Links Between Alcohol Consumption and Breast Cancer

A Look at the Evidence

Ying Liu; Nhi Nguyen; Graham A Colditz

Disclosures

Women's Health. 2015;11(1):65-77. 

In This Article

Epidemiology

Importance of Early-life Exposures to Breast Cancer Development

It is increasingly recognized that early-life exposures can affect a woman's lifetime risk of breast cancer.[11–14] Late onset of menstruation, early pregnancy and early onset of menopause are each associated with decreased risk for breast cancer. Breast cancer risk accumulates across a woman's life course; however, the most rapid accumulation occurs from menarche to first pregnancy.[15–18] Both human and animal model data have demonstrated that environmental exposures during adolescence and early adulthood are more important in breast cancer development than exposures later in life.[6,12,14,19–22] There may be a critical period of increased biologic vulnerability between menarche, when breast tissue undergoes rapid proliferation, until the completion of the first pregnancy, when multiple biologic changes in the breast occur and make epithelial cells resistant to becoming transformed into cancer cells.[22–26] This is well exemplified by the observed higher risk of breast cancer among female survivors from the atomic bomb explosions in Hiroshima and Nagasaki who were less than 20 years old at the time of bombing.[12] Experimental animal models do also support a critical role of early life exposures on breast cancer development. Compared with rats that have undergone full-term pregnancy, young virgin rats with undifferentiated mammary glands are more likely to develop breast tumors when exposed to chemical carcinogens.[27]

Alcohol Consumption During Adolescence & Early Adulthood & Risk of Breast Cancer

Given the increased susceptibility of nulliparous breast tissue to neoplastic transformation, alcohol, a breast carcinogen, consumed in adolescent and early adult years may be relevant to breast cancer development. Several epidemiologic studies have evaluated alcohol consumption across the life course in relation to breast cancer risk. The majority of these studies reported that recent drinking, but not drinking in early adult life, was significantly associated with breast cancer risk.[28–33] However, case–control studies showed a significant increase in breast cancer risk associated with early age at which women started to drink (<25 years)[34] and with alcohol consumption before age 30 years.[35,36] Alcohol consumption before age 30 years was dose dependently associated with premenopausal breast cancer risk, with a 34% increase in risk for every 13 g/day (~1 drink/day) of intake, but not with postmenopausal breast cancer risk.[32] In a prospective analysis of more than 105,000 predominantly postmenopausal women in the Nurses' Health Study (NHS), Chen et al.[2] compared alcohol consumed before and after age 40 with regard to breast cancer risk and reported statistically significant associations of similar magnitude (relative risk [RR]: 1.07–1.08 per 10 g/day consumption) for drinking in age ranges. However, these studies did not distinguish between drinking before first pregnancy and drinking after first pregnancy, but evaluated alcohol consumption at specific chronological age ranges.

Animal studies have demonstrated that dietary exposure to ethanol during puberty stimulates morphologic changes in mouse mammary glands, including increases in ductal branching (targets for malignant transformation) and epithelial proliferation and density.[37,38] However, ethanol exposure of parous mice at the beginning of natural postlactational involution has no effect on mammary gland structure and did not influence the regression of the lactating mammary gland to a resting state.[39]

We recently refined the risk assessment approach to specifically address how alcohol intake between menarche and first pregnancy influences subsequent breast cancer risk among women in the Nurses' Health Study II (NHS II), a separate large cohort of US female nurses born from 1946 to 1964.[6] Parous women ages 24–44 years with no prior history of breast cancer in 1989 (n = 91,005) were included in the analysis. During up to 20 years of follow-up, 1609 women were diagnosed with breast cancer. Compared with women who abstained from alcohol before first pregnancy, the risk of breast cancer was significantly increased by 34% (RR: 1.34; 95% CI: 1.00–1.80) for those with intake of ≥15 g per day (~1.5 drinks/day). Alcohol intake before first pregnancy was dose dependently associated with breast cancer risk, with the relative risk of 1.11 (95% CI: 1.00–1.23; p = 0.05) for each additional 10 g/day intake. In our study, alcohol consumed after first pregnancy was moderately, but nonsignificantly, associated with breast cancer risk, with the relative risk of 1.09 (95% CI: 0.96–1.23) for every 10 g/day consumption. The observed association with alcohol consumption before first pregnancy was independent of drinking after first pregnancy. Moreover, the increase in risk of breast cancer for alcohol intake before first pregnancy was stronger when the time interval between menarche and first pregnancy was longer. For every 10 g/day alcohol consumed before first pregnancy, the risk of breast cancer was increased by 14% among women with an interval of 10–14 years between menarche and first pregnancy and by 25% among women with an interval of 15 or more years.

These epidemiologic results, along with animal data, suggest that alcohol exposure before first pregnancy can lead to morphologic changes in the breast, which may predispose to breast cancer development. In addition, a longer exposure to alcohol during this susceptible period may confer excessive breast cancer risk. Early-life alcohol consumption appears to contribute to both pre- and post-menopausal breast cancer.

Alcohol Intake & Intermediate Markers of Breast Cancer Risk

Proliferative benign breast disease (BBD) and mammographic density are well-confirmed intermediate end points of breast cancer risk that are generally evaluated in epidemiologic studies of the breast cancer etiology. A recent analysis of women participating in the breast cancer surveillance consortium showed that proliferative BBD and high breast density independently predict the risk of subsequent breast cancer.[40] As expected, women with both atypical hyperplasia and high breast density were at the greatest risk of breast cancer, with the relative risk of 5.34 (95% CI: 3.52–8.09). While alcohol consumption is consistently associated with increased risk of breast cancer, studies examining the associations of alcohol intake with proliferative BBD and mammographic density reported inconsistent results.

Benign Breast Disease

BBD encompasses a highly heterogeneous group of lesions that differ in their histopathologic features and clinical prognosis. Based on the criteria of Dupont and Page,[41] BBD is generally divided into nonproliferative lesions, proliferative lesions without atypia and atypical hyperplasias. The presence of proliferative benign lesions influences subsequent breast cancer risk; the risk is increased by 30–90% among women with proliferative BBD and no atypia, and by fourfold to fivefold among those with atypical hyperplasia.[42–45] Women with proliferative BBD have higher risk of breast cancer in the same breast as well as in the contralateral breast.

Few epidemiologic studies have assessed the association between alcohol consumption and risk for BBD. Two case–control studies of risk factors for BBD did not find an association between alcohol consumption in the year preceding diagnosis and BBD risk,[46,47] which is consistent with a prospective analysis of postmenopausal women participating in the Women's Health Initiative (WHI) randomized clinical trials.[48] One potential explanation for the lack of association is that these studies did not focus on an etiologically relevant exposure period. We recently examined the contributions of alcohol consumption before and after first pregnancy to risk of proliferative BBD.[6] We limited the analysis to cases confirmed by centralized pathologic review and diagnosed among parous women in the NHS II cohort. Compared with nondrinkers before first pregnancy, the risk for proliferative BBD was increased by 26% for those with daily intake of 5.0–14.9 g (~0.5–1.5 drinks) before first pregnancy and by 39% for those with daily intake of ≥15 g before first pregnancy. Overall, the risk for proliferative BBD was increased by 16% (95% CI: 2–32%) for each additional 10 g of alcohol consumed daily before first pregnancy. The increase in risk for proliferative BBD was more pronounced among women with a longer time interval between menarche and first pregnancy, although the difference was not statistically significant. In contrast, alcohol consumption after first pregnancy was not related to risk of proliferative BBD. The increased risk of proliferative BBD was also observed among women in the NHS II who reported moderate alcohol consumption between ages 18 and 22 years (RR: 1.15; 95% CI: 1.03–1.28 for each additional 10 g/day intake).[49] Among daughters of women in the NHS II, daily intake of one drink of alcohol between ages 16 and 22 years was associated with a 50% (95% CI: 19–90%) increased risk of biopsy confirmed BBD.[50] Taken together, these results suggest that alcohol consumption during adolescence and early adulthood may have a greater adverse effect on risk of proliferative BBD as compared with alcohol intake in late adult years.

Mammographic Density

Mammographic density is defined as the proportion of radiologically dense fibroglandular tissue in the breast. Mammographic density, assessed by either a qualitative approach or a quantitative measure of the radiodense area of the breast, is consistently associated with increased risk of breast cancer.[51] A meta-analysis of 14,000 cases and 226,000 noncases revealed that women with more than 75% mammographic density have almost five-times the risk of breast cancer compared with women with less than 5% mammographic density.[52]

The relationship between alcohol consumption and mammographic density is inconsistent. Some studies observed a weak, but significant, positive trend of increasing mammographic density with increased adult alcohol consumption in both pre- and post-menopausal women.[53–57] But, there was no significant association between alcohol consumption and mammographic density in other studies.[58–63] In general, a positive association was reported in the studies where the overall alcohol consumption level was higher, such as more than 15% of participants consuming more than 10 g of alcohol per day. Women in the Minnesota Breast Cancer Family cohort, comprising breast cancer patients' first- and second-degree female relatives and spouse of male relatives, were asked about their age at initiation of alcohol intake and alcohol consumption before age 18 during the follow-up.[59] Women who reported ever drinking alcohol before age 18 had a higher mammographic density than women who never drank during adolescence. However, this difference was nullified by adjustment for breast cancer risk factors. There was a suggestive trend toward higher mammographic density for women who reported heavier and frequent drinking before age 18 and those who drank regularly in adolescence and continued throughout adulthood. In a New York birth cohort (born 1959–1963), alcohol consumption was asked separately for each decade of life (prior to age 21, 21–29, 30–39 and 40 or older) and mammograms were obtained during the follow-up of female participants ages of 38–42.[64] In that study, recent alcohol intake was more strongly associated with mammographic density than average lifetime alcohol intake. Compared with nondrinkers, those who reported seven or more drinks per week in the past year had 12.3% (95% CI: 4.3–20.4%) higher density. Mammographic density was inversely associated with alcohol consumption before age 21 but positively associated with alcohol consumption in other periods of life.

Drinking Patterns & Breast Cancer Risk

Alcohol consumption is common in adolescents and young adults in the USA, although the minimum legal drinking age is 21 years. More than one of four people aged 12–20 reported alcohol use during the past 30 days.[65] Nearly 70% of youth alcohol consumption is in the form of binge drinking,[66] defined as consuming four or more alcoholic drinks on one occasion. Having multiple drinks in the same sitting results in higher alcohol levels in blood than having a single drink at one time, which can trigger different metabolic pathways.[9] Hence, women who report seven drinks on the weekend but no alcohol consumption on the weekdays may have higher risk of breast cancer as compared with those who consistently have one drink every day. Breast cancer risk is generally assessed in epidemiologic studies for an average amount of alcohol intake in a specified time/age period, which does not account for the effect of a large amount of alcohol consumed at any one time.

We identified three epidemiologic studies examining the relationship between binge drinking and breast cancer risk. Binge drinking is related to increased risk of breast cancer in two prospective studies among nurses. In the Danish Nurse Cohort study, binge drinking was evaluated on the last weekday and on weekends.[67] Women reporting binge drinking on weekends had a relative risk of 1.49 for 10–15 drinks and a relative risk of 2.51 for 16–21 drinks as compared with women reporting 1–3 drinks, while a lower risk was observed for a small number of women who drank more. Regarding binge drinking on the last weekday, the highest relative risk of 1.55 was observed for four to five drinks compared with intake of one drink. In the NHS, breast cancer risk was increased by 21% in adult binge drinkers compared with nondrinkers, after controlling for cumulative alcohol consumption.[2] A case–control study reported a nonsignificant increase in the risk for binge drinking with an odds ratio of 1.50, which was restricted to women who consumed 91 g/week (~7 drinks/week) or more of alcohol.[68]

Type of Alcoholic Beverage & Breast Cancer

The influence of alcohol on breast cancer development might vary across types of alcohol. Red wine is thought to have a protective effect on cancer development and cardiovascular systems due to polyphenolic compounds from grape skin. Antioxidant, anti-inflammatory and anticancer functions of polyphenols in red wine occur through various molecular and biochemical processes. The compounds resveratrol, quercetin and catechin are three polyphenolic compounds, accounting for 70% of the red wine polyphenols.[69] They are structurally similar to estrogen and act as both antagonists and agonists on estrogen receptor (ER).[70–72] Data from in vitro studies and a small randomized clinical trial suggest that resveratrol suppresses estrogen production from androgens by controlling the activity of aromatases.[73,74] Exposures to resveratrol in breast cancer cells inhibit DNA methyltransferases, the enzymes catalyzing DNA methylation and prevent epigenetic silencing of the BRCA1 tumor suppressor protein.[75]

Beer is a complex mixture of bioactive compounds. The most-studied constituents of beer are phenolic compounds, which are derived from malt (70–80%) and hop (20–30%). Some hop-derived compounds, such as xanthohumol and hop bitter acids, are considered as potential cancer chemopreventive agents that are able to interfere with the initiation, promotion and progression of carcinogenesis.[76] They have impacts on signaling pathways that control carcinogen metabolism, inflammatory reaction, angiogenesis and invasion, and induce apoptosis and cell differentiation.[77] Similar to resveratrol, xanthohumol has mixed estrogenic/antiestrogenic properties and inhibits aromatase activities in vitro.[76] However, these compounds are present in beer at very low levels and their absorption in the body is limited.

Relatively few epidemiologic studies evaluated the associations of types of alcohol with breast cancer and its intermediate risk markers. Although ethanol contents vary across different types of alcoholic beverages, similar breast cancer risk is reported for all types of alcoholic beverages.[2,78,79] Few studies examined types of alcohol in relation to intermediate breast cancer risk markers. In premenopausal women from the New York Women's Birth cohort, mammographic density was inversely associated with red wine consumption during adolescence and early adulthood and positively associated with beer and white wine intake in early adult years.[64] A significant positive association between recent white wine intake and mammographic density was also observed among postmenopausal women,[64] which was consistent with data from the Minnesota breast cancer family cohort showing a positive association for white wine and an inverse association for red wine in postmenopausal women.[60] A study among Mediterranean women reported a positive association between increasing levels of wine intake and mammographic density; it did not examine the associations by types of wine.[80] However, there was no association between adult alcohol intake and risk of proliferative BBD by types of beverages in postmenopausal women.[48] Overall, the epidemiologic evidence supports alcohol content – not type of beverage – that drives breast cancer risk. Available data regarding mammographic density by types of alcohol are limited.

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