1 Department of Clinical Epidemiology, Deutsches Krebs-forschungszentrum, Heidelberg, Germany.
2 Department of Tropical Hygiene and Public Health, Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.
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ABSTRACT |
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alcohol drinking; breast neoplasms; case-control studies; premenopause; wine
Abbreviations: CI, confidence interval; EPIC, European Prospective Investigation in Cancer
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INTRODUCTION |
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Ever since a meta-analysis by Longnecker et al. (1) provided strong evidence for a dose-response relation, admittedly with a very modestly ascending slope, alcohol has been treated as a risk factor for breast cancer even at low- to-moderate daily intake levels. However, subsequently published studies based on more detailed data on lifetime consumption habits have not consistently supported this finding, particularly for low-to-moderate doses. Two cohort studies (2
, 3
) and three case-control studies (4
6
), including two studies of women diagnosed with breast cancer before ages 49 years (2
) and 36 years (4
), respectively, found no association of average lifetime alcohol consumption with breast cancer risk. In another case-control study (7
) of women younger than age 45 that assessed lifetime alcohol intake year by year, there was no risk association for low-to-moderate consumption but a significant increase in risk for 14 or more drinks per week. A linearly increasing risk with increasing alcohol consumption in the recent past was observed more clearly for postmenopausal women in one case-control study (8
) and for premenopausal women in another (9
).
A pooled analysis of six large cohort studies (10) also did not yield results clearly consistent with those of the earlier meta-analysis (1
). The authors found current alcohol consumption at baseline to be linearly associated with an increased risk of 9 percent per 10 g per day, yet evidence was weak for premenopausal women because of large confidence intervals. Although the pooled relative risk was 1.06 (95 percent confidence interval (CI): 0.96, 1.17), the relative risk for moderate intake of 5<15 g per day was more or less equal to 1 for four of the included studies (11
), putting any effect of low-to-moderate alcohol intake on breast cancer risk into question.
To date, effect modification has not been established consistently, although positive associations between alcohol consumption and years of education, ever use of oral contraceptives, ever use of cigarettes, and ever examination by mammography, as well as inverse associations with body mass index and age, have been reported (3, 7
, 12
16
). However, two recent studies (17
, 18
) provided evidence of folate's being a plausible effect modifier of the association between alcohol and breast cancer. Adequate folate consumption appears to reduce excess risk at higher levels of alcohol intake.
There have been only a few studies of lifetime alcohol consumption and breast cancer risk in younger women (2), and the role of alcohol consumption is still unresolved. We conducted a population-based case-control study of German women aged
50 years, assessing lifetime alcohol consumption in three age categories, particularly to evaluate the effect of low-to-moderate doses on breast cancer risk among premenopausal women.
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MATERIALS AND METHODS |
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There were 1,020 eligible patients, of whom 1,005 were alive when identified. Of these living case subjects, 706 (70.2 percent) completed the study questionnaire. Among the 2,257 eligible controls, 1,381 (61.2 percent) participated.
The participants completed a self-administered questionnaire pertaining to demographic, reproductive, menstrual, and anthropometric factors, family history of cancer, hormone replacement therapy, oral contraceptive use, medical history, smoking, and alcohol consumption. If not otherwise specified, all information was truncated at the reference date, which was the date of diagnosis for cases and the date of completion of the questionnaire for controls. Median time between diagnosis and interview was 2 months. Menopausal status was assigned according to the woman's reported status 6 months before the reference date. For women with previous hysterectomy not accompanied by bilateral oophorectomy, menopausal status was not identifiable and was classified as unknown.
Average alcohol consumption was assessed for three time periods: ages 1520 years, ages 2030 years, and ages 3050 years. Neither ages at which drinking began and ended nor information on intermittent periods of abstention was elicited. For five different types of alcoholic beveragesbeer, wine, aperitifs, liqueur, and spiritsparticipants provided information on quantities consumed in either liters or centiliters and designated their frequency of consumption as daily, weekly, or monthly.
We calculated amounts of ethanol ingested by assuming 3.5 g of ethanol per 100 ml of beer, 10 g of ethanol per 100 ml of wine, 16 g of ethanol per 100 ml of aperitifs, 22 g of ethanol per 100 ml of liqueur, and 35 g of ethanol per 100 ml of spirits. A 12-ounce serving of beer contains approximately 12 g of ethanol; 4 ounces of wine contains approximately 12 g, 1.5 ounces of aperitifs about 7 g, 1.5 ounces of liqueur about 10 g, and 1.5 ounces of spirits about 15 g. Ethanol consumption for the latter three beverages was calculated separately and then combined into one category, "hard liquor." Average ethanol consumption was calculated by multiplying daily average alcohol intake in each of the three time periods by the number of years in each period (until the woman reached the reference age, where appropriate), summing over the three time periods, and dividing by the total number of years.
We computed odds ratios and 95 percent confidence limits using multivariate conditional logistic regression analysis. Estimates were produced using the PHREG procedure in the statistical software package SAS (release 6.12; SAS Institute, Inc., Cary, North Carolina). We performed the analyses with stratification for age in 1-year intervals in order to optimize age adjustment. We conducted dose-response analysis using the method of fractional polynomials (20). This method is useful for examining a possibly nonmonotonic relation between the risk factor and disease risk. The covariable x enters the logistic regression model via a set of defined transformations as a polynomial. To allow for a nonmonotonic relation, the polynomial must be of degree 2. The function that best fits the data is then selected. We assessed the association between breast cancer and the different types of beverages with a model including categorized intake of all beverages simultaneously.
In each analysis, we compared alcohol consumers of different intake levels with nondrinkers, defined as those who ingested less than 0.5 g of ethanol per day. Repeat analyses using total lifetime abstainers as the reference group produced essentially the same results; therefore, those data are not reported.
The following terms were included in the multivariate analyses: number of full-term pregnancies and total number of months of breastfeeding, as continuous variables; education (classified as low, intermediate, or high according to type of schooling completed); family history of breast cancer (breast cancer in a mother or sister); and menopausal status (postmenopausal, premenopausal, or unknown). Other factors, such as body mass index, oral contraceptive use, age at first birth, age at menarche, smoking status, study region, and marital status, did not materially alter the estimates and therefore were not included in the statistical models.
The interaction of alcohol consumption with other covariables was investigated using the difference between deviances of the models with and without the interaction terms.
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RESULTS |
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We tested for an interaction between alcohol consumption and educational level, combining the two lower alcohol consumption categories as 111 g/day, thereby adding six multiplicative interaction terms. We found the interaction term for the highest level of alcohol intake (19 g/day) and a high educational level to be significant (p = 0.01). The estimates of the reduced interaction model, which included only two interaction terms for the highest level of alcohol intake and intermediate or high educational level, did not significantly differ from those of the full model; therefore, it was used to calculate odds ratio estimates for alcohol consumption according to educational level.
Odds ratios for differing levels of alcohol consumption by educational level, in reference to the nondrinking group, are shown in table 6. Breast cancer risk for women who consumed 19 g/day varied by educational level: Odds ratios were 3.70 (95 percent CI: 1.23, 11.15) for a low educational level, 1.57 (95 percent CI: 1.03, 2.35) for an intermediate level, and 0.70 (95 percent CI: 0.39, 1.27) for a high level. Odds ratios for the other alcohol consumption categories were unchanged by education status.
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DISCUSSION |
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Other investigators have found no association between alcohol consumption and breast cancer risk overall (26
), and a recent case-control study (26
) found no association among premenopausal women. A pooled analysis of six cohort studies (10
) including 322,647 women and 4,335 breast cancer cases concluded that alcohol consumption is associated with a linear increase in breast cancer incidence. However, the estimated pooled risks for low-to-moderate intakes of 01.5, 1.55, and 515 g/day were near unity and not statistically significant. The lack of association for these low-to-moderate intake levels is apparent for the individual studies, with four of the included studies showing a relative risk close to 1 for moderate intakes of 5<15 g/day. A recent review article on alcohol intake and late-stage promotion of breast cancer deduced that the epidemiologic association between alcohol consumption and increased breast cancer risk is more prominent among postmenopausal women than among premenopausal women and that a significant increase in risk is associated with intakes of >30 g/day over a period of years (24
).
