Seminars in Oncology 44 (2017) 267–272

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Seminars in Oncology
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Male Breast Cancer: Epidemiology and Risk Factors

Ali Jad Abdelwahab Yousef n

a r t i c l e in fo a b s t r a c t

Male breast cancer is a rare malignancy that accounts for less than 1% of all cancers in men and less than
Keywords: 1% of all breast cancers. But the incidence is rising and in some patient groups reaching 15% over the
Male breast cancer course of their lives. The major risk factors for the development of male breast cancer include advancing
Epidemiology age, hormonal imbalance, radiation exposure, and a family history of breast cancer. Regarding the latter,
Risk factors incidence can be linked to mutations in high- or low-penetrance genes. The most relevant risk factor for
Breast cancer the development of male breast cancer is a mutation in the BRCA2 gene. Most cases present late because
BRCA2 of a lack of awareness of the existence of such a malignancy in males and ignorance of the related risk
BRCA1
factors. Additionally, males with breast cancer are at special risk for developing a second cancer. This in
Management
depth review highlights the epidemiology and risk factors for the development of male breast cancer.
& 2017 Elsevier Inc. All rights reserved.

1. Introduction 2. Epidemiology

The breast tissues of males and females are identical from birth
until puberty, when hormonal differences lead to differentiation
[1]. Estrogen stimulates the growth of breast tissue while andro-
gen antagonizes these effects. During puberty in boys, there is an
increase in estrogen level and a 30-fold increase in testosterone
level. This leads to a transient proliferation of the ducts and
stroma followed by involution and ultimately atrophy of the
ducts. Therefore, the normal male breast is characterized
primarily by subcutaneous fat and a remnant of subareolar ductal
tissue [2].
Along with the increase in female breast cancer, there has been
an increase in the incidence of male breast cancer. The age
distribution in men with breast cancer is unimodal, with a peak
at age 71 years; while in women the distribution is bimodal, with
peaks at 52 and 71 years [3]. In a male, delays in diagnosis are
because of the low index of suspicion of breast cancer [4].
Most cases of breast cancer in both sexes have no identified
risk factors. Unfortunately, studies comparing risk factors for female
and male breast cancers have been limited by the small number of
male patients. However, certain differences had been ascertained,
including a higher frequency of BRCA2 mutations in males with
breast cancer.
Male breast cancer comprises o 1% of all cancers in men and
o1% of all breast cancers [5]. With the aging of the population, the
incidence is rising [6] reaching a plateau at age 80, with a mean
age at diagnosis of 63.4 years, compared with 58.2 years in women
[7]. The age-standardized incidence of male breast cancer is only
1/100,000 person-years, with a lifetime risk of 1/1,000. The
incidence varies greatly in different geographical areas and
amongst different ethnic groups [6], with a high proportion of
cases reported in Africa [8]. The high number of cases in Africa is
thought to be because of endemic infectious diseases, such as
bilharziosis and hepatitis B or C causing chronic liver damage that
leads to high levels of estrogen and in turn increases the risk of
breast cancer for males. Despite the scant data, the annual male
breast cancer incidence rates had been shown to range from 5% to
15% [9].
Mortality rates for male breast cancer have remained stable [4], but
differ significantly according to ethnicity, being worse in blacks [10],
and are not significantly different from those observed in women [8].
The prognosis for male and female breast cancers is similar, but
overall survival rates are lower for males because of older age and
advanced stage at diagnosis. Disease-specific survival rates are
higher than overall survival rates because of the older average age
and deaths from other comorbid diseases [10,11].

General Surgery Department, College of Medicine, Mutah University, Karak 3. Risk Factors
61710, Jordan.
n
Corresponding author. Dr. Ali Jad Abdelwahab Yousef, Full-Time Lecturer,
General Surgery Department, College of Medicine, Mutah University, Karak, Jordan.
It is likely male breast cancer results from the interaction of
Tel.: þ 00962372380/6000; fax: þ 0096232375440. concurrent risk factors. According to this hypothesis, genetic risk
E-mail address: alijad30@hotmail.com (A.J.A. Yousef). factors including a positive family history of breast cancer and

https://doi.org/10.1053/j.seminoncol.2017.11.002
0093-7754/& 2017 Elsevier Inc. All rights reserved.

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268 A.J. Abdelwahab Yousef / Seminars in Oncology 44 (2017) 267–272

Table 1
Risk factors for male breast cancer.

