Chronic psychological stress and its impact on the development of aggressive breast cancer

Abstract

Objective:
To investigate the clinicopathological findings of women diagnosed with breast cancer and study the impact of chronic psychological stress on the pathological characteristics of these tumors.

Methods:
We investigated a cohort composed of women diagnosed with breast cancer and divided into two groups. One group was categorized as presenting with chronic psychological stress (by using the Self-Reporting Questionnaire - SRQ-20). Another group of women with breast cancer, but with no previous history of chronic psychological stress, comprised the Control Group. Clinical and pathological data were assessed.

Results:
Women presenting with a history of chronic distress were significantly overweight when compared to the Control Group. Furthermore, it was observed that these stressed women also had a significant percentage of aggressive breast cancer subtype, the HER2 amplified tumor, which could be putatively associated with the loss of immunosurveillance.

Conclusion:
Our findings suggested an interaction among chronic psychological stress, overweight, and the development of more aggressive breast tumors.

Full text

einstein. 2015;13(3):352-6
ORIGINAL ARTICLE
Chronic psychological stress and its impact on the
development of aggressive breast cancer
Estresse psicológico crônico e seu impacto no desenvolvimento
de neoplasia mamária agressiva
Thayse Fachin Cormanique1, Lirane Elize Defante Ferreto de Almeida1, Cynthia Alba Rech2,
Daniel Rech2, Ana Cristina da Silva do Amaral Herrera3, Carolina Panis1
ABSTRACT
Objective: To investigate the clinicopathological findings of women
diagnosed with breast cancer and study the impact of chronic
psychological stress on the pathological characteristics of these
tumors. Methods: We investigated a cohort composed of women
diagnosed with breast cancer and divided into two groups. One group
was categorized as presenting with chronic psychological stress
(by using the Self-Reporting Questionnaire − SRQ-20). Another
group of women with breast cancer, but with no previous history of
chronic psychological stress, comprised the Control Group. Clinical
and pathological data were assessed. Results: Women presenting
with a history of chronic distress were significantly overweight
when compared to the Control Group. Furthermore, it was observed
that these stressed women also had a significant percentage of
aggressive breast cancer subtype, the HER2 amplified tumor, which
could be putatively associated with the loss of immunosurveillance.
Conclusion: Our findings suggested an interaction among chronic
psychological stress, overweight, and the development of more
aggressive breast tumors.
Keywords: Stress, psychological; Breast neoplasms; Overweight; Obesity;
Monitoring, immunologic
RESUMO
Objetivo: Investigar os achados clínico-patológicos de mulheres
diagnosticadas com câncer de mama e estudar o impacto do estresse
psicológico crônico nas características patológicas desses tumores.
Métodos: Investigamos uma coorte composta por mulheres
diagnosticadas com câncer de mama divididas em dois grupos. O
primeiro foi classificado pela apresentação de estresse psicológico
crônico (por meio do Self-Reporting Questionnaire − SRQ-20). Outro
grupo de mulheres com câncer de mama, mas sem história prévia
de estresse psicológico crônico, foi denominado Grupo Controle.
Os dados clínicos e patológicos foram avaliados. Resultados:
As mulheres com histórico de estresse crônico apresentaram-se
significativamente acima do peso quando comparadas com o Grupo
Controle. Além disso, verificou-se que estas mulheres estressadas
apresentaram um porcentual significativo de um subtipo de câncer
de mama agressivo, o HER2, o que poderia estar associado à possível
perda da imunovigilância. Conclusão: Nossos resultados sugeriram
uma ligação entre o estresse psicológico crônico, o excesso de peso
e o desenvolvimento de tumores de mama com maior agressividade.
Descritores: Estresse psicológico; Neoplasias da mama; Sobrepeso;
Obesidade; Monitorização imunológica
INTRODUCTION
Breast cancer is a multifactorial disease, consisting of a
public health problem worldwide. Some factors that
interact among themselves contribute to the high
incidence of breast cancer, including family history,
presence of high-susceptibility genes, excessive body
weight, and chronic stress.(1-3)
In this context, chronic psychological stress is a
common finding reported by cancer patients. Stressful
lif
e events are considered important components that can
affect the emotional state of the individuals, and their
association with loss of social support is even related to
significantly shortened survival in breast cancer patie
nts.(4)
There is a significant positive association between early life
distress and breast cancer development.(5) Furthermore,
1 Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brazil.
2 Hospital do Câncer de Francisco Beltrão, Francisco Beltrão, PR, Brazil.
3 Pontifícia Universidade Católica do Paraná, Londrina, PR, Brazil.
Corresponding author: Carolina Panis – Rua Maringá, 1.200 – Vila Nova – Zip code: 85605-010 – Francisco Beltrão, PR, Brazil – Phone: (55 46) 3055-3026 – E-mail: carolpanis@hotmail.com
Received on: Mar 1, 2015 – Accepted on: Aug 10, 2015
Conflict of interest: none.
DOI: 10.1590/S1679-45082015AO3344

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Chronic psychological stress and its impact on the development of aggressive breast cancer
einstein. 2015;13(3):352-6
a systematic analysis of some studies published in the
last 30 years, investigating the causal attributions in
breast cancer patients, demonstrated that breast cancer
patient survivors consistently associate their disease
with emotional distress, among another factors.(6)
Concerning the biological impact of chronic distress,
the sustained psychological stress alone can lead to weight
gain through several biological mechanisms,(2) which
may potentially result in loss of immunosurveillance.(7)
Competent immune responses are the major defense
against cancer; therefore, their impairment is strongly
associated with the development of several types
of cancer, including breast tumors that confer poor
prognosis.(8)
Although the relation between cancer development
and chronic stress has been described, little is known
concerning the impact of chronic psychological stress
in the phenotype of breast tumors. To clarify this
question, we investigated if women presenting with
chronic emotional distress could exhibit more aggressive
phenotypes of breast cancer.
OBJECTIVE
To investigate clinicopathological findings from women
diagnosed with breast cancer, and study the impact
of chronic psychological stress in the pathological
characteristics of tumors.
METHODS
Study design
This study included women living in the State of Paraná,
diagnosed with infiltrative carcinoma of the breast, in
the period from August 2013 to July 2014. They had
been previously scheduled to undergo chemotherapy
on a set day of the week, the same period. The selection
of patients was conducted at the Centro de Oncologia
de Francisco Beltrão (Ceonc), in the city of Francisco
Beltrão (PR), Brazil. The inclusion criteria adopted
were women with infiltrative ductal carcinoma of breast,
uni- or bilateral, diagnosed between August 2013 and
July 2014, eligible according to the Self-Reporting
Questionnaire (SRQ-20) as stress or non-stress cohorts.
To determine the sample size, we applied the following
statistical calculation, in which: N0 = size number,
Z = confidence interval, P = probability, D = error
margin, n = sample size, and N = population size:
and
Considering that (1) our population was approximately
100 thousand inhabitants; (2) a p value of 0.05; (3)
according to the Instituto Nacional de Câncer estimate,
the incidence of breast cancer in this region was roughly
61 cases per 100 thousand women; (4) there were about
30 thousand women in the age range of risk for breast
cancer in this area, thus, we have that the minimal
sample size of about 18 patients was needed. Taking
into account the period of the study and the fact that
we worked with patients previously scheduled on a fixed
day of the week to undergo chemotherapy, we decided
to include 17 patients in each group. In this context, this
study enrolled 34 women diagnosed with infiltrative
ductal carcinoma of the breast. This study was previously
approved by the Institutional Review Board, and all
participants signed the Informed Consent Form. The
research project was approved by the National Council
of Scientific Research Ethics Committee, under number
497.050 and CAAE: 22027213.7.0000.0107. Clinical
records were assessed and the data collected included
age at diagnosis, weight, height, comorbidities, TNM
classification, and chemotherapy regimen.
For determining the chronic psychological stress
status of patients, we conducted an initial interview to
verify the social support of the patient (family income,
type of residence, level of education, life style, and social
relationships), since we did not know if the patients were
from different social conditions. Because all patients
reported similar socioeconomic data, we continued the
study by applying the SRQ-20 for psychiatric disorder
screening.(9) This interview was applied to patients that
were in the hospital for routine chemotherapy treatment
during the period of the study.
The women enrolled in this study were categorized
into two groups: Control Group (n=17), with women
diagnosed with breast cancer with no previous history of
chronic psychological stress; Stress Group (n=17), with
women diagnosed with breast cancer with a past history
of chronic psychological stress.
Molecular subtyping of breast tumors by immunohis-
to chemistry
Formalin-fixed, paraffin-embedded samples from tumor
biopsies were immunostained with primary antibodies
for estrogen receptor (ER; anti-human estrogen receptor
alpha, clone 1D5 at 1:600; Dako, Dinamarca), progesterone
receptor (PR; anti-human progesterone, clone PGR 636 at
1:500; Dako, Dinamarca), and human epidermal growth
receptor 2 (HER-2, anti-human HER2-pY-1248, clone
PN2A at 1:500; Dako, Dinamarca), in association with
a commercial immunohistochemistry kit. Samples were

einstein. 2015;13(3):352-6
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Cormanique TF, Almeida LE, Rech CA, Rech D, Herrera AC, Panis C
considered positive for ER/PR when at least 10% of the
tumor cell nuclei were stained. HER2 was considered
overexpressed when strong membrane staining (3+)
was detected or when amplification of HER2 in samples
with moderate (2+) membrane staining was observed
in Fluorescent in Situ Hybridization (FISH) analysis.
Samples were scored and categorized. They were
considered HER2-positive when the HER2 IHC score
was 3+, and HER-negative when the score was 1+ or
zero. Samples with a 2+ score were analyzed by FISH to
detect HER2 amplification (HER2 FISH pharmDx™;
Dako, Dinamarca). Samples with a 2+ IHC score and
an amplified result in FISH were considered HER2-
positive, while samples with a 2+ IHC score and a non-
amplified in FISH were considered HER2-negative.(10)
Data analysis
For clinicopathological parameters, data were expressed
as the mean ± standard error of the mean. All data were
compared by using the non-parametric Mann-Whitney
test. A p value <0.05 was considered significant. All
statistical analyses were performed using the GraphPad
Prism software version 5.0 (GraphPad Prism Software,
San Diego, CA, USA).
RESULTS
The mean age at diagnosis was 60.2 years. We found that
40% of patients were diagnosed as having breast cancer
by routine mammograms, and 53% reported perception
of nodules in the breasts by self-examination. The
remaining 7% had no palpable nodules, but felt pain in
breast and went to a doctor for this reason. Regarding
the verification of chronic psychological stress (Table 1),
it was observed that 79% reported a history of chronic
psychological stress. The most common traumas
related were death of family members, abandonment
by a partner, employment loss, sexual abuse, and major
depression. Moreover, 73% of patients associated the
occurrence of chronic psychological stress with breast
cancer development. A total of 47% were classified
as potential carriers of psychic disorders by the SRQ-
20. The patients who reported a positive history of
psychological stress were categorized to form the Stress
Group.
Aiming to understand the clinicopathological impact
of chronic psychological stress on breast cancer and
clinical features, we compared the data from the Stress
Group with a control cohort, composed of women
diagnosed with breast cancer with no past history of
chronic emotional stress. In this context, figure 1 shows
that the Control Group comprised mainly women with
breast cancer presenting with a normal body mass index
(BMI) (90%). On the other hand, patients from the
Stress Group exhibited a significant predominance of
overweight women (54%; p=0.0041). The molecular
subtyping of breast tumors (Figure 2) indicated the
predominance of HER2 positive tumors in the Stress
Group when compared to controls (31±1.41% versus
12±0.05%; p=0.0136).
Table 1. Main parameters employed for chronic psychological stress characterization
Parameter Mean percentage
Family relationships
Good 85
Types of psychological distress reported
Death of relatives 36
Loss of employment 9
Abandonment by partner 18
Sexual abuse 9
Depression 9
Other emotional distress 19
Received support during the treatment
Yes 93
Presented difficulty for abandoning work
Yes 57
Believes that chronic stress is associated as a cause of
the disease
Yes 73
Risk for developing mental disorders
Yes 47
*Statistically significant difference (p<0.05), Mann-Whitney test; BMI: body mass index.
Figure 1. Analysis of body mass indexes. We used the International
Classification of Body Mass Index to categorize the patients into normal weight
(BMI up to 25kg/m2) or overweight (BMI above 25kg/m2)

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Chronic psychological stress and its impact on the development of aggressive breast cancer
einstein. 2015;13(3):352-6
stress and overweight are important risk factors for
breast cancer development.(1,2) Under chronic stress
conditions, there is a systemic rise in cortisol levels,
which increases appetite and favors the storage of lipids
in adipose tissue.(2) This set of biological events that
contributes to weight gain is made up of relevant risk
factors for breast cancer in the modern society,(8) and
may partly help to understand the results found in the
present study. Overweight increases the risk for breast
cancer recurrence after the primary tumor excision, and
significantly reduces the overall survival of patients(13)
by affecting the spreading of breast cancer cells.(14) This
evidence helps to understand the important percentage
of women with locally advanced disease upon diagnosis
in the Stress Group.
It is well-established that chronic inflammation
induced by the excessive availability of lipids found during
overweight and obesity conditions can promote cancer
spreading and aggressiveness, a process mediated by
tumor-driven cytokines.(1) Together, chronic psychological
stress and overweight can impair immunosurveillance
as shown in breast cancer patients by Varker et al.(7)
Altogether, these factors are putative stimuli for developing
breast tumors with aggressive characteristics.
Based on this hypothesis, we investigated the
phenotypic profile of breast tumors in both groups. Our
data revealed that women with a history of psychological
stress displayed a significant percentage of tumors
overexpressing HER2. HER2-amplified breast tumors
promote aggressive disease, with poor prognosis(14-16)
due to its rapid proliferation and spreading.(17,18) These
tumors are reported in overweight/obese women,
which exhibit enhanced disease spreading in relation
to non-obese patients.(8) In this case, the excessive
bioavailability of lipids seems to favor the epithelial
transformation of cells into HER2-amplified neoplastic
cells.(19) Menendez(20) demonstrated that HER2 cancers
take advantage of lipids as their energy source, which
is strongly favored in environments rich in fat, such as
the breast tissue of overweight or obese women. We
further observed that most patients presented with
the HER2-amplified tumor mass located in the left
breast. The left mammary gland frequently presents
more breast tissue than the right, which may benefit fat
accumulation and cancer development.(21)
These data support the hypothesis that the women
enrolled in the present study have a complex chain formed
by historical factors of psychological stress, over
weight,
and development of phenotypically aggressive breast
tumors. Our preliminary findings suggest a “vicious circle”
involving chronic psychological stress, overweight, and
breast cancer aggressiveness.
HER2: human epithelial growth factor receptor 2; TN: triple negative tumors. *Significant statistical difference (p<0.05),
Mann-Whitney’s test.
Figure 2. Molecular subtyping of tumors. The images represent the IHC labeling
for HER2
DISCUSSION
For the last years, breast cancer has been the leading
malignant neoplasm in women worldwide. This fact
deserves attention, since the list of risk factors related
with this disease is growing. Our aim was to investigate
women diagnosed with breast cancer who reported
a past history of chronic psychological stress and its
impact on clinicopathological aspects of breast cancer.
To reach this goal we initially applied the SRQ-20 as a
psychiatric screening tool to compose the stress cohort.
The SRQ-20 is an instrument developed by the World
Health Organization (WHO) to screen psychiatric disorders
in patients. It detects symptoms, such as anxiety, depression,
and psychosomatic complaints with adequate accuracy.
(11)
The SRQ-20 was previously applied and validated in
the Brazilian population,(9) including breast cancer
patients.(12) Our data demonstrated that about 47% of
patients seen during the period of the SRQ-20 application
were categorized as presenting with psychiatric distress
and included in the Stress Group.
We further selected another cohort of patients who
had a similar clinical history (age at diagnosis, family
history, general health status, and family income), but
with no prior report of chronic psychological stress to
compose the Control Group. We employed this approach
aiming to compare the impact of chronic emotional
distress on clinical and pathological characteristics
of breast tumors, in both groups. Our data indicated
that a significant portion of the women enrolled in
the Stress Group were overweight when compared
to those of the Control Group. Both psychological

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Cormanique TF, Almeida LE, Rech CA, Rech D, Herrera AC, Panis C
The main limitations of our study included the small
sample size and the need for a long-term follow-up of
patients to examine the recurrence of the disease and
responsiveness to chemotherapy.
CONCLUSION
Our data suggest that chronic psychological stress may
represent a considerable risk factor for weight gain and
development of aggressive tumors in women diagnosed
with breast cancer, such as human epidermal growth
factor receptor 2-amplified breast tumors.
ACKNOWLEDGEMENTS
The authors are grateful to the Conselho Nacional
de Desenvolvimento Científico e Tecnológico (CNPq)
for grant support, and to the Centro de Oncologia de
Francisco Beltrão (Ceonc) staff for providing excellent
technical support.
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