positives)

Family Pictures II, WMS-III

[49]

A visual analogue of Logical Memory II where subjects try to recall 4 thematic pictures.

Delayed recall was analyzed in order to capture both initial encoding and retention

Delayed Recall, total score

Visuospatial function

Block Design, WAIS-III [47] Subjects attempt to reconstruct geometric designs using 3-dimensional blocks and are

scored according to speed and accuracy

Total raw score

Working memory

Arithmetic, WAIS-III [47] Subjects are required to mentally solve a series of orally presented arithmetic problems Total raw score

Consonant Trigrams (CCCs)

[51]

Subjects attempt to retain orally presented letter trigrams for 0, 3, 9, or 18 s while

simultaneously carrying out a serial subtraction task

Total letters correctly re-

called for all intervals

Digit Span, WAIS-III [47] Subjects recite strings of random digits of increasing length, first forward, then backward Total raw score forward and

backward

Letter-Number-Sequencing,

WAIS-III [47]

Subjects are required to re-order random alphanumeric sequences presented orally Total raw score

Spatial Span, WMS-III [49] Subjects are asked to tap out a spatial sequence illustrated by the examiner, first forward and

then backward

Total raw score forward and

backward

WAIS-III, Wechsler Adult Intelligence Scale-III; WMS-III, Wechsler Memory Scale-III.



DOI. 10.1002/pon

a given test was included as a single score). Anoverall cognitive summary score was obtained byadding all of the domain-specific cognitive sum-mary scores. In calculating the summary scores,missing data on individual neuropsychologicalmeasures were replaced by the group mean. Thesecomposite scores were compared for tamoxifen,anastrozole, and healthy groups using analysis ofcovariance, with age and education included as thecovariates. In the case of a significant omnibus F,post hoc pairwise comparisons were conducted,using the Bonferroni test in the case of homo-geneity of variance and Tamhane’s test in the caseof heterogeneity of variance.

Results

Attrition from the first to the second testing sessionwas less than 10% in all groups and, in all cases,was due to subjects declining retest. Demographiccharacteristics of all three groups, as well as clinicalcharacteristics of the two patient groups, aresummarized in Table 1. The three groups did notdiffer with respect to age or inter-test interval, butthe healthy group had more years of education andhigher T1 Quick Test scores than the anastrozolegroup. Most of the hormonal patients had stage Ibreast cancer, except for four in the tamoxifengroup and one in the anastrozole group who hadstage II disease. The treatment groups did notdiffer with respect to either the percentage ofwomen who had begun treatment prior to T1 ordays on treatment prior to T1 in those who hadbegun their treatment (mean5 11.21 days,SD5 10.68, range5 1–34 in the tamoxifen group;mean5 8.80 days, SD5 5.12, range5 1–15 inanastrozole group; p5 0.64) (Table 1).Means and standard deviations for all groups on

the cognitive measures and POMS subscales at T1and T2 appear in Table 3. The frequency ofcognitive decline from T1 to T2 was 7% in thehealthy group, 39% in the tamoxifen group, and64% in the anastrozole group. The number ofdecliners in the healthy group differed from that inboth the tamoxifen group (w2 5 8.10, p5 0.00) andthe anastrozole group (w2 5 15.77, p5 0.00), butthe difference between the tamoxifen and anastro-zole groups was not significant (w2 5 2.54,p5 0.11). On average, these so-called declinershad lower raw scores at T2 than at T1 on 8 ofthe 23 neuropsychological test scores (range 4–13),but in most cases, these changes were minimal. Thefrequency of cognitive improvement did not differamong the groups (one subject in each group,w2 5 0.41, p5 0.82).The neuropsychological summary scores were

consistently lower in the hormonal groups than inthe healthy group, with the anastrozole groupgenerally scoring the lowest (Table 4). The

differences among groups reached significancein the case of the overall cognitive summaryscore, the processing speed summary score, andthe verbal memory summary score. For all ofthe foregoing, post hoc pairwise comparisonsrevealed significant differences between the healthygroup and the anastrozole group. The processingspeed summary score also differed significantlybetween the healthy group and the tamoxifengroup.There were no main effects of group or time, and

no interaction effect, on POMS anxiety or depres-sion scores in three-group repeated measuresanalysis of variances (ANOVAs). There was,however, a significant group-by-time interactioneffect on fatigue (F5 3.32, p5 0.04). Inspectionof group means (Table 3) indicated that, whereasthe healthy group reported less fatigue at T2than at T1, fatigue scores increased slightly inboth of the hormonal groups. Change in fatiguefrom T1 to T2 did not correlate significantly witheither the overall cognitive summary score or thenumber of SRB scores of �2.0 or less, in any of thethree groups or in the sample as a whole.Furthermore, the aforementioned group differ-ences in the various cognitive summary scoresremained significant even when the T1–T2 changein fatigue score was included as a covariate in theANOVAs.

Re-analyses with matched subgroups

As noted above, the groups differed with respect toeducation and estimated verbal IQ. In recognitionthat these variables might have influenced practiceeffects, and that co-variation is not an idealsolution for dealing with group differences ondemographic variables [58], the data were re-analyzed with a subset of 28 patients who mostclosely matched the members of the healthy controlgroup on education (by eliminating those patientswhose education fell beneath the minimum educa-tion level in the healthy group). To ensure adequatenumbers for these analyses, 20 tamoxifen and 8anastrozole subjects were combined into a singlehormonal group. The resultant healthy and hor-monal groups did not differ on age, education, orT1 Quick Test scores (Table 5). The frequency ofcognitive decline in this matched subgroup ofhormonal patients was still significantly higherthan in the healthy control group (39 and 7%,respectively, w2 5 8.11, p5 0.00). There was againno difference between the groups in the frequencyof reliable cognitive improvement (0% in thehormonal group and 4% in the control group,w2 5 1.02, p5 0.31). At the group level, thehormonal patients had lower mean scores thanthe healthy controls on the overall cognitivesummary score, as well as the speed summary



DOI. 10.1002/pon

Tab

le3.

Mea

ns

and

stan

dar

ddev

iations

for

hea

lthy

group

(n5

28),

tam

oxife

ngr

oup

(n5

31),

and

anas

trozo

legr

oup

(n5

14)

on

cogn

itiv

em

easu

res

and

PO

MS

subsc

ales

atT

1an

dT

2,s

ignifi

cance

of

T1

and

T2

AN

OV

As,

and

sign

ifica

nt

pai

rwis

epost

hoc

com

par

isonsa

T1

T2

Healt

hy

mean

(SD

)

Tam

oxif

en

mean

(SD

)

An

ast

rozo

le

mean

(SD

)S

igF

Sig

nif

ican

tp

ost

ho

cco

mp

ari

son

s

Healt

hy

mean

(SD

)

Tam

oxif

en

mean

(SD

)

An

ast

rozo

le

mean

(SD

)S

igF

Sig

nif

ican

tp

ost

ho

cco

mp

ari

son

s

Exe

cutiv

efu

nctio

n

PA

SAT

41.7

8(8

.25)

39.7

0(9

.75)

35.1

4(8

.78)

0.2

447.0

9(7

.31)

41.3

2(9

.38)

40.1

4(1

0.3

2)

0.0

4

Tra

ilsB

65.1

8(1

5.8

3)

66.9

0(2

2.7

4)

78.3

6(2

2.4

8)

0.1

359.7

9(1

5.9

3)

67.9

4(2

0.5

6)

74.8

6(2

5.2

1)

0.0

6

WC

ST0.0

6(0

.03)

0.0

5(0

.03)

0.0

4(0

.02)

0.1

10.0

6(0

.03)

0.0

6(0

.03)

0.0

4(0

.03)

0.0

2H

–A

T–A

Lang

uage

Bost

on

Nam

ing

Tes

t56.8

6(3

.01)

54.8

4(4

.85)

53.2

9(6

.75)

0.0

657.7

5(2

.46)

55.7

1(4

.35)

54.2

1(6

.44)

0.0

3

FAS

43.0

7(1

3.5

0)

41.2

9(8

.47)

29.3

6(1

0.3

7)

0.0

0H

–A

44.3

6(1

1.6

1)

43.2

3(9

.76)

31.2

1(8

.89)

0.0

0H

–A

T–A

T–A

Mot

orfu

nctio

n

Gro

ove

dPeg

boar

d145.5

4(2

0.4

7)

156.1

3(2

5.6

7)

158.3

1(2

0.9

1)

0.1

3148.8

2(2

5.3

1)

153.6

0(2

8.4

9)

151.8

5(2

1.5

4)

0.7

8

Proc

essing

spee

d

Dig

it-Sy

mbolC

odin

g72.2

5(1

1.2

6)

70.2

9(1

1.5

3)

66.2

9(1

0.7

9)

0.2

875.6

4(1

0.2

4)

70.0

0(1

1.6

7)

67.0

0(1

2.1

2)

0.0

4

Sym

bolSe

arch

30.5

0(5

.88)

31.3

5(4

.57)

28.1

4(5

.35)

0.1

732.1

4(5

.29)

30.5

8(5

.18)

30.7

1(4

.03)

0.4

6

Tra

ilsA

25.3

2(5

.36)

27.0

3(1

0.0

0)

27.7

1(7

.28)

0.5

925.1

4(5

.35)

25.2

3(6

.51)

29.0

0(6

.96)

0.1

2

Verb

alm

emor

y

CV

LTT

rial

16.7

5(1

.71)

6.3

2(1

.35)

5.8

6(1

.03)

0.1

78.5

4(2

.44)

7.4

2(2

.38)

7.0

0(1

.96)

0.0

8

CV

LTD

elay

edR

ecal

l13.4

6(2

.13)

12.1

7(2

.72)

11.7

1(3

.00)

0.0

714.5

4(1

.58)

13.1

0(2

.27)

11.5

7(2

.74)

0.0

0H

–T

H–A

CV

LTD

elay

edR

ecogn

ition

30.2

9(2

.05)

29.5

0(2

.57)

28.5

0(3

.30)

0.1

030.3

6(2

.08)

29.7

4(2

.32)

27.8

6(3

.28)

0.0

1H

–A

Logi

calM

emory

II29.6

1(7

.21)

24.3

5(7

.31)

20.9

3(7

.52)

0.0

0H

–T

32.7

1(7

.23)

28.1

6(5

.81)

23.6

4(8

.57)

0.0

0H

–T

H–A

H–A

Visu

alm

emor

y

RV

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DOI. 10.1002/pon

score and the verbal memory summary score(Table 6).

Conclusions

The current investigation was an unplanned exten-sion of a larger study evaluating the effects ofchemotherapy on cognition in breast cancerpatients. While the original study did include agroup of patients receiving hormonal treatmentswithout chemotherapy, it was not our initial intentto evaluate the cognitive effects of hormonaltherapy per se. Rather, we selected these hormonalpatients to serve as controls because they closelymatched the chemotherapy subjects with respect topotentially confounding disease, host, and treat-ment variables. However, in analyzing the datafrom that initial study, there were indications thatthe women who received hormonal therapy inaddition to chemotherapy had more persistentcognitive disturbances than the women whoreceived chemotherapy alone [7], suggesting thatthe term chemo fog may, at least in some instances,be a misnomer. In light of a growing literatureimplicating estrogen in cognition, these findings led

us to question the role of hormonal treatments inso-called chemo fog. We, therefore, used residualstudy funds to recruit a convenience sample ofhealthy women and we compared our hormonalsubjects with them.Because the hormonal patients in our original

study were meant to serve as controls, we werequite flexible with regard to the parameters of theirhormonal therapy. Hence, they varied considerablyin terms of duration of treatment at time of testingand even in terms of whether or not they had beguntreatment at T1. While we recognize that the lackof systematic control of these variables limits theconclusions that can be drawn from the currentdata, we nonetheless feel that they generateinteresting hypotheses that merit consideration.Our results suggest that hormonal therapies

exert a negative influence on cognition in asignificant proportion of women, particularly thosereceiving anastrozole. Relative to healthy controls,the anastrozole group showed a nine-fold increasein risk of cognitive decline (as compared to a five-fold increase in the tamoxifen group) and, in all butone domain, obtained the lowest cognitive sum-mary scores of the three groups. It stands to reasonthat anastrozole would have a more profoundeffect on cognition than tamoxifen, given thedifferent mechanisms of action of these agents.Tamoxifen is a selective estrogen receptor mod-ulator (SERM), which has anti-estrogen effects inbreast but acts as an estrogen agonist in othertissues such as bone. Its action in the brain is stillnot entirely clear. Anastrozole is an aromataseinhibitor (AI). The AIs bind to the aromataseenzyme preventing the conversion of adrenalandrogens to estrogen in peripheral tissue (theprimary source of estrogen in post-menopausalwomen). The current findings are consistent withpreliminary evidence that the AIs, by causing neartotal estrogen depletion, may pose a greatercognitive risk than the SERMs [59]. Given thatAIs have become first-line therapy for the majorityof breast cancer patients [60,61], it will beimportant to further compare their cognitive effectsto those of other adjuvant hormonal therapies infuture studies.In keeping with our own previous findings [7],

and with preliminary results from the ATAC trial[32,33], the cognitive domains most affected in thehormonal groups described herein were processingspeed and verbal memory. Such findings are alsoconsistent with a growing body of evidenceindicating that estrogen may have particular effectson verbal memory [27,34–38,62–65].The effects in this study were very subtle, such

that most of the mean raw scores in the hormonalgroups were actually higher at T2 than T1, and stillfell within the normal range relative to publishednorms. It was only when we examined change fromT1 to T2 in the hormonal group relative to that in

Table 5. Demographic and clinical characteristics of healthygroup (n 5 28) and subgroup of hormonal patients matched tohealthy group on education (n 5 28)

Characteristic

Healthy mean

(SD)

Hormonal mean

(SD) p

Age 59.32 (4.23) 58.04 (4.17) 0.26

Educationa 15.93 (2.54) 15.43 (2.55) 0.47

Quick Testb (AT BASE-

LINE)

46.00 (2.45) 44.86 (3.04) 0.13

T1–T2 interval (in days) 151.89 (30.07) 164.32 (37.02) 0.17

SD, standard deviation.aNumber of years in educational program leading to a diploma or degree.bQuick Test raw score of 44 corresponds to an IQ of 104.

Table 6. Means and standard deviations of overall neuropsy-chological summary score and domain-specific summary scoresfor healthy group (n 5 28) and matched hormonal subgroup(n 5 28), and significance of ANCOVAs with age and educationas covariates

Healthy mean

(SD)

Hormonal mean

(SD)

Sig

F

Overall 0.00 (0.31) �0.24 (0.37) 0.01

Executive 0.01 (0.47) �0.23 (0.37) 0.09

Language 0.01 (0.64) �0.28 (1.16) 0.33

Motor 0.00 (0.98) 10.22 (0.89) 0.42

Processing speed 0.00 (0.54) �0.35 (0.58) 0.02

Verbal memory 0.00 (0.62) �0.43 (0.82) 0.04

Visual memory 0.00 (0.75) �0.27 (0.94) 0.11

Visuospatial 0.00 (0.98) �0.39 (0.94) 0.16

Working mem-

ory

0.00 (0.46) �0.11 (0.58) 0.52

SD, standard deviation; Sig F, significance of F of two- group ANCOVA.



DOI. 10.1002/pon

the healthy group that we detected a treatmenteffect. Although subtle, it is important not toassume that this effect is clinically non-significant.Recent functional imaging studies have showndifferent patterns of brain activation in chemother-apy treated breast cancer patients compared withpatient and healthy controls even in the absence ofany group differences in performance scores[66,67]. Findings such as these suggest that cancertreatments may induce changes in brain functionthat patients experience as disturbing, but thatstandard neuropsychological tests may fail todetect.The hormonal groups scored lower than the

healthy group on most neuropsychological mea-sures at baseline. There are a number of possibleexplanations for this. Firstly, it may be that otherdisease- and host-related factors contribute tocognitive disturbance in cancer patients, as hasbeen suggested in previous reports [68,69]. Sec-ondly, it could be that the T1 differences intest scores were themselves due to treatmenteffects, given that almost half of the patients inour study had started hormonal treatment prior toinitial testing (although this explanation seemsunlikely as we found no significant differences onany T1 neuropsychological score between thosehormonal subjects who had begun therapy andthose who had not). Thirdly, the baselinedifferences in neuropsychological test scoresmay have been due to the fact that the patientgroups, and the anastrozole group in particular,had less education and lower IQ than the healthygroup. Although group differences on stablepatient characteristics such as education andintelligence are controlled to a large extent withthe SRB approach, wherein each individualserves as her own control, they are still a concernin so far as they might systematically influencethe magnitude of practice effects. We furtherexplored this possibility by repeating our analyseswith a sub-sample of hormonal patients matched tothe healthy group on education. We still found arobust effect of hormonal therapy on cognition atboth the individual and group level.Almost three-quarters of the cancer patients in

our sample received radiation between T1 and T2,raising the possibility that radiation-induced fati-gue, rather than exposure to hormonal therapy,may have been responsible for the cognitive declineobserved in the cancer patients. Indeed, thepatients did show an increase in fatigue from T1to T2, as compared with a decrease in the healthygroup. However, change in fatigue from T1 to T2did not correlate with neuropsychological changemeasures. Furthermore, the group differences incognitive summary scores remained significanteven when change in fatigue score was includedas a covariate in the ANOVAs. Thus, it wouldseem that fatigue does not fully account for the

increased risk of cognitive decline observed in thehormonal patients.Given the fact that the hormonal therapies can

severely deplete estrogen levels, are administeredfor long periods of time, and are being usedincreasingly in primary preventive settings, thecognitive effects of these treatments demand morerigorous study that addresses the methodologicalissues raised here. The subtlety of the effectsnoted herein underscores the importance of acontrolled prospective design. Selection of thecontrol group is critical. Control subjects shouldbe matched to the study patients on key demo-graphic variables such as age and education.Ideally, the control group would comprisebreast cancer patients not receiving any systemicadjuvant therapy. As this is a rare occurrence incurrent clinical practice, an alternative approachto controlling for confounding disease and treat-ment variables would be to study women at highrisk for breast cancer who are taking prophylactichormonal therapy. Future studies would also begreatly strengthened by ensuring that baselinetesting is routinely conducted prior to commence-ment of hormonal treatment. It is hoped thatfuture studies, by incorporating these very practic-able methodological refinements, will significantlyadvance our understanding of the cognitive effectsof cancer treatments and, thereby, mitigate theirimpact on the quality of life of breast cancersurvivors.

Acknowledgements

This research was funded by the Canadian Breast CancerFoundation—Ontario Chapter. We would like to thank theparticipants in our study, as well as the oncologists, nurses,and support staff at the Ottawa Hospital Cancer Centre fortheir assistance. Particular thanks to Ms Julie Wells.Statement of Originality: This manuscript reports originaldata. Some of these data were previously presented in posterformat at the American Neuropsychiatric AssociationAnnual Conference in 2003 and in previous paperspublished or in press in Psycho-Oncology and in the Journalof Clinical and Experimental Neuropsychology. Some of theanalyses reported in the present manuscript were presentedin poster format at the International NeuropsychologicalSociety Annual Meeting in 2008.Conflicts of Interest: The authors have no conflicts ofinterest to report.

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DOI. 10.1002/pon

Cognitive effects of hormonal therapy in early stage breast cancer patients: a prospective study

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