Combination of hormone treatments and alcohol consumption influences the risk of breast cancer in women
Horn-Ross PL, Canchola AJ, Bernstein L, Clarke CA, Lacey JV, Neuhausen SL, Reynolds P, Ursin G. Alcohol consumption and breast cancer risk among postmenopausal women following the cessation of hormone therapy use: the California Teachers Study. Cancer Epidemiol Biomarkers Prev 2012. [Epub ahead of print]
Background: Alcohol consumption increases breast cancer risk, but its effect may be modified by hormone therapy (HT) use, such that exposure to both may be synergistic. Because many women stopped taking HT after mid-2002, it is important to quantify risks associated with alcohol consumption in the context of HT cessation, as these risks may be more relevant to cancer prevention efforts today.
Methods: Among 40,680 eligible postmenopausal California Teachers Study cohort participants, 660 were diagnosed with invasive breast cancer before 2010. Multivariate Cox proportional hazards regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI).
Results: Increased breast cancer risk associated with alcohol consumption was observed among postmenopausal women who were current HT users (RR=1.60, 95% CI: 1.13-2.26 and RR=2.11, 95% CI: 1.41-3.15 for <20 and ≥20 g/d of alcohol), with risks being similar by HT preparation. Alcohol did not increase risk among women who had stopped using HT within 3 years or 3-4 years before completing the follow-up questionnaire or in the more distant past. Results were similar for ER+ and ER+PR+ tumors; while power was limited, no increase in risk was observed for ER- tumors.
Conclusions: Following the cessation of HT use, alcohol consumption is not significantly associated with breast cancer risk, although a non-significant increased risk was observed among women who never used HT. Our findings confirm that concurrent exposure to HT and alcohol has a substantial adverse impact on breast cancer risk. However, after HT cessation, this risk is reduced.
Background: The majority of epidemiologic studies in recent years have supported the early findings of Willett and coworkers1 and Longnecker2 that breast cancer risk is greater among women who consume alcohol than among abstainers, although there have been some notable exceptions to such an association (such as results from the Framingham Study3,4). An initial report from the Women’s Health Initiative–Observational Study (WHI-OS)5 described a slight non–dose-dependent increase in risk of breast cancer for consumers of alcohol. In comparison with no alcohol, in that large study the adjusted relative risk for up to 5 g of alcohol per day (less than 1/2 of a typical drink) was 1.10 (95% CI, 0.97-1.24); for 5 to 15 g/day, the relative risk was 1.14 (95% CI, 0.99-1.31); and for >15 g/day, it was 1.13 (95% CI, 0.96-1.32).
In meta-analyses, the estimated increase in risk of breast cancer for the average consumption of one drink per day is usually between 6% and 15%. Stronger associations appear to be more common in hospital-based case-control studies than in cohort studies or community-based case-control studies, in studies published before 1990 than in studies published later, in studies with shorter follow-up periods, and in studies conducted outside of the United States than in US studies.6
Some studies have shown that the risk of breast cancer among drinkers appears to be greater among women who also are taking hormone replacement therapy (HT), are binge drinking, or are low in folate intake.7-9 As summarized by Forum reviewer Stockley, “Accumulating data suggests that alcohol consumption is most strongly associated with the risk of breast cancers that are hormonally responsive, such as lobular (5-10% of all cancers) and hormone receptor positive tumors (estrogen receptor positive (ER+), such as ER+PR+ and ER+PR- subtypes) (66%).10,11 The suggestion of a further increased risk of breast cancer by post-menopausal woman who use estrogen replacement therapy and who are also light to moderate consumers of alcohol remains controversial.”8,12
Given than the use of HT has greatly diminished within the past decade, the present paper is of particular interest as it provides data on the risk of invasive cancer among women who have stopped taking HT.
Comments on the present paper: The key results of this paper suggest that the risk of breast cancer associated with alcohol is diminished for women who no longer take HT. As stated by the authors, “Alcohol consumption of <20 g/d at follow-up was not associated with breast cancer risk overall or when stratified by time since HT cessation, with the exception of an increase in risk among current HT users (RR=1.60, 95% CI: 1.13-2.26). Women who had stopped using HT before follow-up were not at increased risk even when consuming ≥20 g/d of alcohol.”
Forum reviewer Gretkowski commented: “This study suggests what others have intimated before: the potential additive or synergistic effect of alcohol and its potential role as a phytoestrogen with the use of hormone replacement therapy in menopausal women. It supports a large part of the data with respect to higher rates or ER+ or PR+ or ER+/PR+, but no necessary association with triple negative cancers and DCIS. No information was provided on Her 2 neu cancers.
“The SEER data base is a highly reliable resource for oncology reporting. Methods of data collection for types of alcohol are well-delineated, types of estrogen replacement/HRT less so. Transdermal vs. oral use may alter this association and should be studied. It is interesting that the lower BMI cohort in the California teachers vs. the Women’s Health Initiative (WHI), which was from a national group, suggested that these were the patients at the greatest risk for this synergistic or additive effect. Is this potentially related to receptor saturation by peripheral production of estrogen in adipose tissue? In any case, the present study continues to support the role for limited use of hormone replacement therapy in only truly symptomatic women at the lowest doses for the shortest period of time, knowing that the average patient is most likely to succumb to heart disease than to breast cancer.”
Reviewer Waterhouse stated: “I am intrigued by the difference between never HT subjects and former HT subjects in this study. Never subjects seemed more at risk from alcohol use than former users. Could it be that former HT subjects had lower ‘natural’ hormone levels after menopause, thus the initiation of therapy with HT?” We have no data on why certain women, but not others, ended up receiving HT therapy (which could have related more to the health-care providers than to the women themselves).
Conflicting results among epidemiologic studies: Forum reviewer Finkel conveyed some of the confusion of other reviewers on this topic: “The role of alcohol in the genesis of breast cancer has continued to be confusing, even conflicted. There must be subsets of individuals not yet precisely dissected out that contribute to the differences among the results from epidemiologic studies. One could hope that studies such as the present one will help, although we are clearly not nearly ready to write down a standard theory. Researchers should be careful to refrain from drawing conclusions, even while claiming not to, from insignificant differences.”
Reviewer Van Velden agrees that “there is confusion about a possible interaction of alcohol and HT in affecting the risk of breast cancer.” He adds: “An interesting paper is the report on patterns of alcohol (especially wine) consumption and breast cancer risk; a case-control study among a population in Southern France found that low and regular wine consumption does not increase breast cancer risk.”13
Reviewer Waterhouse points out that the authors cite two studies that have previously evaluated cancer risk among drinkers according to previous or current hormone therapy, that of Lew et al14 Chen et al.15 As have so many other studies, these had divergent results.
Forum member Skovenborg described the results of the Million Women Study16 in which “alcohol consumption was associated with a 12% (9-14%) increase in relative risk of breast cancer per 10 g/day even with HT included in the equation as a confounder. On the other hand, a meta-analysis of the worldwide data from 50 studies17 did not show an interaction between the effects of hormone therapy and alcohol consumption with respect to breast cancer risk.” Thus, there is conflict even among studies based on very large groups of subjects. Skovenborg adds: “Nielsen and Gronbaek8 found that women who used hormones also had a higher risk of breast cancer compared to non-hormone users; 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).”
The bottom line is that we have very poor predictors of breast cancer, with some increase in risk for women with a family history of such cancers and those who are obese. However, the percentage increase in risk associated with HT, alcohol consumption, and with other environmental factors is generally small (unlike the many-fold increase in the risk of lung cancer among smokers). This may explain why the results of individual studies may reach apparently conflicting conclusions. Even with large datasets, such as used in the present analyses, the interpretation of results that do not reach statistical significance as “negative” or “no effect” may further complicate comparisons among studies.
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An analysis among more than 40,000 postmenopausal women who were in the California Teachers Study was carried out to determine if there were differences in risk of breast cancer among women consuming alcohol according to their previous or current use of hormone therapy (HT). In the cohort, 660 women were diagnosed with invasive breast cancer during follow up.
Results from multivariate Cox proportional hazards regression models showed an increase in risk of breast cancer among alcohol consumers of more than 20 grams of alcohol per day (about 1.5 to 2 typical drinks) who were current users of HT but not among those who were ex-users of HT. The authors conclude: “Following the cessation of HT use, alcohol consumption is not significantly associated with breast cancer risk, although a non-significant increased risk was observed among women who never used HT. Our findings confirm that concurrent exposure to HT and alcohol has a substantial adverse impact on breast cancer risk. However, after HT cessation, this risk is reduced.”
Forum reviewers considered this to be a very well-done analysis on a large group of post-menopausal women with repeated assessments of alcohol consumption and HT use. However, results from even very large studies on the relation between alcohol, HT, and breast cancer risk have often been conflicting. Even with numerous studies on this topic, we still have very poor predictors of which women will develop breast cancer. There is some increase in risk for women with a family history of such cancers and those who are obese who also drink. However, the percentage increases in risk associated with HT, alcohol consumption, and other environmental factors are generally small (unlike the many-fold increase in the risk of lung cancer among smokers in comparison with never smokers). This may explain why the results of individual studies may reach apparently conflicting conclusions. While the present study suggests that women who consume alcohol may have a decrease in their risk of breast cancer if they stop taking hormone replacement therapy, our current understanding of factors affecting breast cancer risk remains quite inadequate.
Comments on this paper were provided by the following members of the International Scientific Forum on Alcohol Research:
Lynn Gretkowski, MD, Obstetrics/Gynecology, Mountainview, CA, Stanford University, Stanford, CA, USA
Creina Stockley, PhD, MBA, Clinical Pharmacology, Health and Regulatory Information Manager, AWRI, Australia
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
Andrew L. Waterhouse, PhD, Marvin Sands Professor, University of California, Davis; Davis, CA, USA
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
Francesco Orlandi, MD, Dept. of Gastroenterology, Università degli Studi di Ancona. Italy
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA