Critique 175: An update on the association of alcohol consumption with breast cancer: Effects of BMI — 24 November 2015

Shin A, Sandin S, Lof M, Margolis KL, Kim K, Couto E, Adami HO, Weiderpass E.   Alcohol consumption, body mass index and breast cancer risk by hormone receptor status: Women’ Lifestyle and Health Study.  BMC Cancer 2015;15:881 (DOI 10.1186/s12885-015-1896-3)

Authors’ Abstract

Background: We aimed to estimate the effect of alcohol consumption on breast cancer risk and to test whether overweight and obesity modifies this association.

Methods: We included in the analysis 45,233 women enrolled in the Swedish Women’s Lifestyle and Health study between 1991 and 1992. Participants were followed for occurrence of breast cancer and death until December 2009. Poisson regression models were used, and analyses were done for overall breast cancer and for estrogen receptor positive or negative (ER+, ER-) and progesterone receptor positive and negative (PR+, PR-) tumors separately.

Results: A total of 1,385 breast cancer cases were ascertained during the follow-up period. Overall, we found no statistically significant association between alcohol intake and breast cancer risk after adjustment for confounding, with an estimated relative risk (RR) of 1.01 (95 % CI: 0.98–1.04) for an increment in alcohol consumption of 5 g/day.  A statistically significant elevated breast cancer risk associated with higher alcohol consumption was found only among women with BMI ≤25 (RR 1.03, 95 % CI 1.0–1.05 per 5 g/day increase).

Conclusion: An increase in breast cancer risk with higher alcohol consumption was found for breast cancers in women with a BMI ≤25 kg/m2.

Forum Comments

Most observational epidemiologic studies have shown a slight increase in the risk of breast cancer for women who consume alcohol.  Taking the type of study, the pattern of drinking, and known confounders into consideration, the risk among women who report up to one typical drink per day has been estimated to be about 10% (Ellison et al), although a number of studies have shown higher risk.  Having adequate intake of folate, not binge drinking, and not taking hormone replacement therapy have often been found to ameliorate, or even abolish, the risk attributed to alcohol.  As summarized in a meta-analysis by Larsson et al, a number of studies (e.g., Zhang S et al, Rohan et al) have found a statistically significant reduction in breast cancer risk for high versus low folate intake among women who consumed moderate or high amounts of alcohol (summary estimate = 0.51, 95% CI = 0.41 to 0.63).  Other studies have supported such a finding (Tjønneland et al, Stolzenberg-Solomon et al).  However, some studies (e.g., Feigelson et al) do not support an inverse association for folate and breast cancer among alcohol consumers.  It has also been shown that the risk of breast cancer among obese women tends to be higher than among non-obese women (Morimoto et al), but there are limited data on how obesity interacts with alcohol in affecting the risk of breast cancer.

The present study is based on a large cohort of Swedish women who were examined as part of the Women’s Lifestyle and Health Study in 1991 – 1992, then followed through 2009 for the development of breast cancer: 1,385 cases were ascertained among the more than 45,000 women in the study.  Alcohol was assessed at baseline and again at the follow-up examination.  Almost all of the women were pre-menopausal at baseline.

Specific comments by Forum members on study:  Forum members considered this to be a very well-done study, with almost complete ascertainment of cancer cases.  Forum member Ellison had some concerns that the authors state at the beginning of their abstract that there was “no statistically significant association between alcohol intake and breast cancer risk after adjustment for confounders.”  While this is indeed supported by their data, some casual readers may stop reading at this point and not notice that the authors also state that there was an increase in risk among less-obese women.

For total breast cancer, the RR for women who had a BMI of ≤ 25 kg/m2 showed a step-wise increase in the risk ratio (from 1.0, to 1.05, to 1.19, to 1.32) with increasing category of alcohol intake.  A similar relation was seen in two of the three sub-categories of breast cancer.  This association was not seen in the more obese women for total cancer or sub-categories.  Hence, while the overall results may not show an increase in risk from alcohol intake, the results among non-obese women are similar to those seen in many other studies, and suggest a slight increase in the risk of breast cancer associated with alcohol for at least some women.  The differences according to BMI reported by the investigators are interesting, and are supported by the data.  Thus, this study adds to our understanding of the association of alcohol with breast cancer which, however, remains unclear.

Reviewer Barrett-Connor agreed that it was a good study, but warned about “missing data bias and failure to consider season of blood samples, sunlight and vitamin D, Swedish use of fish oil in youth, and other striking diet differences with other populations; the importance of such effects on health have been described by Khaw et al.”  Forum member Lanzmann-Petithory had other objections to the study: “I have concern about the way by which the authors calculated alcohol consumption: ‘One 1 glass (of wine) = 1 dl; alcohol by volume = 10 %.’  In this condition, 1 glass of wine would = 8 g of alcohol.  We know that a glass of 12 cl of wine at 13% contains 12.5 g of alcohol, 13.5 g if 14%, and 14.5 g if it is a 125 ml glass (6 glasses/bottle) of a wine at 14.5% alcohol.  Such calculations could lead to a 36% to 45% underestimate of alcohol intake.  Further, women consuming >15 g/d of alcohol appeared to be older at enrollment, and more frequently had a positive family history of breast cancer.  Despite attempts at controlling for some of these factors in the analyses, I am afraid that there is a large chance of residual confounding.”

Forum member Keil stated that there may be a number of reasons why the authors did not find an overall meaningful association between alcohol consumption and breast cancer:

“1. The Swedish women of this cohort hardly drank any alcohol; 72% of the cohort drank either zero alcohol or below 5 g per day. Perhaps there is major underreporting?

2. The observation period of the cohort is rather long, namely 19 years; the age groups covered are mainly between 40-59 years. Thus a large group of women are premenopausal.  Breast cancer risk starts increasing at age 50 and, if I remember correctly, the peak of breast cancer incidence is around age 62.  A-ten year longer follow up might provide a different picture.

3. Height and weight were reported on a questionnaire and not actually measured.  This is a real drawback of the study (which puts an emphasis on BMI as a confounder or effect modifier), because we know that women tend to underestimate their weight (while men tend to overestimate their height).  BMI values seem to be underestimated in this study.”

Keil continued: “Most cohort studies on this topic have found slight increases of the RR for breast cancer with alcohol consumption.  Pathophysiologically, this seems plausible to me, because we know that alcohol intake increases oestrogen levels and elevated oestrogen levels are associated with increased risk of breast cancer, but with a decreased risk of osteoporosis.

Reviewer Van Velden agreed with Keil’s comments: “I agree that we are not sure about the BMI values in this study, and these results must be interpreted cautiously.  Alcohol increases oestrogen, and oestrogen stored in the fat cells will increase the risk of hormone-dependant cancers in obese woman.  It would be interesting to see whether the investigators did genetic analysis on these woman; the presence of the BRCA 1&2 genes might affect the risk of cancer in the lean women.”

Forum member Finkel states that he has “always been somewhat dismayed with the blanket indictment of alcohol as an inciter of breast cancer, and refusal to view breast cancer and those afflicted therewith as monoliths. Here we have one facet of the heterogeneous realities of the disease, its hosts, and, perhaps, one of its inciters.  By some means, likely sexual endocrine levels, alcohol, at least in its manifestation among this population, and obesity may work their evil ways to promote breast cancer in some women via shared pathways.”

Forum member Skovenborg had a number of comments on alcohol and breast cancer, and on this study:

“1.  The association between obesity and breast cancer risk was explored in the WHI Observational study where a five-unit increase in BMI was associated with 50 extra cases of breast cancer per 100,000 women at-risk per year.  Of these 23.8%, could be attributed to estradiol and 65.8% through insulin pathways.  Consuming 7+ drinks/wk compared with abstinence was associated with 164.9 breast cancer cases per 100,000, but no significant contribution from estradiol was found.  The effect of alcohol on breast cancer was restricted to ER+ breast cancers (Hvidtveldt et al).

2.  The finding of an increased risk in leaner women may be due to confounding by socioeconomic status (Nordahl et al).

3.  The suggestion of a step-wise increase in breast cancer risk associated with higher alcohol consumption for estrogen-receptor negative cancers (in women with BMI ≤25) is very unusual and flies in the face of previous findings and also the proposed mechanistic hypothesis of increased estrogen levels in alcohol users.

4.  Reports of an overall null-association between alcohol intake and breast cancer risk is not that uncommon. The first example appeared in 1983 (Webster et al) following 3 reports of a positive alcohol-breast cancer association from 1974, 1977 and 1982. With a brief look at the literature, I found 19 such papers consisting mostly of case-control studies but also including the Framingham original cohort and Offspring cohort studies [Zhang Y (1), et al].

5.  Firm conclusions about the risk of breast cancer at low intake levels of alcohol cannot be drawn because of the likelihood of measurement errors, particularly the tendency for underestimation. The report from the Swedish MDC cohort study (Mattisson et al) supported a threshold effect with no indication of elevated risk for reported total alcohol consumption <30 g/day. ‘High wine consumption’ was the only category with a median total alcohol intake >30 g/day.  However, information on alcohol habits is sensitive in Sweden and prone to reporting bias: it is possible that the Swedish women report wine more accurately than beer and spirits.  Thus, because wine is the major source of alcohol in this population, it is difficult to separate the effect of wine from that of total alcohol.

6.  A population-based cohort study of 36,856 women diagnosed with alcoholism in Sweden between 1965-95 (Kuper et al) found that alcoholic women had a surprisingly small 15% increase in breast-cancer incidence compared to the general female population.”

Skovenborg concluded: “The alcohol-breast cancer hypothesis remains intriguing, but causality has not yet been definitively established.  As for what advice should be given to women, the conclusion of the Framingham investigators from 1999 is still valid today: ‘The best approach seems to be to provide women with scientifically sound, balanced information on the effects of light drinking so that they can make informed decisions regarding their own lifestyle habits’ [Zhang Y (2) et al].”

References from Forum critique

Ellison RC, Zhang Y, McLennan CE, Rothman KJ.  Exploring the Relation of Alcohol Consumption to Risk of Breast Cancer.  Am J Epidemiol 2001;154:740–747.

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.

Hvidtfeldt UA, Gunter MJ, Lange T, et al. Quantifying Mediating Effects of Endogenous Estrogen and Insulin in the Relation between Obesity, Alcohol Consumption, and Breast Cancer. Cancer Epidemiol Biomarkers Prev 2012;21:1203–1212.

Khaw K-T, Luben R, Wareham N.  Serum 25-hydroxyvitamin D, mortality, and incident cardiovascular disease, respiratory disease, cancers, and fractures: a 13-y prospective population study.  Am J Clin Nutr 2014; doi:10.3945/ajcn.114.086413.

Kuper H, Ye W, Weiderpass E, et al. Alcohol and breast cancer risk: the alcoholism paradox. British Journal of Cancer 2000;83:949–951.

Larsson SC, Giovannucci E, Wolk A.  Folate and Risk of Breast Cancer: A Meta-analysis.  J Natl Cancer Inst 2007;99:64-76.

Mattisson I, Wirfät E, Wallströn P, Gullberg B, Olsson H, Berglund G.  High fat and alcohol intakes are risk factors of post-menopausal breast cancer: a prospective study from the Malmö diet and cancer cohort. Int J Cancer 2004;110:589-597.

Morimoto LM, White E, Chen Z, et al.  Obesity, body size, and risk of postmenopausal breast cancer: the Women’s Health Initiative (United States).  Cancer Causes and Control 2002;13: 741–751.

Nordahl H, Hvidtfeldt UA, Diderichsen F.  Cohort Profile: The Social Inequality in Cancer (SIC) cohort study.  Int J Epidemiol 2003;32:218-224.

Rohan TE, Jain MG, Howe GR, Miller AB.  Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92:266-269.

Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, Johnson KA, Johnson C, Buys SS, 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.

Tjønneland A, Christensen J, Olsen A, Stripp C, Nissen SB, Overvad K, et al. Folate intake, alcohol and risk of breast cancer among postmenopausal women in Denmark. Eur J Clin Nutr 2006;60:280-286.

Webster LA, Wingo PA, Layde PM, Ory HW.  Alcohol consumption and risk of breast cancer.   The Cancer and Steroid Hormone Study Group.  Lancet 1983;322:724-726.

Zhang S, Hunter DJ, Hankinson SE, et al.  A prospective study of folate intake and the risk of breast cancer . JAMA 1999;281:1632-1637.

Zhang Y (1), Kreger BE, Dorgan JF, Splansky GL, Cupples LA, Ellison RC.  Alcohol consumption and risk of breast cancer: the Framingham Study revisited. Am J Epidemiol 1999;149:93–101.

Zhang Y (2), Kreger B, Dorgan JF, Splansky GL, Cupples LA, Ellison RC. Authors’ response to “The Framingham results on alcohol and breast cancer”. Am J Epidemiol 1999;149:105.

Forum Summary

Most observational epidemiologic studies have shown a slight increase in the risk of breast cancer for women who consume alcohol; the degree of increase is usually small for light-to-moderate drinkers (between 5% and 15% increase for consumers of no more than one drink/day), but the risk may be higher for women consuming greater amounts of alcohol.  However, there are a number of factors that affect this relationship, including the type of study (cohort or case-control), the pattern of drinking (regular versus binge), the type of beverage consumed, folate intake, use of hormone replacement therapy, as well as genetic factors.  It has also been shown that the risk of breast cancer among obese women tends to be higher than among non-obese women, but there are limited data on how obesity interacts with alcohol in affecting the risk of breast cancer.  It is clear that alcohol consumption cannot be evaluated in isolation, without considering other factors that relate to the development of breast cancer.

The present study is based on a large cohort of Swedish women who were examined as part of the Women’s Lifestyle and Health Study in 1991 – 1992, then followed through 2009 for the development of breast cancer: 1,385 cases were ascertained among the more than 45,000 women in the study.  Alcohol was assessed at baseline and again at the follow-up examination, and the diagnosis of breast cancer was gleaned through linkage to the nationwide health registries in Sweden.  Almost all of the women were pre-menopausal at baseline.

Forum members considered this to be a very well-done study, with almost complete ascertainment of cancer cases.  There were some concerns, however, including the fact that the height and weight of subjects was not measured but self-reported, perhaps resulting in less accurate estimates of BMI.  Further there may have been residual confounding from other factors related to breast cancer that were not assessed.  Finally, the reported levels of alcohol consumption among the women in this study were very low (72% of the cohort drank either zero alcohol or below 5 g per day), but it cannot be determined if these are indeed the levels in this population or whether there may have been under-reporting of consumption.

The key findings as reported by the authors were that, overall, there was “no statistically significant association between alcohol intake and breast cancer risk after adjustment for confounders.”  While this is indeed supported by their data, Forum members warned that readers should also note that there was an increase in risk found in less-obese women (BMI ≤ 25 kg/m2), among whom there was a step-wise increase in the risk ratio for cancer from 1.0, to 1.05, to 1.19, to 1.32 with increasing category of alcohol intake.  This association was not seen in the more obese women for total cancer or for any of the sub-categories of cancer.

While the overall results did not show an increase in risk from alcohol intake, the results among non-obese women are similar to those seen in many other studies, and suggest a slight increase in the risk of breast cancer associated with alcohol for at least some women.  The differences in effect according to BMI reported by the investigators are interesting and add to our understanding of the association of alcohol with breast cancer which, however, remains unclear.

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Comments for this critique were provided by the following members of the International Scientific Forum on Alcohol Research:

Elizabeth Barrett-Connor, MD, Distinguished Professor, Division of Epidemiology, Department of Family Medicine and Public Health and Department of Medicine, University of California, San Diego, La Jolla, CA USA

Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy

R. Curtis Ellison, MD, Professor of Medicine & Public Health, Boston University School of Medicine, Boston, MA, USA

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

Ulrich Keil, MD, PhD, Professor Emeritus, Institute of Epidemiology & Social Medicine, University of Muenster, Germany

Dominique Lanzmann-Petithory,MD, PhD, Nutrition/Cardiology, Praticien Hospitalier Hôpital Emile Roux, Paris, France

Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa