Critique 016 29 August 2010
Li CI, Chlebowski RT, Freiberg M, Johnson KC, Kuller L, Lane D, Lessin L, O’Sullivan MJ, Wactawski-Wende J, Yasmeen S, Prentice R. Alcohol Consumption and Risk of Postmenopausal Breast Cancer by Subtype: the Women’s Health Initiative Observational Study. J Natl Cancer Inst 2010 Aug 23. [Epub ahead of print]
Background: Alcohol consumption is a well-established risk factor for breast cancer. This association is thought to be largely hormonally driven, so alcohol use may be more strongly associated with hormonally sensitive breast cancers. Few studies have evaluated how alcohol-related risk varies by breast cancer subtype.
Methods: We assessed the relationship between self-reported alcohol consumption and postmenopausal breast cancer risk among 87,724 women in the Women’s Health Initiative Observational Study prospective cohort from 1993 through 1998. Multivariable adjusted Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
Results: A total of 2,944 invasive breast cancer patients were diagnosed during follow-up through September 15, 2005. In multivariable adjusted analyses, alcohol consumption was positively related to risk of invasive breast cancer overall, invasive lobular carcinoma, and hormone receptor-positive tumors (all P(trend) ≤ 0.022). However, alcohol consumption was more strongly related to risk of certain types of invasive breast cancer compared with others. Compared with never drinkers, women who consumed seven or more alcoholic beverages per week had an almost twofold increased risk of hormone receptor + invasive lobular carcinoma (HR = 1.82; 95% CI = 1.18 to 2.81) but not a statistically significant increased risk of hormone receptor + invasive ductal carcinoma (HR = 1.14; 95% CI = 0.87 to 1.50; difference in HRs per drink per day among current drinkers = 1.15; 95% CI = 1.01 to 1.32, P = .042). The absolute rates of hormone receptor+ lobular cancer among never drinkers and current drinkers were, 5.2 and 8.5 per 10,000 person-years, respectively, whereas for hormone receptor+ ductal cancer they were 15.2 and 17.9 per 10,000 person-years, respectively.
Conclusions: Alcohol use may be more strongly associated with risk of hormone-sensitive breast cancers than hormone-insensitive subtypes, suggesting distinct etiologic pathways for these two breast cancer subtypes.
Comments on the present study: This is a very well-done analysis of a large dataset from the Women’s Health Initiative. It supports previous research indicating that the lobular subtype of breast cancer (which makes up 15-20% of cancers) is more strongly associated with alcohol than the much more common ductal type of cancer. There was no statistically significant association between alcohol intake and ductal carcinomas. The association of alcohol consumption was seen for hormome + tumors but not for hormone – tumors.
The authors report that the overall rates of breast cancer for never drinkers and current drinkers was 5.2 and 8.5 per 10,000 person-years, respectively, for lobular cancer, and 15.2 and 17.9 per 10,000 person-years, respectively, for ductal cancer. Although the magnitude of the increase is not large, the differences in risk according to subtype of cancer support a causal effect of alcohol on the risk of breast cancer, and suggest that hormonal factors may be the mechanism.
Previous research on the topic: Most previous studies have suggested the same association between alcohol intake and estrogen + breast cancer as this study, but the present study is much larger and permits more precise estimates of effect. There were no significant differences according to type of beverage in this study, although in Table 5 it can be noted that, especially for women reporting ≥ 1 drink/day, the point estimates for cancer were lower for wine consumers than for consumers of other beverages.
Folate intake, alcohol and risk of breast cancer: Several cohort studies show an interaction between folate intake and the risk of breast cancer associated with alcohol intake. The present study1, however, did not include diet or folate intake among the variables considered as potential confounders. Tjønnneland et al2 evaluated the possible interaction between alcohol and folate in a paired nested case-control study among 24,697 postmenopausal women included in the ‘Diet, Cancer and Health’ follow-up study between December 1993 and May 1997. The cohort was followed until December 2000. The study included 388 cases of breast cancer and 388 randomly selected controls were used to estimate the breast cancer incidence rate ratio (IRR) in conditional logistic regression analysis. A previously established association between alcohol intake and risk of breast cancer was present mainly among women with low folate intake. An IRR of 1.19 (95% CI: 0.99-1.42) per 10 g average daily alcohol intake was found for women with a daily folate intake below 300 mg, while among women with a folate intake higher than 350 mg, there was not an association between the alcohol intake and the breast cancer incidence rate (e.g. folate intake 4400 mg; IRR of 1.01 (95% CI: 0.85-1.20)). The findings support the evidence that adequate folate intake may attenuate the risk of breast cancer associated with high alcohol intake.
In another study on the interaction of alcohol and folate intake, the most protective combination with regard to cardiovascular disease appeared to be high folate (>600 ug/day) and high alcohol (>30 g/day), with a RR = 0.573. This raises the question as to whether there is some common mechanism that is providing a reduction in observed morbidity. (That study did not report the combined effect of alcohol and folate on breast cancer risk, but there was little effect of folate on the associations when breast and colon cancer were considered together3.) An earlier study by Rimm et al4 showed an even more striking inverse association between folate intake and coronary heart disease risk among drinkers.
Interaction between intake of alcohol and postmenopausal hormones on risk of breast cancer: Nielsen and Grønbaek5 studied whether alcohol interacts with hormone use on risk of breast cancer among 5,035 postmenopausal women who participated in the Copenhagen City Heart Study. Alcohol consumption was associated with a small increased risk of breast cancer (hazard ratio = 1.11 per drink/day, 95% CI: 0.99-1.25). Unlike the results in the present study1, women who used hormones also had a higher risk of breast cancer (HR = 2.00, 95% CI: 1.52-2.61) compared to non-hormone users. The Danish study found an interaction between these two factors: those who had an intake of more than 2 drinks per day and took hormones had a risk of 4.74 (95% CI: 2.61-8.59) for breast cancer compared to abstainers who did not use hormones. Alcohol was not associated with breast cancer among women who did not use hormones (HR = 0.98 per drink/day, 95% CI: 0.82-1.78)5.
It is provocative that hormone-dependent cancers appear to be associated with alcohol consumption while BRCA gene mutation-related cancers do not6. As stated, the data presented do not take into account folate consumption, but other studies have shown no beneficial effect of higher folate intake to compensate for the effects of alcohol consumption in the same study population7. If ethanol and other components of wine, beer and spirits do indeed share similarities molecularly with estrogen-like compounds as it has been proposed, it is clear that further studies need to elucidate which compounds (is it resveratrol and its striking molecular similarity to DES or 17-beta E2?) might be acting like estrogen or anti estrogen when it comes to breast tissue.
Other factors affecting the association of alcohol with breast cancer: It would be interesting to know the ADH allele information in the lobular and ductal carcinoma patients in the present study, as this may have related to the observed associations between alcohol and breast cancer risk. Benzon Larsen et al8 found that carriers of the variant allele of ADH1C Arg272Gln, who are slow converters of ethanol to acetaldehyde, are at increased risk of breast cancer from alcohol intake. They interpreted this to suggest that ethanol rather than the metabolite acetaldehyde is the carcinogenic substance in relation to alcohol induced breast cancer in postmenopausal Caucasian women8.
Forum Summary: This large study of women with different subtypes of breast cancer shows that alcohol was associated with an increase in the risk of lobular carcinoma, but there was not a statistically significant association with the more-common ductal carcinoma. Hormone + cancers showed an association with alcohol intake, but not hormone – cancers. The findings support the importance of hormonal mechanisms in mediating the relation between alcohol use and breast cancer risk.
References from Forum review:
1. Li CI, Chlebowski RT, Freiberg M, et al. Alcohol Consumption and Risk of Postmenopausal Breast Cancer by Subtype: the Women’s Health Initiative Observational Study. J Natl Cancer Inst 2010 Aug 23. [Epub ahead of print]
2. Tjønneland A, Christensen J, Olsen A, Stripp C, Nissen SB, Overvad K, Thomsen BL. Folate intake, alcohol and risk of breast cancer among postmenopausal women in Denmark. Eur J Clin Nutr 2006:60:280-286.
3. Jiang R, Hu FB, Giovannucci EL, Rimm EB, Stampfer MJ, Spiegelman D, Rosner BA, Willett WC. Joint association of alcohol and folate intake with risk of major chronic disease in women, Am J Epidemiol Am J Epidemiol 2003;158:760-771.
4. Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stampfer MJ. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998 279:359-364.
5. Nielsen NR, Grønbaek M. Interactions between intakes of alcohol and postmenopausal hormones on risk of breast cancer. Int J Cancer 2008;122:1109-1113.
6. Dennis J, Ghadirian P, Little J, Lubinski J, Gronwald J, Kim-Sing C, Foulkes W, Moller P, Lynch HT, Neuhausen SL, Domchek S, Armel S, Isaacs C, Tung N, Sweet K, Ainsworth P, Sun P, Krewski D, Narod S; the Hereditary Breast Cancer Clinical Study Group. Alcohol consumption and the risk of breast cancer among BRCA1 and BRCA2 mutation carriers. The Breast 2010;e-pub prior to publication.
7. Duffy CM, Assaf A, Cyr M, Burkholder G, Coccio E, Rohan T, McTiernan A, Paskett E, Lane D, Chetty VK. Alcohol and folate intake and breast cancer risk in the WHI Observational Study. Breast Cancer Res Treat 2009;116:551-562.
8. Benzon Larsen S, Vogel U, Christensen J, Hansen RD, Wallin H, Overvad K, Tjønneland A, Tolstrup I. Interaction between ADH1C Arg272Gln and alcohol intake in relation to breast cancer risk suggests that ethanol is the causal factor in alcohol related breast cancer. Cancer Letters 2010;295:191-197.
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Contributions to these comments from the International Scientific Forum on Alcohol Research were from the following:
Yuqing Zhang, MD, DSc, Epidemiology, Boston University School of Medicine, Boston, MA, USA
Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis, CA, USA
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Lynn Gretkowski, MD, Obstetrics/Gynecology, Mountainview, CA, Stanford University, Stanford, CA, USA
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA