Etiology of breast cancer (C50) in Central and South America

Alejandro Di Sibio1, Graciela Abriata1, Rosana Buffa1, María Viniegra1, David

Forman2, Mónica S. Sierra2
1
National Cancer Institute, Argentina.
2
Section of Cancer Surveillance, International Agency for Research on Cancer,
France.

How to cite:
Di Sibio A, Abriata G, Buffa R, Viniegra M Forman D, Sierra MS (2016). Etiology of breast cancer
(C50) in Central and South America. In: Cancer in Central and South America. Lyon: International
Agency for Research on Cancer. Available from: http://www-dep.iarc.fr/CSU_resources.htm,
accessed [date].

Breast cancer is a complex, heterogeneous, and multifactorial disease. Although

some genetic factors have a strong and well-defined impact, such as mutations in
the breast cancer 1 (BRCA1) and BRCA2 genes, most of the women who develop
the disease do not present a clearly identifiable risk profile [1, 2]. Only 5–10% of all
breast cancers are considered to be due to mutations in inherited high penetrance
genes [3]. The risk of breast cancer has been consistently associated with age, a
family or personal history of breast cancer, reproductive and hormonal factors (i.e.,
early menarche, late age at first pregnancy, small number of pregnancies, short or
no periods of breastfeeding, and a later menopause), hormone replacement therapy
(HRT), obesity (for postmenopausal breast cancer only), alcohol consumption,
physical inactivity, exposure to ionizing radiation, and genetic predisposition [4–6].
This section briefly describes these factors and especially focuses on those that are
modifiable and could guide efforts for prevention in the Central and South American
region.

Reproductive factors and hormones

Age at menarche and menopause

Age at menarche and age at menopause can be used to calculate the reproductive
years of a woman. During this time, the ovary produces steroid hormones that affect
the development and function of the breast [7]. Early age at menarche and late age
at menopause have been consistently associated with an increased risk of breast
cancer development [7]. The Collaborative Group on Hormonal Factors in Breast
Cancer (CGHFBC) recently conducted a meta-analysis of 117 studies (35 cohort and
56 case–control) that included 118 964 women with breast cancer and showed that
the risk of breast cancer increased by 5% (95% confidence interval [CI], 4.4–5.7%)
for each year younger at menarche and by 2.9% (95% CI, 2.5–3.2%) for each year
older at menopause [7]. The CGHFBC also showed that the risk of breast cancer
was 43% (95% CI, 33–52%) higher in premenopausal women (aged 45–54 years)
than in postmenopausal women of the same age [7].

Long-term exposure to high concentrations of endogenous estrogens increases the

risk of breast cancer in pre- and postmenopausal women, the related mechanisms of
which have been suggested to be involved in the risk factors associated with
estrogen receptor/progesterone receptor (ER/PR)-positive tumours, while the etiology
of ER/PR-negative tumours could be non-hormonal [8, 9]. Ma et al. [10] found that

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late age at menarche reduced the risk of ER/PR-positive tumours by 28% and that of
ER/PR-negative tumours by 16% compared with a younger age at menarche (< 12
or < 13 years) (summary rate ratio [RR], 0.72; 95% CI, 0.64–0.80 for ER/PR-positive
tumours; summary RR, 0.84; 95% CI, 0.75–0.94 for ER/PR-negative tumours). A
pooled analysis of 14 795 breast cancer cases (10 900 ER-positive and 3895 ER-
negative) and 17 399 controls revealed that women who were younger at menarche
(< 12 years) were at a higher risk of ER-positive tumours than those who were older
at menarche (> 15 years) (pooled odds ratio [OR], 1.16; 95% CI, 1.07–1.25), but the
association with ER-negative tumours was less clear (pooled OR, 1.11; (95% CI,
0.99–1.03) [11]. In a subanalysis by tumour characteristics, the CGHFBC found that
the risk of breast cancer varied by age and menopausal status [7].

Early menarche has also been suggested to be related to a higher risk for luminal
cancers. However, a pooled analysis by Phipps et al. [12] found that early menarche
(< 13 years) was not associated with luminal cancers (OR, 1.0; 95% CI, 0.9–1.2) but
early menarche was associated with an increased risk of tumours that
overexpressed human epidermal growth factor receptor 2 compared with late
menarche (> 13 years) (OR, 2.7; 95% CI, 1.4–5.5).

Nulliparity and later age at first pregnancy

Delayed childbirth due in part to increases in both socioeconomic development and

more effective contraception has been postulated to increase the burden of breast
cancer [13, 14]. Nulliparity and delayed childbearing have been associated with an
increased risk of ER-positive but not ER-negative tumours. In a meta-analysis of
eight studies, Ma et al. [10] found that older age at first pregnancy (≥ 30 years)
increased the risk of ER/PR-positive tumours by 27% (95% CI, 7–50%) compared
with pregnancy at a younger age and that each birth reduced the risk of ER/PR-
positive tumours by 11% (95% CI, 6–16%), but did not find associations between
parity or age at first birth and ER/PR-negative tumours.

The age of the mother at births and birth spacing seem to change the magnitude and
the timing of the increased risk associated with breast cancer, suggesting that the
associations between reproductive history and the risk of breast cancer are complex.
Furthermore, changes in childbearing patterns (fewer children and later age at births)
over the past decades could probably affect the burden of breast cancer incidence in
the future [15, 16]. In the Central and South American region, fertility rates (number
of births per woman) have been declining since the 1960s and this decline has
coincided with an increased burden of breast cancer [17, 18]. This is particularly
noticeable in Argentina, Brazil, and Uruguay where the incidence of breast cancer is
among the highest and the fertility rates are the lowest in the region (average ~2
children per woman, similar to the fertility rate in the USA), whereas in Ecuador,
Guatemala, Nicaragua, and Peru, the mortality rates are among the lowest and
fertility rates are among the highest (~3–4 children per woman) in the region [19].

Breastfeeding

The effect of breastfeeding on the risk of breast cancer has been a subject of debate
[20]. However, a growing body of evidence indicates that breastfeeding reduces the
risk of developing breast carcinoma [8, 21]. In a recent meta-analysis of 27 studies

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that included 13 907 women with breast cancer, Zhou et al. [21] found that women
who had ever breastfed had a 39% lower risk of breast cancer than those who had
never breastfed (pooled RR, 0.613; 95% CI, 0.442–0.850) and that the longest
duration of breastfeeding was associated with a 53% lower risk of breast cancer
compared with the shortest breastfeeding categories (RR, 0.471; 95% CI, 0.368–
0.602). In a pooled analysis of two population-based studies, Phipps et al. [12] found
that, compared with women who had never breastfed, those who had breastfed for
6 months or longer had a 20% (95% CI, 0–40%) reduced risk of luminal cancers and
a 50% (95% CI, 10–70%) reduced risk of triple-negative cancers (ER/PR/human
epidermal growth factor receptor 2-negative).

In a hospital-based case–control study conducted in Mexico City, Mexico, Romieu et

al. [22] found that the risk of breast cancer was 61% lower in parous women who
reported ever having breastfed than in parous women who had never breastfed after
adjusting for age (OR, 0.39; 95% CI, 0.25–0.62), and the effect was stronger for
postmenopausal than for premenopausal women (OR, 0.29 for postmenopausal
women; OR, 0.48 for premenopausal women). They also reported a dose–response
relationship showing stronger protective effects with longer durations of lactation (P
for trend < 0.001). Women who reported breastfeeding four children or more had a
61% lower risk of breast cancer than those who had never breastfed (adjusted
OR, 0.39; 95% CI, 0.21–0.70); the protective effect was also observed for those who
had breastfed one to two and three to four children (OR, 0.57 for 1–2 children; 0.52
for 3–4 children).

Exogenous hormones

In the evaluation of pharmaceuticals as human carcinogens, the International

Agency for Research on Cancer (IARC) concluded that there was sufficient evidence
for the causative effect of combined estrogen–progestogen contraceptives (OC) and
combined estrogen–progestogen menopausal therapy on breast cancer [23]. The
evidence suggests that the risk of breast cancer increases with increasing duration
of OC use among current users, but whether all current formulations and treatment
regimens have similar carcinogenic effects has yet to be elucidated [24].
Furthermore, OC use has been associated with an increased radiological breast
density [24]. The CGHFBC showed that current OC users had a 24% (95% CI, 15–
33%) higher risk of breast cancer than never-users and the risk remained even 1–
4 years or 5–9 years after cessation of use (RR, 1.16; 95% CI, 1.08–1.23 for 1–
4 years; RR, 1.07; 95% CI, 1.02–1.13 for 5–9 years) [25].

Epidemiological evidence has consistently suggested that OC use is associated with

an increased risk of breast cancer among carriers of BRCA1 or BRCA2 mutations
[24, 26, 27], which may explain the risk of breast cancer among young women (aged
< 35 years) who began using OC at a young age and were current or recent users
(as cited in [24]). In a meta-analysis of eight studies in carriers of BRCA1 and
BRCA2 mutations, Moorman et al. [28] showed that OC users had a 21% increased
risk of breast cancer than non-users (summary OR, 1.21; 95% CI, 0.93–1.58).
Another meta-analysis showed that BRCA1/BRCA2 carriers who stopped using OC
10 years before the diagnosis had a 46% lower risk of breast cancer then never-
users (RR, 1.46; 95% CI, 1.07–2.07) [26]. In a recent meta-analysis of three cohort
studies, Friebel et al. [27] found that the risk of breast cancer in BRCA1 carriers was

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59% higher among ever-users of OC compared with never-users (hazard rate ratio
[HR], 1.59; 95% CI, 1.32–1.92) and that in BRCA2 carriers was 85% higher among
ever-users of OC compared with never-users (HR, 1.85; 95% CI, 1.30–2.64 in 2
cohort studies) [27]. The differences in these meta-analyses were due to the way in
which the studies were stratified to evaluate the associations.

Exposure to estrogen-only menopausal therapy has been linked to an increased risk

of breast cancer, although IARC concluded that there was limited evidence for its
causative effect [24]. Some studies suggested that longer-term use estrogen therapy
increases the risk of breast cancer (as cited in [24]).The Women’s Health Initiative
Randomized Trial showed that the use of combined HRT for more than 2 years may
increase mammographic density and thus reduce the sensitivity of mammography to
provide an early diagnosis [29]. Lee et al. [30] evaluated the menopausal use of
estrogen–progesteron therapy on the risk of breast cancer by histological subtype
and found that it increased the risk by 7.6% per year of use. In a recent meta-
analysis, Reeves et al. [31] showed that current use of HRT increases the risk of in-
situ and invasive ductal breast cancers compared with never use (RR, 1.51; 95% CI,
1.39–1.63 for in-situ cancer; RR, 1.67; 95% CI, 1.62–1.73 for invasive ductile
cancer).

Personal history of breast cancer

A personal history of in-situ or invasive breast cancer increases the risk of

developing a contralateral invasive cancer. In the USA, the incidence of contralateral
breast cancer steadily declined from 1985 to 2006 by 3% (95% CI, –3.5% to −2.7%]
per annum, which was mainly due to greater declines in contralateral breast cancer
rates after an ER-positive primary breast cancer than after an ER-negative cancer
(estimated annual percentage change, −3.18%; 95% CI, –4.2% to −2.2% for ER-
positive; estimated annual percentage change, –1.68%; 95% CI, 0.0% to −3.4% for
ER-negative). The declines were more evident for contralateral breast tumours
diagnosed 1–4 years after a diagnosis of ER-positive primary breast cancer
(estimated annual percentage change, −3.71%; 95% CI, –4.9% to −2.5% per year).
Such declines are thought to be due to the widespread use of adjuvant hormone
therapies [32]. Women with a history of atypical lobular or atypical ductal hyperplasia
had a 4.4 (95% CI, 3.1–6.3) times higher risk of developing breast cancer than the
general population and the association was nearly doubled in those with a family
history of breast cancer (RR, 8.9; 95% CI, 4.8–17) [33].

Family history of breast cancer and genetic susceptibility

Some genome-wide association studies conducted in Asia, Europe, and North

America have shown that susceptibility genes and genomic sequences account for
less than one third of all inherited breast cancers (as cited in [34]). The BRCA1 and
BRCA2 tumour suppressor genes account for 5% of all breast cancers and 85% of
all hereditary breast and ovarian epithelial cancers. Women with Cowden or Li-
Fraumeni syndromes have an increased risk of developing breast cancer with a
lifetime risk of 50% and 1%, respectively (as cited in [34]).

Women with any relative, a first-degree relative, a mother or a sister with breast
cancer have about twice the risk of developing breast cancer. The risk is noticeably

4
higher among women who have a mother and a sister with breast cancer (RR, 3.6;
95% CI, 2.5–5.0) and among younger women (RR, 2.5–3.3 for women < 50 years of
age who have relatives with breast cancer diagnosed before the age of 50 years)
[35].

The most frequent hereditary syndrome is hereditary breast and ovarian cancer
(through a BRCA1 or BRCA2 gene mutation), with a 50–80% risk of breast cancer
throughout the course of a lifetime. BRCA1-related cancers are frequently triple
negative, while BRCA2-related cancers are often hormone-dependent but highly
proliferative [36, 37]. Both gene mutations are associated with carcinomas appearing
at an earlier age and also an increased risk of developing ovarian cancer (lifetime
risk, 10–50%), especially with BRCA1 mutations [38]. However, considerable inter-
individual variability has been found among BRCA1 and BRCA2 carriers in terms of
age at and site of cancer diagnosis which maybe a result of modifying factors (i.e.,
breastfeeding, oral contraceptive use, tubal ligation, alcohol consumption, exposure
to X-rays or mammography, use of tamoxifen (and other selective estrogen receptor
modulators), obesity, and physical activity) that influence cancer penetrance in
carriers. A similar variability has also been described between families carrying the
same BRCA1/BRCA2 mutation genes [27].

In a population-based study conducted in the USA among white and black women
aged 35–64 years, the overall prevalence of BRCA1 and BRCA2 carriers was 4.6%
(2.4% and 2.3%, respectively) in the cases and 0.4% (0.04% and 0.4%, respectively)
in the controls. Among the cases, the prevalence of BRCA1 was higher in those of
Jewish ancestry than in those of non-Jewish ancestry (10.2% vs 2.4%) and in whites
than in blacks (2.9% vs 1.4%), whereas the prevalence of BRCA2 was slightly higher
in non-Jewish than in Jewish women (2.3% vs 1.1%) and in blacks than in whites
(2.6% vs 2.1%) [38]. Some mutations are particularly frequent in specific populations
through a ‘founder effect’, for example, in Ashkenazi Jewish ethnics, whose carrier
frequency is higher [39, 40].

In the Central and South American region, genetic screening for BRCA mutations in
patients with a family history of breast cancer is uncommon, probably because of the
high costs and limitations of infrastructures [41]. However, a few studies were
conducted in Central and South American women with a family history of breast
cancer which revealed considerable variation in the frequency of BRCA1/BRCA2
point mutations in the patients tested: 28% in Argentina [42], 2.3–13% in Brazil [43],
15.9% in Chile [43], 25% in Colombia [44], 4.5% in Costa Rica [45], 28% in Mexico
[46], 5% in Peru [47], and 6.9–10.3% in Venezuela [46]. The reported prevalence of
BRCA1 and BRCA2 mutations in Hispanic women with a personal or family history of
the disease residing in the USA was 25% [48].

