Critique 125: Effects of alcohol consumption on risk of colorectal cancer; potential modification by folate intake — 25 September 2013

Nan H, Lee JE,  Rimm EB, Fuchs CS, Giovannucci EL, Cho E.  Prospective study of alcohol consumption and the risk of colorectal cancer before and after folic acid fortification in the United States.  Annals of Epidemiology 2013;23:558-563.

Authors’ Abstract

Purpose: To evaluate the influence of alcohol consumption on the risk of colorectal cancer according to folic acid fortification period in the United States.

Methods: We evaluated the association between alcohol consumption and colorectal cancer by fortification period (before 1998 vs. after 1998) in 2 prospective cohort studies, the Nurses’ Health Study (NHS) of women and the Health Professionals Follow-up Study (HPFS) of men, in which 2793 cases of invasive colorectal cancer were documented.

Results: Alcohol consumption was associated with an increased risk of colorectal cancer.  Among nonusers of multivitamins and/or folic acid supplements, the pooled multivariate relative risk for ≥ 30 g/d drinkers versus nondrinkers was 1.36 (95% confidence interval [95% CI], 1.09 – 1.70; P for trend, 0.02).  The effect of alcohol consumption was slightly stronger in the prefolic acid fortification period (1980 NHS/1986 HPFS-1998) than in the postfortification period (1998 – 2008); the pooled multivariate relative risks for ≥ 30 g/d drinkers versus nondrinkers were 1.31 (95% CI, 1.00 – 1.71; P for trend, 0.10) in the prefortification period and 1.07 (95% CI, 0.69 – 1.65; P for trend, 0.67) in the postfortification period.

Conclusions:  Folic acid fortification may attenuate the adverse effect of high alcohol consumption on the risk of colorectal cancer.

Forum Comments

Background:  Colorectal cancer is a very common type of malignancy, and even small beneficial or adverse effects from an environmental factor could affect large numbers of people.  Most studies, including both case-control and cohort studies, suggest a slight increase in the risk of colorectal cancers from even moderate drinking; in many of these studies, the increase in risk does not reach statistical significance.

In a recent large meta-analysis (Fedirko V, Tramacere I, Bagnardi V, Rota M, Scotti L, Islami F, Negri E, Straif K, Romieu I, La Vecchia C, Boffetta P, Jenab M.  Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies.  Annals of Oncology 2011;22:1958-1972), it was reported that light drinking (up to 12.5 g of alcohol/day, versus non/occasional drinking) had no effect on risk, but what was defined as “moderate drinking” (12.6-49.9g/day) was associated with an 8% increased risk for women and a 24% increased risk for men.  That meta-analysis does not permit an estimate of effect when “moderate drinking” is defined at lower limits.

It has been shown in many studies of breast cancer in women that the association with alcohol and the risk of cancer varies according to folate intake.  There appears to be an interaction between folate and alcohol, with an increase in risk of breast cancer only for women with low folate levels.  In a 2002 review, Giovannucci found an inverse association between folate intake and colorectal cancer (Giovannucci E.  Epidemiologic studies of folate and colorectal neoplasia: a review.  J Nutr 2002;132:2350S-2355S).  Further, it has been shown that the risk of colon cancer in men who consume alcohol and also have a low-methionine-low folate diet is much higher than in non-drinkers with higher intake of these nutrients (Giovannucci et al.  Alcohol, low-methionine-low folate diets, and risk of colon cancer in men.  J Natl Cancer Inst 1995;87:265-273).

The excellent paper by Lee et al (Lee JE, Willett WC, Fuchs CS, Smith-Warner SA, Wu K, Ma J, Giovannucci E.  Folate intake and risk of colorectal cancer and adenoma: modification by time. Am J Clin Nutr 2011;93:817-825) concluded that “folate intake is inversely associated with risk of colorectal cancer only during early preadenoma stages.”  Hence, it is reasonable that the present study sought to evaluate whether the relation of alcohol to colorectal cancer risk is different prior to and after 1998, when the US began to fortify many foods with added folate.

Specific comments by Forum reviewers on the present paper:  The authors of this paper conclude that “Folic acid fortification may attenuate the adverse effect of high alcohol consumption on the risk of colorectal cancer.”  However, their summary does not emphasize the lack of a clear dose-response curve between alcohol and cancer risk in either the prefortification period or the postfortification period.  For the highest category of alcohol consumption, the overall multivariable-adjusted RR for men and women not taking supplemental folate in the earlier period was 1.31 (95% CI 1.00-1.71); it was 1.07 (95% CI 0.69-1.65) in the postfortification period.  However, none of the RRs for other levels of alcohol intake showed a significant effect in either period.  In fact, the authors state further that alcohol consumption was not significantly associated with an increased risk of colorectal cancer in the postfortification period, and that the test for heterogeneity by period was not statistically significant (P-value 0.46).

The authors of the present study state: “We also examined drinking pattern in relation to colorectal cancer risk; neither frequency of drinking nor quantity of drinking was associated with the risk of colorectal cancer (data not shown).”  It is interesting to see that, in the postfortification period, the authors show that for the 5.0-9.9, 10-14.9, 15.0-29.9, and 30+ g/day alcohol intake categories, the multivariate-adjusted RRs were 1.21, 1.13, 1.11, and 1.07, respectively.  While none of the RRs was statistically significant, the trend of a decreasing, rather than an increasing, risk certainly does not support very much of an effect of alcohol on cancer risk.  Despite this finding, the authors begin their Discussion stating: “We found that the adverse effect of alcohol on colorectal cancer appeared to increase with greater intake of alcohol.”  Their results in the present paper do not provide much support for that statement.

Overall, despite the implications of the authors in their abstract and closing remarks, the data presented do not support a very important role for alcohol consumption in the etiology of colorectal cancer, regardless of the potentially modifying effects of folate.  As for such effects, at the end of the discussion, the authors admit that their study only “suggests the hypothesis that folic acid fortification may attenuate the adverse effect of high alcohol on colorectal cancer.”  As stated by Forum reviewer Troup, “Suggesting a hypothesis is one thing; validating it is another.”  Reviewer Finkel agreed, saying “the numbers are not strong.”

Reviewer Waterhouse believed that “the authors are being a bit disingenuous by not mentioning the weak p values for the trends of the dose response curve, especially during the postfortification period.  In fact, the data for this period suggest that folate fortification has diminished the relationship between high alcohol consumption and colon cancer such that it might not exist any longer.”  Waterhouse wished that the authors had presented more data on the various categories of alcohol intake used in their analyses; for example, it is not possible to know the number of serious alcohol abusers, or the pattern of drinking, among subjects in their top alcohol category.

Reviewer De Gaetano agreed that the data presented in this paper “do not support any statistically relevant role for alcohol consumption (at any dose) in the etiology of colorectal cancer, regardless of the potentially modifying effects of folate.  Are confidence intervals there for nothing?  An additional hypothesis, not tested by the present study, is that abnormal DNA methylation and gene expression due to folate deficiency may contribute to carcinogenesis, especially colorectal cancer and that folate supplementation might act (if it does…) by reducing abnormal DNA methylation.  The present paper does not add to nor reduce our knowledge of such a relation in this respect.”  Reviewer Skovenborg added that despite the lack of key findings in this study, “The hypothesis of an alcohol-folate-cancer interaction is interesting and the interaction has been found in breast cancer (Larsson SC et al. Folate and risk of breast cancer: A meta-analysis.  J Natl Cancer Inst 2007;99: 64-76).”

Reviewer Djoussé  added: “There is no evidence for dose-response, especially in men where data suggest threshold effect with elevated risk in heavy drinkers.  In women, there is no clear pattern, irrespective of folate fortification period.  For a number of alcohol categories, there are very limited events in some groups, making it more difficult to obtain stable estimates.  However, the conclusion of the authors is reasonable as it focuses on potential effect modification by folate in heavy drinkers.”

Is there potential harm from supplemental folate? Forum member Thelle reminded us that “Life is still more complicated!  I draw your attention to the paper by Ebbing et al (Ebbing M, Bønaa KH, Nygård O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njølstad I, Refsum H, Nilsen DW, Tverdal A, Meyer K, Vollset SE.  Cancer incidence and mortality after treatment with folic acid and vitamin B12.  JAMA 2009;302:2119-2126. doi: 10.1001/jama.2009.1622).”  That paper described results from two randomized, double-blind, placebo-controlled clinical trials in Norway, where there is no folic acid fortification of foods (the Norwegian Vitamin Trial and the Western Norway B Vitamin Intervention Trial).  A total of 6,837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005.  Subjects were followed up for cancer outcomes and mortality through the end of 2007.  These authors reported: “Treatment with folic acid plus vitamin B-12 was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease.”  Thelle adds: “These trials had nothing to do with alcohol, but a lot to do with folic acid.  Thus, I believe that a cautious attitude on this topic is warranted.”

Importance of studying gene-diet interactions:  Despite the problems with the analysis that have been described, Forum members Van Velden and Kotze considered this to be “an important paper because it sheds more light on the effect of abnormal DNA methylation and gene expression due to folate deficiency that may contribute to carcinogenesis, especially colorectal cancer.  The same association was found in breast cancer; alcohol is associated with risk of breast cancer in people with a folate deficiency since excessive intake may interfere with uptake of B-vitamins, especially in genetically predisposed individuals.”  Van Velden added: “Nutrigenetics that considers the role of gene-diet interaction is becoming increasingly important in understanding carcinogenesis due to environmental influences that may trigger variations in genes found to contribute to cancer development.  In our ageing population, we will find an increase in cancer, and diet factors, including alcohol consumption, will always be scrutinized for a possible carcinogenetic effect.”  According to Kotze, “Measurement of homocysteine levels may provide the best indicator to identify individuals at risk of cancer development; high levels reflect impairment of the methylation process caused by a combination of multiple genetic and environmental risk factors.”

While the hypothesis that folate intake reduces the risk of coloectal cancer associated with alcohol consumption is important, the present analyses have not provided very strong support for such an effect.  In the data presented in this paper for cancers occurring since 1998, when the US began to fortify food products to increase folate intake in the population, little effect of alcohol on colorectal cancer is evident, and even in the prefortification period, there is no dose-response curve for the relation of alcohol to colorectal cancer risk.

Forum Summary

Many epidemiologic studies have shown a small increase in the risk of breast cancer and colorectal cancer to be associated with alcohol consumption.  Some have found that higher intakes of folic acid may attenuate such an increase in risk.  The present study was designed to evaluate the influence of alcohol consumption on the risk of colorectal cancer according to folic acid fortification period in the United States.  The relation of alcohol intake to colorectal cancer in two prospective studies (the Nurses’ Health Study and the Health Professionals Follow-up Study) was compared for a prefortification period (before 1998) with such risk estimates during the postfortification period, which began in 1998.  A total of 2,793 cases of invasive colorectal cancer were documented.

The authors concluded that their data support an increase in colorectal cancer with high alcohol intake, and suggest that the risk may be lower in the postfortification period due to a higher folate intake in the US population.  Forum reviewers had some concerns about these conclusions, as they point out that no dose-response relation between alcohol and colorectal cancer was shown in either period, and in data since 1998 no significant relation is seen between alcohol and such cancers.  In fact, the authors of the present study state: “We also examined drinking pattern in relation to colorectal cancer risk; neither frequency of drinking nor quantity of drinking was associated with the risk of colorectal cancer;” they do not report their data upon which that statement is based.

Overall, the present paper does not answer the question as to the extent to which alcohol may relate to the risk of colorectal cancer, or if folate intake may modify any relation that may exist.  Given that colorectal cancer and breast cancer in women are so common, it is important to evaluate how dietary folate and other nutrients may relate to such cancers.  Further research on the relation of alcohol to these cancers, and potentially modifying factors, is greatly needed.

*                      *                      *

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

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

Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA, USA

Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia

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

Maritha J. Kotze, PhD, Human Genetics, Dept of Pathology, University of Stellenbosch, Tygerberg, South Africa

Creina Stockley, PhD, MBA, Clinical Pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia

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

Luc Djoussé, MD, DSc, Dept. of Medicine, Division of Aging, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark

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

Pierre-Louis Teissedre, PhD, Faculty of Oenology – ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France

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

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA