Epidemiology and Pathophysiology of Alcohol and Breast Cancer
Update 2012
Helmut K. Seitz; Claudio Pelucchi; Vincenzo Bagnardi; Carlo La Vecchia
Authors and Disclosures
Posted: 05/24/2012; Alcohol Alcohol. 2012;47(3):204-212. © 2012 Oxford
University Press
Abstract and General Introduction
Abstract
Aims: To update epidemiological data on
alcohol and breast cancer, with special emphasis on light alcohol consumption, and to review
mechanisms of alcohol mediated mammary carcinogenesis.Methods: For epidemiological data, in November 2011 we performed a
literature search in various bibliographic databases, and we conducted a meta-analysis of data on
light alcohol drinking. Relevant mechanistic studies were also reviewed to November
2011. Results:A significant increase of the
order of 4% in the risk of breast cancer is already present at intakes of up to one alcoholic
drink/day. Heavy alcohol consumption, defined as three or more drinks/day, is associated with an
increased risk by 40–50%. This translates into up to 5% of breast cancers attributable to alcohol
in northern Europe and North America for a total of approximately 50 000 alcohol-attributable cases
of breast cancer worldwide. Up to 1–2% of breast cancers in Europe and North America are
attributable to light drinking alone, given its larger prevalence in most female populations when
compared with heavy drinking. Alcohol increases estrogen levels, and estrogens may exert its
carcinogenic effect on breast tissue either via the ER or directly. Other mechanisms may include
acetaldehyde, oxidative stress, epigenetic changes due to a disturbed methyl transfer and decreased
retinoic acid concentrations associated with an altered cell cycle. Conclusions: Women should not exceed one drink/day, and women at elevated
risk for breast cancer should avoid alcohol or consume alcohol occasionally only.
General Introduction
Alcohol consumption is a risk factor for cancer of various organs including the upper alimentary
tract, the liver, the colorectum and the female breast (Seitz and Stickel, 2007). Among these
organs, ethanol-mediated mammary carcinogenesis seems different since even small doses of ethanol
stimulate breast cancer development. This is of considerable concern since in Europe and in the USA
breast cancer is the most common cancer in women and alcohol use is widespread. In this review, up
to date epidemiological data on alcohol and breast cancer have been analyzed with special emphasis
on light alcohol consumption. In addition, possible mechanisms of ethanol-mediated mammary
carcinogenesis have been briefly discussed. For more detailed information, it is referred to
various overview articles (Wright et al.,
1999; Mill et al., 2009; Fernandez,
2011).
Epidemiology of Alcohol and Breast Cancer
Introduction
An association between alcohol and breast cancer was first suggested in the early 1980s by
case–control studies. A network of case–control studies from several areas of North America
(Rosenberg et al., 1982) reported a
relative risk (RR) of 1.9 (95% confidence interval, CI, 1.5–2.4) for ever vs. never-drinkers. A
case–control study from Italy, where alcohol consumption in women was frequent and particularly
high at that time (Talamini et al., 1984;
Bosetti et al., 2007), gave a
corresponding RR of 2.5 (95% CI, 1.7–3.7).
More than 100 epidemiological studies on alcohol consumption and female breast cancer were
published afterwards, and a positive association is now established. Two recent International
Agency for Research on Cancer (IARC) Monographs considered the effect of alcohol drinking in cancer
aetiology, and concluded that female breast cancer is causally related to alcohol consumption
(Secretan et al., 2009; IARC, 2010).
Several aspects of alcohol consumption on breast cancer risk are, however, still under discussion.
Among these are the effects of low amount of drinking (i.e. up to one drink/day) and the risk of
breast cancer defined by estrogen receptor (ER) and progesterone receptor (PR) status.
In this section, we review the epidemiological evidence on alcohol drinking—with particular focus
on different levels of consumption—and the risk of breast cancer. We also present a meta-analysis
of data on light alcohol drinking.
Light Alcohol Drinking
It is particularly important to quantify the relation between light alcohol drinking and breast
cancer risk. In fact, it is still unclear whether there is any threshold in intake below which no
effect of alcohol on breast cancer is evident.
We performed a literature search in MEDLINE, ISI Web of Science (Science Citation Index Expanded)
and EMBASE for epidemiological studies published prior to November 2011. We also reviewed
references cited by the relevant retrieved articles. Articles were included in the meta-analysis
only if they satisfied the following criteria: (a) case–control or cohort studies published as
original articles; (b) studies that reported findings expressed as odds ratio, RR or hazard ratio
(or reporting sufficient data to compute them) for light drinkers (≤12.5 g/day ethanol; ≤1
drink/day) vs. non-drinkers; (c) studies that reported standard errors or CIs of the risk
estimates, or provided sufficient data to calculate them. We thus computed a pooled RR of breast
cancer for light drinkers vs. non-drinkers, using random-effects models (DerSimonian and Laird,
1986). Statistical heterogeneity among studies was evaluated using I 2, which
is the proportion of total variation contributed by between-study variance (Higgins and Thompson,
2002). Subgroup analyses and meta-regression models were carried out to investigate potential
sources of between-study heterogeneity. We used a χ 2 statistics to test for differences of summary estimates among
subgroups (Greenland, 1987).
A total of 3431 papers were retrieved from the literature search. Of these, 113 papers reporting
breast cancer risk estimates for light drinkers were included in the meta-analysis. The complete
reference list is reported in Appendix.
The analysis included 44,552 cases in the reference category of non-drinkers (40,899 incident cases
and 3653 deaths) and 77,539 cases in the light drinkers' category (76,303 incident cases and 1236
deaths). These numbers are slightly underestimated, since for six studies the number of exposed
and/or non-exposed cases was not reported. Case–control was the most common study design (64% of
studies); 51% of the included studies were from North America, 38% from Europe, 6% from Asia and
10% from other regions or from more than one region; 36% of the reported estimates were adjusted
for the main risk factors (age, family history, parity, menopausal status, oral
contraceptive/hormonal replacement therapy use), while 16% of the estimates included occasional
drinkers in the reference category.
Figure 1 shows the RR of breast cancer in light drinkers vs. non-drinkers in each of the 113
included studies. We found substantial heterogeneity among single study estimates
(I 2 = 64%).
The random-effect summary RR was 1.04 (95% CI, 1.02–1.07). We did not find evidence of
heterogeneity in pooled estimates by design (P = 0.93) and area in which the study was carried out
(P = 0.71). Results did not appreciably
change from those of the overall analysis when considering only estimates adjusted for the main
risk factors (pooled RR = 1.03, 95% CI, 1.00–1.07), as well as including only estimates not
considering occasional drinkers in the reference category of non-drinkers (pooled RR = 1.04, 95%
CI, 1.01–1.07).
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Figure 1.
RRs of breast cancer for light drinkers vs. non-drinkers. Squares indicate
study-specific RRs. Horizontal lines indicate the 95% CIs. Diamond indicates pooled
RR with its corresponding 95% CI.
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Therefore, this meta-analysis reported a modest but significant association between light drinking
and breast cancer. The estimate was based on the results of more than one hundred studies. Women
drink less than men (Gronbaek et
al., 1994) and therefore low and moderate
intakes are usually investigated more frequently and more in detail in women than in men, though
the bias due to under reporting of even moderate alcohol consumption may be more relevant for women
than for men (Allen et
al., 2009). Since several populations
show a high prevalence of light drinkers among women, even the small increase in risk we
reported—in the order of 5%—represents a major public health issue in terms of breast cancers
attributable to alcohol consumption.
Heavy Alcohol Drinking
High levels (i.e. ≥3 drinks/day) of alcohol consumption were associated with increased risk of
breast cancer in the largest available studies (Hamajima et al. 2002; Allen et al., 2009; Chen et al., 2011). In the collaborative reanalysis of 53 epidemiological
studies on breast cancer (Hamajima et
al., 2002), the RRs were 1.32 (95% CI,
1.19–1.45) for consumption of 35–44 g/day and 1.46 (95% CI, 1.33–1.61) for consumption of ≥45 g/day
of alcohol, when compared with non-drinkers. The association was similar in never- and
ever-smokers. In the Million Women Study (Allen et al., 2009), the RR was 1.29 (95% CI, 1.23–1.35) for the highest
level of consumption considered, i.e. ≥21 g/day, after adjustment for smoking and several other
covariates. A 51% (95% CI, 35–70%) increase in risk emerged for drinkers of ≥30 g/day vs.
non-drinkers in the Nurses' Health Study (Chen et al., 2011). Further, a case–control study of over 2500 women with
breast cancer conducted in Italy, in a population characterized by relatively high alcohol
drinking, reported an RR of 1.41 (95% CI, 1.17–1.71) for consumption >27 g/day when compared
with abstainers (Ferraroni et
al. 1998). Therefore, these results
consistently indicate a 40–50% elevated risk of breast cancer in women consuming three or more
alcohol drinks/day.
Dose–risk Relation
With reference to the dose–risk relation, the collaborative reanalysis on alcohol and breast cancer
(Hamajima et al., 2002) found that the RR of breast cancer increased by 7.1%
(95% CI, 5.5–8.7%) for each additional 10 g/day of alcohol intake. In the Million Women Study
(Allen et al., 2009), the corresponding increase in alcohol consumption was
associated to a 12% (95% CI, 9–14%) increased risk of breast cancer. A meta-analysis based on 49
studies and over 44,000 cases gave a dose–risk function which approached a RR of 1.5 at 40 g/day,
and further increased for highest levels of intake (Fig. 2) (Bagnardi et al., 2001). A subsequent meta-analysis of about 100 epidemiological
studies provided results according to the degree of control for confounding and the overall quality
of the studies identified (Key et
al., 2006). The increase in risk for
additional 10 g/day of alcohol varied between 10 and 13%, according to the inclusion criteria used.
Further, the trend in risk was highly significant (P < 0.001). There is, therefore, consistent evidence for a
positive dose–risk relation between alcohol drinking and breast cancer.
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