Chhim A-S, Fassier P, Latino-Martel P, Druesne-Pecollo N, Zelek L, Duverger L, Hercberg S, Galan P, Deschasaux M, Touvier M. Prospective association between alcohol intake and hormone dependent cancer risk: modulation by dietary fiber intake. Amer J Clin Nutr 2015; pre-publication. Doi: 10.3945/ajcn.114.098418.
Background: Alcohol intake is associated with increased circulating concentrations of sex hormones, which in turn may increase hormone dependent cancer risk. This association may be modulated by dietary fiber intake, which has been shown to decrease steroid hormone bioavailability (decreased blood concentration and increased sex hormone–binding globulin concentration). However, this potential modulation has not been investigated in any prospective cohort.
Objectives: Our objectives were to study the relation between alcohol intake and the risk of hormone-dependent cancers (breast, prostate, ovarian, endometrial, and testicular) and to investigate whether dietary fiber intake modulated these associations.
Design: This prospective observational analysis included 3,771 women and 2,771 men who participated in the Supplémentation en Vitamines et Minéraux Antioxydants study (1994–2007) and completed at least 6 valid 24-h dietary records during the first 2 y of follow-up. After a median follow-up of 12.1 y, 297 incident hormone-dependent cancer cases, including 158 breast and 123 prostate cancers, were diagnosed. Associations were tested via multivariate Cox proportional hazards models.
Results: Overall, alcohol intake was directly associated with the risk of hormone-dependent cancers (tertile 3 vs. tertile 1: HR: 1.36; 95% CI: 1.00, 1.84; P-trend = 0.02) and breast cancer (HR: 1.70; 95% CI: 1.11, 2.61; P-trend = 0.04) but not prostate cancer (P-trend = 0.3). In stratified analyses (by sex-specific median of dietary fiber intake), alcohol intake was directly associated with hormone-dependent cancer (tertile 3 vs. tertile 1: HR: 1.76; 95% CI: 1.10, 2.82; P-trend = 0.002), breast cancer (HR: 2.53; 95% CI: 1.30, 4.95; P-trend = 0.02), and prostate cancer (HR: 1.37; 95% CI: 0.65, 2.89; P-trend = 0.02) risk among individuals with low dietary fiber intake but not among their counterparts with higher dietary fiber intake (P-trend = 0.9, 0.8, and 0.6, respectively). The P-interaction between alcohol and dietary fiber intake was statistically significant for prostate cancer (P = 0.01) but not for overall hormone-dependent (P = 0.2) or breast (P = 0.9) cancer.
Conclusion: In line with mechanistic hypotheses and experimental data, this prospective study suggested that dietary fiber intake might modulate the association between alcohol intake and risk of hormone dependent cancer.
The positive association between alcohol intake and certain hormone-dependent cancers (e.g., breast, prostate) noted in some studies has been attributed to the effect of alcohol through an increase in levels of estrogen and other hormones. Higher intake of alcohol has been shown to increase estrogen levels in women, although the effects of light drinking are less clear.
The present study had extensive dietary data on more than 5,000 men and women in France in a clinical trial of the effects of antioxidant vitamin supplementation for 8 years on the risk of cardiovascular disease and cancer developing during a 12-year follow-up period. Comparisons were made between the sex-specific tertile of alcohol intake (≤3.0, >3.0 – 12.1, >12/1 grams/day for women; ≤ 15.3, >15.3 – 35.4, >35.4 g/day for men). The authors report that, in comparison with the lowest tertile of alcohol intake, the risk of any hormone-dependent cancer among men and women was higher in tertile 2 (adjusted HR 1.52, 95% CI 1.13-2.04) and higher in tertile 3 (HR 1.36, CI 1.00 – 1.84).
The key results reported by the authors are that when the risks of cancer were related to alcohol while adjusting for fiber intake, subjects whose fiber intake was below the median value showed higher risks of cancer related to alcohol than subjects with higher fiber intake. For example, when the risk of breast cancer in women was related to the tertile of their alcohol intake, the 2nd tertile showed a HR of 1.55 (1.01 – 2.38) and the 3rd tertile a HR of 1.70 (CI 1.11 – 2.61), when compared with women in the lowest tertile. For prostate cancer in men, however, there was not a linear increase, as the 2nd tertile showed a HR of 1.28 (CI 0.82 – 2.00) and the 3rd tertile a HR of 0.89 (CI 0.55 – 1.45), neither statistically significant.
The interaction terms between alcohol intake and cancer were not significant for all hormone-dependent cancers or for breast cancer. Only the interaction term for prostate cancer reached statistical significance, but here the relationship between tertile of alcohol intake among subjects with low dietary fiber did not show a clear dose response: the HR for the 2nd tertile of alcohol versus the 1st was 2.45 (CI 1.23 – 4.87), and for the 3rd tertile the HR was 1.37 (CI 0.65 – 2.89). Thus, there was not a clear-cut message from the data. Nevertheless, the authors conclude that fiber intake modulates the effect of alcohol on hormone-dependent cancers, and that several risk factors may cumulate and act in synergy to increase cancer risk.
Specific comments on paper by Forum members: Reviewer Ellison noted: “There was no reference to folate levels in this paper, despite the fact that earlier studies have shown that low folate increases the risk of certain of these cancers. Also, the subjects were involved in a clinical trial in which they were given a placebo or a combination of vitamins C, E, beta-carotene, selenium, and zinc, but no comments were given regarding the potential effect of any of these.”
An invited comment from former Forum member Roger Corder stated: “It’s conceivable that higher dietary fibre intake is just an indication of higher dietary folate, i.e., consistent with other studies showing high folate confers protection from alcohol-related cancers.” Forum member Stockley agreed that folate may be a factor. Reviewer Skovenborg stated: “I also agree with Corder that fiber consumption may be a proxy marker of folate intake. And folate is just one of several possible confounders. People with a high intake of fiber may have a regular consumption of moderate amounts of alcohol/wine with meals as opposed to the participants with small fiber intake, who might prefer beer/spirits, prefer drinking without food and prefer drinking during the weekend. The paper has no information about drinking patterns in this study.” Reviewer Lanzmann-Petithory commented: “Fiber is not homogeneous: soluble, non-soluble, different sources with different cancer correlation. In addition to the potential mechanisms of effect regarding the gut described in the paper, there are many other factors affecting intestinal flora. Unfortunately, there are just too many confounders to allow us to reach clear conclusions.”
Forum member Zhang had several concerns about the paper: “It is unclear from the paper whether the ‘follow-up period’ began after the 2-year period during which food diaries were initially collected, which would be correct, or at the beginning of the study. Further, when stratified by median levels of fiber intake, the number of cases of cancer is relatively small. Sometimes there is no indication of trend, but test for trend of alcohol tertile and cancer risk is statistically significant, which is a little bit strange. For example, there was no dose-response relation of alcohol consumption and risk of all hormone-dependent cancer and prostate cancer among those whose fiber intake was below the median, but test for trend was statistically significant. Finally, using the tertile of alcohol as an ordinal variable for testing for trend is also problematic, and few people use this method. The preferred method is to use either the real value of alcohol or the median value of alcohol from each tertile group.”
Reviewer Finkel was also worried about the analytic approach used in this paper: “How do the authors know whether any, and which, of the cancers in question are alcohol related, or hormonally related? They seem to me to be mining data that is being contorted to fit another paper. They repeat the mistake of too many others of relying on data that they’d like to see as statistically significant. One sets up statistical standards a priori and sticks to them, come what may.” Forum member de Gaetano agreed with Finkel, and added: “Unfortunately, the numbers of tumors for each of the sub-groups were too small to give meaningful results.” Added Skovenborg: “I agree with the caveats mentioned so far: there are problems from the small number of cases in sub-groups and lack of statistical significance.”
The positive association between alcohol intake and certain hormone-dependent cancers, especially breast cancer) noted in many studies has been attributed to an effect of alcohol through an increase in levels of estrogen and other hormones. The present study had extensive dietary data on more than 5,000 men and women in France, among whom comparisons were made between the sex-specific tertile of alcohol intake and the risk of hormone-related cancers (breast, prostate, ovarian, endometrial, and testicular).
The study found that, overall, the risk of some cancers (e.g., breast) but not others (e.g., prostate) were positively related to reported alcohol intake. The key results reported by the authors are that when the risks of cancer were related to alcohol while adjusting for fiber intake, subjects whose fiber intake was below the median value showed higher risks of cancer related to alcohol, but not subjects with higher fiber intake. For example, when the risk of breast cancer in women was related to the tertile of their alcohol intake, the 2nd tertile showed a HR of 1.55 (1.01 – 2.38) and the 3rd tertile (HR 1.70, CI 1.11 – 2.61), when compared with women in the lowest tertile.
For prostate cancer in men, however, the 2nd tertile showed a HR of 1.28 (CI 0.82 – 2.00) and the 3rd tertile a HR of 0.89 (CI 0.55 – 1.55). The interaction terms between alcohol intake and cancer were not significant for all hormone-dependent cancers or for breast cancer. Only the interaction term for prostate cancer reached statistical significance, but here the relationship between tertile of alcohol intake even among subjects with low dietary fiber did not show a clear dose-response relation.
Forum members had concerns about the large number of potential confounders in these analyses (e.g., different effects for different types of fiber, the intake of fiber being just a marker for folate intake or for other dietary or lifestyle factors), that made it difficult for the authors to reach firm conclusions. Unfortunately, the numbers of tumors for each of the sub-groups were often too small to give meaningful results. And there was no data on alcohol drinking pattern (regular moderate versus binge drinking) or type of beverage consumed. Thus, while this study indicates that alcohol intake may relate to certain hormone-dependent cancers, the analyses do not present a clear demonstration as to whether it is fiber intake or some other related factor that may modify the association.
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Contributions to this critique by the International Scientific Forum on Alcohol Research were provided by the following members*:
Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy
R. Curtis Ellison, MD. Section of Preventive Medicine & Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
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
Creina Stockley, PhD, MSc Clinical Pharmacology, MBA; Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia
Dag S. Thelle, MD, PhD, Senior Professor of Cardiovascular Epidemiology and Prevention, University of Gothenburg, Sweden; Senior Professor of Quantitative Medicine at the University of Oslo, Norway
Yuqing Zhang, MD, DSc, Clinical Epidemiology, Boston University School of Medicine, Boston, MA, USA
*Also included in this review was an invited comment from Roger Corder, Professor of Experimental Therapeutics, Centre for Translational Medicine and Therapeutics Barts and The London, Queen Mary’s School of Medicine and Dentistry in London, UK.