Seminars in Oncology: Male Breast Cancer: Epidemiology and Risk Factors
Seminars in Oncology: Male Breast Cancer: Epidemiology and Risk Factors
Seminars in Oncology: Male Breast Cancer: Epidemiology and Risk Factors
Seminars in Oncology
journal homepage: www.elsevier.com/locate/ysonc
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 Male breast cancer comprises o 1% of all cancers in men and
until puberty, when hormonal differences lead to differentiation o1% of all breast cancers [5]. With the aging of the population, the
[1]. Estrogen stimulates the growth of breast tissue while andro- incidence is rising [6] reaching a plateau at age 80, with a mean
gen antagonizes these effects. During puberty in boys, there is an age at diagnosis of 63.4 years, compared with 58.2 years in women
increase in estrogen level and a 30-fold increase in testosterone [7]. The age-standardized incidence of male breast cancer is only
level. This leads to a transient proliferation of the ducts and 1/100,000 person-years, with a lifetime risk of 1/1,000. The
stroma followed by involution and ultimately atrophy of the incidence varies greatly in different geographical areas and
ducts. Therefore, the normal male breast is characterized amongst different ethnic groups [6], with a high proportion of
primarily by subcutaneous fat and a remnant of subareolar ductal cases reported in Africa [8]. The high number of cases in Africa is
tissue [2]. thought to be because of endemic infectious diseases, such as
Along with the increase in female breast cancer, there has been bilharziosis and hepatitis B or C causing chronic liver damage that
an increase in the incidence of male breast cancer. The age leads to high levels of estrogen and in turn increases the risk of
distribution in men with breast cancer is unimodal, with a peak breast cancer for males. Despite the scant data, the annual male
at age 71 years; while in women the distribution is bimodal, with breast cancer incidence rates had been shown to range from 5% to
peaks at 52 and 71 years [3]. In a male, delays in diagnosis are 15% [9].
because of the low index of suspicion of breast cancer [4]. Mortality rates for male breast cancer have remained stable [4], but
Most cases of breast cancer in both sexes have no identified differ significantly according to ethnicity, being worse in blacks [10],
risk factors. Unfortunately, studies comparing risk factors for female and are not significantly different from those observed in women [8].
and male breast cancers have been limited by the small number of The prognosis for male and female breast cancers is similar, but
male patients. However, certain differences had been ascertained, overall survival rates are lower for males because of older age and
including a higher frequency of BRCA2 mutations in males with advanced stage at diagnosis. Disease-specific survival rates are
breast cancer. 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: [email protected] (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.
mutations in breast cancer predisposing genes, such as the BRCA diagnosis of male breast cancer has varied significantly, from 3.7%
genes, interact with hormonal imbalances and certain environ- to 40% (Table 3) [14–30]. The high result (40%) may have been
mental and occupational hazards (Table 1). affected by a strong founder effect in the Icelandic population [15].
Currently, BRCA2 mutations are considered the principal
3.1. High risk factors genetic risk factor of male breast cancer, with an earlier age at
diagnosis among individuals harboring BRCA2 mutations (median,
3.1.1. Advancing age 58.8 years) than non-carriers (median, 63.4 years) [25]. Addition-
Male breast cancer is a disease of advanced age. In their case ally, individuals harboring a BRCA2 mutation have a lifetime risk
control study of 21 cases of breast cancer and 82 controls for developing breast cancer of 6.9%, which is approximately 80–
conducted from 1988 to 1994, D'Avanzo and La Vecchia [12] 100 times higher than the general population [31].
showed that over 80% of cases and controls resided in the same
older age group (Table 2).
3.1.3Conditions that alter the androgen-to-estrogen ratio
Male breast cancers are highly sensitive to hormonal imbal-
3.1.2BRCA2 mutations
ance, which leads to an excess of estrogen and a deficiency of
Genetic susceptibility to develop male breast cancer can result
testosterone [32]. In one study, the mean total serum estradiol
from mutations in high-penetrance genes such as BRCA1 and
level and the calculated mean free estradiol index were signifi-
BRCA2, which occur rarely but confer a high risk, or from low-
cantly higher in eight male patients with a diagnosis of breast
penetrance genes mutations such as CHECK2, which occur more
cancer compared with eight controls (P o .01 and P o .01,
frequently but confer a small to moderate risk.
respectively) [33]. However, in another study there was no
The genetic factors contributing to male breast cancer are
significant reduction in testosterone level in males with breast
similar, but not identical, to those contributing to female breast
cancer and across studies no constant relation has been found with
cancer. BRCA2 mutations are the most important risk factor for
estradiol levels [34]. Different causes of androgen-to-estrogen
developing male breast cancer. Hereditary breast cancer in females
imbalance and their relevant statistical data are summarized in
result from autosomal dominant inheritance, particularly BRCA1
Table 4 [12,34–41].
and BRCA2 mutations, and constitutes 5%–10% of all female breast
Klinefelter’s syndrome (47XXY karyotype), with low testoster-
cancers [13]. Unlike BRCA1, a considerable number of BRCA2
one and high gonadotropin concentrations, imposes a risk for
mutations have been reported in heritable cases of male breast
breast cancer that is 20–50 times higher than the risk within the
cancer. The reported frequencies of BRCA2 germ-line mutations in
general male population, with mortality rates similar to those of
male breast cancer vary between populations because of small
females diagnosed with breast cancer [42]. Additionally, any
sample sizes, different type of mutations, and differences in
condition that decreases exposure to androgens or increases
sensitivities of mutation screening. Amongst published studies,
exposure to estrogen, such as the use of anti-androgens and
the reported percentage of BRCA2 mutations in patients with a
estrogens in the treatment of prostate cancer or the administration
of estrogen to transsexuals, have been reported to be associated
Table 2
Distribution of male breast cancer cases and controls according to age. with an increased risk of male breast cancer [43,44]. First preg-
nancies are known to have higher estrogen levels than later ones,
Age group Cases number % Cases Controls number % Controls and first-born male children have a risk of male breast cancer that
is 1.71 times higher than their younger brothers [45].
o45 3 14.3 14 17.1
≥45 18 85.7 68 82.9
Although a disturbance in the balance of androgens and estro-
gens is a well-known risk factor for the development of gyneco-
Modified from D’Avanzo and La Vecchia [12]. 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.
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)
cancer − gynecomastia per se is not a risk factor of male breast A positive family history of either female or male breast
cancer [46], and there is no significant reduction in testosterone cancer among first-degree relatives confers a 2- to 3-fold increase
level in males with breast cancer and no constant relation has in male breast cancer risk, and the risk increases with increasing
been found with estradiol levels [34]. 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
3.1.4.Personal and family history of cancer syndrome and hereditary non-polyposis colorectal cancer
Up to 33% of male breast cancer cases arise within families with (HNPCC) syndrome, although the risk in these cases is best
a background of familial breast and ovarian cancers [24]. Family characterized as moderate to low [48]. A personal history of male
history is important for both sexes; in males a positive family breast cancer in one breast is associated with a 30-fold increased
history confers a relative risk of 2.5 [37]; while population-based risk of breast cancer in the contralateral breast [49]. Males
studies have shown that about 15%–20% of all males with a who have a first primary breast cancer have a 16% increased
diagnosis of breast cancer have a history of breast cancer in a risk of developing a second primary cancer in comparison with
first-degree female relative [29] (Table 5). 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.
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.
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 reaching 60% to 76% frequency, whereas the BRCA1 mutation
patients [50]. 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%
3.1.5. Radiation of male breast cancer cases, increase the risk of male breast cancer
In studying ionizing radiations as an etiologic factor in the 10-fold above the general population [56]. The risk is significantly
development of male breast cancer, an increased risk in men with higher with a positive family history, and varies amongst ethnic
three or more diagnostic or therapeutic radiographic examinations groups and from one country to another [57].
was found. The relative risk after fluoroscopy is 2.4 [51], and after Data are conflicting regarding the relevance of other germ-line
radiotherapy are 7.2 [9]. Risk was increased in the interval from 20 mutations such as those in PALB2, the androgen receptor (AR), and
to 35 years after initial exposure from either radiographic exami- CYP17 in the etiology of male breast cancer [30,58]. Two cases of
nations or X-ray treatments, and declined after three to four male breast cancer in families with Cowden syndrome harboring
decades since last exposure, suggesting a wave of increased risk germline PTEN mutations have been reported [59]; however, no
of finite duration following exposure [52]. cases have been reported in families with the Li-Fraumeni syn-
drome caused by germline TP53 mutations.
3.2. Moderate to low risk
Table 6
Studies summarizing increased risk of male breast cancer because of occupations.
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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