Alcohol and Breast Cancer: A Final Answer?
By Howell Sasser, PhD
Breast cancer is the most common non-skin cancer, and second most lethal cancer, in women. More than 200,000 new cases of breast cancer will be diagnosed in the United States this year, and nearly 40,000 women will die from the disease. Early detection and improved treatment options have produced marked improvements in survival over the last 30 years, and considerable resources continue to be devoted to identifying factors that place a woman at increased risk for breast cancer. (It should be noted that an estimated 1,300 men also will be diagnosed with breast cancer this year. However, this article will focus on women.)
The roster of confirmed and theoretical risk factors for breast cancer is long. The American Cancer Society lists: personal or family history of breast cancer, biopsy-confirmed atypical hyperplasia, increased breast density, a long menstrual history, obesity after menopause, recent use of oral contraceptives or post-menopausal estrogens or progestin, nulliparity or first conception after age 30, and consumption of one or more alcoholic drinks per day.1 Of these, several are not readily modifiable. One that appears to be is alcohol consumption.
Aside from equivocal evidence of cardioprotection, even light-to-moderate drinking has not been shown to have any measurable health benefit. Numerous studies have sought to describe the biology and epidemiology of the relationship between alcohol consumption and breast cancer risk. This article will summarize that work and offer some suggestions on how the findings to date might influence the decisions of physicians and their patients.
Mechanism of Action
Numerous mechanisms of action by which alcohol consumption might impact breast cancer risk have been proposed. The effect may be direct. Alcohol’s main metabolite, acetaldehyde, is a known mutagen/carcinogen. Certain types of breast tissue have been shown in vitro to metabolize alcohol to acetaldehyde. However, other published studies appear to show that this action is not uniform. One reported that the process varies according to the hormone-receptor status of the cells used, and another posits that the fault might lie with a mutation of the gene regulating the enzyme (alcohol dehydrogenase) used to metabolize alcohol.2,3 These findings suggest that this is at best a partial explanation.
Contaminants and by-products of alcohol production, such as sulfites and nitrites, also may play a role. However, most recent research focuses on more complex explanations, most involving alcohol’s potential to alter the levels or action of hormones and dietary micronutrients.
Alcohol has been directly related to levels of circulating hormones. Its effect on estrone sulfate is of special interest because of the highly active nature of this hormone. Separate studies have shown an association between alcohol consumption and serum estrone levels in pre- and post-menopausal women.4,5 Other studies have shown hormonal variation among drinkers who are also on hormone replacement therapy (HRT). Alcohol drinkers were found to have hormone levels higher than would have been predicted by their HRT dose.6,7
Another potential explanation focuses on the density of breast tissue, a well-established influencing factor in breast cancer.8 Alcohol consumption, in turn, increases breast density, probably through changes in fat patterns resulting from alcohol-related hormone disturbances.9
A second possibility is interference with uptake and action of vitamins and antioxidants. Alcohol is a folate antagonist10 and alters absorption or metabolism of several other substances including methionine,11 beta-carotene, lutein-zeaxanthin, and ascorbic acid.12,13 These are among the agents known or believed to be important free-radical scavengers and mediators of DNA repair.14 It also has been suggested that the combination of alcohol consumption and inadequate folate intake may alter cancer risk to a greater extent than either factor alone.15
Epidemiologic Evidence
The first report of a possible relationship between alcohol consumption and breast cancer was published in 1977.16 It showed a modest association, and alcohol was classified only as "drinks per day." However, it raised awareness of the issue and led to a substantial body of studies that continues to grow.
Singletary and Gapstur list 18 mouse and rat studies published between 1979 and 2000.17 Of these, five showed no effect and two appeared to find a protective effect of alcohol. The remaining 11 found evidence of reduced tumor latency (one study), increased tumor incidence (four studies), increased tumor multiplicity (four studies), and increased metastasis (two studies). It should be noted that many of these studies used artificial means to induce tumorigenesis. Of seven studies that used a naturalistic "spontaneous" model, only three found that alcohol promoted tumor activity.
The same paper also summarizes the results of 37 human studies published from 1977 to 2001. Of these, 17 (46%) showed statistically significant associations (odds ratios or relative risks ranged from 1.2 to 4.0). Most compared the highest and lowest consumption categories, which generally meant no alcohol consumption vs. at least three to five drinks a day. Twelve of the studies were prospective, offering at least potential avoidance of recall and selective survival bias. Five (42%) showed statistically significant associations.
In 2002, the U.K.-based Collaborative Group on Hormonal Factors in Breast Cancer published a major re-analysis of research on the relationships of smoking and drinking with breast cancer.18 Their goal was to sort out the individual contribution of each risk factor to the chance of developing breast cancer. Original data, not summary statistics, were assembled from 53 published and unpublished studies, yielding 58,515 women with breast cancer and 95,067 women as comparitors.
In a sample of this size, it was possible to classify exposure in small units and to measure correspondingly small changes in risk. Because the data came from studies conducted in many countries over nearly 15 years, it was thought necessary to apply a new standard definition of exposure. Most studies reported alcohol consumption in terms of drinks per day. For the re-analysis, drinks were translated into grams of alcohol. Based on prior reports and private communications, the investigators determined that an average drink contains 12 g of alcohol in the United States and Italy, 8 g in the United Kingdom, and 10 g everywhere else.
The results showed a steady rise in breast cancer risk with rising alcohol consumption. For each 10 g of alcohol (or one drink, on average) consumed per day, there was a 7% increase in breast cancer risk (P < 0.000001). Importantly, drinkers who smoked did not differ meaningfully in risk from those who did not. Alcohol also remained a significant predictor of breast cancer after adjusting for age, race, parity, family history of breast cancer, body mass index, history of oral contraceptive use, history of HRT use, history of breast feeding, and age at menarche and menopause.
A study worth mentioning individually assessed the association of alcohol consumption with fatal breast cancer.19 Using data from the American Cancer Society’s Cancer Prevention Study (CPS-II), the investigators identified 1,442 breast cancer deaths among 242,010 women in 14 years of follow-up. Alcohol consumption was assessed in drinks per day and any major change in drinking pattern also was recorded. Among postmenopausal women, a small, but statistically significant increase in the risk of death secondary to breast cancer was seen at all levels of drinking as compared to those who reported not drinking at all. No similar pattern was seen among pre- or peri-menopausal women. There did not appear to be a clear dose-response relationship between increasing alcohol consumption and risk of death, even among postmenopausal women, nor was the type of alcohol most often consumed a factor.
Qualifications
While the results of these studies are interesting, especially in light of the speculation about potential mechanisms, they are limited by factors that are common in observational research. Although the definition of a case is fairly clear, assessment of exposure is difficult. Because cancer is a relatively rare disease, most studies are retrospective. Participants are asked to recall what they did years or even decades earlier. The inherent difficulty in this is made worse by the often-negative social constructions placed on drinking, especially among women. Periodic binge drinking may go unreported. Even with perfect recall, standardization remains an issue. The Collaborative Group study is a good example of the sometimes arbitrary decisions investigators must make. The results they report are only as strong as the assumptions they make will permit. This is especially true when meaningful differences in risk are claimed for small changes in the amount of alcohol consumed.
A second cautionary factor is the incomplete understanding of the mechanism by which alcohol influences breast cancer. Several studies have shown associations with specific genetic polymorphisms and numerous others have found associations with circulating hormone levels. The latter is likely a key confounding factor for the apparent difference in risk before and after menopause. If these potential explanations prove to be valid, it will not be possible to explain risk simply in terms of age or years of alcohol consumption at any level.
Conclusion
There appears to be at least a small association of alcohol consumption with breast cancer, independent of other risk factors. The exact mechanism of this relationship remains unclear. Aside from a small population with known breast cancer risk factors, the clinical relevance of the rising risk associated with a small increase in alcohol consumption is unclear. The overall contribution of alcohol consumption to breast cancer incidence is modest.
Recommendation
With all of this in mind, what advice should the primary care physician give to patients? The weight of evidence is too great to justify denying any association. At the same time, the risk should not be overstated. By one estimate, if alcohol consumption were eliminated altogether, the risk of breast cancer might be reduced by about 2%.20 Other factors, such as hormone levels, are known to be much more influential. The evidence that alcohol can interact with other risk factors suggests that those who have known susceptibilities—high hormone levels, BRCA-1 allele—would be wise to limit their alcohol intake. For others, while excessive alcohol consumption should be discouraged for a variety of reasons, moderate drinking appears to play only a small role in overall breast cancer risk.
Although it is notoriously difficult to apply precise quantities to these terms, some guidance can be inferred from the risk categories used in the studies cited above. The evidence shows increased risk of breast cancer in a general population with as little as one drink per day (or about 10 g of alcohol). Those with known risk factors clearly should strive to consume less than this amount, if not abstain altogether. Those without known risk factors should be advised that each alcoholic drink consumed per day increases breast cancer risk, but that to concentrate on alcohol at the expense of other factors with greater impact on risk (such as body mass index and hormones) would be misguided.
Dr. Sasser is Director, Research Epidemiology, R. Stuart Dickson Institute for Health Studies, Carolinas HealthCare System, Charlotte, NC.
References
1. American Cancer Society. Cancer Facts and Figures. Atlanta, GA; 2003.
2. Sellers TA, et al. Interaction of dietary folate intake, alcohol, and risk of hormone receptor-defined breast cancer in a prospective study of postmenopausal women. Cancer Epidemiol Biomarkers Prev 2002;11: 1104-1107.
3. Stürmer T, et al. 2002. Interaction between alcohol dehydrogenase II gene, alcohol consumption, and risk for breast cancer. Br J Cancer 2002;87:519-523.
4. Reichman ME, et al. Effects of alcohol consumption on plasma and urinary hormone concentrations in premenopausal women. J Natl Cancer Inst 1993;85: 722-727.
5. Hankinson SE, et al. Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J Natl Cancer Inst 1995;87: 1297-1302.
6. Zumoff B. Does postmenopausal estrogen administration increase the risk of breast cancer? Contributions of animal, biochemical, and clinical investigative studies to a resolution of the controversy. Proc Soc Exp Biol Med 1998;217:30-37.
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8. Boyd NF, et al. Quantitative classification of mammographic densities and breast cancer risk: Results from the Canadian National Breast Screening Study. J Natl Cancer Inst 1995;87:670-675.
9. Vachon CM, et al. Association of mammographically defined percent breast density with epidemiologic risk factors for breast cancer (United States). Cancer Causes Control 2000;11:653-662.
10. Zhang SM, et al. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 2003;95:373-380.
11. Giovannucci E, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993;85:875-884.
12. Forman MR, et al. Effect of alcohol consumption on plasma carotenoid concentrations in premenopausal women: A controlled dietary study. Am J Clin Nutr 1995;62:131-135.
13. Drewnowski A, et al. Serum beta-carotene and vitamin C as biomarkers of vegetable and fruit intakes in a community-based sample of French adults. Am J Clin Nutr 1997;65:1796-1802.
14. Smith SS, Crocitto L. DNA methylation in eukaryotic chromosome stability revisited: DNA methyltransferase in the management of DNA conformation space. Mol Carcinog 1999;26:1-9.
15. Sellers TA, et al. Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology 2001;12:420-428.
16. Williams R, Horm J. Association of cancer sites with tobacco and alcohol consumption and socioeconomic status of patients: Interview study from the Third National Cancer Survey. J Natl Cancer Inst 1977;58:525-547.
17. Singletary KW, Gapstur SM. Alcohol and breast cancer: Review of epidemiologic and experimental evidence and potential mechanisms. JAMA 2001;286:2143-2151.
18. Collaborative Group on Hormonal Factors in Breast Cancer. Alcohol, tobacco and breast cancer—Collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 2002;87:1234-1245.
19. Feigelson HS, et al. Alcohol consumption increases risk of fatal breast cancer (United States). Cancer Causes Control 2001;12:895-902.
20. Tseng M, et al. Calculation of population attributable risk for alcohol and breast cancer (United States). Cancer Causes Control 1999;10:119-123.
Sasser H. Alcohol and breast cancer: A final answer? Altern Med Alert 2003;6(9):101-104.
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