Combined anxiety and depressive symptoms before diagnosis of breast cancer.

Abstract

To determine the relationship between pre-diagnosis state anxiety, depressive symptoms, and combined state anxiety and depressive symptoms (CADS) with quality of life (QOL), fatigue, state anxiety and depressive symptoms one and two years after surgery in women with breast cancer.
Women with breast problems referred to a Dutch outpatient clinic were recruited for the study. Participants (N=428) completed a set of questionnaires before diagnosis (Time0) and the women with breast cancer subsequently received questionnaires at 12 (Time1) and 24 months (Time2) after surgical treatment. The questionnaire set consisted of questionnaires on demographics, state anxiety, depressive symptoms, fatigue, QOL, neuroticism, and trait anxiety. Chi-square tests, independent samples T-tests, and multivariate linear regression analyses were used to do the analyses.
Before their diagnosis of breast cancer, 111 women (28%) had CADS. Of the CADS-group, a higher percentage had elevated levels of anxiety, depressive symptoms, and CADS at all follow-up moments than of the non-CADS-group. CADS-score at before diagnosis and neuroticism were the most important predictors of outcome measures at Time1 and Time2.
More than one in four women, who later received the diagnosis breast cancer, had elevated levels of both state anxiety and depressive symptoms (CADS) just before diagnosis. This factor was also a major predictor of QOL, state anxiety, depressive symptoms, and fatigue 12 and 24 months after surgery. This implies that women with a higher score on both state anxiety and depressive symptoms should be identified as soon as possible in the process of diagnosis and treatment of breast cancer using validated questionnaires or screening instruments. Only by identifying this group of patients, tailored psychological care can be accomplished.

Full text

Page 1

Research report
Combined anxiety and depressive symptoms before diagnosis
of breast cancer
Lotje Van Escha, Jan A. Roukemaa,b, Miranda F. Ernstc,
Grard A.P. Nieuwenhuijzend, Jolanda De Vriesa,e,⁎
aCoRPS — Center of Research on Psychology in Somatic Diseases, Tilburg University, Tilburg, The Netherlands
bDepartment of Surgery, St. Elisabeth Hospital, Tilburg, The Netherlands
cDepartment of Surgery, Jeroen Bosch Hospital, 's Hertogenbosch, The Netherlands
dDepartment of Surgery, Catharina Hospital, Eindhoven, The Netherlands
eDepartment of Medical Psychology, St. Elisabeth Hospital, Tilburg, The Netherlands
a r t i c l ei n f oa b s t r a c t
Article history:
Received 28 June 2011
Received in revised form 12 September 2011
Accepted 12 September 2011
Available online xxxx
Purpose: To determine the relationship between pre-diagnosis state anxiety, depressive symp-
toms, and combined state anxiety and depressive symptoms (CADS) with quality of life (QOL),
fatigue, state anxiety and depressive symptoms one and two years after surgery in women
with breast cancer.
Methods: Women with breast problems referred to a Dutch outpatient clinic were recruited for
the study. Participants (N=428) completed a set of questionnaires before diagnosis (Time0)
and the women with breast cancer subsequently received questionnaires at 12 (Time1) and
24 months (Time2) after surgical treatment. The questionnaire set consisted of questionnaires
on demographics, state anxiety, depressive symptoms, fatigue, QOL, neuroticism, and trait
anxiety. Chi-square tests, independent samples T-tests, and multivariate linear regression an-
alyses were used to do the analyses.
Results: Before their diagnosis of breast cancer, 111 women (28%) had CADS. Of the CADS-
group, a higher percentage had elevated levels of anxiety, depressive symptoms, and CADS
at all follow-up moments than of the non-CADS-group. CADS-score at before diagnosis and
neuroticism were the most important predictors of outcome measures at Time1 and Time2.
Conclusions: More than one in four women, who later received the diagnosis breast cancer, had
elevated levels of both state anxiety and depressive symptoms (CADS) just before diagnosis.
This factor was also a major predictor of QOL, state anxiety, depressive symptoms, and fatigue
12 and 24 months after surgery. This implies that women with a higher score on both state
anxiety and depressive symptoms should be identified as soon as possible in the process of di-
agnosis and treatment of breast cancer using validated questionnaires or screening instru-
ments. Only by identifying this group of patients, tailored psychological care can be
accomplished.
© 2011 Published by Elsevier B.V.
Keywords:
Breast cancer
Anxiety
Depressive symptoms
Personality
Quality of life
1. Introduction
In Europe, breast cancer incidence has increased from 76
per 100,000 inhabitants in 1995 to 88 per 100,000 inhabitants
in 2008. Mortality, however, decreased from 27.3 per 100,000
inhabitants in 1995 to 24.3 per 100,000 inhabitants in 2008
(Bray et al., 2002; Ferlay et al., 2010), resulting in a growing
group of breast cancer survivors every year.
Journal of Affective Disorders xxx (2011) xxx–xxx
⁎ Corresponding author at: Center of Research on Psychology in Somatic
Diseases (CoRPS), Tilburg University, P.O. Box 90153, 5000 LE, Tilburg, The
Netherlands. Tel.: +31 134662705; fax: +31 134662067.
E-mail addresses: J.devries@uvt.nl, jvries@elisabeth.nl (J. De Vries).
JAD-05231; No of Pages 7
0165-0327/$ – see front matter © 2011 Published by Elsevier B.V.
doi:10.1016/j.jad.2011.09.012
Contents lists available at SciVerse ScienceDirect
Journal of Affective Disorders
journal homepage: www.elsevier.com/locate/jad
Please cite this article as: Van Esch, L., et al., Combined anxiety and depressive symptoms before diagnosis of breast cancer, J.
Affect. Disord. (2011), doi:10.1016/j.jad.2011.09.012

Page 2

Both anxiety and depressive symptoms are common in
cancer patients. A recent meta-analysis showed a prevalence
of clinical depression of 16.3% and a prevalence of all types of
depression in 20.7% of oncological and hematological patients.
Anxiety prevalence was 10.3% (Mitchell et al., 2011). In this
meta-analysis only studies that used a clinical interview to
assess depression and anxiety were included. Massie (2004)
reviewed the literature on the prevalence of depression/de-
pressive symptoms in patients with cancer and concluded
that in women with breast cancer the prevalence of depres-
sion/depressivesymptomsrangedfrom1.5%to46%,depending
on the instrument used toassess depression and thecharacter-
istics of the patient group. Although many studies mention the
co-existence of depressive symptoms and elevated anxiety
levels, there is not much information on the prevalence of
combined anxiety/depressive symptoms (CADS) in women
with breast cancer. Brintzenhofe-Szoc et al. (2009) published
a cross-sectional study in which the prevalence of CADS in
cancer patients was presented. In breast cancer patients 2.8%
had only depressive symptoms, 14.9% had only anxiety symp-
toms, and 10.8% had CADS. A study in Hong Kong (So et al.,
2010) showed that 21.1% had elevated anxiety symptoms,
34.4% had elevated depressive symptoms, and 15.6% had
both. According to Ollonen et al. (2005) and Eskelinen and
Ollonen (2011) 18% had moderate depressive symptoms and
12% oftenhad feelings of anxiety, but there wasnoinformation
on the combination of depressive symptoms and anxiety.
It is important to focus on the effects of baseline anxiety and
depressivesymptomslevelsonqualityoflife(QOL)intheperiod
afterinitialtreatmentofbreastcancer,sinceanxietyanddepres-
sive symptoms are manageable factors if a patient receives psy-
chological counseling. The literature on the relationship of
anxiety and/or depression with QOL is, however, scarce. A few
cross-sectional studies reported a negative correlation between
depression and QOL (Brown et al., 2010; Karakoyun-Celik et al.,
2010;Soetal.,2010;Weitzneretal.,1997;Yenetal.,2006),anx-
iety and QOL (Brown et al., 2010; Karakoyun-Celik et al., 2010;
So et al., 2010; Weitzner et al., 1997), and CADS and QOL
(Brown et al., 2010; So et al., 2010) in breast cancer patients. In
thestudyofSchreierandWilliams(2004)stateanxietywasneg-
atively associated with QOL at the start of treatment, and higher
levels of state anxiety were a significant predictor of decreased
QOL at one year after the start of treatment. Also, changes in de-
pressive symptoms scores were shown to be a predictor of QOL
six months after baseline measure (Wong and Fielding, 2007),
and there is one recent study (Taira et al., 2011) that showed
that depressive symptoms at baseline predicted worse health-
related QOL at six, 12, and 24 months after surgery, and anxiety
at baseline predicted worse health-related QOL at six and
12 months after surgery. The quality and methodology of those
studies was far from optimal, most were cross-sectional
(Brown et al., 2010; Karakoyun-Celik et al., 2010; So et al.,
2010; Weitzner et al., 1997; Yen et al., 2006), some had a low
number of participants (Nb75) (Schreier and Williams, 2004;
Weitzneretal.,1997;Yenetal.,2006),andthemeasurementin-
struments were not always validated (Wong and Fielding,
2007).
In this multicentre prospective study, we therefore
determinedtherelationshipbetweenanxiety,depressivesymp-
toms, andCADS (measured before diagnosis) with QOL, fatigue,
and mood one and two years after surgery in women with
breast cancer. Since previous studies showed that personality
factors influence the QOL of women with breast cancer (Hartl
et al., 2010; Schreier and Williams, 2004; Van der Steeg et al.,
2007; van der Steeg et al., 2010), trait anxiety and neuroticism
were also included in this study. We hypothesized that CADS,
more than elevated levels of anxiety or depressive symptoms
alone, would be a significant predictor for QOL, fatigue, state
anxiety, and depressive symptoms one and two years after
surgery.
2. Methods
2.1. Patients
Womenreferredbythenationalscreeningprogramortheir
general practitioner (GP) to the outpatient clinic of the St
Elisabeth Hospital (Tilburg), the Maasland Hospital (Sittard),
the Jeroen Bosch Hospital (Den Bosch), VieCuri Medical Center
(Venlo), Medical Center Alkmaar (Alkmaar), or the Catharina
Hospital (Eindhoven) in the Netherlands between 2003 and
2010, were asked to participate in this study. A specialized
mamma-carenurseinformedthepatients about thestudydur-
ingtheirfirstappointment.Whenwomenagreedtoparticipate
in the study, they completed an informed consent and a set of
questionnaires (Time0). Women were not yet informed about
the diagnosis of their breast problem at the time they complet-
ed the first set of questionnaires. The women who appeared to
have breast cancer subsequently received questionnaires at 12
(Time1) and 24 months (Time2) after surgical treatment.
Exclusion criteria were: not being able to complete Dutch
questionnairesforlinguistic,
reasons, and a medical history with breast disease. The Dutch
Medical Ethical Committee (ccMo NL15659.008.06) approved
this study.
cognitiveorpsychiatric
2.2. Questionnaires
State anxiety, i.e. the level of momentary anxiety, was mea-
sured with the State scale of the short version of the State-Trait
Anxiety Inventory (STAI). The STAI State short version consists
of6items(MarteauandBekker,1992)andithasgoodreliability
and validity (Marteau and Bekker, 1992; Van der Bij et al.,
2003). The answers range from 1 (almost never) to 4 (al-
most always). The total score ranges from 6 to 24. To de-
fine a CADS-score (high level of anxiety and high level of
depressive symptoms at Time0) state anxiety scores
were dichotomized in high or not high. High state anxiety
was defined by a score of 14 or higher (Henselmans et al.,
2009; Marteau and Bekker, 1992). Patients completed this
questionnaire at all measure moments.
The presence and degree of depressive symptoms over the
past week were measured with the Center for Epidemiological
Studies-Depression Scale (CES-D) (Radloff, 1977). This is a 20-
item self-report scale. The CES-D showedtohavegood psycho-
metric properties in breast cancer patients (Hann et al., 1999).
In this study the 16-item version (Schroevers et al., 2000) was
used, which consists of negative formulated items only. It was
found to be a more valid assessment of depressive symptoms
in cancer patients (Schroevers et al., 2000). The rating scale
ranges from 0 (seldom or never) to 3 ((almost) always), and
total scores can range from 0 to 48. To define the CADS-score
2
L. Van Esch et al. / Journal of Affective Disorders xxx (2011) xxx–xxx
Please cite this article as: Van Esch, L., et al., Combined anxiety and depressive symptoms before diagnosis of breast cancer, J.
Affect. Disord. (2011), doi:10.1016/j.jad.2011.09.012

Page 3

depressive symptoms scores were dichotomized in high or not
highbya cut-offscoreof12, based onthe ratioofhighand not-
high scores in the 20-item scale. Patients completed this ques-
tionnaire at all measure moments.
The 10-item Fatigue Assessment Scale (FAS) (Michielsen et
al., 2003) was used to measure fatigue. The FAS has a 5-point
response scale ranging from 1 (never) to 5 (always); thus,
scores on the FAS can range from 10 to 50. The reliability and
validity of the FAS appeared to be good in women with breast
problems (Michielsen et al., 2007). Patients completed this
questionnaire at all measure moments.
ToassessQOL,theWorldHealthOrganizationsQualityofLife
instrument, short form (WHOQOL-BREF) (WHOQOL-Group,
1998) was used. This 26-item questionnaire consists of four do-
mains (Physical Health, Psychological health, Social relationships,
and Environment) and two items concerning Overall QOL and
General health. The WHOQOL-BREF has a 5-point Likert re-
sponsescalerangingfrom1(notatall/never/verydissatisfied/very
poor) to 5 (extremely/always/very satisfied/very good). The ques-
tions refer to the previous two weeks. Higher scores indicate a
better QOL. Reliability and validity are reported to be good in
women with breast problems (Van Esch et al., 2011). Patients
completed this questionnaire at all measure moments.
Thepersonalitytraitneuroticismwasmeasuredbytheneu-
roticism part (12 items) of the Neuroticism-Extraversion-
Openness-Five Factor Inventory (NEO-FFI) (Costa and McCrae,
1992; Hoekstra et al., 1996). The reliability and validity of this
questionnaire are acceptable to good (Hoekstra et al., 1996).
TheNEO-FFIhasa 5-pointresponsescalerangingfrom1 (total-
ly disagree) to 5 (totally agree). Scores can range from 12 to 60.
Patients completed this questionnaire only at Time0.
Trait anxiety, i.e. a personality trait that reflects the disposi-
tion to experience anxiety in threatening situations, was
measured with the Trait part of the short version of the STAI
(Spielberger et al., 1970; Van der Ploeg et al., 1980). This
short version of the STAI Trait has 10 items and has good
psychometric properties (Bogaarts et al., 2011). The answers
rangefrom1(almostnever)to4(almostalways),sototalscores
can range from 10 to 40. Patients completed this questionnaire
only at Time0.
2.3. Demographics
Demographic data were assessed by self-report questions
concerning age, marital status, having children, education
level, and work status.
2.4. Medical Information
Informationondiseasestageatdiagnosis(Greeneetal.,2002),
type of operation, and adjuvant treatment (chemotherapy,
radiotherapy, hormone treatment) was retrieved from patients'
medical files.
2.5. Statistical procedure
To compare patients with and without CADS at Time0
they were divided in two groups: patients that had high anx-
iety and depressive symptoms (CADS-group) at Time0 and pa-
tients that did not havehigh anxiety and depressive symptoms
at Time0 (non-CADS-group), based on the cut-off scores of the
anxiety and depressive symptoms questionnaires.
To compare participants and non-participants on diagno-
sis and way of referring (by national screening program or
GP) Chi-square tests were used. Age of participants and
non-participants was compared with independent samples
T-test. Frequencies were used to examine the level of anxiety
and depressive symptoms at all measurement points in the
CADS- and the non-CADS-group.
Multivariate linear regression analyses (method backward)
were done to predict scores on QOL, anxiety, depressive symp-
toms,andfatigueatTime1andTime2.Thedependentvariables
inthemultivariateregressionanalyseswerethedomainsofthe
WHOQOL-BREF (Physical Health, Psychological health, Social re-
lationships, and Environment), Overall QOL and General Health
(WHOQOL-BREF), state anxiety score, depressive symptoms
score, and fatigue score at Time1 and Time2. Independent
variables were age, partner no/yes, children no/yes, education,
work no/yes, screening referral no/yes, disease stage at
diagnosis, surgical treatment (lumpectomy or mastectomy),
chemotherapy no/yes, radiotherapy no/yes, hormone therapy
no/yes, state anxiety score at Time0, depressive symptoms
score at Time0, CADS at Time0 (no/yes), trait anxiety score,
and neuroticism score. All analyses were performed with the
Statistical Package for Social Sciences (SPSS) version 17.0.
3. Results
Of the 2425 women who visited one of the outpatient
clinics with a problem of the breast, 1501 (62%) agreed to par-
ticipate in the study. The most important reason for women to
decline participation was thetimingoftheinclusion,namely in
the period they awaited the diagnosis of their breast problem.
Most women reported they had too much stress to complete
a questionnaire. Of the 1501 women that agreed to participate,
407 (27%) received the diagnosis breast cancer. The remaining
1093 women had a benign breast problem. Between Time0
and Time1 75 women dropped out of the study, between
Time1 and Time2 24 women dropped out. Since 62 women
were included in the study less than two years before ana-
lyses were done, their data on Time2 was missing (see
Fig. 1). There were no differences between participants and
non-participants, except that participants were more often
referred by the national screening program and not by the
GP (pb.001) than non-participants. The demographic and
medical characteristics of theparticipants with breast cancer
are summarized in Table 1.
Before diagnosis, 111 women (28%) that would later receive
the diagnosis breast cancer had CADS. A year later 14% of the
women had CADS and after two years this percentage had de-
creasedto10%.Elevateddepressivesymptomsandstateanxiety
wasfoundinrespectively21%and20%ofthetotalgroup,bothat
Time1andTime2.OfthegroupthathadCADSatTime0,ahigher
percentage of women had elevated levels of anxiety, depressive
symptoms,andCADSatTime1andTime2thanofthegroupthat
did not have CADS at Time0 (see Fig. 2).
The multivariate regression analyses showed that having
CADS at Time0 was a significant predictor for worse Physical
Health, Psychological Health, Overall QOL, and anxiety at
Time1, and for worse scores on all outcome measures except
Social Relationships at Time2. A higher level of depressive
3
L. Van Esch et al. / Journal of Affective Disorders xxx (2011) xxx–xxx
Please cite this article as: Van Esch, L., et al., Combined anxiety and depressive symptoms before diagnosis of breast cancer, J.
Affect. Disord. (2011), doi:10.1016/j.jad.2011.09.012

Page 4

symptoms at Time0 predicted worse scores on Social Rela-
tionships, depressive symptoms, and fatigue at Time1.
The personality trait neuroticism was a significant predictor
forallQOLdomains,depressivesymptoms,andfatigueassessed
at Time1 and Time2. Neuroticism also predicted state anxiety
scoresatTime1.TraitanxietywaspredictivefortheQOLdomain
Environmental Health and state anxiety at Time1, and for all
outcome measures, except Physical Health, at Time2.
Furthermore, some medical factors predicted outcomes. A
higher disease stage at diagnosis predicted worse Physical
Health and fatigue at Time2. Having a lumpectomy predicted
worse Social Relationships at Time1 and better Overall QOL at
Time2 compared with a mastectomy. Surprisingly, receiving
chemotherapy predicted less fatigue at Time1, and receiving
hormone therapy predicted better Physical and Environmental
Health, better Overall QOL, and less fatigue at Time2.
Finally, there were demographic variables that played a role
in QOL at Time1 and Time2. Having a job a Time0 was a
predictor for better Physical Health at Time2. A higher
educational level predicted better Environmental Health at
Time2, and higher age at Time0 predicted better Psychological
Health at Time1 (see Tables 2 and 3).
4. Discussion
At baseline, 28% of the women that would later receive
the diagnosis breast cancer had CADS. This CADS-group had
elevated levels of state anxiety, depressive symptoms and
CADS at all follow-up measure moments in the two years
after baseline compared with the non-CADS-group. In both
groups these scores decreased over time, but after 24 months
the CADS, state anxiety, and depressive symptoms scores of
the CADS group were still about three times as high as the
scores in the non-CADS group. This implies that the CADS
group experiences considerably more anxiety and/or depres-
sive symptoms even 24 months after surgery.
As hypothesized, CADS, more than anxiety and depressive
symptoms alone, significantly predicted patients' QOL, fatigue,
332 participants 12 months
after surgery
246 participants 24 months
after surgery
407 baseline participants that
later received diagnosis breast cancer
- Drop-out: 24
- Not yet 24 months in study: 62
- Drop-out: 75
Fig. 1. Flowchart of the study.
50
40
30
20
10
0
% of CADS/non-CADS group
high Anx & DS
T1 (12 months
after surgery)
high Anx & DS
high DS
high DS
high Anx
high Anx
high Anx & DS
T2 (24 months
after surgery)
high Anx & DS
high DS
high DS
high Anx
high Anx
CADS group
non-CADS group
Fig. 2. High anxiety and/or depressive symptoms in CADS and non-CADS
groups definedatbaseline. Abbreviations: CADS=combinedanxiety andde-
pressive symptoms at baseline; Anx = anxiety; DS = depressive symptoms.
Table 1
Demographic and medical information of the breast cancer patients
(N=407).
Demographic informationMedical information
AgeScreening referrala
Yes
No
Disease stage
Mean±SD
Partner
Yes
58.9±9.8272 (66.8%)
135 (33.2%)
318
(78.1%)
77
(18.9%)
12 (2.9%)
NoStage 040 (9.8%)
Unknown
Children
Yes
Stage I
Stage IIa
Stage IIb
186 (45.7%)
114 (28.0%)
55 (13.5%)341
(83.8%)
58 (1.3%)
8 (2.0%)
No
Unknown
Educational
level
Low
(b10 years)
Middle
(10–14 years)
High
(N14 years)
Unknown
Work status
Employed
Stage III
Stage IV
Indefinable
3 (0.7%)
5 (1.2%)
4 (1.0%)
54
(13.3%)
277
(68.1%)
64
(15.7%)
12 (2.9%)
Type of operation
Breast Conserving
Therapy
Mastectomy
229 (56.3%)
170 (41.0%)
No operation
Adjuvant therapy
Received chemotherapy
8 (2.0%)
154
(37.8%)
249
(61.2%)
4 (1.0%)
120 (29.5%)
UnemployedReceived radiotherapy252 (61.9%)
UnknownReceived hormone
treatment
156 (38.3%)
aScreening referral = women referred by the national breast cancer
screening program.
4
L. Van Esch et al. / Journal of Affective Disorders xxx (2011) xxx–xxx
Please cite this article as: Van Esch, L., et al., Combined anxiety and depressive symptoms before diagnosis of breast cancer, J.
Affect. Disord. (2011), doi:10.1016/j.jad.2011.09.012

Page 5

depressive symptoms, and state anxiety 12 and 24 months after
surgery. It especially predicted worse outcomes at 24 months
after surgery. This implies that, in addition to stable personality
characteristicssuchasneuroticismandtraitanxiety,alsoa com-
binationofsituationalfactorscanpredictthepsychologicalwell-
being of women with breast cancer, even up to 2 years after
their initial surgery. Those results were comparable with two
cross-sectional studies on the relationship between CADS and
QOL (Brown et al., 2010; So et al., 2010).
Another important predictor of QOL, fatigue, depressive
symptoms,andanxiety12and24 monthsaftersurgerywasneu-
roticism. In breast cancer, there is ample research on the predic-
tive value of neuroticism on QOL, fatigue, and mood (De Vries et
al.,2009;DenOudstenetal.,2009;Hartletal.,2010;Sugawaraet
al., 2005; van der Steeg et al., 2010). One study found that neu-
roticism was a significant predictor of QOL two years after initial
surgery (Hartl et al., 2010), and a cross-sectionalstudy showed a
positive relationship between neuroticism and fatigue in dis-
ease-free breast cancer survivors (Sugawara et al., 2005). These
findings are consistent with results from studies with other can-
cerpatientgroups(Aarstadetal.,2003,2008,2011;Goncalveset
al.,2008;Laietal.,2010).Studiesinthegeneralpopulationfound
that neuroticism is positively associated with physical com-
plaints, psychological symptoms, QOL, and health costs (Lahey,
2009; Weinstock and Whisman, 2006). In the Netherlands, a re-
cent studyshowed that health costs associated with neuroticism
were about 2.5 times as high as health costs of common mental
disorders such as anxiety and depression (Cuijpers et al., 2010).
Not much research has been performed on the relationship be-
tween trait anxiety and QOL either. The available studies
showed that breast cancer patients scoring high on trait
anxiety generally score lower on QOL (Den Oudsten et al.,
2010; Karakoyun-Celik et al., 2010; Van der Steeg et al., 2007;
van der Steeg et al., 2010).
The most unexpected outcome was the positive effect of
chemotherapy on fatigue at Time2 and the positive effect of
hormone therapy on Physical and Environmental Health,
Overall QOL, and fatigue at Time2. We found no studies
with the same result regarding the positive effect of receiving
chemotherapy on fatigue. A possible explanation for this ef-
fect at Time1 may be that women who received chemothera-
py rate their QOL and fatigue according to their subjective
situation, so they take the physical and psychological conse-
quences of this medication into account. The questionnaires
were completed a year after surgery, so also after completion
of the chemotherapy treatment. Sometimes this phenome-
non is referred to as a form of response shift (Andrykowski
et al., 2009; Sprangers, 1996).
For hormone therapy there are studies that report on QOL
outcomes, but most studies compare different types of
hormone and/or chemotherapy (Montazeri, 2008). One
study compared hormone therapy with no hormone therapy
in women with and without chemotherapy, and the results
showed that hormone therapy had no significant effect on
fatigue, anxiety, and depressive symptoms in the two years
Table 2
Predictors of the quality of life, anxiety, depressive symptoms, and fatigue at
12 months after surgery.
12 months after surgery
βp
Tot. adj. R2
Physical QOLCADS
Neuroticism
Age
CADS
Neuroticism
Type of surgery
Depressive
symptoms
Neuroticism
Trait anxiety
Neuroticism
CADS
Neuroticism
CADS
Trait anxiety
Neuroticism
Depressive
symptoms
Neuroticism
Chemotherapy
Depressive
symptoms
Neuroticism
−.247
−.295
.104
−.243
−.416
.118
−.184
b.001
b.001
.040
b.001
b.001
.036
.008
20.2%
Psychological QOL
32.9%
Social QOL
−.228
−.180
−.332
−.232
−.318
.229
.257
.258
.400
.001
.020
b.001
b.001
b.001
b.001
b.001
b.001
b.001
14.1%
Environmental QOL
21.3%
Overall QOL
21.0%
Anxiety
38.1%
Depressive
symptoms
.252
−.108
.276
b.001
.039
b.001
33.8%
Fatigue
.308
b.00127.8%
Abbreviations: QOL = quality of life; CADS = combined anxiety and
depressive symptoms at T0.
Table 3
Predictors of the quality of life, anxiety, depressive symptoms, and fatigue at
24 months after surgery.
24 months after surgery
βp
Tot. adj. R2
Physical QOLWork status
Disease stage at
diagnosis
Hormone therapy
CADS
Neuroticism
CADS
Trait anxiety
Neuroticism
Trait anxiety
Neuroticism
Educational level
Hormone therapy
CADS
Trait anxiety
Neuroticism
Type of surgery
Hormone therapy
CADS
Trait anxiety
Neuroticism
CADS
Trait anxiety
CADS
Trait anxiety
Neuroticism
Disease stage at
diagnosis
Hormone therapy
CADS
Trait anxiety
Neuroticism
.145
−.175
.018
.016
.200
−.247
−.284
−.176
−.164
−.338
−.274
−.187
.119
.143
−.143
−.220
−.270
−.147
.122
−.213
−.177
−.264
.135
.439
.151
.261
.216
.152
.006
b.001
b.001
.007
.049
b.001
.001
.028
.040
.013
.029
.008
.001
.014
.041
.001
.036
.001
.044
b.001
.023
.002
.007
.028
22.7%
Psychological QOL
30.4%
Social QOL
17.2%
Environmental
QOL
31.6%
Overall QOL
28.5%
Anxiety
25.9%
Depressive
symptoms
26.3%
Fatigue
−.189
.133
.181
.312
.006
.043
.032
b.00126.3%
Abbreviations: QOL = quality of life; CADS = combined anxiety and
depressive symptoms at T0.
5
L. Van Esch et al. / Journal of Affective Disorders xxx (2011) xxx–xxx
Please cite this article as: Van Esch, L., et al., Combined anxiety and depressive symptoms before diagnosis of breast cancer, J.
Affect. Disord. (2011), doi:10.1016/j.jad.2011.09.012

Page 6

following diagnosis (Nystedt et al., 2003). Galalae et al.
(2005) found that women who received radiotherapy and
chemotherapy had worse QOL than women who received
radiotherapy and hormone therapy, but there were no signif-
icant differences with the group of women that received ra-
diotherapy alone. A possible reason for this positive effect of
hormone therapy may be that women feel safer and worry
less about possible metastases or recurrences because they
are still under active treatment for their disease. There is
some evidence that making the step from active treatment
to being a cancer survivor can cause a decrease in QOL if guid-
ance is not available (Lobb et al., 2009). However, given the
small amount of literature on this topic, there is a need for
more research. Another factor that could potentially have a
role in the effect of hormone therapy is the discontinuation
rate of hormone therapy. According to recent research, proba-
bly about 20% of the patients discontinue the use of Tamoxifen
or other hormone medication after one year, and this number
can reach almost 30% after two years (Barron et al., 2007; van
Herk-Sukel et al., 2010). In our study, data on whether or not a
patient received hormone therapy was retrieved from the med-
ical record of the patient. We could not tracewhat percentageof
the women that were on hormone therapy according to the
medicalrecordactuallytook theirmedication.This information
should be taken into account when interpreting the results.
Thestrengthofthestudyisitsprospective,multicenter,and
longitudinal design. One of the limitations is that part of the
data was not (yet) available due to drop-out and the fact that
some women were included in the study less than two years
ago. Second, a high level of stress was an important reason for
declining participation. Therefore, it is plausible that in the
non-participant group, anxiety levels were higher than in the
groupthatdidparticipate,whichcancauseanunderestimation
of the level of anxiety at baseline. Third, no distinction was
made between the different types of chemotherapy and hor-
monetherapy.Thereisapossibilitythatdifferenttypesofacer-
tain treatmentcan havedifferenteffectson outcomemeasures.
In conclusion, about one in four women, who later receive
the diagnosis breast cancer, had elevated levels of state anxiety
and depressive symptoms (CADS) just before diagnosis. As
expected, this group of patients did worse than the other
participants regarding state anxiety and depressive symptoms
during the two years following primary surgery. CADS at
baseline also emerged as a predictor of worse Physical and
Psychological Health, Overall QOL, and anxiety at 12 months
after surgery, and for worse scores on all outcome measures,
except Social Relationships, at 24 months after surgery.
This implies that women with a higher score on both state
anxiety and depressive symptoms should be identified as soon
as possible in the process of diagnosis and treatment of breast
cancerusingvalidatedquestionnairesorscreeninginstruments.
Onlybyidentifyingthisgroupofpatients,tailoredpsychological
care can be offered.
Role of funding source
This study had no sponsor(s). The funding source had no involvement in
the study design.
Conflict of interest
None of the authors have conflicts of interest to declare.
Acknowledgment
We like to thank the collaborators of the Jeroen Bosch Hospital, Cathar-
ina Hospital, St. Elisabeth Hospital, VieCuri Medical Center, and Medical Cen-
ter Alkmaar for their contribution to the data collection of this study.
References
Aarstad, H.J., Aarstad, A.K., Birkhaug, E.J., Bru, E., Olofsson, J., 2003. The person-
ality and quality of life in HNSCC patients following treatment. European
Journal of Cancer 39, 1852–1860.
Aarstad, A.K., Aarstad, H.J., Olofsson, J., 2008. Personality and choice of coping
predict quality of life in head and neck cancer patients during follow-up.
Acta Oncologica 47, 879–890.
Aarstad, A.K., Beisland, E., Osthus, A.A., Aarstad, H.J., 2011. Distress, quality of
life, neuroticism and psychological coping are related in head and neck
cancer patients during follow-up. Acta Oncologica 50, 390–398.
Andrykowski, M.A.,Donovan, K.A.,Jacobsen,P.B., 2009.Magnitude andcorrelates
of response shift in fatigue ratings in women undergoing adjuvant therapy
for breast cancer. Journal of Pain and Symptom Management 37, 341–351.
Barron, T.I., Connolly, R., Bennett, K., Feely, J., Kennedy, M.J., 2007. Early
discontinuation of tamoxifen: a lesson for oncologists. Cancer 109,
832–839.
Bogaarts, M.P., Den Oudsten, B.L., Roukema, J.A., Van Riel, J.M., Beerepoot, L.V.,
De Vries, J., 2011. Development of the Psychosocial Distress Question-
naire-Breast Cancer (PDQ-BC): a breast cancer-specific screening instru-
mentforpsychosocialproblems.SupportiveCareinCancer19,1485–1493.
Bray, F., Sankila, R., Ferlay, J., Parkin, D.M., 2002. Estimates of cancer incidence
and mortality in Europe in 1995. European Journal of Cancer 38, 99–166.
Brintzenhofe-Szoc, K.M., Levin, T.T., Li, Y., Kissane, D.W., Zabora, J.R., 2009.
Mixedanxiety/depression symptoms
prevalence by cancer type. Psychosomatics 50, 383–391.
Brown, L.F., Kroenke, K., Theobald, D.E., Wu, J., Tu, W., 2010. The association
of depression and anxiety with health-related quality of life in cancer
patients with depression and/or pain. Psycho-Oncology 19, 734–741.
Costa, P.T., McCrae, R.R., 1992. NEO-PI-R: Professional Manual. Psychological
Assessment Resources, Odessa, FL.
Cuijpers, P., Smit, F., Penninx, B.W., de Graaf, R., ten Have, M., Beekman, A.T.,
2010. Economic costs of neuroticism: a population-based study.
Archives of General Psychiatry 67, 1086–1093.
De Vries, J., Van der Steeg, A.F., Roukema, J.A., 2009. Determinants of fatigue
6 and 12 months after surgery in women with early-stage breast cancer:
a comparison with women with benign breast problems. Journal of
Psychosomatic Research 66, 495–502.
Den Oudsten, B.L., Van Heck, G.L., Van der Steeg, A.F., Roukema, J.A., De Vries,
J., 2009. Predictors of depressive symptoms 12 months after surgical
treatment of early-stage breast cancer. Psycho-Oncology 18, 1230–1237.
Den Oudsten, B.L., Van Heck, G.L., Van der Steeg, A.F., Roukema, J.A., De Vries,
J., 2010. Clinical factors are not the best predictors of quality of sexual
life and sexual functioning in women with early stage breast cancer.
Psycho-Oncology 19, 646–656.
Eskelinen, M., Ollonen, P., 2011. Assessment of general anxiety in patients
with breast disease and breast cancer using the Spielberger STAI self
evaluation test: a prospective case–control study in Finland. Anticancer
Research 31, 1801–1806.
Ferlay, J., Parkin, D.M., Steliarova-Foucher, E., 2010. Estimates of cancer
incidence and mortality in Europe in 2008. European Journal of Cancer
46, 765–781.
Galalae, R.M., Michel, J., Siebmann, J.U., Kuchler, T., Eilf, K., Kimmig, B., 2005.
Significant negative impact of adjuvant chemotherapy on health-related
quality of life (HR-QoL) in women with breast cancer treated by
conserving surgery and postoperative 3-D radiotherapy. A prospective
measurement. Strahlentherapie und Onkologie 181, 645–651.
Goncalves, V., Jayson, G., Tarrier, N., 2008. A longitudinal investigation of
psychological morbidity in patients with ovarian cancer. British Journal
of Cancer 99, 1794–1801.
Greene, F.L., Page, D.L., Fleming, I.D., Fritz, A.G., Balch, C.M., Haller, D.G.,
Morrow, M., 2002. American Joint Committee on Cancer Staging Manu-
al. Springer, New York, NY.
Hann, D., Winter, K., Jacobsen, P., 1999. Measurement of depressive symptoms
incancerpatients:evaluationoftheCenterforEpidemiologicalStudiesDe-
pression Scale (CES-D). Journal of Psychosomatic Research 46, 437–443.
Hartl, K., Engel, J., Herschbach, P., Reinecker, H., Sommer, H., Friese, K.,
2010. Personality traits and psychosocial stress: quality of life over 2
years following breast cancer diagnosis and psychological impact fac-
tors. Psycho-Oncology 19, 160–169.
Henselmans, I., Coyne, J.C., Sanderman, R., De Vries, J., Ranchor, A.V., 2009. Dis-
tinct trajectories of anxiety, depression and nonspecific distress following
diagnosis of breast cancer. In: Psychological well-being and perceived
ina largecancer cohort:
6
L. Van Esch et al. / Journal of Affective Disorders xxx (2011) xxx–xxx
Please cite this article as: Van Esch, L., et al., Combined anxiety and depressive symptoms before diagnosis of breast cancer, J.
Affect. Disord. (2011), doi:10.1016/j.jad.2011.09.012

Page 7

control after a breast cancer diagnosis. Dissertation, University of Groning-
en, Groningen.
Hoekstra, H.A., Ormel, J., De Fruyt, F., 1996. Handleiding bij de NEO
Persoonlijkheids vragenlijsten NEO-PI-R, NEO-FFI [Manual for the NEO
Personality Inventories NEO-PI-R and NEO-FFI]. Swets & Zeitlinger B.V.,
Lisse, the Netherlands.
Karakoyun-Celik, O., Gorken, I., Sahin, S., Orcin, E., Alanyali, H., Kinay, M.,
2010. Depression and anxiety levels in woman under follow-up for
breast cancer: relationship to coping with cancer and quality of life.
Medical Oncology 27, 108–113.
Lahey, B.B., 2009. Public health significance of neuroticism. The American
Psychologist 64, 241–256.
Lai, B.P., Tang, C.S., Chung, T.K., 2010. A prospective longitudinal study
investigating neuroticism and mastery as predictors of quality of life
among Chinese gynecologic cancer survivors. Quality of Life Research
19, 931–941.
Lobb, E.A., Joske, D., Butow, P., Kristjanson, L.J., Cannell, P., Cull, G., August-
son, B., 2009. When the safety net of treatment has been removed: pa-
tients' unmet needs at the completion of treatment for haematological
malignancies. Patient Education and Counseling 77, 103–108.
Marteau, T.M., Bekker, H., 1992. The development of a six-item short-form of
the state scale of the Spielberger State-Trait Anxiety Inventory (STAI).
The British Journal of Clinical Psychology 31 (Pt 3), 301–306.
Massie, M.J., 2004. Prevalence of depression in patients with cancer. Journal
of the National Cancer Institute. Monographs 57–71.
Michielsen, H.J., De Vries, J., Van Heck, G.L., 2003. Psychometric qualities of a
brief self-rated fatigue measure: The Fatigue Assessment Scale. Journal
of Psychosomatic Research 54, 345–352.
Michielsen, H.J., Van der Steeg,A.F., Roukema,J.A., DeVries,J., 2007. Personality
andfatigueinpatientswithbenignormalignantbreastdisease.Supportive
Care in Cancer 15, 1067–1073.
Mitchell, A.J., Chan, M., Bhatti, H., Halton, M., Grassi, L., Johansen, C., Meader, N.,
2011. Prevalence of depression, anxiety, and adjustment disorder in
oncological, haematological, and palliative-care settings: a meta-analysis
of 94 interview-based studies. The Lancet Oncology 12, 160–174.
Montazeri, A., 2008. Health-related quality of life in breast cancer patients: a
bibliographic review of the literature from 1974 to 2007. Journal
of Experimental & Clinical Cancer Research 27, 32.
Nystedt, M., Berglund, G., Bolund, C., Fornander, T., Rutqvist, L.E., 2003. Side
effects of adjuvant endocrine treatment in premenopausal breast cancer
patients: a prospective randomized study. Journal of Clinical Oncology
21, 1836–1844.
Ollonen, P., Lehtonen, J., Eskelinen, M., 2005. Anxiety, depression, and the
history of psychiatric symptoms in patients with breast disease: a pro-
spective case–control study in Kuopio, Finland. Anticancer Research 25,
2527–2533.
Radloff, L.S., 1977. The CES-D Scale: a self-report depression scale for research in
the general population. Applied Psychological Measurement 1, 385–401.
Schreier, A.M., Williams, S.A., 2004. Anxiety and quality of life of women who
receive radiation or chemotherapy for breast cancer. Oncology Nursing
Forum 31, 127–130.
Schroevers, M.J., Sanderman, R., van Sonderen, E., Ranchor, A.V., 2000. The
evaluation of the Center for Epidemiologic Studies Depression (CES-D)
scale: depressed and positive affect in cancer patients and healthy
reference subjects. Quality of Life Research 9, 1015–1029.
So, W.K., Marsh, G., Ling, W.M., Leung, F.Y., Lo, J.C., Yeung, M., Li, G.K., 2010.
Anxiety, depression and quality of life among Chinese breast cancer
patients during adjuvant therapy. European Journal of Oncology Nursing
14, 17–22.
Spielberger, C.D., Gorsuch, R.L., Lushene, R.E., 1970. The State-Trait Anxiety
Inventory Manual. Consulting Psychologists Press, Palo Alto, CA.
Sprangers, M.A., 1996. Response-shift bias: a challenge to the assessment of
patients' quality of life in cancer clinical trials. Cancer Treatment Reviews
22 (Suppl A), 55–62.
Sugawara, Y., Akechi, T., Okuyama, T., Matsuoka, Y., Nakano, T., Inagaki, M.,
Imoto, S., Fujimori, M., Hosaka, T., Uchitomi, Y., 2005. Occurrence of
fatigue and associated factors in disease-free breast cancer patients
without depression. Supportive Care in Cancer 13, 628–636.
Taira, N., Shimozuma, K., Shiroiwa, T., Ohsumi, S., Kuroi, K., Saji, S., Saito, M.,
Iha, S., Watanabe, T., Katsumata, N., 2011. Associations among baseline
variables, treatment-related factors and health-related quality of life 2
years after breast cancer surgery. Breast Cancer Research and Treatment
128, 735–747.
Van der Bij, A.K., De Weerd, S., Cikot, R.J., Steegers, E.A., Braspenning, J.C.,
2003. Validation of the Dutch short form of the state scale of the
Spielberger State-Trait Anxiety Inventory: considerations for usage in
screening outcomes. Community Genetics 6, 84–87.
Van der Ploeg, H.M., Defares, P.B., Spielberger, C.D., 1980. ZBV. A Dutch-
language Adaptation of the Spielberger State-Trait Anxiety Inventory.
Swets&Zeitlinger, Lisse, The Netherlands.
Van der Steeg, A.F., De Vries, J., Van der Ent, F.W., Roukema, J.A., 2007.
Personality predicts quality of life six months after the diagnosis and
treatment of breast disease. Annals of Surgical Oncology 14, 678–685.
van der Steeg, A.F., De Vries, J., Roukema, J.A., 2010. Anxious personality and
breast cancer: possible negative impact on quality of life after breast-
conserving therapy. World Journal of Surgery 34, 1453–1460.
Van Esch, L., Den Oudsten, B.L., De Vries, J., 2011. The World Health
Organization Quality of Life instrument-Short Form (WHOQOL-BREF)
in women with breast problems. International Journal of Clinical and
Health Psychology 11, 5–22.
van Herk-Sukel, M.P., van de Poll-Franse, L.V., Voogd, A.C., Nieuwenhuijzen,
G.A., Coebergh, J.W., Herings, R.M., 2010. Half of breast cancer patients
discontinue tamoxifen and any endocrine treatment before the end of
the recommended treatment period of 5 years: a population-based anal-
ysis. Breast Cancer Research and Treatment 122, 843–851.
Weinstock, L.M., Whisman, M.A., 2006. Neuroticism as a common feature of
the depressive and anxiety disorders: a test of the revised integrative hi-
erarchical model in a national sample. Journal of Abnormal Psychology
115, 68–74.
Weitzner, M.A., Meyers, C.A., Stuebing, K.K., Saleeba, A.K., 1997. Relationship
between quality of life and mood in long-term survivors of breast cancer
treated with mastectomy. Supportive Care in Cancer 5, 241–248.
WHOQOL-Group, 1998. The World Health Organization Quality of Life
Assessment (WHOQOL): development and general psychometric prop-
erties. Social Science & Medicine 46, 1569–1585.
Wong, W.S., Fielding, R., 2007. Change in quality of life in Chinese women
with breast cancer: changes in psychological distress as a predictor.
Supportive Care in Cancer 15, 1223–1230.
Yen, J.Y., Ko, C.H., Yen, C.F., Yang, M.J., Wu, C.Y., Juan, C.H., Hou, M.F., 2006.
Quality of life, depression, and stress in breast cancer women
outpatients receiving active therapy in Taiwan. Psychiatry and Clinical
Neurosciences 60, 147–153.
7
L. Van Esch et al. / Journal of Affective Disorders xxx (2011) xxx–xxx
Please cite this article as: Van Esch, L., et al., Combined anxiety and depressive symptoms before diagnosis of breast cancer, J.
Affect. Disord. (2011), doi:10.1016/j.jad.2011.09.012