Our study had relatively small proportions of participants who consumed more than 19 g of alcohol per day: 14.5 percent of the cases and 8.7 percent of the controls. Our odds ratio of 1.35 for this group, albeit not statistically significant, is of the same order of magnitude as estimates from other studies which have found an effect of high alcohol intake on breast cancer risk (7, 9
, 15
, 22
, 27
29
). Risk elevations of approximately twofold, comparable to that found in this study for consumption of
31 g/day, were reported by several investigators (7
, 8
, 15
, 23
, 28
). In accordance with this study, some researchers have reported a significantly increased breast cancer risk only for alcohol intakes varying between 24 and 40 g/day (7
, 9
, 10
, 21
, 27
). Some other studies may not have been able to find an association because the numbers of women consuming higher amounts of alcohol were too small. For assessment of high levels of intake, it seems important to consider sporadic heavy drinking using questionnaires with graduated frequency measures (30
). This should be considered in future studies involving alcohol assessment.
The variance in the alcohol intake levels above which breast cancer risk is increased may be accounted for by small numbers of women at high intake levels, as well as by arbitrary categorization, differing consumption patterns between countries, and differing methods of data assessment. Valid associations between alcohol intake and disease are identifiable; however, the strength of sensible limits of acceptable alcohol intake depends to a great extent on the assessment methods used (31).
Temporal aspects of alcohol consumption have not consistently been shown to be relevant (1, 32
). Recent results (7
) suggested that alcohol may be more of a tumor enhancer and promoter than a tumor initiator. We did not observe a significant difference in breast cancer risk associated with intake in different time periods. However, because of the large age category of 3050 years used in our study and the unknown exact ages at which drinking ended, we may not have been able to differentiate alcohol consumption at late stages of breast cancer adequately.
We found that education status modified the effect of alcohol intake on breast cancer risk. Other studies have observed that higher socioeconomic status or a higher level of education is associated with higher alcohol intake (3, 7
, 12
16
), but none have reported a significant interaction. Striking in our data was the significantly increased risk for the consumption category of
19 g/day, with odds ratios of 3.7 for women with low education and 1.6 for somewhat better educated women, as compared with no change in risk for highly educated women across all levels of alcohol intake.
Educational level may be a surrogate for an effect modifier or confounder that is not yet clearly established. Two recent studies suggested the possibility of a breast cancer risk reduction from adequate folate intake among consumers of high amounts of alcohol, alcohol's acting as a folate antagonist (17, 18
). In Germany, folate intake has been found to be positively associated with years of education (33
, 34
). Our findings are plausible if high folate consumption among better educated women alleviates the effect of alcohol on breast cancer risk. Overall, a better diet according to currently recommended guidelines may lessen deleterious effects of alcohol, since health effects may depend on overall dietary patterns and not only on single nutrients or food groups (35
).
Different types of alcoholic beverages have been inconsistently associated with breast cancer risk and have been postulated not to have a differential effect (1, 3
). We believe this discussion is still open, since preferences for beverage types vary considerably across subpopulations, rendering comparisons extremely difficult. It has been suggested that detrimental associations with particular types of beverages are found for the beverages most commonly consumed and merely reflect ethanol intake, implying that ethanol (or its metabolites) is the causal agent (5
). On the contrary, we found that risk was increased at a lower consumption level for beer than for wine, although wine was the preferred drink among our participants.
We were able to compare our data on alcohol consumption with alcohol data from the Heidelberg EPIC (European Prospective Investigation in Cancer) cohort, which comprises 13,597 women and shows very similar consumption patterns (36). The mean average daily alcohol consumption of EPIC subjects of comparable age is somewhat higher than in our study. This may be due to the higher socioeconomic status of the cohort (37
), since alcohol intake has been found to be more common among persons of higher socioeconomic status in other studies (12
). In another large prevalence study in the German population, comparable alcohol consumption patterns were observed, as well as our finding that proportions of women who consume moderate to high amounts are greater among wine drinkers than among beer drinkers (38
).
These corroborating findings indicate that the controls in our study are representative of the female German population. However, selection bias could explain the finding of a significant protective effect at low levels of alcohol consumption, if the patients who participated were less likely to drink alcohol.
Data collected on alcohol consumption in the distant past appear reliable (39), and recall bias seems to play only a modest role in reported intake (40
). Nonetheless, recall bias cannot be ruled out, since the self-reported data were collected after diagnosis among cases. Recall bias may have led to the smaller risk estimate for the highest intake category at ages 3050 years, compared with intake in the other two age categories, as well as the low risk estimates for lower lifetime consumption levels, if cases tended to underreport their alcohol intake. The assessed categories were fairly large, forcing women to average their alcohol consumption over 5-, 10-, and 20-year intervals, and did not allow for intermittent abstention phases such as pregnancies or breastfeeding periods. Information on the date of initiation or cessation of drinking was not specifically collected, but initiation date was set at the lower cutpoint of the first age period for which drinking was reported, and cessation date analogously was set at the higher cutpoint of the last age period for which drinking was reported. However, because the data were treated in the same manner, this should not have led to differential assessment of alcohol consumption in cases and controls.
The biologic mechanisms of alcohol's effects on breast cancer etiology are widely discussed but not proven in detail. Effects on hormone metabolism have been shown, with higher estradiol and estrone levels being described in women with chronic alcohol intake (41). Recent developments suggest that insulin-like growth factors may mediate the effect of alcohol on breast cancer risk by acting as estrogen synergists and apoptosis suppressants (42
). Another model suggests the involvement of alcohol-derived reactive oxygen species in inducing DNA modifications and carcinogenesis (43
).
Although several plausible mechanisms exist which may link chronic alcohol consumption to breast cancer in a dose-response fashion, the critical effects on cancer and other outcomes may have thresholds. Thus, the absence of adverse effects on breast cancer risk for low-to-moderate alcohol consumption in our study is plausible.
The unexpected finding of a significant protective effect of alcohol consumption at low levels seems to pertain primarily to wine. Wine, particularly red wine, contains a range of polyphenols with antioxidant effects. One of these compounds is resveratrol, a triphenolic stilbene found in grapes and other plants which has been considered responsible for the beneficial effects of red wine consumption on coronary heart disease risk. Recent studies revealed that resveratrol can inhibit each step of multistage carcinogenesis (44) and that it has an antiproliferative effect on human breast epithelial cells (45
), possibly because of the inhibiting properties of the enzymes cyclooxygenase 1 and 2 (45
47
) and cytochrome P-450 (48
, 49
).
In general, it is possible that at low-to-moderate levels of wine consumption, the beneficial role of polyphenols may counteract the cancer-promoting function of the alcoholic component in wine and account for the results presented here. For higher levels of regular alcohol intake, the balance may shift to outweigh the beneficial effects. However, we cannot exclude the possibility that this may be a chance finding. Individual genetic variation in alcohol metabolism, as has been observed in other studies (50, 51
), may also partly explain our results. The risk:benefit ratio of alcohol consumption appears to be very complex, because of the multilevel interactions of ethanol, wine phytochemicals, carcinogens, dietary factors, and genetic variations in metabolizing enzymes.
Public health recommendations on alcohol consumption must take numerous factors into consideration. Most important is the established association of less than one drink per day with the lowest all-cause mortality for women (12). In our view, another crucial facet of this discussion is that low intake of alcohol does not appear to raise premenopausal breast cancer risk.
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ACKNOWLEDGMENTS |
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The authors gratefully thank the many gynecologists and oncologists in the 38 clinics of the Rhein-Neckar-Odenwald and Freiburg study regions for allowing them to contact patients; Ursula Eilber for competent data coordination and management; and Silke Schieber, Andrea Busche-Bässler, Regina Hübner, Ruth Schäuble, Heike Wiedensohler, Renate Birr, Ulla Gromer, and Ulrike Bussas for data collection.
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NOTES |
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REFERENCES |
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