Risk Environmental Genetic

High risk • Age • BRCA2 mutations

• Treatment related (antiandrogens in prostate cancer, radiotherapy in Hodgkin’s disease) • Family history of breast cancer
• Hormonal imbalance (testicular or liver damage) • History of contralateral male
breast cancer
• Klinefelter’s syndrome (47XXY
karyotype)

Moderate to • High socio-economic status • BRCA1 mutations

low risk • Occupational exposure to heat • CHECK2 mutations
• Co morbidity (cirrhosis) • PALB2 mutations
• Inactivity • Cowden syndrome (germline
• Obesity PTEN mutations)
• Hyperprolactinemia
• Occupational exposure to vehicle combustion products, polycyclic hydrocarbons, and industrial solvents with
volatile organic compounds (eg, tetrachloroethylene, perchloroethylene, trichloroethylene, dichloroethylene, and
benzene)

Suspected • Occupational exposure to magnetic fields • AR

risk • Alcohol • CYP17
• Birth order (first born)
• Bone fracture after age 45
• Gynecomastia

mutations in breast cancer predisposing genes, such as the BRCA
genes, interact with hormonal imbalances and certain environ-
mental and occupational hazards (Table 1).
3.1. High risk factors
3.1.1. Advancing age
Male breast cancer is a disease of advanced age. In their case
control study of 21 cases of breast cancer and 82 controls
conducted from 1988 to 1994, D'Avanzo and La Vecchia [12]
showed that over 80% of cases and controls resided in the same
older age group (Table 2).
3.1.2BRCA2 mutations
Genetic susceptibility to develop male breast cancer can result
from mutations in high-penetrance genes such as BRCA1 and
BRCA2, which occur rarely but confer a high risk, or from low-
penetrance genes mutations such as CHECK2, which occur more
frequently but confer a small to moderate risk.
The genetic factors contributing to male breast cancer are
similar, but not identical, to those contributing to female breast
cancer. BRCA2 mutations are the most important risk factor for
developing male breast cancer. Hereditary breast cancer in females
result from autosomal dominant inheritance, particularly BRCA1
and BRCA2 mutations, and constitutes 5%–10% of all female breast
cancers [13]. Unlike BRCA1, a considerable number of BRCA2
mutations have been reported in heritable cases of male breast
cancer. The reported frequencies of BRCA2 germ-line mutations in
male breast cancer vary between populations because of small
sample sizes, different type of mutations, and differences in
sensitivities of mutation screening. Amongst published studies,
the reported percentage of BRCA2 mutations in patients with a
Table 2
Distribution of male breast cancer cases and controls according to age.
Age group Cases number % Cases Controls number
o45 3 14.3 14
≥45 18 85.7 68
Modified from D’Avanzo and La Vecchia [12].
diagnosis of male breast cancer has varied significantly, from 3.7%
to 40% (Table 3) [14–30]. The high result (40%) may have been
affected by a strong founder effect in the Icelandic population [15].
Currently, BRCA2 mutations are considered the principal
genetic risk factor of male breast cancer, with an earlier age at
diagnosis among individuals harboring BRCA2 mutations (median,
58.8 years) than non-carriers (median, 63.4 years) [25]. Addition-
ally, individuals harboring a BRCA2 mutation have a lifetime risk
for developing breast cancer of 6.9%, which is approximately 80–
100 times higher than the general population [31].
3.1.3Conditions that alter the androgen-to-estrogen ratio
Male breast cancers are highly sensitive to hormonal imbal-
ance, which leads to an excess of estrogen and a deficiency of
testosterone [32]. In one study, the mean total serum estradiol
level and the calculated mean free estradiol index were signifi-
cantly higher in eight male patients with a diagnosis of breast
cancer compared with eight controls (P o .01 and P o .01,
respectively) [33]. However, in another study there was no
significant reduction in testosterone level in males with breast
cancer and across studies no constant relation has been found with
estradiol levels [34]. Different causes of androgen-to-estrogen
imbalance and their relevant statistical data are summarized in
Table 4 [12,34–41].
Klinefelter’s syndrome (47XXY karyotype), with low testoster-
one and high gonadotropin concentrations, imposes a risk for
breast cancer that is 20–50 times higher than the risk within the
general male population, with mortality rates similar to those of
females diagnosed with breast cancer [42]. Additionally, any
condition that decreases exposure to androgens or increases
exposure to estrogen, such as the use of anti-androgens and
estrogens in the treatment of prostate cancer or the administration
of estrogen to transsexuals, have been reported to be associated
with an increased risk of male breast cancer [43,44]. First preg-
nancies are known to have higher estrogen levels than later ones,
% Controls and first-born male children have a risk of male breast cancer that
is 1.71 times higher than their younger brothers [45].
17.1
82.9
Although a disturbance in the balance of androgens and estro-
gens is a well-known risk factor for the development of gyneco-
mastia − which is found in 6% to 38% of males affected by breast

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 A.J. Abdelwahab Yousef / Seminars in Oncology 44 (2017) 267–272 269

Table 3
Studies of BRCA2 mutation rates in male breast cancer cases.

Study (Year) Country N Study design Outcome

Couch (1996) USA 50 Germline mutation analysis; patients not selected for family history BRCA2 mutation in 14% of MBC
[14]
Thorlacius Iceland 9 Nine families with history of MBC evaluated for BRCA2 mutation BRCA2 mutation [999del5] in 12/30 (40%)
(1996) [15]
Friedman (1997) USA 54 Population-based series looking for germline mutations in BRCA 1 or 2 BRCA2 mutation in 2/54 (3.7%) BRCA1 mutation in
[16] 0/54 (0%)
Mavraki (1997) UK 26 DNA screening of 26 MBC patients BRCA2 mutation in 3/26 (12%)
[17]
Haraldsson Sweden 34 Germline mutation analysis BRCA2 mutation in 7/34 (21%)
(1998) [18]
Csokay (1999) Hungary 18 Germline mutation analysis in BRCA1 and 2 BRCA 2 mutation in 6/18 (33%)
[19]
Wolpert (2000) Canada 14 Case series BRCA2 mutation in 2/14 (14%)BRCA1 mutation in
[20] 0/14 (0%)
Diez (2000) [21] Spain 17 Germline mutation analysis BRCA2 mutation in 3/17 (18%)
Pages (2001) France 12 Screening of BRCA2 mutations BRCA2 mutation in 3/12 (25%)
[22]
Kwiatkowska Poland 37 Germline mutation analysis BRCA2 mutation in 4/37 (11%)
(2001) [23]
Evanz et al UK 33 Germline mutation analysis BRCA mutation in 14/38 (37%)BRCA2 mutation in
(2001) [24] 12/38 (32%)BRCA1 mutation in 2/38 (5%)
Basham (2002) UK 94 Population-based series to study prevalence of BRCA1 and 2 mutations in MBC Carrier frequency of BRCA2 mutation was 6% (95%
[25] CI: 2-13)
Syrjakoski Finland 154 Cohort study to determine frequency of BRCA2 founder mutations BRCA2 mutation in 12/154 (8%)
(2004) [26]
Risch (2006) Canada 1171 1171 ovarian cancer patients screened for BRCA1/2 mutations with respect to MBC risk higher in individuals harboring BRCA2
[27] cancers reported among their relatives mutation (RR¼ 102, 95% CI: 9.9−1.05)
Tai et al (2007) USA 97 Retrospective analysis of MBC risk for BRCA1/2 mutation carriers Estimated cumulative risk of MBC for individuals
[28] harboring BRCA2 mutation ¼ 6.8% (95% CI:
3.2−12)
Ottini (2009) Italy 108 Population-based study 8/108 (7.4%) harbored BRCA2 mutations
[29]
Ding (2011) [30] USA 115 Germline mutations analysis BRCA2 BRCA2 mutations in 18/115 (16%, 95% CI: 11−24)

Abbreviations: MBC, male breast cancer; CI, confidence interval.

cancer − gynecomastia per se is not a risk factor of male breast
cancer [46], and there is no significant reduction in testosterone
level in males with breast cancer and no constant relation has
been found with estradiol levels [34].
3.1.4.Personal and family history of cancer
Up to 33% of male breast cancer cases arise within families with
a background of familial breast and ovarian cancers [24]. Family
history is important for both sexes; in males a positive family
history confers a relative risk of 2.5 [37]; while population-based
studies have shown that about 15%–20% of all males with a
diagnosis of breast cancer have a history of breast cancer in a
first-degree female relative [29] (Table 5).
A positive family history of either female or male breast
cancer among first-degree relatives confers a 2- to 3-fold increase
in male breast cancer risk, and the risk increases with increasing
numbers of affected first-degree relatives and with early
onset (age o 35 years) in affected relatives [47]. Additionally,
male breast cancer has been reported in families with Cowden
syndrome and hereditary non-polyposis colorectal cancer
(HNPCC) syndrome, although the risk in these cases is best
characterized as moderate to low [48]. A personal history of male
breast cancer in one breast is associated with a 30-fold increased
risk of breast cancer in the contralateral breast [49]. Males
who have a first primary breast cancer have a 16% increased
risk of developing a second primary cancer in comparison with
the general male population, and a second primary tumor has

Table 4
Studies of androgen-to-estrogen imbalance causes as risk factors for male breast cancer.

Study (Year) N Cause of androgen/estrogen imbalance Results

Casagrande (1988) [34] 150 Overweight [ 4 90 kg] and obesity RR ¼ 5.45 [P ¼ .04]
D’Avanzo (1995) [12] 81 Higher weight 2 years before interview OR ¼ 2·2
Hsing (1998) [36] 690 Overweight [ 4 90 kg] and obesity OR ¼ 2.3 [95% CI: 1.1−5.0]
Sorensen (1998) [40] 11,642 Liver cirrhosis SIR ¼ 4.0 [95% CI: 0.8−11.7]
Ewertz (2001) [37] 624 Diabetes OR ¼ 2.6 [95% CI: 1.3−5.3]
Obesity 10 years before diagnosis OR ¼ 2.1 [95% CI: 1.0−4.5]
Johnson (2002) [38] 1986 Very overweight v others OR ¼ 2.19 [95% CI: 1.08−4.43]
Guenel (2004) [41] 1506 Alcohol consumption (4 90 grams/day) OR ¼ 5.89 [95% CI: 2.2−15.69]
Brinton (2008) [39] 121 Overweight [ 4 90 kg] and obesity RR ¼ 1.79 [95% CI: 1.10−2.91]
Brinton (2010) [35] 642 Klinefelter’s syndrome RR ¼ 29.64 [95% CI: 12.26−71.68]
Orchitis/epididymitis RR ¼ 1.84 [95% CI: 1.10−3.08]
Gynecomastia RR ¼ 5.86 [95% CI: 3.74−9.17]
Diabetes RR ¼ 1.30 [95% CI: 1.05−1.60]

Abbreviations: CI, confidence interval; OR, odds ratio; RR, relative risk; SIR, standardized incidence ratio.

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270 A.J. Abdelwahab Yousef / Seminars in Oncology 44 (2017) 267–272

Table 5
Population-based studies evaluating family history as a risk for male breast cancer.

Study (Year) Design Results

D’Avanzo (1995) [12] Case-control: 21 patients; 82 controls OR ¼ 8.5; 95% CI: 1.1−69.0 if there is history of
female breast cancer
Haraldsson (1996) [18] Germline mutation analysis of 34 MBC cases 13% had a positive family history of BC
Ewertz (2001) [37] Case-control: 156 patients; 468 controls Increased risk with positive family history
OR ¼ 3.3; 95% CI: 2.0−5.6
Johnson (2002) [38] Case-control: 81 patients; 1905 controls Increased risk with positive family history in a
mother or a sister
Adjusted OR ¼ 3.65; 95% CI: 1.62−8.19]
Brinton (2008) [39] Prospective National Institutes of Health-AARP Increased risk with first degree relative affection
Diet and Health Study of 324,920 men, among RR ¼ 1.92; 95% CI: 1.19−3.09
whom 121 developed MBC

Abbreviations: CI, confidence interval; OR, odds ratio; RR, relative risk; MBC, male breast cancer; BC, breast cancer.

been reported in more than 11% of breast cancer in male
patients [50].
3.1.5. Radiation
In studying ionizing radiations as an etiologic factor in the
development of male breast cancer, an increased risk in men with
three or more diagnostic or therapeutic radiographic examinations
was found. The relative risk after fluoroscopy is 2.4 [51], and after
radiotherapy are 7.2 [9]. Risk was increased in the interval from 20
to 35 years after initial exposure from either radiographic exami-
nations or X-ray treatments, and declined after three to four
decades since last exposure, suggesting a wave of increased risk
of finite duration following exposure [52].
3.2. Moderate to low risk
reaching 60% to 76% frequency, whereas the BRCA1 mutation
frequency is from 10% to 16% [53].
Gene mutations in CHEK2, a cell cycle checkpoint kinase,
particularly, the CHEK2 1100delC mutation that accounts for 9%
of male breast cancer cases, increase the risk of male breast cancer
10-fold above the general population [56]. The risk is significantly
higher with a positive family history, and varies amongst ethnic
groups and from one country to another [57].
Data are conflicting regarding the relevance of other germ-line
mutations such as those in PALB2, the androgen receptor (AR), and
CYP17 in the etiology of male breast cancer [30,58]. Two cases of
male breast cancer in families with Cowden syndrome harboring
germline PTEN mutations have been reported [59]; however, no
cases have been reported in families with the Li-Fraumeni syn-
drome caused by germline TP53 mutations.

3.2.1. High socioeconomic class 3.2.3. Prolactin

An increased risk of male breast cancer has been found in
association with higher socioeconomic class (odds ratio, 3.2), and
higher education (odds ratio, 2.6) [12].
3.2.2. Genetic mutations other than BRCA2
The frequency of BRCA1 mutations in male breast cancer is
about 10% to 16% [53], and patients harboring BRCA1 mutations
have a life-time risk of 5.8% [54]. BRCA mutations in males also
increase the risk for other types of cancer, including prostate (most
commonly), pancreas, colon, stomach, melanoma, and non-mela-
noma skin cancers [55]. The occurrence of male breast cancer in
high-risk families indicates a high likelihood of BRCA2 mutations
Although case-control studies have shown no difference in the
level of serum prolactin between affected male patients and
controls [60], several case reports of male breast cancer have been
reported in men with hyperprolactinaemia caused by pituitary
adenomas [61].
3.2.4. Occupation
Male breast cancer risk has been observed in men who have
worked in hot environments, or with chemical and hormonal
synthetics, and in electromagnetic fields. Table 6 summaries the
results of studies of increased male breast cancer in certain
occupations [62–66].

Table 6
Studies summarizing increased risk of male breast cancer because of occupations.

Study design (Year) N Occupation Result

Systematic review 333 Soap- and perfume-manufacturing industry SIR ¼ 7.6; P o .01
McLaughlin (1988) [62]
Case- control, 178 patients; 1041 controls 1219 Blast furnaces, steel works, and rolling mills OR ¼ 3.4; 95% CI: 1.1−10.1
Cocco (1988) [63] Motor vehicle industry OR ¼ 3.1; 95% CI: 1.2−8.2
Case-control, 230 patients; 12,880 controls 13,110 Men with 4 3 months of employment in occupations OR ¼ 2.5; 95% CI: 1.3−4.5
Hansen (2000) [64] with potential exposure to gasoline and combustion products
Men employed at o 40 years of age OR ¼ 5.4; 95% CI: 2.4−11.9
Case-control, 104 patients; 1901 controls 2005 Motor vehicle mechanics OR ¼ 2.1; 95% CI: 1.0−4.4
Villeneuve (2010) [65] If employed ≥10 years in motor mechanics OR ¼ 5.9; 95% CI: 2.4−14.6
In sale/repair of motor vehicles OR ¼ 1.8; 95% CI: 1.0−3.2
Meta-analysis of 18 studies: 356 Electromagnetic field exposure Pooled ORs ¼ 1.32; 95% CI:
7 case-control and 11 cohort 1.14−1.52, P o .001
Sun (2013) [66]

Abbreviations: CI, confidence interval; OR, odds ratio; RR, relative ratio; SIR, standardized incidence ratio.

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 A.J. Abdelwahab Yousef / Seminars in Oncology 44 (2017) 267–272
4. Conclusions
The incidence of male breast cancer is rising because of the
aging of the population. Incidence varies widely across geograph-
ical areas and can reach up to 15%. The advanced stage of male
breast cancer at presentation is mainly because of a lack of
awareness of the disease. The first step toward awareness for
patients and health workers should be education about the
existence of breast cancer in men and it’s known multiple risk
factors.
Many patients with prostate cancer as well as other patients
receiving hormonal therapy should be aware of the serious side
effect of developing male breast cancer; therefore, any breast
complaint in these patients should be evaluated fully and thor-
oughly. The same applies to patients with hyperestrogenism
because of liver failure or other causes and in their evaluation
the health care provider should consider the possibility of cancer
and not just gynecomastia.
Most importantly, there should be a change in attitude con-
cerning screening high-risk families beyond the current practice of
screening only women. Males in such families should also undergo
screening. Follow-up of males after treatment should emphasize to
the patient that the other breast is at risk more than in females,
and the clinical examination should concentrate on detecting
second cancers that are more likely to occur in males with breast
cancer.
Conflict of Interest Statement
Dr. Ali Jad Yousef discloses no conflict of interest regarding the
article (Male Breast Cancer: Epidemiology and Risk Factors).
Acknowledgment and Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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