In this large pooled analysis of over 15,000 participants in eleven studies of the BEACON consortium, we found no evidence for an association between higher alcohol intake and increased risk of EA or EGJA. Indeed, risks among alcohol drinkers tended to be below those among non-drinkers, albeit mostly statistically non-significant. We found no evidence that any particular type of beverage (beer, liquor, or wine) was especially associated with increased or decreased cancer risk. Further, we exploited the large numbers of cases and controls in the BEACON dataset to examine associations by stratum of sex, gastroesophageal reflux disease, cigarette smoking, and body mass index. Of the examined strata, alcohol intake was associated with increased EA risk in just one, women who drank ≥ 3 drinks per day. Given that the category comprised only 14 cases, the p-for linear trend was not significant, and no association was observed with less intake, with EGJA, or in men, we conclude that this single association is most likely a chance finding.
Our results for EA and EJGA stand in remarkable contrast to results for ESCC in this and previously published studies.[2
] The ESCC results, generated from the same studies as the EA and EGJA results, should allay concerns about non-differential misclassification of alcohol intake, recall bias, and reverse causation as explanations for our null findings. Associations between other environmental risk factors and esophageal cancer have also been shown to vary by histologic type. For example, higher body mass index is a consistent risk factor for EA but not ESCC risk.[23
] Cigarette smoking is a risk factor for both tumor sites, though the magnitude of the association appears greater for ESCC than EA.[6
] Distinct associations between Helicobacter pylori
infection and ESCC and EA risk have also been observed.[25
] Together with opposing incidence trends over time,[3
] these results indicate distinct etiologies for ESCC and EA.
In our study, the association for alcohol intake was generally similar for EA and EGJA. It is difficult to distinguish these sites clinically[26
] and whether the etiology of these sites are similar or different is unclear. Whereas EA were defined in our study as those above the esophagogastric junction, EGJA were more heterogeneous and included tumors overlapping the junction. Even so, results were generally similar for both endpoints and only modest heterogeneity was observed between studies which used distinct diagnostic criteria. Together, these data provide little evidence for an association between alcohol intake and increased risk of tumors either proximal or overlapping the esophagogastric junction.
We observed suggestive evidence that modest alcohol drinking, particularly less than one drink per day, might be associated with reduced EA and EGJA risk. Such findings may be due to chance, particularly as multiple comparisons were made. As in all observational studies, the observed inverse association with modest alcohol drinking may also reflect additional unknown or poorly measured confounders. For example, moderate alcohol drinking could be associated with aspects of a healthy lifestyle, such that the observed association reflects confounding. In our study, similar results were observed in smokers and in participants with a BMI between 18.5 to <25 and those with a BMI ≥ 25. Yet, other aspects of a healthy lifestyle could still be responsible for these findings.
Inverse associations may also reflect recall bias or reverse causality as nine of the eleven studies participating in Beacon had a case-control design. Patients diagnosed with cancer may alter their alcohol intake or their report of it. In addition, individuals with undetected tumors or their precursor conditions, such as gastroesophageal reflux, might avoid alcohol because it provokes symptoms. Supporting this hypothesis, reflux symptoms have been shown to be associated with less alcohol intake in past studies [13
Of the two participating prospective cohorts, results from the NIH-AARP Diet and Health study[6
] and the Kaiser-Permanente Multiphasic Health Checkup Study[20
] showed little evidence for an inverse association ( and ). Published results from two other cohorts are mixed. Risk estimates for EA were 1.17 (0.69-1.98) for drinking up to 5 grams (~ 1/3 a drink) per day and 0.91 (0.51-1.60) for 5-<15 grams (~ 1 drink) per day relative to non-drinking in the Netherlands Cohort Study.[11
] In the Million Women Study, risk estimates were 0.78 (0.61-0.99) for drinking ≤ 2 drinks per week relative to not drinking.[27
] Future prospective studies are needed.
Alternatively, inverse associations with moderate alcohol drinking may reflect contamination of the non-drinking referent group with formerly heavy drinkers. But, we found no evidence for increased cancer risk with higher alcohol intake in our study, even among those drinking ≥ 7 drinks per day, so contamination with heavy drinkers would not alter the associations in this manner. Furthermore, seven studies restricted the non-drinking category to those who reported never drinking alcohol.[7
] Inverse associations with modest alcohol drinking persisted in these seven studies ( and ).
It is also possible that these results reflect a true association. For example, ethanol intake may have beneficial effects on insulin resistance or levels of serum lipids and lipoproteins,[28
] which might be important for EA and EGJA risk. Also, wine,[29
] and to some extent beer,[30
] is thought to contain antioxidants which could affect cancer risk. Intriguingly, similar results have been observed for alcohol intake in two recent studies of Barrett’s esophagus,[13
] a precursor of EA.
One striking aspect of EA and EGJA epidemiology is the profoundly higher incidence in men relative to women.[3
] As such, previous studies have had little power to examine the association of alcohol with EA and EGJA in men and women separately. In sex-stratified analyses, we generally found comparable results between men and women, with the exception of EA risk among women drinking ≥3 drinks per day. As there were just 14 EA cases in this group, this result may be due to chance variation. Either way, since men typically drink more alcoholic beverages than women, our results suggest differences in alcohol use are very unlikely to explain differences in the incidence of these cancers between men and women.
Strengths of our study include its large size, inclusion of both population based case-control and cohort studies, inclusion of both histologic types of esophageal cancer and adjacent adenocarcinomas of the esophagogastric junction, and adjustment for major EA risk factors. We defined variables for alcohol intake in the same way for each study. Furthermore, risk estimates from each study were adjusted for a standard set of covariates. We also investigated risk estimate heterogeneity between studies. Alcohol intake was comprehensively assessed, with analyses of drinks per day, duration, drink-years, and beverage types. Furthermore, we exploited the large dataset to examine possible differences by major risk factors, including body mass index, cigarette smoking, and gastroesophageal reflux disease. Finally, we found similar risk estimates in studies performed in different regions of the world and with different study designs, adding credence to our findings.
Limitations include possible recall and selection bias, as most participating studies had a case-control design. However, results were generally similar for the two cohort studies. In addition, though our study is the largest to date, case numbers were small in some strata of the stratified analyses, such as women, and we lacked ability to assess associations in non-Caucasian ethnic groups.
In conclusion, in contrast to results for ESCC, we observed little evidence for an association between higher alcohol consumption with either EA or EGJA risk. Moderate alcohol consumption was associated with reduced EA and EGJA cancer risk, though these findings need to be examined further in future prospective cohort studies.