CancerCausesand Control, 2, 247- 252
Alcohol consumption and breast cancer risk in Denmark Marianne Ewertz
(Received 23 April 1991; accepted2 May 1991) The influence of alcohol consumption on breast cancer risk was evaluated in a population-based case-control study, including 1,486 cases diagnosed over a one-year (1983-84) period in Denmark. Cases were identified from the files of the nationwide clinical trial of the Danish Breast Cancer Cooperative Group and the Danish Cancer Registry. The control group was an age-stratified random sample of 1,336 women from the general population. Data on risk factors were collected by self-administered questionnaires. The association of alcohol consumption with breast cancer risk varied with age and dietary fat intake. Among women aged 50-59 years, with a fat intake in the lowest quartile, the risk of breast cancer increased with increasing consumption of alcohol. A consumption of 24 g or more per day was associated with an 18-fold increased risk compared with abstainers. For women in other age groups, alcohol consumption had no significant association with breast cancer risk.
Key words: Age, alcohol, breast neoplasms, Denmark, dietary fat. Introduction
Materials a n d m e t h o d s
Prior to 1982, little attention was paid to the association of alcohol consumption with risk of developing breast cancer. Since that time, the issue has been addressed in at least five cohort studies l-s and 20 casecontrol studies. 62s Longnecker et a126 performed a meta-analysis of data available up to 1988 and observed a dose-response relation of increasing breast cancer risk with increasing alcohol consumption. Relative to abstaining, a daily consumption of 24 g of ethanol (or about two drinks) was associated with a risk of 1.4 in the case-control data and 1.7 in the cohort data. Results of some later studies 21-24agree with these risk estimates, though others s'ls-2°as do not. To evaluate the influence of diet, alcohol, and hormones on breast cancer risk, a population-based casecontrol study was conducted in Denmark, including almost all incident cases over a one-year period. The risk associated with use of exogenous estrogens, 27 reproductive factors, 28 diet, 29 and smoking3° has been presented elsewhere. The present paper examines the association of alcohol consumption with breast cancer risk.
Details of the study population and methods have been described. 28'29 The cases consisted of 1,694 women, aged less than 70 years, diagnosed with breast cancer in Denmark between 1 March 1983 and 29 February 1984. They were identified from the files of the nationwide, clinical breast-cancer trial of the Danish Breast Cancer Cooperative Group and the Danish Cancer Registry. AS controls, an age-stratified random sample of 1,705 women was selected from the general population identified from the Central Population Register. Women with a breast cancer predating the study period were excluded from both case and control groups. A total of 1,486 cases (88 percent) and 1,336 controls (78 percent) completed self-administered questionnaires on potential risk factors, including alcohol consumption. These were mailed to the cases one year after their month of diagnosis. To promote comparability of recollection in the controls, the preselected pool was divided into monthly batches which were assigned the same date of diagnosis as the cases. Usual consumption of alcoholic beverages in the
The author is with the Danish CancerRegistry, Institute of Cancer Epidemiology, Danish CancerSociety, RosenvaengetsHovedvej 3 5, Box 839 DK-2100 Copenhagen 0, Denmark. The study wasfunded by The Danish Cancer Society, the Danish Medical Research Council, and Astrid Thaysen's Legat. © 1991 Rapid Communications of Oxford Ltd
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year prior to diagnosis was assessed from open-ended questions on how often (per day, week, or month) the subjects drank beer (330 ml bottle), table wine (120 ml glass), fortified wine such as sherry and port (40 ml glass), and spirits (20 ml glass). Frequencies less than once per month were recorded as 'never'. Some women were not able to indicate any frequency of consumption but stated that they only drank the particular item at parties. For this group, the lowest frequency'of consumption was assigned, i.e. once per month. Finally, the women were asked to indicate whether their current alcohol consumption was higher, lower, or the same as 10-15 years ago. Intake of ethanol for each woman was computed as the sum of the contribution from each type of drink. Based on average alcohol concentrations, the contributions were estimated as 11.6 g for a bottle of beer, 11.4 g for a glass of table wine, 5.7 g for a glass of fortified wine, and 6.3 g for a glass of spirit. 31 The measure of association between study factors and breast cancer was the relative risk (RR) estimated from odds ratios. Comparisons of cases and controls were made by logistic regression techniques32using the statistical package EGRET for the computations. This provides RR estimates with corresponding estimates of precision, adjusted for the effect of other factors where necessary, including tests for interaction between risk factors. In the case of ordered variables, significance also was evaluated by testing for a linear trend in RR. Although cases and controls were frequency-matched on age at diagnosis, all RR estimates were adjusted for age.