Breast density

Breast density (radio dense fibroglandular tissue in the breast) has been suggested
for use as a predictor of breast cancer risk [49]. A meta-analysis of the percentage
density measured using pre-diagnostic mammograms in the general population
revealed that women with a breast density of 5–24%, 25–49%, 50–74%, and 75% or
more had a 1.79 (95% CI, 1.48–2.16), 2.11 (95% CI, 1.70–2.63), 2.92 (95% CI,
2.49–3.42), and 4.64 (95% CI, 3.64–5.91) times higher risk of developing breast

5
cancer than women with a breast density of less than 5% [49]. High breast density
(dense tissue in ≥ 75% of the breast) has been strongly associated with an increased
risk of breast cancer (4–6 times higher than women with little to no breast density)
[50, 51]. Younger women (aged 40–49 years) with an extremely dense or
heterogeneously dense breast on mammographic examination had approximately
twice the risk of having breast cancer than those with fibroglandular densities
(RR, 2.04; 95% CI, 1.84–2.26 for extremely dense; RR, 2.33; 95% CI, 2.04–2.66 for
heterogeneously dense) (as cited in [4]). Breast density is associated with age,
gynaecological and obstetric history, HRT, body mass index (BMI), and genetic
determinants. In addition to an increase in risk, high breast density reduces
mammographic sensitivity at screening [52].

Ionizing radiation

IARC has classified radiation (X-radiation or gamma-radiation) as a causative agent

for female breast cancer [53]. The evidence was mainly found in survivors from
atomic bomb outbursts and those exposed to radiation for medical purposes or in
utero (offspring of pregnant medical patients and of atomic bomb survivors) [53]. In a
review of 17 studies, Clemons et al. [54] found that women exposed to radiation for
the treatment of Hodgkin lymphoma (usually between puberty and the age of 30
years) had 5.2 times the risk of developing breast cancer with an average latency
period of approximately 14 years (range, 5–15.1 years). Women exposed to X-ray
fluoroscopy for the treatment of tuberculosis (1 Gy per treatment with average of 88
treatments) have been shown to have a 61% increased risk of developing breast
cancer approximately 10 years after exposure, with younger women having a higher
risk than older women (as cited in [55]).

Alcohol consumption and tobacco smoking

IARC has classified the consumption of alcoholic beverages as a carcinogenic agent

for the female breast [56] and a dose–response relationship has been found
between alcohol consumption and the risk of breast cancer [57]. The CGHFBC
reported that women who consumed 35–44 g or 45 g or more of alcohol per day had
a 32% (95% CI, 19–45%) or 46% (95% CI, 33–61%) higher risk of developing breast
cancer than non-drinkers and the risk increased by 7.1% (95% CI, 5.5–8.7%) for
each additional drink (10 g) of alcohol per day regardless of smoking status. For
each additional drink of alcohol per day, the risk of breast cancer increased by 6.3%
in premenopausal women and by 8.1% in postmenopausal women [8].

IARC considered tobacco smoking to be an agent with limited evidence of causing

breast cancer because the number of women included in the available
epidemiological studies was too small to draw conclusions [56]. However, in a recent
meta-analysis of 15 cohort studies that included nearly 100 000 women, Gaudet et
al. [58] showed that current smokers had a 12% (95% CI, 8–16%) higher risk of
developing breast cancer than never-smokers and that former smokers had a 9%
(95% CI, 4–15%) higher risk than never-smokers, although evidence of
heterogeneity between studies was observed. In another meta-analysis of 10 studies
on the association with smoking status at the time of diagnosis among 5892 women
with invasive breast cancer (1987–2008), Berube et al. [59] found that breast cancer-
specific mortality was 10% (95% CI, 1–20%) higher in smokers than in never-

6
smokers (in 6 studies) and increased with increasing intensity and duration of
smoking (P for trend < 0.005). These results suggested that tobacco smoking should
be avoided due to its serious adverse effects on health.

Increased body weight

Obesity and increased BMI have been consistently associated with an increased risk
of breast carcinoma although the relationship differs according to pre-and
postmenopausal status and ER/PR tumour status [8;60;61]. The World Cancer
Research Fund/American Institute for Cancer Research (WCRF) panel evaluated the
evidence of body fatness and the risk of cancer and concluded that there is
convincing evidence indicating that greater body fatness causes postmenopausal
breast cancer [57].

In a meta-analysis of 31 studies (9 cohort and 22 case–control), Suzuki et al. [61]

found that each 5-kg/m2 increase in BMI was associated with a 33% (95% CI, 20–
48%) increase in ER-positive and PR-positive tumours (in 8 studies) but was
protective against the incidence of ER/PR-positive tumours in premenopausal
women (RR, 0.90; 95% CI, 0.82–0.99 in 4 studies). However, no associations were
observed between increased BMI and ER/PR-negative tumours or ER-positive/PR-
negative tumours in either pre- or postmenopausal women. In a meta-analysis of 31
prospective studies, Renehan et al. [62] found that a 5-kg/m2 increase in BMI
increased the risk of postmenopausal breast cancer by 12% (95% CI, 8–16%). Of
the postmenopausal breast cancer cases occurring worldwide in 2012, 10% were
estimated to be attributable to high BMI (≥ 25 kg/m2) with noticeable variations by
region (4–6% in SubSaharan Africa and Asia, and 10–15% in Europe, Latin America
and the Caribbean, the Middle East and North Africa, North America, and Oceania)
[63].

Diet

Evidence for the influence of nutritional factors on the risk of breast cancer is
heterogeneous, controversial, and inconclusive [57, 64–67]. The WCRF panel
evaluated the available evidence on the consumption of several dietary products,
such as meat, egg, or dairy foods, cereals, dietary fibre, vegetables and fruit,
legumes, soya and soya products, and vitamins (i.e., A, B6, B12, folate, and
riboflavin), and found limited non-conclusive evidence on their possible association
with the risk of breast cancer [57], but concluded that red meat was a ‘possible
cause’ of breast cancer. Although the WCRF found weak positive associations with
fats and oils and an increased risk of postmenopausal breast cancer (RR, 1.06; 95%
CI, 0.99–1.14 per 20 g per day in 5 cohorts with moderate heterogeneity; OR, 1.11;
95% CI, 1.06–1.16 in 7 case–control studies with no evidence of heterogeneity), the
panel concluded that there was “limited evidence suggesting that [the] consumption
of total fat is a cause of postmenopausal breast cancer” [57]. The impact of diet as a
sole and isolated factor is difficult to determine because of the concurrence of other
confounding factors.

In Uruguay, De Stefani et al. [68] evaluated the association between four dietary
patterns and the risk of breast cancer and found an inverse association with having a

7
diet pattern ‘typical of industrialized countries’ (high intake of red meat, processed
meat, and total eggs) or a drinker diet pattern (consumption of beer, wine, hard
liquor, and processed meat) were positively associated with the risk of breast cancer
(OR, 1.81; 95% CI, 1.32–2.50 vs low intake for ‘industrialized’; OR, 1.40; 95% CI,
1.05–1.87 vs low intake for drinker), whereas having a ‘traditional’ diet pattern (high
intake of cooked vegetables, all tubers, and legumes) was protective against breast
cancer (OR, 0.53; 95% CI, 0.36–0.71 vs low intake). Having a ‘prudent’ diet pattern
(high intake of white meat, dairy foods, raw vegetables, and total fruit) was not
associated with the risk of breast cancer.

In a systematic review of 27 studies conducted in Central and South America

(Argentina, Brazil, Chile, Colombia, Mexico, and Uruguay),Torres-Sanchez et al. [69]
described the protective effects found in some studies for the consumption of fruit
and vegetables, fish, fibre, vitamin B12, folate, phytoestrogens, and lycopene against
breast cancer as well as the causative effects of high caloric diets, meat
consumption (red and processed), cooking process (fried, roasted, and barbequed),
saturated fats, and some dairy products on breast cancer. However, because of the
lack of methodological rigor in some studies, the authors called for more research on
dietary components and breast cancer in the region before any conclusions could be
drawn [69]. In a review of meat consumption and exposure to their heterocyclic
amines and cancer risk in the South American region, Matos and Brandani [70]
highlighted the challenges of comparing results across the region due to the wide
definitions of meat (may include poultry) and differences in cooking methods (i.e.,
grilled, barbequed, roasted, and stewed) and also called for further research
regarding the potential association between meat consumption and cancer risk.

Physical activity

The WCRF panel concluded that physical activity (all forms, recreational, or
occupational) ‘probably protects’ against postmenopausal breast cancer but the
evidence is limited for pre-menopausal breast cancer. The proposed mechanisms by
which physical activity may be beneficial against breast cancer are related to effects
on body fatness, endogenous steroid hormone metabolism, and the immune system
(strengthening) [57]. In a recent meta-analysis of 31 prospective studies, Wu et al.
[71] found that physical activity was protective against breast cancer (RR, 0.88; 95%
CI, 0.85–0.91), with similar effects by type of activity (RR, 0.87; 95% CI, 0.83–0.91
for non-occupational activity (including recreational activity and household activity) in
27 studies; RR, 0.90; 95% CI, 0.83–0.97 for occupational activity in 7 studies).
However, the inverse association between physical activity and the risk of breast
cancer was stronger for women with a BMI of less than 25 kg/m2 (RR, 0.72; 95% CI,
0.65–0.81), for premenopausal women (RR, 0.77; 95% CI, 0.72–0.84), and for
ER/PR-negative tumours (RR, 0.80; 95% CI, 0.73–0.87).

A dose–response relationship between increased physical activity and the lower risk
of breast cancer has been described. In a meta-analysis of five case–control studies,
the WCRF showed a 10% reduction in the risk of breast cancer per 7-metabolic
equivalent (MET) hours per week of recreational physical activity (OR, 0.90; 95% CI,
0.88–0.93). Wu et al. [71] also found a 2% reduction in the risk of breast cancer for
every 25-MET hours per week increment in non-occupational physical activity, 3%
for every 10-MET hours per week increment in recreational activity (i.e., 4 h per

8
week of walking 2 miles per hour or 1 h per week of running 6 miles per hour), and
5% for every 2-h per week increment in moderate/vigorous recreational activity. In an
age-matched case–control conducted study of 1074 Mexican women, Angeles-
Llerenas et a [72] showed that women who participated in moderate-to-intense
physical activity had a lower risk of having breast cancer compared with controls; for
every 3 h per week of moderate-to-intense physical activity, the risk of breast cancer
was 4% in premenopausal (OR, 0.96; 95% CI, 0.92–0.99) and 10% in
postmenopausal women (OR, 0.90; 95% CI, 0.86–0.93).

In a meta-analysis of 75 studies, Lee et al. [73] found that physical inactivity

(insufficient physical activity to meet current recommendations) increased the risk of
breast cancer by 33% (95% CI, 26–42%). In a case–control study in low-income
women in Brazil that included 106 incident cases of breast cancer and 181 hospital
controls, women who had a sedentary lifestyle had a 2.39 (95% CI, 1.43–3.99) times
higher risk of developing malignant breast diseases than controls; the strength and
direction of the association remained the same after further adjustment for hormone-
related factors, a family history of breast cancer, and the percentage of body fat [74].

Acknowledgements

This work was undertaken during the tenure of a Postdoctoral Fellowship by Dr

Mónica S. Sierra from the International Agency for Research on Cancer, partially
supported by the European Commission FP7 Marie Curie Actions – People – Co-
funding of regional, national and international programmes (COFUND). The authors
wish to thank Drs Raul Murillo and Leticia Fernandez for their valuable comments.

9
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