Allergy-Related Diseases and Risk of Breast Cancer: The Role of Skewed Immune System on This Association

Abstract

Background:
The role of allergy in breast cancer (BC) development remains inconclusive. A comprehensive review article is required to present and discuss all findings on this topic and to clarify the association between allergic disorders and the risk of BC.

Objective:
We aimed to explain the association between atopy, different types of allergic disorders, and the risk of BC. Moreover, we explored the immunological mechanism behind this association.

Methods:
We electronically reviewed publications in PubMed from 1979 to 2018 relating to atopy, allergy, asthma, atopic dermatitis, allergic rhinitis, food allergy, drug allergy, immunoglobulin E (IgE) or prick test, and BC.

Results:
Most of the identified studies demonstrated nonsignificant results. However, the pattern of the results indicated an increased risk of BC in individuals with a history of allergies. The majority of studies reported higher prevalence of atopic dermatitis and allergic rhinitis among individuals with BC compared to the control groups. Similarity, most of the studies revealed an increased risk of BC among people with a positive history of atopic using IgE specific or prick test. However, a null association was reported in most of the asthmatic studies, and controversial results were detected in the individuals with history of food and drug allergies.

Conclusion:
The majority of findings were not statistically significant. Moreover, bias and other methodological problems are the major issues, which make it challenging to compare the findings of different studies and reach a strong conclusive result. However, the pattern of the results from most studies indicated that allergic diseases might be associated with an increased risk of BC. Skewed immune system toward T-helper 2 might have an important role in this association.