Table 1. Risk of breast cancer associated with current consumption of alcoholic beverages
Results
alcohol and breast cancer risk. No consistent relationship was observed between alcohol consumption and parity, age at first birth, and dietary ~l-carotene intake. However, there were significant interactions (P < 0.01) between alcohol consumption and age at diagnosis and dietary fat intake, i.e. the association of alcohol consumption with breast cancer risk differed by age group and fat intake. Whether the interaction between age and alcohol could be explained by menopausal status or years since menopause was tested, but the age-alcohol interaction still remained significant taking the menopause variables into account. Consequently, an age-stratified analysis was performed and, for each age group, the interaction between alcohol and fat intake was tested. Among women aged less than 50 years at diagnosis (Table 3), no significant interaction between alcohol and fat intake was detected. The risk of breast cancer decreased with increasing consumption of alcohol, though neither the association nor the test for trend was significant. There was a significant trend
Table 1 presents the information on current consumption of specific types of alcoholic beverage. Compared with nondrinkers, elevated risks were seen for consumptions exceeding seven bottles of beer or glasses of table wine, and with three glasses of fortified wine per week, but none of the associations was significant. Indications of prior consumption did not appear to be related to risk of breast cancer. However, about a third of cases and controls did not state their prior consumption. Analyses of consumption of ethanol from all beverages showed a considerable variation in relation to breast cancer risk factors (Table 2). The frequency of an alcohol consumption of 24 g or more per day was higher for women living in the capital and capital suburbs, for women with a longer education, for eversmokers, for ever-users of oral contraceptives, and for leaner women. This pattern was similar for cases and controls and did not confound the association between 248
Cancer Causes and Control. Vol 2. 1991
Type of alcoholic beverage
Cases No. %
Controls No. %
Age-adjusted RR (95% CI) a
401 520 91 65 29 230
30 39 7 5 2 17
1.0 0.94 0.99 0.84 1.27 --
(R) b (0.79-1.13) (0.72-1.35) (0.58-1.22) (0.78-2.07)
Table wine, glasses per week 0 279 19 7 72 5 Unstated 199 13
246 659 141 53 51 186
18 49 11 4 4 14
1.0 1.00 0.99 1.01 1.30 --
(R) (0.81-1.23) (0.74-1.32) (0.67-1.53) (0.87-1.94)
Fortified wine, glasses per week 0 482 32 6 36 Unstated 380 26
453 505 20 26 332
34 38 1 2 25
1.0 1.03 1.73 1.29 --
(R) (0.86-1.23) (0.98-3.03) (0.76-2.17)
Spirits, glasses per week 0 489 6 58 Unstated 261
434 548 68 59 227
32 41 5 4 17
1.0 0.96 1.19 0.89 --
(R) (0.81-1.15) (0.84-1.67) (0.59-1.27)
Beer, bottles per week 0 473 7 43 Unstated 236
32 38 7 4 3 16
33 40 6 4 17
Relative risk (95% confidence interval). b R denotes reference category.
Alcohol and breast cancer
Table 2. Distribution of alcohol consumption by selected breast cancer risk factors Risk factors
No. of cases/ controls
0 1-23 />24 cases/ cases/ cases/ controls (%)controls (%) controls (%) 10/8 15/18 24/21
82/84 77/79 69/75
8/8 8/3 7/4
Residence at diagnosis Capital 198/113 Suburbs 212/167 Provincial towns 489/498 Rural areas 462/448
12/7 10/9
74/81 77/83
14/12 13/8
17/15 19/17
78/81 76/78
5/4 5/5
Years of education 12 342/266
25/23 11/10 8/6
7O/75 83/85 78/82
5/2 6/5 14/12
203/108 199/176 529/473 279/274 148/192
21/15 15/11 14/13 14/14 20/23
72/81 73/83 79/82 79/80 76/72
7/4 12/6 7/5 7/6 4/5
Age atfirst birth ~24
1.0 0.74 0.63
(R)b (0.47-1.15) (0.34-1.17)
0.15
Fatintake (quartiles) 1 (low) 2 3 4 (high)
1.0 1.02 1.19 1.42
(0.70-1.51) (0.82-1.74) (0.97-2.07)
Alcohol consumption (g/day)
Age of diagnosis, years 60 383/320
Parity 0 1 2 3 >3
Table 3. Effect of intake of alcohol and dietary fat on breast cancer risk in women aged less than 50 years at diagnosis
20/20 13/12
Alcoholintake
(R)
0.04
Adjusted for age at diagnosis as a continuous variable, place of residence, years of education, parity, and the other variable in the table. b R denotes reference category.
(P = 0.04) of increasing risk with increasing dietary fat intake. In women aged 50-59 years at diagnosis, there was a significant interaction (P = 0.03) between intake of alcohol and dietary fat (Table 4). Among women in the lowest quartile of fat intake, the risk of breast cancer increased with increasing alcohol consumption, women drinking 24 g or more per day having an 18fold higher risk than abstainers. The very wide confidence interval reflects that the estimate was based on 14 cases and two controls. For women consuming more dietary fat, a high alcohol consumption did not appear to be associated with the risk of breast cancer. The association of dietary fat intake also varied with alcohol consumption. Among nondrinkers, a high fat intake was associated with increased risk of breast cancer, whereas a decreased risk was noted among those who drank 24 g or more per day. Combining the effects of alcohol and dietary fat--all compared with the lowest intakes of--increased risks, varying from 2.2 to 18. In the oldest age group, 60 years or more at diagnosis, the interaction between alcohol and fat intake was not significant (Table 5). There was no association between alcohol and breast cancer risk. Increased risks were found for all levels of fat intake, but the estimate for the top quartile was not significant. This was also the case for the test for trend.
Discussion Evaluating the association of alcohol consumption with breast cancer risk, the present study demonstrated a complex interaction with age and dietary fat Cancer Causes and Control. Vol 2. 1991
249
M. Ewertz Table 4. Relative risk a (95% confidence interval) of breast cancer associated with intake of
alcohol and dietary fat in women aged 50-59 years at diagnosis Fat intake
Alcohol intake (g/day)
(quartiles)
a b
0
1-23
1(low) 2 3 4(high)
1.0 1.0 1.0 1.0
(R) b (R) (R) (R)
2.53 0.63 1.20 0.62
(1.11-5.74) (0.30-1.35) (0.51-2.83) (0.28-1.40)
17.9 1.55 1.08 1.18
(3.31-97.0) (0.33-7.22) (0.25-4.72) (0.24-5.76)
1 2 3 4
1.0 3.48 2.84 5.11
(R) (1.28-9.46) (0.95-8.45) (1.79-14.6)
1.0 0.87 1.35 1.25
(R) (0.54-1.41) (0.85-2.15) (0.78-2.01)
1.0 0.30 0.17 0.33
(R) (0.04-2.28) (0.02-1.19) (0.04-2.60)
1 2 3 4
1.0 3.48 2.84 5.11
(R) (1.28-9.46) (0.95-8.45) (1.79-14.6)
2.53 2.20 3.41 3.17
(1.11-5.74) (0.97-5.00) (1.52-7.62) (1.41-7.11)
17.9 5.41 3.06 6.04
(3.31-97.0) (1.13-25.9) (0.72-13.0) (1.24-29.3)
Adjusted for age as a continuous variable, place of residence, years of education, and parity. R denotes reference category. Estimates in the three sections of the table are based on the same numbers but use different referents.
intake. A subgroup of women was identified, aged 50-59 years with a fat intake in the lowest quartile, in whom the risk of breast cancer rose with increasing alcohol consumption. We found an 18-fold increase for those consuming 24 g or more per day (or about two drinks) compared with abstainers. In other women, alcohol consumption had no significant association with breast cancer risk. Among studies taking dietary fat intake into account, the present results agree with those of Richardson et a121 who also found a significant interaction between alcohol and fat intake, and that the association with alcohol was most pronounced in women with a low fat intake. In other studies, an increased risk of breast cancer associated with alcohol Table 5. Effect of intake of alcohol and dietary fat on breast cancer risk in women aged 60 years or more at diagnosis
Alcohol intake (g/day) 0 1-23 1>24 Fat intake (quartiles) 1 (low) 2 3 4 (high)
Relative risk~ (95% confidence interval)
P-value for linear trend
1.0 (R)b 0.73 (0.50-1.06) 0.95 (0.44-2.07)
0.6
1.0
(R) 1.69 (1.11-2.57) 1.53 (1.00-2.35) 1.43 (0.94-2.18)
0.1
" Adjusted for age at diagnosis as a continuous variable, place of residence, years of education, parity, and the other variable in the table, b R denotes reference category. 250
1>24
CancerCauses and Control. Vol 2. 1991
consumption was not influenced by adjustment for diet, whether the dietary assessment was relatively simple 1°'12'2aor more sophisticated, z'3:6'z3 In most studies, the association with alcohol did not vary with age. However, Adami et al TM detected a slightly decreasing risk with increasing alcohol consumption in women aged less than 45 years. The results of this study go in the same direction although they were not statistically significant. In other studies 2'3'12'16the association of breast cancer risk with alcohol consumption was most pronounced in younger women. Thus, present findings appear to be at variance with those of most other investigations. It is unlikely that the interaction between alcohol, age, and fat intake arose because of bias related to the selection of cases and controls since the study was population-based. It cannot be ruled out, though, that nonresponders had a consumption of alcohol and fat that differed from women who completed the questionnaire. Although the possibility of information bias cannot be excluded, the data give no evidence for a greater tendency among cases than controls to report changes in alcohol consumption. Errors in the measurement of alcohol consumption generally lead to under-reporting of high consumptions and thus an underestimation of the magnitude of the true association. Finally, the possibility remains that the interactions between alcohol consumption, age, and fat intake in this study were due to chance. Testing the alcohol-fat interaction in each of the three age groups, the possibility of it being significant (P < 0.05) in at least one group, by chance, is 14 percent. There was a remarkable similarity between Danish
Alcohol and breast cancer and American women in the relation between alcohol consumption and several breast cancer risk factors. In the United States 2'3's'17'19 as well as in Denmark, consumers of alcohol tended to be younger, to have more education, to have fewer children, to be lean, to smoke, and to use oral contraceptives. In two of these studies,5'19 alcohol consumption did not affect the risk of breast cancer. In the other three, 2"3'17higher risk estimates for alcohol were obtained in lean than in heavy women. In trying to reconcile the evidence on alcohol consumption and breast cancer risk, the literature 21'22'24'26 seems to support a weak positive association, the risk being in the order of 1.4-1.7 for 24 g or more alcohol per day, corresponding to about two drinks. The risk increase does not seem to be confined to any particular type of beverage, suggesting an effect of alcoholper se. In some studies, including the present, a pronounced risk increase has been observed when women, otherwise at a low risk of developing breast cancer, had a high alcohol consumption. The carcinogenic action of alcohol is not fully understood 33 and no biological mechanism has been established to explain how alcohol should affect breast carcinogenesis. Alcohol has a variety of direct as well as indirect effects on sex hormones, through stimulation of the pituitary and adrenals to the extraglandular conversion of androgen to estrogen. 3446 The interaction between alcohol and fat consumption in this study raises the possibility that high-density lipoprotein cholesterol (HDL-C) may be involved. H D L - C levels correlate positively with intakes of both dietary fat and alcohol. However, the literature does not provide sufficient evidence to conclude whether H D L - C is causally related to breast cancer or is merely associated with risk factors. 3z In conclusion, the present study provides some support of a positive association between alcohol and breast cancer risk. The interaction with fat intake illustrates the importance of considering alcohol as a dietary factor which, as other components of diet, deserves further study.
Acknowledgements--The author thanks Dr O. M. Jensen, the Danish Cancer Registry, Dr H. T. Mouridsen on behalf of the Danish Breast Cancer Cooperative Group, Dr N. E. Day and Mr S. W. Duffy, MRC Biostatistics Unit, Cambridge, UK, for their scientific support, as well as Mrs J. F. Larsen, Mrs G. Mathiesen and Ms S. I. Hartkopp for technical assistance.
References 1. Hiatt RA, Bawol RD. Alcoholic beverage consumption and breast cancer incidence. AmJ Epidemio11984; 120: 676-83. 2. Schatzkin A, Jones DY, Hoover RN, et al. Alcohol consumption and breast cancer in the epidemiologic follow-up study of the first national health and nutrition examination survey. N EnglJ Med 1987; 316: 1169-73. 3. Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Hennekens CH, Speizer FE. Moderate alcohol consumption and the risk of breast cancer. N EnglJ Med 1987; 316: 1174-80. 4. Hiatt RA, Klatsky AL, Armstrong MA. Alcohol consumption and the risk of breast cancer in a prepaid health plan. Cancer Res 1988; 48: 2284-7. 5. Schatzkin A, Carter CL, Green SB, et al. Is alcohol consumption related to breast cancer? Results from the Framingham heart study.JNCI 1989; 81: 31-5. 6. Rosenberg L, Shapiro S, Slone D, et al. Breast cancer and alcoholic beverage consumption. Lancet 1982; i: 267-71. 7. Byers T, Funch DP. Alcohol and breast cancer. Lancet 1982; i: 799-800. 8. Begg CB, Walker AM, Wessen B, Zelen M. Alcohol consumption and breast cancer. Lancet 1983; i: 293-4. 9. Paganini-Hill A, Ross RK. Breast cancer and alcohol consumption. Lancet 1983; ii: 626-7. 10. Talamini R, La Vecchia C, Decarli A, et al. Social factors, diet and breast cancer in a northern Italian population. BrJ Cancer 1984; 49: 723-9. 11. Le MG, Hill C, Kramar A, Flamant R. Alcoholic beverage consumption and breast cancer in a French casecontrol study. ArnJ Epidemiol 1984; 120: 350-7. 12. La Vecchia C, Decarli A, Franceschi S, Pampallona S, Tognoni G. Alcohol consumption and the risk of breast cancer in women.JNCI 1985; 75: 61-5. 13. Katsouyanni K, Trichopoulos D, Boyle P, etaL Dietand breast cancer: a case-control study in Greece. IntJ Cancer 1986; 38: 815-20. 14. Harvey EB, Schairer C, Brinton LA, Hoover RN, Fraumeni JF Jr. Alcohol consumption and breast cancer. JNCI 1987; 78: 657-61. 15. O'Connell DL, Hulka BS, Chambless LE, Wilkinson WE, Deubner DC. Cigarette smoking, alcohol consumption, and breast cancer risk. JNCI 1987; 78: 229-34. 16. Rohan TE, McMichael AJ. Alcohol consumption and risk of breast cancer. IntJ Cancer 1988; 41: 695-9. 17. Harris RE, Wynder EL. Breast cancer and alcohol consumption. A study in weak associations. JAMA 1988; 259: 2867-71. 18. Adami H-O, Lund E, Bergstr6m R, Meirik O. Cigarette smoking, alcohol consumption and risk of breast cancer in young women. BrJ Cancer 1988; 58: 832-7. 19. Chu SY, Lee NC, Wingo PA, Webster LA. Alcohol consumption and the risk of breast cancer. Am J Epiderniol 1989; 130: 867-77. 20. MearaJ, McPherson K, Roberts M, Jones L, Vessey M. Alcohol, cigarette smoking and breast cancer. BrJ Cancer 1989; 60: 70-3. 21. Richardson S, de Vincenzi I, Pujol H, Gerber M. Alcohol consumption in a case-control study of breast cancer in southern France. IntJ Epidemiol 1989; 44: 84-9. 22. Young TB. A case-control study of breast cancer and alcohol consumption habits. Cancer t989; 64: 552-8. Cancer Causes and Control. Vol 2. 1991
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M. Ewertz 23. Vant't Veer P, Kok FJ, Hermus RJJ, Sturmans F. Alcohol dose, frequency and age at first exposure in relation to the risk of breast cancer. IntJ Epidemiol 1989; 18: 511-7. 24. Nasca PC, Baptiste MS, Field NA, et al. An epidemiological case-control study of breast cancer and alcohol consumption. IntJ Epidemiol 1990; 19: 532-8. 25. Rosenberg L, Palmer JR, Miller DR, Clarke EA, Shapiro S. A case-control study of alcohol beverage consumption and breast cancer. AmJ Epidemio11990; 131: 6-14. 26. Longnecker MP, Berlin JA, Orza MJ, Chalmers TC. A meta-analysis of alcohol consumption in relation to risk of breast cancer. JAMA 1988; 260: 652-6. 27. Ewertz M. Influence of non-contraceptive exogenous and endogenous sex hormones on breast cancer risk in Denmark. IntJ Cancer 1988; 42: 832-8. 28. Ewertz M, Duffy SW. Risk of breast cancer in relation to reproductive factors in Denmark. BrJ Cancer 1988; 58: 99-104. 29. Ewertz M, Gill C. Dietary factors and breast cancer risk in Denmark. IntJ Cancer 1990; 46: 779-84. 30. Ewertz M. Smoking and breast cancer risk in Denmark. Cancer Causes and Control 1990; 1: 31-7.
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31. Moller A. Food Tables. Copenhagen: National Food Agency, 1986. 32. Breslow NE, Day NE. Statistical Methods in Cancer
Research. Vol. 1. The Analysis of Case-control Studies Lyon: International Agency for Research on Cancer, 1980; IARC Sci. Pub. No. 32. 33. International Agency for Research on Cancer. Alcohol Drinking. Lyon: IARC, 1988; IARC Monographs on the Evaluation of Carcinogenesic Risks to Humans, No. 44.
34. Williams RR. Breast and thyroid cancer and malignant melanoma promoted by alcohol-induced pituitary secretion of prolactin, TSH, and MSH. Lancet 1976; i: 996-8. 35. Siiteri PK. Extraglandular oestrogen formation and serum binding of oestradiol: relationship to cancer. J Endow 1981; 89: 119P-29P. 36. Gavaler JS. Effects of alcohol on endocrine function in postmenopausal women: a review. J Stud Alcohol 1985; 46: 495-516. 37. Boyd NF, McGuire V. Evidence of association between plasma high-density lipoprotein cholesterol and risk factors for breast cancer.JNCI 1990; 82: 460-8.
Alcohol consumption and breast cancer risk in Denmark Marianne Ewertz
(Received 23 April 1991; accepted2 May 1991) The influence of alcohol consumption on breast cancer risk was evaluated in a population-based case-control study, including 1,486 cases diagnosed over a one-year (1983-84) period in Denmark. Cases were identified from the files of the nationwide clinical trial of the Danish Breast Cancer Cooperative Group and the Danish Cancer Registry. The control group was an age-stratified random sample of 1,336 women from the general population. Data on risk factors were collected by self-administered questionnaires. The association of alcohol consumption with breast cancer risk varied with age and dietary fat intake. Among women aged 50-59 years, with a fat intake in the lowest quartile, the risk of breast cancer increased with increasing consumption of alcohol. A consumption of 24 g or more per day was associated with an 18-fold increased risk compared with abstainers. For women in other age groups, alcohol consumption had no significant association with breast cancer risk.
Key words: Age, alcohol, breast neoplasms, Denmark, dietary fat. Introduction
Materials a n d m e t h o d s
Prior to 1982, little attention was paid to the association of alcohol consumption with risk of developing breast cancer. Since that time, the issue has been addressed in at least five cohort studies l-s and 20 casecontrol studies. 62s Longnecker et a126 performed a meta-analysis of data available up to 1988 and observed a dose-response relation of increasing breast cancer risk with increasing alcohol consumption. Relative to abstaining, a daily consumption of 24 g of ethanol (or about two drinks) was associated with a risk of 1.4 in the case-control data and 1.7 in the cohort data. Results of some later studies 21-24agree with these risk estimates, though others s'ls-2°as do not. To evaluate the influence of diet, alcohol, and hormones on breast cancer risk, a population-based casecontrol study was conducted in Denmark, including almost all incident cases over a one-year period. The risk associated with use of exogenous estrogens, 27 reproductive factors, 28 diet, 29 and smoking3° has been presented elsewhere. The present paper examines the association of alcohol consumption with breast cancer risk.
Details of the study population and methods have been described. 28'29 The cases consisted of 1,694 women, aged less than 70 years, diagnosed with breast cancer in Denmark between 1 March 1983 and 29 February 1984. They were identified from the files of the nationwide, clinical breast-cancer trial of the Danish Breast Cancer Cooperative Group and the Danish Cancer Registry. AS controls, an age-stratified random sample of 1,705 women was selected from the general population identified from the Central Population Register. Women with a breast cancer predating the study period were excluded from both case and control groups. A total of 1,486 cases (88 percent) and 1,336 controls (78 percent) completed self-administered questionnaires on potential risk factors, including alcohol consumption. These were mailed to the cases one year after their month of diagnosis. To promote comparability of recollection in the controls, the preselected pool was divided into monthly batches which were assigned the same date of diagnosis as the cases. Usual consumption of alcoholic beverages in the
The author is with the Danish CancerRegistry, Institute of Cancer Epidemiology, Danish CancerSociety, RosenvaengetsHovedvej 3 5, Box 839 DK-2100 Copenhagen 0, Denmark. The study wasfunded by The Danish Cancer Society, the Danish Medical Research Council, and Astrid Thaysen's Legat. © 1991 Rapid Communications of Oxford Ltd
Cancer Causes and Control. Vol 2. 1991
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M. Ewertz
year prior to diagnosis was assessed from open-ended questions on how often (per day, week, or month) the subjects drank beer (330 ml bottle), table wine (120 ml glass), fortified wine such as sherry and port (40 ml glass), and spirits (20 ml glass). Frequencies less than once per month were recorded as 'never'. Some women were not able to indicate any frequency of consumption but stated that they only drank the particular item at parties. For this group, the lowest frequency'of consumption was assigned, i.e. once per month. Finally, the women were asked to indicate whether their current alcohol consumption was higher, lower, or the same as 10-15 years ago. Intake of ethanol for each woman was computed as the sum of the contribution from each type of drink. Based on average alcohol concentrations, the contributions were estimated as 11.6 g for a bottle of beer, 11.4 g for a glass of table wine, 5.7 g for a glass of fortified wine, and 6.3 g for a glass of spirit. 31 The measure of association between study factors and breast cancer was the relative risk (RR) estimated from odds ratios. Comparisons of cases and controls were made by logistic regression techniques32using the statistical package EGRET for the computations. This provides RR estimates with corresponding estimates of precision, adjusted for the effect of other factors where necessary, including tests for interaction between risk factors. In the case of ordered variables, significance also was evaluated by testing for a linear trend in RR. Although cases and controls were frequency-matched on age at diagnosis, all RR estimates were adjusted for age.
Table 1. Risk of breast cancer associated with current consumption of alcoholic beverages
Results
alcohol and breast cancer risk. No consistent relationship was observed between alcohol consumption and parity, age at first birth, and dietary ~l-carotene intake. However, there were significant interactions (P < 0.01) between alcohol consumption and age at diagnosis and dietary fat intake, i.e. the association of alcohol consumption with breast cancer risk differed by age group and fat intake. Whether the interaction between age and alcohol could be explained by menopausal status or years since menopause was tested, but the age-alcohol interaction still remained significant taking the menopause variables into account. Consequently, an age-stratified analysis was performed and, for each age group, the interaction between alcohol and fat intake was tested. Among women aged less than 50 years at diagnosis (Table 3), no significant interaction between alcohol and fat intake was detected. The risk of breast cancer decreased with increasing consumption of alcohol, though neither the association nor the test for trend was significant. There was a significant trend
Table 1 presents the information on current consumption of specific types of alcoholic beverage. Compared with nondrinkers, elevated risks were seen for consumptions exceeding seven bottles of beer or glasses of table wine, and with three glasses of fortified wine per week, but none of the associations was significant. Indications of prior consumption did not appear to be related to risk of breast cancer. However, about a third of cases and controls did not state their prior consumption. Analyses of consumption of ethanol from all beverages showed a considerable variation in relation to breast cancer risk factors (Table 2). The frequency of an alcohol consumption of 24 g or more per day was higher for women living in the capital and capital suburbs, for women with a longer education, for eversmokers, for ever-users of oral contraceptives, and for leaner women. This pattern was similar for cases and controls and did not confound the association between 248
Cancer Causes and Control. Vol 2. 1991
Type of alcoholic beverage
Cases No. %
Controls No. %
Age-adjusted RR (95% CI) a
401 520 91 65 29 230
30 39 7 5 2 17
1.0 0.94 0.99 0.84 1.27 --
(R) b (0.79-1.13) (0.72-1.35) (0.58-1.22) (0.78-2.07)
Table wine, glasses per week 0 279 19 7 72 5 Unstated 199 13
246 659 141 53 51 186
18 49 11 4 4 14
1.0 1.00 0.99 1.01 1.30 --
(R) (0.81-1.23) (0.74-1.32) (0.67-1.53) (0.87-1.94)
Fortified wine, glasses per week 0 482 32 6 36 Unstated 380 26
453 505 20 26 332
34 38 1 2 25
1.0 1.03 1.73 1.29 --
(R) (0.86-1.23) (0.98-3.03) (0.76-2.17)
Spirits, glasses per week 0 489 6 58 Unstated 261
434 548 68 59 227
32 41 5 4 17
1.0 0.96 1.19 0.89 --
(R) (0.81-1.15) (0.84-1.67) (0.59-1.27)
Beer, bottles per week 0 473 7 43 Unstated 236
32 38 7 4 3 16
33 40 6 4 17
Relative risk (95% confidence interval). b R denotes reference category.
Alcohol and breast cancer
Table 2. Distribution of alcohol consumption by selected breast cancer risk factors Risk factors
No. of cases/ controls
0 1-23 />24 cases/ cases/ cases/ controls (%)controls (%) controls (%) 10/8 15/18 24/21
82/84 77/79 69/75
8/8 8/3 7/4
Residence at diagnosis Capital 198/113 Suburbs 212/167 Provincial towns 489/498 Rural areas 462/448
12/7 10/9
74/81 77/83
14/12 13/8
17/15 19/17
78/81 76/78
5/4 5/5
Years of education 12 342/266
25/23 11/10 8/6
7O/75 83/85 78/82
5/2 6/5 14/12
203/108 199/176 529/473 279/274 148/192
21/15 15/11 14/13 14/14 20/23
72/81 73/83 79/82 79/80 76/72
7/4 12/6 7/5 7/6 4/5
Age atfirst birth ~24
1.0 0.74 0.63
(R)b (0.47-1.15) (0.34-1.17)
0.15
Fatintake (quartiles) 1 (low) 2 3 4 (high)
1.0 1.02 1.19 1.42
(0.70-1.51) (0.82-1.74) (0.97-2.07)
Alcohol consumption (g/day)
Age of diagnosis, years 60 383/320
Parity 0 1 2 3 >3
Table 3. Effect of intake of alcohol and dietary fat on breast cancer risk in women aged less than 50 years at diagnosis
20/20 13/12
Alcoholintake
(R)
0.04
Adjusted for age at diagnosis as a continuous variable, place of residence, years of education, parity, and the other variable in the table. b R denotes reference category.
(P = 0.04) of increasing risk with increasing dietary fat intake. In women aged 50-59 years at diagnosis, there was a significant interaction (P = 0.03) between intake of alcohol and dietary fat (Table 4). Among women in the lowest quartile of fat intake, the risk of breast cancer increased with increasing alcohol consumption, women drinking 24 g or more per day having an 18fold higher risk than abstainers. The very wide confidence interval reflects that the estimate was based on 14 cases and two controls. For women consuming more dietary fat, a high alcohol consumption did not appear to be associated with the risk of breast cancer. The association of dietary fat intake also varied with alcohol consumption. Among nondrinkers, a high fat intake was associated with increased risk of breast cancer, whereas a decreased risk was noted among those who drank 24 g or more per day. Combining the effects of alcohol and dietary fat--all compared with the lowest intakes of--increased risks, varying from 2.2 to 18. In the oldest age group, 60 years or more at diagnosis, the interaction between alcohol and fat intake was not significant (Table 5). There was no association between alcohol and breast cancer risk. Increased risks were found for all levels of fat intake, but the estimate for the top quartile was not significant. This was also the case for the test for trend.
Discussion Evaluating the association of alcohol consumption with breast cancer risk, the present study demonstrated a complex interaction with age and dietary fat Cancer Causes and Control. Vol 2. 1991
249
M. Ewertz Table 4. Relative risk a (95% confidence interval) of breast cancer associated with intake of
alcohol and dietary fat in women aged 50-59 years at diagnosis Fat intake
Alcohol intake (g/day)
(quartiles)
a b
0
1-23
1(low) 2 3 4(high)
1.0 1.0 1.0 1.0
(R) b (R) (R) (R)
2.53 0.63 1.20 0.62
(1.11-5.74) (0.30-1.35) (0.51-2.83) (0.28-1.40)
17.9 1.55 1.08 1.18
(3.31-97.0) (0.33-7.22) (0.25-4.72) (0.24-5.76)
1 2 3 4
1.0 3.48 2.84 5.11
(R) (1.28-9.46) (0.95-8.45) (1.79-14.6)
1.0 0.87 1.35 1.25
(R) (0.54-1.41) (0.85-2.15) (0.78-2.01)
1.0 0.30 0.17 0.33
(R) (0.04-2.28) (0.02-1.19) (0.04-2.60)
1 2 3 4
1.0 3.48 2.84 5.11
(R) (1.28-9.46) (0.95-8.45) (1.79-14.6)
2.53 2.20 3.41 3.17
(1.11-5.74) (0.97-5.00) (1.52-7.62) (1.41-7.11)
17.9 5.41 3.06 6.04
(3.31-97.0) (1.13-25.9) (0.72-13.0) (1.24-29.3)
Adjusted for age as a continuous variable, place of residence, years of education, and parity. R denotes reference category. Estimates in the three sections of the table are based on the same numbers but use different referents.
intake. A subgroup of women was identified, aged 50-59 years with a fat intake in the lowest quartile, in whom the risk of breast cancer rose with increasing alcohol consumption. We found an 18-fold increase for those consuming 24 g or more per day (or about two drinks) compared with abstainers. In other women, alcohol consumption had no significant association with breast cancer risk. Among studies taking dietary fat intake into account, the present results agree with those of Richardson et a121 who also found a significant interaction between alcohol and fat intake, and that the association with alcohol was most pronounced in women with a low fat intake. In other studies, an increased risk of breast cancer associated with alcohol Table 5. Effect of intake of alcohol and dietary fat on breast cancer risk in women aged 60 years or more at diagnosis
Alcohol intake (g/day) 0 1-23 1>24 Fat intake (quartiles) 1 (low) 2 3 4 (high)
Relative risk~ (95% confidence interval)
P-value for linear trend
1.0 (R)b 0.73 (0.50-1.06) 0.95 (0.44-2.07)
0.6
1.0
(R) 1.69 (1.11-2.57) 1.53 (1.00-2.35) 1.43 (0.94-2.18)
0.1
" Adjusted for age at diagnosis as a continuous variable, place of residence, years of education, parity, and the other variable in the table, b R denotes reference category. 250
1>24
CancerCauses and Control. Vol 2. 1991
consumption was not influenced by adjustment for diet, whether the dietary assessment was relatively simple 1°'12'2aor more sophisticated, z'3:6'z3 In most studies, the association with alcohol did not vary with age. However, Adami et al TM detected a slightly decreasing risk with increasing alcohol consumption in women aged less than 45 years. The results of this study go in the same direction although they were not statistically significant. In other studies 2'3'12'16the association of breast cancer risk with alcohol consumption was most pronounced in younger women. Thus, present findings appear to be at variance with those of most other investigations. It is unlikely that the interaction between alcohol, age, and fat intake arose because of bias related to the selection of cases and controls since the study was population-based. It cannot be ruled out, though, that nonresponders had a consumption of alcohol and fat that differed from women who completed the questionnaire. Although the possibility of information bias cannot be excluded, the data give no evidence for a greater tendency among cases than controls to report changes in alcohol consumption. Errors in the measurement of alcohol consumption generally lead to under-reporting of high consumptions and thus an underestimation of the magnitude of the true association. Finally, the possibility remains that the interactions between alcohol consumption, age, and fat intake in this study were due to chance. Testing the alcohol-fat interaction in each of the three age groups, the possibility of it being significant (P < 0.05) in at least one group, by chance, is 14 percent. There was a remarkable similarity between Danish
Alcohol and breast cancer and American women in the relation between alcohol consumption and several breast cancer risk factors. In the United States 2'3's'17'19 as well as in Denmark, consumers of alcohol tended to be younger, to have more education, to have fewer children, to be lean, to smoke, and to use oral contraceptives. In two of these studies,5'19 alcohol consumption did not affect the risk of breast cancer. In the other three, 2"3'17higher risk estimates for alcohol were obtained in lean than in heavy women. In trying to reconcile the evidence on alcohol consumption and breast cancer risk, the literature 21'22'24'26 seems to support a weak positive association, the risk being in the order of 1.4-1.7 for 24 g or more alcohol per day, corresponding to about two drinks. The risk increase does not seem to be confined to any particular type of beverage, suggesting an effect of alcoholper se. In some studies, including the present, a pronounced risk increase has been observed when women, otherwise at a low risk of developing breast cancer, had a high alcohol consumption. The carcinogenic action of alcohol is not fully understood 33 and no biological mechanism has been established to explain how alcohol should affect breast carcinogenesis. Alcohol has a variety of direct as well as indirect effects on sex hormones, through stimulation of the pituitary and adrenals to the extraglandular conversion of androgen to estrogen. 3446 The interaction between alcohol and fat consumption in this study raises the possibility that high-density lipoprotein cholesterol (HDL-C) may be involved. H D L - C levels correlate positively with intakes of both dietary fat and alcohol. However, the literature does not provide sufficient evidence to conclude whether H D L - C is causally related to breast cancer or is merely associated with risk factors. 3z In conclusion, the present study provides some support of a positive association between alcohol and breast cancer risk. The interaction with fat intake illustrates the importance of considering alcohol as a dietary factor which, as other components of diet, deserves further study.
Acknowledgements--The author thanks Dr O. M. Jensen, the Danish Cancer Registry, Dr H. T. Mouridsen on behalf of the Danish Breast Cancer Cooperative Group, Dr N. E. Day and Mr S. W. Duffy, MRC Biostatistics Unit, Cambridge, UK, for their scientific support, as well as Mrs J. F. Larsen, Mrs G. Mathiesen and Ms S. I. Hartkopp for technical assistance.
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