Critique 060: A new analysis from the Nurses’ Health Study on the association of alcohol with risk of breast cancer — 3 November 2011
Chen WY, Rosner B, Hankinson SE, Colditz GA, Willett WC. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA 2011;306:1884-1890.
Context: Multiple studies have linked alcohol consumption to breast cancer risk, but the risk of lower levels of consumption has not been well quantified. In addition, the role of drinking patterns (ie, frequency of drinking and “binge” drinking) and consumption at different times of adult life are not well understood.
Objective: To evaluate the association of breast cancer with alcohol consumption during adult life, including quantity, frequency, and age at consumption.
Design, Setting, and Participants: Prospective observational study of 105,986 women enrolled in the Nurses’ Health Study followed up from 1980 until 2008 with an early adult alcohol assessment and 8 updated alcohol assessments.
Main Outcome Measures: Relative risks of developing invasive breast cancer.
Results: During 2.4 million person-years of follow-up, 7,690 cases of invasive breast cancer were diagnosed. Increasing alcohol consumption was associated with increased breast cancer risk that was statistically significant at levels as low as 5.0 to 9.9 g per day, equivalent to 3 to 6 drinks per week (relative risk, 1.15; 95% CI, 1.06-1.24; 333 cases/100,000 person-years). Binge drinking, but not frequency of drinking, was associated with breast cancer risk after controlling for cumulative alcohol intake. Alcohol intake both earlier and later in adult life was independently associated with risk.
Conclusions Low levels of alcohol consumption were associated with a small increase in breast cancer risk, with the most consistent measure being cumulative alcohol intake throughout adult life. Alcohol intake both earlier and later in adult life was independently associated with risk.
Background: A large percentage of observational prospective studies have shown that women who consume alcohol show an increase in their risk of developing breast cancer. In general, the relation seems to be stronger for women who drink in binges, are also taking post-menopausal hormonal therapy, and/or have low intakes of dietary folate. Most studies have shown that heavier drinkers are at the greatest risk.
The present analysis is from the Nurses’ Health Study, which is one of the first prospective studies to point out an association between alcohol consumption and breast cancer. It attempts to determine if both the amount of alcohol and the frequency of drinking affect risk, and also whether the cumulative alcohol intake over the adult years relates to the risk of breast cancer.
Comments on present paper: As is usual from the Nurses’ Health Study, the present analyses are very well done. Theoretically, the repeated assessments of consumption over time should provide a better estimate of long-term alcohol intake. It is interesting, however, that in these analyses, the risks of cancer associated with alcohol were almost the same whether based on the amounts of alcohol consumed at baseline in 1980 or on the cumulative average based on repeated assessments of intake through the years.
When adjusting for the cumulative lifetime consumption, there was no effect of the frequency of consumption (1-2, 3-4, or 5-7 days per week). This is different from the usual findings for the association between alcohol intake and cardiovascular disease, where more frequent intake is associated with greater protection.
Again, when adjusting for cumulative intake, there was only a weak relation with cancer from the reported maximum number of drinks per day; While there was not a clear trend, the highest risk ratio (RR = 1.21, CI 0.99-1.47) was for women reporting 6 or more drinks/day.
Both for the reported intake between ages 18 and 40 (based on recall) and the intake after age 40, the adjusted estimate of cancer risk showed a sharp increase at 10-19.9 g/day, although an increase in risk was present to a lesser degree in both age groups at 5 – 9.9 g/day. There was little difference in the effects of intake before 40 years and intake thereafter. No differences in association with breast cancer risk were seen according to type of beverage consumed.
Several reviewers pointed out that observational studies report “associations,” and often provide hypotheses to explain their findings; but “causation” cannot be proved from such studies alone. As one Forum reviewer stated: “The authors correctly present data as associations. Sometimes, the general population, health authorities, and the media automatically assume that an association clearly identifies a cause, and often advise very stringent measures based on such observational data.”
Modification of breast cancer risk associated with alcohol consumption by folate: A primary concern of several Forum reviewers was that the investigators did not evaluate folate intake as a potential confounder, even though the Nurses’ Health Study has extensive dietary data on its subjects. Previous reports from this study suggest that the excess risk of breast cancer associated with alcohol consumption may be reduced (or eliminated) by adequate folate intake.1,2 These investigators had previously reported that the risk of breast cancer associated with alcohol intake was strongest among women with total folate intake of less than 300 μg/d (for alcohol intake >15 g/d versus less than 15 g/d, multivariate RR 1.32, CI 1.15-1.50). For women who consumed at least 300 μg/d of total folate, the multivariate RR for intake of at least 15 g/d of alcohol versus less than 15 g/d was 1.01 (CI 0.92-1.20).
Similarly, Baglietto et al3 reported that the estimated hazard ratio for breast cancer of an alcohol consumption of 40 g/day or more was 2.00 (CI 1.14-3.49) for women with intakes of 200 μg/day of folate and 0.77 (0.33-1.80) for those with intakes of 400 μg/day of folate. Further, Beilby et al4 observed marked reductions in odds ratios for breast cancer among women with higher levels of serum folate, as have many others.5-10
Tjønneland et al11 also reported that an association between alcohol intake and risk of breast cancer was present mainly among women with low folate intake. A RR of 1.19 (CI 0.99-1.42) per 10 g average daily alcohol intake was found for women with a daily folate intake below 300 μg, while among women with a folate intake higher than 350 μg, they could not show an association between the alcohol intake and the breast cancer incidence rate (e.g., for folate intake >400 μg, the RR was 1.01, CI 0.85-1.20). On the other hand, Feigelson et al12 found no evidence of an interaction between levels of dietary folate and alcohol and associations with breast cancer risk.
One reviewer stated: “This is a well conducted cohort study, with good assessment of the exposure variable and good assessment of the outcome variable. While a number of potential confounders have been considered and controlled for, it is unfortunate that diet as a potential confounder has not been taken into account.”
Another reviewer commented: “The results are plausible from the pathophysiological point of view: alcohol intake increases estrogen levels and this means that women have a slightly lower risk for osteoporosis and a slightly higher risk for breast cancer. When we tell the public that current data suggest small to moderate amounts of alcohol protect against cardiovascular disease, osteoporosis, diabetes mellitus, and vascular dementia, we should also state that breast cancer risk in women is slightly increased.”
He adds that the authors of this paper put their findings into perspective when they conclude: “An individual will need to weigh the modest risks of light to moderate alcohol use on breast cancer development against the beneficial effects on cardiovascular disease to make the best personal choice regarding alcohol consumption.”
1. Zhang SM, Hunter DJ, Hankinson SE, Giovannucci EL, Rosner BA, Colditz GA, et al. A prospective study of folate intake and the risk of breast cancer. JAMA 1999;281:1632-1637.
2. Zhang SM, Willett WC, Selhub J, et al. Plasma folate, Vitamin B6, Vitamin B12, homocysteine, and the risk of breast cancer. J Natl Cancer Inst 2003;95:373-380.
3. Baglietto L, English DR, Gertig DM, Hopper JL, Giles GG. Does folate intake modify effect of alcohol consumption on breast cancer risk? Prospective cohort study. BMJ 2005;331:807-811.
4. Beilby J, Ingram D, Hahnel R, Rossi E. Reduced breast cancer risk with increasing serum folate in a case-control study of the C677T genotype of the methylenetetrahydrofolate reductase gene. Eur J Cancer 2004;40:1250-1254.
5. Levi F, Pasche C, Lucchini F, La Vecchia C. Dietary intake of selected micronutrients and breast-cancer risk. Int J Cancer 2001;91:260-263.
6. Negri E, La Vecchia C, Franceschi S. Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92:1270-1271
7. Rohan TE, Jain MG, Howe GR, Miller AB. Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92:266-269.
8. Rossi E, Hung J, Beilby JP, Knuiman MW, Divitini ML, Bartholomew H. Folate levels and cancer morbidity and mortality: Prospective cohort study from Busselton, Western Australia. Ann Epidemiol 2006;16:206-212.
9. Shrubsole MJ, Jin F, Dai Q, et al. Dietary folate intake and breast cancer risk: Results from the Shanghai Breast Cancer Study. Cancer Research 2001;61:7136-7141.
10. Stolzenberg-Solomon RZ et al. Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Clin Nutr 2006;83:895-904.
11. Tjønneland A, Christensen J, Olsen A, et al. Folate intake, alcohol and the risk of breast cancer among post-menopausal women in Denmark. Eur J Clin Nutr 2006;60:280-286.
12.. Feigelson HS, Jonas CR, Robertson AS, McCullough ML, Thun MJ, Calle EE. Alcohol, folate, methionine, and risk of incident breast cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 2003;12:161-164.
In a well-done analysis using prospectively collected data from the Nurses’ Health Study, the risk of breast cancer was found to be modestly increased among consumers of alcohol, even those whose total alcohol consumption was reported to be in the range of 3 to 6 drinks/week. Similar small increases in the risk of breast cancer have been found from alcohol consumption in the majority of previous studies observational studies. A strength of this study was the very large number of subjects, permitting the investigators to attempt to determine if both the amount of alcohol and the frequency of consumption were important in this association; strong effects were not found for either. A weakness is the failure to report the effects of folate intake on the association between alcohol and cancer; the same investigators have previously shown that folate is a potential moderator of the effects of alcohol on breast cancer risk.
The authors describe well the dilemma that women face regarding alcohol intake, which may increase slightly the risk of breast cancer but markedly decrease the risk of other more common diseases, especially cardiovascular conditions. Given that the National Cancer Institute has estimated that a woman’s lifetime risk of breast cancer is 12%, it must be appreciated that even if there were a 15% increase in the relative risk of breast cancer from moderate drinking, the absolute risk would increase only to 13.6%. Other studies show that the increase associated with consuming one drink/day is more in the range of 7 to 10%, suggesting that the absolute increase in risk from such alcohol consumption is even less. Indeed, the authors of this paper state that regarding breast cancer, “We did find an increased risk at low levels of use, but the risk was quite small.”
Forum members agree with the statement of the authors that “An individual will need to weigh the modest risks of light to moderate alcohol use on breast cancer development against the beneficial effects on cardiovascular disease to make the best personal choice regarding alcohol consumption.”
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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:
Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis, USA
Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy
Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
Francesco Orlandi, MD, Department of Gastroenterology, Università degli Studi di Ancona, Italy
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
Ulrich Keil, MD, PhD, Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
Lynn Gretkowski, MD, Obstetrics/Gynecology, Mountainview, CA, Stanford University, Stanford, CA, USA
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA