Light Alcohol Drinking and Cancer

A Meta-Analysis

V. Bagnardi; M. Rota; E. Botteri; I. Tramacere; F. Islami; V. Fedirko; L. Scotti; M. Jenab; F. Turati; E. Pasquali; C. Pelucchi; R. Bellocco; E. Negri; G. Corrao; J. Rehm; P. Boffetta; C. La Vecchia

Disclosures

Ann Oncol. 2013;24(2):301-308. 

In This Article

Discussion

Quantitative estimates of the association between alcohol and cancer are mainly based on the effect of moderate to high intake, while little is known about light drinking. Our meta-analysis provided sufficient evidence that alcohol, even at low intakes, significantly increases the risk of oropharyngeal cancer, esophageal SCC and breast cancer. Albeit small in absolute terms, the estimated effects might be important at the population level because of the high prevalence of light drinkers. We estimated that in 2004, ~24 000 deaths from esophageal SCC, 5000 deaths from oropharyngeal cancer and 5000 deaths from breast cancer were attributable to light drinking worldwide.

The risk of cancer for alcohol drinkers may be modulated by genetic factors, such as variants in genes for alcohol metabolism, folate and methionine metabolism and DNA repair.[16,17]

Acetaldehyde, a toxic metabolite of alcohol that damages DNA, is considered a major cause of the observed carcinogenic effect on the upper aerodigestive tract. Ingested ethanol is oxidized by the enzymes alcohol dehydrogenase (ADH), cytochrome P-450 2E1 (CYP2E1) and catalase to form acetaldehyde, which is subsequently oxidized by aldehyde dehydrogenase 2 (ALDH2) to produce acetate, not toxic to the body. Polymorphisms of the genes that encode enzymes for ethanol metabolism affect the ethanol/acetaldehyde oxidizing capacity, and are responsible for the limited action of the enzyme that converts acetaldehyde to acetate.[18] As a confirmation to this, the risk of cancers of the upper aerodigestive tract associated with alcohol is highest in East Asia, where 28%–45% of the population has a variation of the gene ALDH2.[19,20]

The association between light alcohol drinking and the risk of oropharyngeal cancer was consistent across studies. On the other hand, estimates for esophageal SCC were heterogeneous by the geographical region; the risk for Asia was the highest and the only statistically significant risk (RR 1.49 (95% CI 1.12–1.98)). This can be explained by the fact that Asian populations have a higher prevalence of polymorphisms of the genes encoding enzymes for ethanol metabolism[19] than other populations.

This meta-analysis suggests that light drinking is not associated with the risk of laryngeal cancer (RR = 0.90, (95% CI 0.73, 1.10)). The estimates were homogenous among studies. The results from a recent pooled analysis of 15 case–control studies on the risk associated with alcohol drinking among never-smokers were similar to our findings: the RR estimate for less than one drink versus non-drinking was 0.92 (0.50–1.69).[21]

While excessive alcohol intake is a consistent risk factor for colorectal neoplasia,[22] we did not find a significant increase of risk of colorectal cancer due to low doses of alcohol. The association did not differ by colon and rectal subsites (data not shown), consistently with previous pooled analysis.[23,24]

These findings suggest that, even at low doses, alcohol increases the risk of cancer in those sites where there is direct contact with alcohol. This observation can be related to the local formation of acetaldehyde in the saliva via microbial ADHs.[25] Since metabolism of acetaldehyde to acetate by oral bacterial is limited, salivary acetaldehyde comes into direct contact with the mucosa of the upper digestive tract, resulting in mucosal hyperproliferation.[25,26] As a consequence of high acetaldehyde concentrations in hyper-regenerative environment, the generation of DNA adducts may be facilitated in these tissues.[27] Moreover, hyperproliferation itself increases susceptibility to other inhaled or ingested carcinogens.[6] As an example, a synergic effect involving alcohol and tobacco smoking was shown in the upper aero-digestive tract.[28,29]

There was a moderate but significant association with breast cancer, based on the results of more than 100 studies. Women drink less than men,[30] and therefore, low and moderate intakes are usually investigated more frequently and more in detail in women than in men.[31] The mechanism responsible for this association may involve increased estrogen and androgen levels[32,33] or increased levels of plasma insulin-like growth factors produced by the liver following consumption of alcohol.[34]

Alcohol intake has been recognized as a cause of several liver diseases, including cirrhosis and cancer.[35] However, no significant association was observed between light drinking and cancer of the liver (RR = 1.03, 95% CI 0.90–1.17). Given the association between heavy alcoholic beverage consumption and liver cancer, our results suggest the existence of a threshold dose below which the effect of alcohol is negligible.

Our study has several limitations. The first one is that the heterogeneity across studies reporting on esophageal, breast and liver cancer was high. Therefore, even if we used random-effects models to take heterogeneity into account, our pooled estimates should be interpreted with caution. We tried to overcome this problem by calculating pooled estimates in more homogeneous subsets of studies (subgroup analysis) and by additionally reporting pooled RRs of adjusted estimates only. A second limitation is that we could not investigate the role of different drinking patterns in modifying the effect of the total amount of alcohol consumed. In fact, the great majority of studies on the alcohol–cancer association reported information on the total amount of alcohol consumed during a period that includes both drinking and non-drinking days. A third issue is the possible interaction effect between alcohol consumption and tobacco smoking on the development of cancer. A simple yet effective way to clarify whether alcohol is an independent risk factor for cancer is to stratify the investigation by smoking status, but only a small number of studies reported the effect of light drinking in different smoking strata. A fourth limitation is the possible existence of publication bias. Anyway, the focus of many included studies was not only alcohol, so that in those studies data on alcohol were published even in the absence of significant findings. Also, the funnel plots and Begg's test did not reveal any evidence for publication bias for any cancer site. Finally, an under-reporting of alcohol consumption in drinkers may partly explain the association with light alcohol drinking. In fact, alcohol consumption might be systematically under-reported by both cases and controls (non-differential under-reporting). This would lead to an overestimation of the RR for low doses. However, studies investigating reproducibility and validity of self-reported alcohol drinking in various populations found generally satisfactory correlation coefficients.[36–41] Another problem regarding misclassification is the possible inclusion of former drinkers in the non-drinkers category. Subjects with cancer symptoms or signs might tend to stop drinking more frequently than controls, thus diluting the risk of cancer among current drinkers. We could not address this issue because the majority of the studies did not report separate estimates between former drinkers and lifelong never drinkers.

In conclusion, alcohol increases the risk of cancer of the oral cavity and pharynx, SCC of the esophagus and breast even at low doses. Given the high proportion of light drinkers in the population and the high prevalence of these tumors, especially of breast cancer,[42] even small increases in cancer risk are of great public health relevance.

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