Full text

Review
Allergy-Related Diseases and Risk of Breast
Cancer: The Role of Skewed Immune
System on This Association
Fatemeh Sadeghi, MSc
1,2
and Mohammad Shirkhoda, MD
3
Abstract
Background: The role of allergy in breast cancer (BC) development remains inconclusive. A comprehensive review article
is required to present and discuss all findings on this topic and to clarify the association between allergic disorders and the
risk of BC.
Objective: We aimed to explain the association between atopy, different types of allergic disorders, and the risk of BC.
Moreover, we explored the immunological mechanism behind this association.
Methods: We electronically reviewed publications in PubMed from 1979 to 2018 relating to atopy, allergy, asthma, atopic
dermatitis, allergic rhinitis, food allergy, drug allergy, immunoglobulin E (IgE) or prick test, and BC.
Results: Most of the identified studies demonstrated nonsignificant results. However, the pattern of the results indicated an
increased risk of BC in individuals with a history of allergies. The majority of studies reported higher prevalence of atopic
dermatitis and allergic rhinitis among individuals with BC compared to the control groups. Similarity, most of the studies
revealed an increased risk of BC among people with a positive history of atopic using IgE specific or prick test. However,
a null association was reported in most of the asthmatic studies, and controversial results were detected in the individuals
with history of food and drug allergies.
Conclusion: The majority of findings were not statistically significant. Moreover, bias and other methodological problems
are the major issues, which make it challenging to compare the findings of different studies and reach a strong conclusive
result. However, the pattern of the results from most studies indicated that allergic diseases might be associated with an
increased risk of BC. Skewed immune system toward T-helper 2 might have an important role in this association.
Keywords
breast cancer, allergy, atopy, asthma, atopic dermatitis, allergic rhinitis, immunoglobulin E
Introduction
The dual role of allergy in cancer prevention or cancer
development is highly controversial over the past few
decades. Several hypotheses have been put forward to
explicit the controversial findings.
It is proposed that allergic disorders could protect the
body against cancer development via promoting the
“immune surveillance,”
1
which states that the immune
system is able to detect and eliminate malignant cells
more effectively in a hypersensitive state such as allergy.
In immunoglobulin E (IgE)-mediated allergies, high level
of IgE could bind to the tumor-specific antigens and
facilitate the antibody-dependent cellular cytotoxicity
and antibody-dependent cellular phagocytosis mecha-
nisms.
2
Moreover, IgE could stimulate the production
of reactive oxygen metabolites and nitric oxide, which
are important in tumor eradication.
3
1
Department of Immunology, School of Medicine, Iran University of
Medical Sciences, Tehran, Iran
2
Cancer Immunology Project (CIP), Universal Scientific Education and
Research Network (USERN), Tehran, Iran
3
Department of Surgical Oncology, Cancer Institute of Iran, Tehran
University of Medical Sciences, Tehran, Iran
Corresponding Author:
Mohammad Shirkhoda, Department of Surgical Oncology, Cancer Institute
of Iran, Imam Khomeini Clinical Complex, Western Pole of Keshavarz
Boulevard, Tehran 14197, Iran.
Email: mshirkhoda@sina.tums.ac.ir
Allergy & Rhinology
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Another theory which declares the protective role of
allergic disorders in cancer development is prophylaxis
theory.
1,4
This theory explains that allergic reactions
could prophylactically expel toxins, microorganisms, or
environmental particles that may contain carcinogens
from the body.
5
The decreased risk of brain and lung
cancers in some epidemiological studies supports this
hypothesis.
6–8
In contrast to the previous theories, the antigenic
stimulation theory supports a positive association
between history of allergic disorders and the risk of
cancer. It suggests that inflammatory conditions associ-
ated with the allergic diseases may induce oxidative
damage.
9
The oxidative damage cause mutations in the
genes that are involved in cell cycle, DNA damage
repair, and apoptosis, increasing the risk of cancer devel-
opment.
1,10,11
Another recent hypothesis proposes that
the recurrent injury and repair processes in the chronic
inflammatory condition associated with an allergy could
eventually skew T-lymphocyte response from T-helper 1
(Th1) toward Th2, which implies an important role in
carcinogenesis.
10
Th1 cells are associated with the sup-
pression and eradication of tumor disease, and Th-2 cells
are involved in the allergy and parasite diseases. Skewed
immune system toward Th2 in the long term is associat-
ed with the suppression of immune system, which is
involved in the tumor suppression. Th2 polarization
could increase the systemic level of types 2 cytokines
such as interleukin (IL)-4, IL-5, and IL-13 or cause the
systemic suppression of interferon-c, IL-12, and IL-18,
which are important in tumor eradication.
12
Recent studies demonstrated that the association
between history of allergic disorders and the risk of
cancer varied by types of cancer.
13–16
An inverse associ-
ation between allergy markers and risk of colorectal
cancer, pancreatic cancer, and larynx cancer; a direct
association for lymphoma, prostate cancer, and myelo-
ma; and controversial results in breast cancer (BC) and
lung cancer have been reported in several studies.
10,16–18
In addition, the complex findings show that the
allergy–cancer relationship is not only governed by the
specific cancer site but also with the specific allergic dis-
orders. For instance, the risk of lung cancer significantly
increased in patients with asthma-specific history, but no
strong evidence was reported between lung cancer and
the other types of allergic conditions.
13
Therefore, the
role of different types of allergic disorders in each
cancer type should be investigated specifically.
BC is the most commonly diagnosed cancer among
women worldwide,
19,20
which imposes high financial
burden to health-care systems.
21
A negative associa-
tion,
22,23
a positive association,
24–26
and no association
27
relating to the allergic disorders and risk of BC have
been reported in the several studies. These conflicting
results may be due to the pleiotropic nature of allergic
immunity or different methods of measurement in the
epidemiological studies. To best of our knowledge, no
comprehensive study had been conducted to clarify the
association between different types of allergic disorders
and the risk of BC. Therefore, this review was designed
to be more focus on BC and present and discuss all
published epidemiological studies concerning the effect
of atopy and different types of allergic disorders in the
risk of BC. Moreover, we have tried to explore
the immunological mechanism, mainly, the role of
Th2-type immune system, behind this association.
History of Any Allergic Condition
A positive association between combined history of any
allergic condition and risk of BC has been observed con-
sistently in the cohort studies,
25,26,28
although the results
did not reach statistically significant (Table 1). The
cohort of Sweden reported a history of any allergy
could increase the risk of BC by 50% (standardized
incidence rate [SIR]: 1.5; 95% confidence interval [CI],
0.8–2.6).
28
Similarity, a slightly elevated risk of BC was
detected in 2 cohort studies conducted in the
United States.
25,26
In contrast, case–control studies did not clearly indi-
cate a history of any allergic condition as a risk factor
for BC developments. A case–control study designed in
Canada found a significant small reduction in the risk of
BC (odds ratio [OR]: 0.9; 95% CI, 0.8–1.0) among par-
ticipant with history of any types of allergic disorders.
23
The other case–control studies reported no association
between asthma and the risk of BC.
16,29,30
History of Asthma
With 1 exception,
29
the epidemiological studies reported
no strong association or a positive association between
history of asthma and the risk of BC (Table 2).
23,27,31–36
A nonsignificant increased risk of BC among people
with a history of physician-diagnosed asthma was
observed in a case–control study in Germany (OR: 1.2;
95% CI, 0.7–2.2).
16
Likewise, a cohort study designed in
Sweden demonstrated 40% increased incidence risk of
BC (SIR: 1.4; 95% CI, 0.6–2.7).
28
In this cohort study,
individuals who reported symptoms such as dyspnea or
wheezing on exposure to allergens were classified as
bronchial asthmatic participants. Another study con-
ducted in the United States reported a nonsignificant
positive association between BC incidence rate and his-
tory of physician-diagnosed asthma (relative risk [RR]:
1.2; 95% CI, 0.7–2.0).
26
The other epidemiological studies reported no associ-
ation between asthma and risk of BC. The asthmatic
participants who were diagnosed by physician were
included in these studies.
23,27,31–36
2Allergy & Rhinology 10(0)

Table 1. Studies of the Association Between History of Any Types of Allergic Disorder and the Risk of Breast Cancer.
Studies Country Study Design Sample Size
How Allergies
Are Defined
RR/OR/SIR/HR/SMR
(95% CI) Main Finding Reference Group
Confounding
Factors
Shirkhoda
et al.
29
Iran Case–control Case (168)
Control (165)
Physician-diagnosed
or ISAAC
questionnaire
OR: 1.0 (0.6–1.7) No association No history of allergy Yes
a
Lowcock
et al.
23
Canada Case–control Case (3101)
Control (3471)
Physician-diagnosed All participant:
OR: 0.9 (0.8–1.0)
Premenopausal:
OR: 0.9 (0.7–1.1)
Postmenopausal:
OR: 0.8 (0.7–1.0)
All participant:
reduced risk
Premenopausal:
no association
Postmenopausal:
reduced risk
No history of allergy Yes
b
Wang et al.
16
Germany Case–control Case (381)
Control (2367)
Physician-diagnosed OR: 1.1 (0.8–1.6) No association No atopy (no specific/
total IgE positive)
Ye s
c
Hedderson
et al.
30
USA Case–control Cases (723)
Controls (958)
Physician-diagnosed Overall: OR: 0.9
(0.8–1.1)
Age <35 years:
OR: 1.3 (0.9–1.8)
Age >35 years:
OR: 0.8 (0.6–0.1)
Overall: no
association
Age <35 years:
increased risk
Age >35 years:
reduced risk
No history of allergy Age, smoking and
education
Eriksson
et al.
28
Sweden Cohort Participant with
any allergy (N/S)
Self-reported
symptoms
SIR: 1.5 (0.8–2.6) Increased risk Incidence rate in the
general population
in the country
No
Mills et al.
26
USA Cohort Participant with
any allergy (N/S)
Self-reported RR: 1.2 (0.9–1.6) Increased risk No history of allergy Yes
d
McWhorter
25
USA Cohort Participant with
any allergy (N/S)
Physician-diagnosed ROR: 1.2 (0.6–2.4) Increased risk No history of allergy Yes
e
Abbreviations: CI, confidence interval; HR, hazard ratio; IgE, Immunoglobulin E; ISAAC, International Study of Asthma and Allergies in Childhood; N/S, not specified; OR, odds ratio; ROR, risk OR; RR,
relative risk; SIR, standardized incidence rate; SMR, standardized mortality ratio.
Bold values indicate statistical significance.
a
Age, breast-feeding time (month), parity, family history of breast and ovarian cancer, and smoking.
b
Body mass index, smoking, physical activity, education, income, country of birth, and ethnicity.
c
Age, education, body mass index, family history of cancer, cigarette smoking and alcohol consumption, menopausal status, use of hormone replacement, and age at first full-term pregnancy.
d
Age, age at menarche, first pregnancy, menopause, education, maternal history of breast cancer, smoking, and time since last physician contact.
e
Age, race, sex, and smoking status; number of pregnancies; and Quetelet’s index.
3

Table 2. Studies of the Association Between History of Asthma and the Risk of Breast Cancer.
Studies Country
Study
Design Sample Size
How Allergies
Are Defined
RR/OR/SIR/HR/
SMR (95% CI) Main Finding Reference Group
Confounding
Factors
Shirkhoda
et al.
29
Iran Case–
control
Case (168)
Control (165)
Physician-diagnosed
or ISAAC
questionnaire
a
OR: 0.5 (0.2–1.0) Reduced risk No history of asthma Yes
b
Lowcock
et al.
23
Canada Case–
control
Case (3101)
Control (3471)
Physician-diagnosed All participant:
OR: 1.0 (0.9–1.2)
Premenopausal:
OR: 0.7 (0.5–1.0)
Postmenopausal:
OR: 1.1 (0.9–1.4)
All participant:
no association
Premenopausal:
reduced risk
Postmenopausal:
no association
No history of asthma Yes
c
Hwang et al.
31
Taiwan Cohort Participant with
asthma
(107 601)
Physician-diagnosed SIR: 1.0 (0.9–1.1) No association Incidence rate in the
general population
in the country
Age
Ji et al.
32
Sweden Cohort Participant with
asthma
(140 425)
Subjects who had
hospital
admission
for asthma
SIR: 1.0 (1.0–1.1) No association Incidence rate in the
general population
in the country
(excluding
asthmatic)
Ye s
d
Wang et al.
16
Germany Case–
control
Case (381)
Control (2367)
Physician-diagnosed OR: 1.2 (0.7–2.2) Increased risk No atopy (no specific/
total IgE positive)
Ye s
e
Gonza
´lez-Pe
´rez
et al.
33
UK Case–
control
Case (827)
Control
(10 092)
Physician-diagnosed OR: 0.9 (0.8–1.1) No association Incidence rate in the
general population
in the country
(excluding asthmatic
and COPD)
Age, BMI, smoking,
alcohol intake,
and certain
comorbidities
Turner et al.
34
USA Cohort Participant with
asthma
(26 097)
Self-reported RR: 1.1 (0.9–1.3) No association No history of asthma
and allergic rhinitis
Ye s
f
Talbot-Smith
et al.
27
Australia Cohort Women with
asthma (155)
Physician-diagnosed HR: 1.1 (0.5–2.6) No association N/S Yes
g
Eriksson et al.
28
Sweden Cohort Participant with
asthma
(2512)
Self-
reported
symptoms
SIR: 1.4 (0.6–2.7) Increased risk Incidence rate in the
general population
in the country
No
Vesterinen
et al.
35
Finland Cohort Participant with
asthma
(78 000)
Physician-diagnosed SIR: 1.0 (0.9–1.1) No association Incidence rate in the
general population
in the country
Age
(continued)
4

History of Allergic Rhinitis
The majority of the identified studies indicated a higher
prevalence of allergic rhinitis among BC patients com-
pared to the general population (Table 3).
Two cohort studies conducted in Taiwan
31
and the
United States
26
found a history of diagnosed-physician
rhinitis to be associated with an increased incidence rate
of BC. In the cohort of the United States, the association
was borderline statistical significance (RR: 1.3; 95% CI,
1.0–1.9). A Swedish cohort study, which considered rhi-
nitis symptoms rather than physician-diagnosed, found
a 50% increased incidence risk of BC (SIR: 1.5; 95% CI,
0.8–2.6).
28
However, it was not statistically significant.
Similarity, in our recent case–control study, we found
50% increased odds of BC (OR: 1.5; 95% CI, 0.7–
3.0).
29
We designed the first study that used
International Study of Asthma and Allergies in
Childhood (ISAAC) questionnaire to consider the differ-
ent types of allergic symptoms for better identification of
patients with allergic rhinitis. Another case–control study
in Germany found that physician-diagnosed positive his-
tory is associated with nonsignificant increased risk of BC
(OR: 1.2, 95% CI, 0.8–1.8).
16
Inconsistent results appeared from the recent study
conducted in Poland, reporting allergic rhinitis was sig-
nificantly less prevalent in patients with BC.
37
However,
the authors did not adjust the potential confounding
factors. In their study, allergic rhinitis was defined by
laryngological examinations and history of clinical
symptoms according to Allergic Rhinitis and its
Impact on Asthma guidelines.
In addition, some studies found no association
between history rhinitis and BC. In Busselton’s cohort
study (hazard ratio [HR]: 0.9; 95% CI, 0.51–1.7)
27
and
U.S. case–control study (OR: 0.9),
36
no correlation
reported between physician-diagnosed positive history
and risk of BC.
History of Atopic Dermatitis
With 1 exception, epidemiological studies indicated that
individuals with a history of atopic dermatitis have an
elevated risk of BC, although all results did not reach
statistically significant (Table 4).
A cohort study conducted in Taiwan indicated a
slightly increased risk of BC among subjects with a his-
tory of atopic dermatitis (SIR: 1.2; 95% CI, 0.8–1.6).
31
In their study, dermatitis disease had been diagnosed by
a specialist. Moreover, a Danish cohort population-
based study demonstrated 40% increased cancer preva-
lence among hospitalized children with atopic dermatitis
(standardized mortality ratio: 1.4; 95% CI, 0.7–2.7).
38
A similar finding was observed in our recent case–con-
trol study.
29
We found an increased risk of BC among
Table 2. Continued
Studies Country
Study
Design Sample Size
How Allergies
Are Defined
RR/OR/SIR/HR/
SMR (95% CI) Main Finding Reference Group
Confounding
Factors
Mills et al.
26
USA Cohort Participant with
asthma (N/S)
Physician-diagnosed RR: 1.2 (0.7–2.0) Increased risk No history of allergy Yes
h
Vena et al.
36
USA Case–control Case (1835)
Control (2500)
Physician-diagnosed OR: 1.0 No association N/S Age and smoking
Abbreviations: BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; IgE, Immunoglobulin E; ISAAC, International Study of Asthma and Allergies in
Childhood; N/S, not specified; OR, odds ratio; RR, relative risk; SIR, standardized incidence rate; SMR, standardized mortality ratio.
Bold values indicate statistical significance.
a
“Have you had wheezing or whistling in the chest in the last 12 months?” OR “Did a doctor ever tell you that you had respiratory allergies?”
b
Age, breast-feeding time (month), parity, family history of breast and ovarian cancer, and smoking.
c
BMI, smoking, physical activity, education, income, country of birth, and ethnicity.
d
5-year age, gender, period (5-year group), socioeconomic status, and residential area.
e
Age, education, BMI, family history of cancer, cigarette smoking and alcohol consumption, menopausal status, use of hormone replacement, and age at first full-term pregnancy.
f
Race, smoking, education, BMI, exercise, alcohol drinking, use of oral contraceptives, estrogen replacement therapy, age at first birth, age at menarche, age at menopause, height, and family history of
breast cancer.
g
Age, smoking status, BMI, number of pregnancies, and menopausal status.
h
Age, age at menarche, first pregnancy, menopause, education, maternal history of breast cancer, smoking, and time since last physician contact.
Sadeghi and Shirkhoda 5

Table 3. Studies of the Association Between History of AR and the Risk of Breast Cancer.
Studies Country
Study
Design Sample Size
How Allergies
Are Defined
RR/OR/SIR/HR/
SMR (95% CI) Main Finding Reference Group
Confounding
Factors
Shirkhoda
et al.
29
Iran Case–
control
Case (168)
Control (165)
Physician-diagnosed or
ISAAC
questionnaire
a
OR: 1.5 (0.7–3.0) Increased risk No history of AR Yes
b
Kozłowska
et al.
37
Poland Case–
control
Case (231)
Control (754)
Laryngological exami-
nations, and history
of clinical symptoms
according to
ARIA guidelines
Significant OR Reduced risk N/S N/S
Hwang et al.
31
Taiwan Cohort Participant with
AR (225 315)
Physician-diagnosed SIR: 1.2 (1.1–1.3) Increased risk Incidence rate in
the general pop-
ulation in
the country
Age
Wang et al.
16
Germany Case–
control
Case (381)
Control (4271)
Physician-diagnosed OR: 1.2 (0.8–1.8) Increased risk No atopy (no
specific/total
IgE positive)
Ye s
c
Talbot-Smith
et al.
27
Australia Cohort Participant
with AR (597)
Physician-diagnosed HR: 0.9 (0.5–1.7) No association N/S Yes
d
Eriksson
et al.
28
Sweden Cohort Participant
with AR (5006)
Self-reported
symptoms
SIR: 1.5 (0.8–2.6) Increased risk Incidence rate in
the general
population in
the country
No
Mills et al.
26
USA Cohort Participant with
AR (N/S)
Self-reported RR: 1.3 (1.0–1.9) Increased risk No history
of allergy
Ye s
e
Vena et al.
36
USA Case–
control
Case (1835)
Control (2500)
Physician-diagnosed OR: 0.9 No association N/S Age and
smoking
Abbreviations: AR, allergic rhinitis; ARIA, Allergic Rhinitis and its Impact on Asthma; CI, confidence interval; HR, hazard ratio; IgE, Immunoglobulin E; ISAAC, International Study of Asthma and Allergies in
Childhood; N/S, not specified; OR, odds ratio; RR, relative risk; SIR, standardized incidence rate; SMR, standardized mortality ratio.
Bold values indicate statistical significance.
a
Answer yes to both “In the past 12 months, have you had a problem with sneezing, or a runny, or blocked nose when you DID NOT have a cold or the flu?” AND “In the past 12 months, has this nose
problem been accompanied by itchy-watery eyes?”
b
Age, breast-feeding time (month), parity, family history of breast and ovarian cancer, and smoking.
c
Age, education, body mass index, family history of cancer, cigarette smoking and alcohol consumption, menopausal status, use of hormone replacement, and age at first full-term pregnancy.
d
Age, smoking status, body mass index, number of pregnancies, and menopausal status.
e
Age, age at menarche, first pregnancy, menopause, education, maternal history of breast cancer, smoking, and time since last physician contact.
6

subjects who were diagnosed dermatitis by a doctor or
have dermatitis symptoms according to ISAAC quesion-
nire (OR: 1.3; 95% CI, 0.5–3.1).
In contrast, a population-based case–control study in
Germany found no association between physician-
diagnosed atopic dermatitis and BC (OR: 1.0; 95% CI,
0.5–1.9).
16
History of Food and Drug Allergy
To date, few studies have investigated the association
between history of food and drug allergies and the risk
of BC, with inconsistency results (Table 5).
A population-based case–control study in the United
States found lower prevalence of doctor-diagnosed food
allergy among BC patients compared to the control
group (OR: 0.8; 95% CI, 0.6–1.2).
30
However, a differ-
ent pattern was observed among women 35 years or
younger (OR: 1.2; 95% CI, 0.7–2.1) and women older
than 35 years (OR: 0.7; 95% CI, 0.5–1.0) in the stratified
analysis.
30
The authors considered “individuals with no
history of any allergy” as the reference group in the
case–control analysis, which was different from our
recent study conducted in Iran.
29
In our case–control
study, individuals with no history of food allergy was
considered as the reference group, and we found that
food allergy prevalence was higher among BC patients
(OR: 1.4; 95% CI, 0.7–3.0), although it was not statisti-
cally significant, which might be due to small
sample size.
29
Of the identified studies, which investigate the rela-
tionship between a history of drug allergy and BC, 2
studies found no association
26,30
and 1 study reported
a nonsignificant decreased risk
29
(Table 5).
A population-based case–control study
30
and a
population-based cohort study
26
conducted in the
United States reported no association between BC and
physician-diagnosed drug allergy with OR: 1.0; 95% CI,
0.7–1.3 and RR: 1.0; 95% CI, 0.7–1.3, respectively.
However, our recent case–control study in Iran found
a history of drug allergy was associated with a nonsig-
nificant decreased risk of BC (OR: 0.6; 95% CI,
0.2–1.8).
29
Total IgE Level
The studies, which investigated the association between
total IgE level and risk of BC, had varying outcomes
(Table 6). Two studies found a positive association,
29,39
1 study reported an inverse association,
40
and 2 studies
demonstrated no association.
9,41
Two case–control studies conducted in India
39
and
Iran
29
found an association between total IgE level
and increased risk of BC. In the Indian study, total
IgE level significantly elevated in BC and the levels
Table 4. Studies of the Association Between History of AD and the Risk of Breast Cancer.
Studies Country
Study
Design Sample Size
How Allergies
Are Defined
RR/OR/SIR/HR/
SMR (95% CI) Main Finding Reference Group
Confounding
Factors
Shirkhoda
et al.
29
Iran Case–
control
Case (168)
Control (165)
Physician-diagnosed
or ISAAC
questionnaire
a
OR: 1.3 (0.5–3.1) Increased risk No history of AD Yes
b
Hwang et al.
31
Taiwan Cohort Participant with
AD (34 263)
Physician-diagnosed SIR: 1.2 (0.8–1.6) Increased risk Incidence rate in the
general population
in the country
Age
Wang et al.
16
Germany Case–
control
Case (381)
Control (4271)
Physician-diagnosed OR: 1.0 (0.5–1.9) No association No atopy (no specific/
total IgE positive)
Ye s
c
Olesen et al.
38
Denmark Cohort Participant with
AD (2030)
Physician-diagnosed SMR: 1.4 (0.7–2.7) Increased risk Incidence rate in the
general population
in the country
N/S
Abbreviations: AD, atopic dermatitis; CI, confidence interval; HR, hazard ratio; IgE, Immunoglobulin E; ISAAC, International Study of Asthma and Allergies in Childhood; N/S, not specified; OR, odds ratio;
RR, relative risk; SIR, standardized incidence rate; SMR, standardized mortality ratio.
Bold values indicate statistical significance.
a
Answered yes to both “Have you had itchy rash at any time in the last 12 months?” AND “Has this itchy rash at any time affected the folds of the elbows, behind the knees, in front of the ankles, under the
buttocks, or around the neck, ears or eyes?”
b
Age, breast-feeding time (month), parity, family history of breast and ovarian cancer, and smoking.
c
Age, education, body mass index, family history of cancer, cigarette smoking and alcohol consumption, menopausal status, use of hormone replacement, and age at first full-term pregnancy.
Sadeghi and Shirkhoda 7

Table 5. Studies of the Association Between History of Food or Drug Allergy and the Risk of Breast Cancer.
Studies Country
Study
Design Sample Size
How Allergies
Are Defined
RR/OR/SIR/HR/SMR
(95% CI) Main Finding
Reference
Group
Confounding
Factors
Food allergy
Shirkhoda
et al.
29
Iran Case–
control
Case (168)
Control (165)
Physician-diagnosed
or Self-reported
OR: 1.4 (0.7–3.0) Increased risk No history of
food allergy
Ye s
a
Hedderson
et al.
30
USA Case–
control
Cases (723)
Controls (958)
Physician-diagnosed Overall: OR: 0.8
(0.6–1.2)
Age <35 years:
OR: 1.2 (0.7–2.1)
Age >35 years:
OR: 0.7 (0.5–1.0)
Overall: reduced risk
Age <35 years:
increased risk
Age >35 years:
reduced risk
No history of
allergy
Age, smoking
and education
Drug allergy
Shirkhoda
et al.
29
Iran Case–
control
Case (168)
Control (165)
Physician-diagnosed
or Self-reported
OR: 0.6 (0.2–1.8) Reduced risk No history of
drug allergy
Ye s
a
Hedderson
et al.
30
USA Case–
control
Cases (723)
Controls (958)
Physician-diagnosed Overall: OR: 1.0
(0.8–1.3)
Age <35 years: OR:
1.3 (0.9–2.1)
Age >35 years:
OR: 0.8 (0.6–1.2)
Overall: no association
Age <35 years:
increased risk
Age >35 years:
reduced risk
No history
of allergy
Age and
education
Mills et al.
26
USA Cohort Participant
with drug
allergy (N/S)
Self-reported RR: 1.0 (0.7–1.3) No association No history
of allergy
Ye s
b
Abbreviations: CI, confidence interval; HR, hazard ratio; N/S, not specified; OR, odds ratio; RR, relative risk; SIR, standardized incidence rate; SMR, standardized mortality ratio.
Bold values indicate statistical significance.
a
Age, breast-feeding time (month), parity, family history of breast and ovarian cancer, and smoking.
b
Age, age at menarche, first pregnancy, menopause, education, maternal history of breast cancer, smoking, and time since last physician contact.
8

were found to increase with clinical stage.
39
In our recent
study, total IgE level above 25 IU/mL was determined as
borderline significantly associated with BC in univariate
analysis (OR: 1.5; 95% CI, 1–2.3).
29
However, the asso-
ciation was not significant in multivariate analysis.
Inconsistent results appeared from the study in
China, indicating a significantly reduced risk of BC
cancer among participant with high IgE level (OR: 0.5;
95% CI, 0.3–0.7).
40
However, a cross-sectional study
conducted in Jordan
41
and a cohort study in
Netherland
9
detected no difference association between
the level of total IgE and BC.
Specific IgE or Prick Test
Most studies revealed an increased risk of BC among
people with a positive history of atopic using IgE specific
or prick test (Table 7).
Two case–control studies designed in Greece
42
and Germany
16
found high risk of BC in relation
to the positive IgE specific with OR of 1.7, 95% CI,
1.0–3.1 and 1.2, 95% CI, 0.9–1.7, respectively.
However, 1 population-based prospective study in
Denmark reported no association (HR: 1.00; 95% CI,
0.73–1.37).
43
In all studies, the cutoff value for positivity
of the specific IgE was considered as 0.35 kU/L.
In term of prick test, a cohort study designed in
Sweden
28
reported a significantly elevated risk of BC
among individuals with positive patch test (SIR: 2.5;
95% CI, 1.0–5.2) (Table 7). Likewise, the cohort study
in Australia reported nonsignificant high risk of BC
(HR: 1.4; 95% CI, 0.6–3.4).
27
However, a significantly
reduced risk of BC was reported in the study conducted
in Denmark (OR: 0.8; 95% CI, 0.7–1.0).
44
Beside, a
population-based cohort study in Netherlands showed
no association between any types of atopic diseases
and cancer hospitalization patients (OR: 1.0; 95% CI,
0.5–2.0).
9
Discussion
Most of the identified studies demonstrated nonsignifi-
cant results. However, the pattern of the results indicat-
ed an increased risk of BC in individuals with history of
allergies. The majority of studies reported a higher prev-
alence of atopic dermatitis and allergic rhinitis among
individuals with BC compared to the control groups.
Similarity, most of the studies revealed an increased
risk of BC among people with a positive history of
atopic using IgE specific or prick test. However, a null
association was reported in most of the asthmatic stud-
ies, and controversial results were detected in the indi-
viduals with history of food and drug allergies.
One of the possible immunological mechanisms
behind the role of allergy in cancer is related to the
chronic inflammation in allergic disorders, which could
directly or indirectly lead to cancer development and
progression.
45
In addition, the polarization of T cells
toward Th2 in allergic diseases has been demonstrated
to be pro-carcinogenesis. Previous studies reported that
the epithelial cells in the atopic dermatitis secrete high
level of thymic stromal lymphopoietin (TSLP).
46
TSLP
is an IL-17 like cytokine, which activates dendrite cells
Table 6. Studies of the Association Between Total IgE and the Risk of Breast Cancer.
Studies Country
Study
Design Sample Size
The Defined
Cutoff
RR/OR/SIR/HR/SMR
(95% CI) Main Finding
Reference
Group
Confounding
Factors
Shirkhoda
et al.
29
Iran Case–
control
Case (168)
Control (165)
25 IU/mL OR: 1.6 (0.9–2.7) Increased risk IgE level
<25 IU/mL
Ye s
a
Zhang et al.
40
China Case–
control
Case (102)
Control (100)
32.6 IU/mL OR: 0.5 (0.3–0.7) Reduced risk IgE level
<32.6 IU/mL
N/S
Taghizadeh
et al.
9
Netherland Cohort Participant with
high total IgE
level (N/S)
Continues
variable
HR: 0.9 (0.5–1.6) No association N/S Yes
b
Vijayakumar
et al.
39
India Case–
control
Case (166)
Control (100)
Continues
variable
Case: Mean SD:
65.4 31.4
Control:
Mean SD:
9.4 8.4
Increased risk — No
Alsabti
41
Jordan Cross-
sectional
Case (31)
Control (50)
Continues
variable
Case: Mean SD:
29.5 0.8
Control: Mean SD:
31.2 0.8
No association — No
Abbreviations: CI, confidence interval; HR, hazard ratio; IgE, Immunoglobulin E; N/S, not specified; OR, odds ratio; RR, relative risk; SD, standard deviation;
SIR, standardized incidence rate; SMR, standardized mortality ratio.
Bold values indicate statistical significance.
a
Age, breast-feeding time (month), parity, family history of breast and ovarian cancer, and smoking.
b
Age, body mass index (all at the first survey), and place of residence.
Sadeghi and Shirkhoda 9

Table 7. Studies of the Association Between Specific IgE and Prick Test and the Risk of Breast Cancer.
Studies Country
Study
Design Types of Allergen Sample Size
The
Defined Cutoff
RR/OR/SIR/HR/SMR
(95% CI) Main Finding Reference Group
Confounding
Factors
Specific IgE
Skaaby et al.
43
Denmark Cohort 19 common inhalant aller-
gens, mite, cat, grass,
and birch
Patients with specific
IgE positivity
(14 849)
Specific IgE level
0.35 kU/l
HR: 0.3 (0.1–0.8) Reduced risk Mortality rate in the
general population
in the country
Ye s
a
Petridou et al.
42
Greece Case–
control
12 most prevalent allergens
in Greece
Case (103)
Control (103)
Specific IgE level
0.35 kU/l
OR: 1.7 (1.0–3.1) Increased risk N/S Yes
b
Wang et al.
16
Germany Case–
control
Pollen of timothy, rye, birch
and mugwort, house dust
mite, cat, dog, and
Cladosporium
Case (381)
Control (2367)
Specific IgE level
0.35 kU/l
OR: 1.2 (0.9–1.7) Increased risk No atopy (no specific/
total IgE positive)
Ye s
c
Patch/prick test
Taghizadeh et al.
9
Netherland Cohort House dust, mixed pollen,
epidermal products, and
mixed molds
Participant with patch
test positivity (N/S)
Positive patch test Cancer hospitalization:
HR: 1.0 (0.5–2.0)
Cancer
hospitalization:
no association
N/S Yes
d
Engkilde et al.
44
Denmark Cohort 23 allergens contained in the
European Standard
Screening Tray
Participant with patch
test positivity
(6065)
Positive patch test OR: 0.8 (0.7–1.0) Reduced risk N/S Age
Talbot-Smith
et al.
27
Australia Cohort House dust mites, cat dander,
cattle dander, 2 molds
(Aspergillus fumigatus and
Alternariae tenius), and 7
local pollens (rye grass,
barley, capeweed, orchard
grass, plantago, pepper-
mint tree, couchweed
grass, and wild oat)
Participant with prick
test positivity (239)
Positive prick test HR: 1.4 (0.6–3.4) Increased risk N/S Yes
e
Eriksson et al.
28
Sweden Cohort Dermatophagoides pteronyssi-
nus, horse, dog, cat, timo-
thy, mugwort, birch, and
Cladosporium
Participant with
prick test
positivity (2435)
Positive prick test SIR: 2.5 (1.0–5.2) Increased risk Incidence rate in the
general population
in the country
No
Abbreviations: CI, confidence interval; HR, hazard ratio; IgE, Immunoglobulin E; N/S, not specified; OR, odds ratio; RR, relative risk; SIR, standardized incidence rate; SMR, standardized mortality ratio.
Bold values indicate statistical significance.
a
Education, season of blood sample, physical activity, smoking habits, alcohol intake, body mass index, systolic and diastolic blood pressure, serum triglycerides, and total cholesterol.
b
Age, education, height, age at menarche, parity, age at menopause, and alcohol consumption.
c
Age, education, body mass index, family history of cancer, cigarette smoking and alcohol consumption, menopausal status, use of hormone replacement, and age at first full-term pregnancy.
d
Age, body mass index (all at the first survey), and place of residence.
e
Age, smoking status, body mass index, number of pregnancies, and menopausal status.
10

(DCs) migration to the draining lymph nodes, differen-
tiates T naive cells into the inflammatory Th2, and ini-
tiates the secretion of type 2 cytokines.
46,47
Studies
demonstrated that TSLP fosters human breast tumor
growth by promoting inflammation
47,48
and provides a
suitable environment for the establishment, growth, and
metastasis of the primary BC cell line via Th2 polariza-
tion.
49
Antibodies neutralizing TSLP or TSLP receptor
inhibit tumor development and the secretion of IL-13 in
the BC xenografts model. In addition, systemic increased
types 2 cytokines such as IL-4, IL-5, and IL-13 due to
Th2 polarization can contribute tumorgenesis in several
ways. For instance, IL-13 induces myeloid cells to
release transforming growth factor beta (TGF-b),
which ultimately inhibits cytotoxic T cell activity.
50
Another possible mechanism behind the association
of allergy–cancer is mast cells. Mast cells are the prom-
inent cells in the immediate-type allergic reactions that
reside skin and mucous membranes.
51,52
The role of
mast cells in cancer development or protection is contro-
versy over the studies. However, in vitro and in vivo
studies support that mast cells could induce carcinoge-
nicity through releasing several factors involved in gene
instability (reactive oxygen species), angiogenesis (vascu-
lar endothelial growth factor), extracellular matrix
degradation (Protease), immune suppressive (TGF-b
and IL-10), and shifting immune system balance
toward Th2 pathways (Figure 1).
53
Effective mast cell
targeting immunotherapy will shift the balance toward
promoting the antitumor activities of mast cells.
Moreover, mast cells release several mediators such as
histamine, prostaglandins, and leukotrienes. Histamine,
the main mediator in the allergic disorders, plays an
important role in attracting DC and skewing immune
system toward Th2.
54
In the mammary gland, histamine
plays a critical role in growth regulation, differentiation
and functioning during development, pregnancy, and
lactation.
55–57
High level of histamine production and
secretion has been found in human breast tumors and
induced mammary tumors in rats.
58–61
In addition, his-
tamine elevates the production of IL-10 and reduces the
secretion of IL-12,
62
which have a beneficial effects on
cancer development and progression.
In another route, mast cell–histamine promotes sur-
vival and proliferation of myeloid-derived suppressor
cells (MDSCs).
63
Histamine can alter the cytokine
milieu, transcription factors, and signaling pathways
important for MDSCs accumulation. The role of
MDSCs in pro-tumorgenesis has been well defined
before. MDSCs release small soluble oxidizers, impair
Figure 1. An overview on the role of allergy-related mechanisms in cancer development and progression. Epithelial cells in allergic
disease secrete high level of TSLP, which lead to cancer initiation and progression by effecting mast cell (A) or DC (B). CTL, cytotoxic
T cell; DC, dendrite cell; IL, interleukins; MDSC, myeloid-derived suppressor cells; MMP9, matrix metalloproteinase 9; PAF, platelet-
activating factor; ROS, reactive oxygen species; TGF-b, transforming growth factor beta; Th, T-helper cells; TSLP, thymic stromal
lymphopoietin; VEGF, vascular endothelial growth factor.
Sadeghi and Shirkhoda 11

T cell antigen recognition, and ultimately cause the sup-
pression of T cell activity and cancer development.
63–65
There are important issues in the interpretation of
epidemiological studies, such as how the allergic disor-
ders are defined in different studies (by a physician, by
questionnaire, standardized, or self-reported?). In this
review, we demonstrated that most of the identified stud-
ies reported no association between asthma and risk of
BC, in contrast to the atopic dermatitis and allergic rhi-
nitis. It is worth mentioning that the most impressive
misclassification was predicted to appear in the
asthma-specific studies due to overlapping between
asthma and other chronic lung diseases. Moreover, the
variable etiology of asthma, which may involve a
number of immunologic and nonimmunologic factors,
including allergy could affect the final results in the asth-
matic studies.
66
The other issue is immunosuppressive and anti-
inflammatory treatment in many allergic disorders.
Studies reported long-term risk of malignancy among
patients treated with immunosuppressive.
67
Moreover,
animal models suggest that some antihistamines might
be carcinogenic and increase the risk of cancer.
68
This
confounding factor was less considered in the epidemio-
logical studies, as the treatment of allergy may be criti-
cally associated with the overall risk of cancer
development in allergic people.
Moreover, the disparity in the methodology of epide-
miological studies such as lack of adjustment for other
possible confounding or inadequate statistical power
and the design of study make it challenging to compare
different studies and reach a strong conclusive result. No
particular difference was found between the cohort find-
ing and the case–control results. However, an important
factor, which was neglected in the interpretation of
results, is that the reference group in the statistically
analysis is more variable among studies, and it affects
the final results for the OR in the studied patients.
Therefore, considerable caution is needed in interpreting
the results of epidemiological studies.
In this article, we have tried to comprehensively
review the studies reporting the associations between dif-
ferent types of allergy and BC. However, it is not sys-
temic review and might be susceptible to bias. Further
research should reduce the heterogeneity of the studies
and include high-quality evidence in order to eliminate
bias and other methodological problems.
Conclusion
Bias is considered as a major issue in the observational
studies, therefore interpreting of the results should be
done carefully. Moreover, there are different methodo-
logical problems in different studies, which make it chal-
lenging to compare the findings and reach a strong
conclusive result. However, the pattern of the results
from the most studies indicates that allergic diseases
might be associated with an overall risk for BC, and
skewed immune system toward Th2 implies an impor-
tant role in this association.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of
this article.
Ethical Approval
This study was approved by our institutional review board.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
Statement of Human and Animal Rights
This article does not contain any studies with human or
animal subjects.
Statement of Informed Consent
There are no human subjects in this article and informed con-
sent is not applicable.
ORCID iD
Fatemeh Sadeghi https://orcid.org/0000-0002-0018-2954
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