This prospective cohort study is one of the first to examine the independent and joint associations between cigarette smoking, alcohol, BMI and central adiposity and risk of neoplastic progression among persons diagnosed with BE. We observed a statistically-significant dose-response relationship with pack-years of smoking and smoking duration, but no apparent beneficial effect of smoking cessation. No evidence was found that alcohol consumption increased EA risk, when tested as total alcohol intake or by individual beverage type. We also found no indication that BMI was predictive of EA development. Rather, we found suggestive evidence that measures of central (abdominal) obesity, including WHR, waist and abdominal circumference, may modestly increase EA risk. The non-statistically significant increases we observed were stronger among males.
Cigarette smoking has long been known to be a major risk factor for esophageal squamous cell carcinoma; early reports examining the histology-specific relative risk estimates indicated a significant, but more modest role for smoking in EA 
. Subsequent population-based case-control and cohort studies and a large pooled analysis based in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) have since confirmed an approximately two-fold increase in risk among ever-smokers, with a strong and significant dose-response relationship with cumulative exposure, yielding a relative risk estimate of 2.7 (95%CI 2.2–3.4) among those with 45 or more pack-years of smoking 
The above studies examine the overall effect of smoking on EA development. Several case-control studies have also examined the association between smoking and development of BE, representing an intermediate stage in EA development 
. Three of these studies have observed statistically significant increases in risk among those in the highest cumulative exposure (pack-years) category, ranging from 1.7 to 2.5 
whereas a fourth 
observed a more modest and non-significant 30% increased risk.
Our results, which indicate that high cumulative smoking exposure also raises risk of neoplastic progression from BE to EA (adjusted HR
2.3), begin to fill in some gaps with regard to the overall role of smoking in EA development and the stages at which it acts among those already diagnosed with BE. Specifically, it appears that cigarette smoking likely plays roles of similar magnitude in both the development of BE and progression from BE to EA. This observation is in line with a recent study by Coleman et al.
that reported a 2-fold increase in EA risk associated with current smoking among patients with BE 
. The frequent observation that smoking cessation reduces EA risk only modestly and after many years is also consistent with a role of smoking in BE development, which can occur decades before EA diagnosis 
. The specific mechanisms by which smoking increases risk of both development of BE and progression from BE to EA are unknown, but may be a combination of exposure to chemicals such as N-nitrosoamines 
, the promotion of GERD through the relaxing effects of tobacco smoke on the lower esophageal sphincter 
, and the continued inflammatory effects of smoking which promote cellular proliferation 
As with smoking, alcohol consumption is a strong established risk factor for esophageal squamous cell carcinoma 
. In contrast, there is little evidence to suggest that total alcohol consumption, or specific alcoholic beverages, modifies risk of EA in the general population. A pooled analysis of 1,821 EA cases and 10,854 controls in BEACON revealed an odds ratio of 0.97 (95%CI 0.68–1.36) among the heaviest drinkers, in marked contrast to the association with esophageal squamous cell carcinoma (odds ratio
9.62; 95%CI 4.26–21.71) observed in the same analysis 
. Fewer studies have examined the relationship between alcohol intake and risk of BE in the general population, but these also suggest no relationship 
. There is little previous data examining the possible role of alcohol in the progression from BE to EA. However, our study, in combination with the large pooled analysis of EA risk in population-based studies, indicates that alcohol intake should not be a target for prevention activities.
The important role that obesity plays in EA development was recently summarized by Lagergren et al.
, and has been confirmed in numerous population-based case-control and cohort studies 
. Case-control studies generally rely on recalled height and body-weight at various points in participants' lives, since anthropometric measurements after cancer diagnosis will often be modified by the cancer's wasting effects; therefore they cannot address the relative importance of weight (or BMI) and central adiposity. One cohort study with multiple pre-cancer measurements available found similar increased risk for BMI, WHR, waist circumference and fat mass 
. However this study was limited by the small number of cancers observed, necessitating the combination of gastric cardia (n
19) and EA (n
11) in the analyses. Another cohort study had pant/skirt size available as proxy measures for waist circumference. Both BMI and pant/skirt size were significantly associated with risk of EA when analyzed separately; models adjusted for both factors suggested that BMI was more important although neither of the trend tests were significant 
. Similarly, results from the EPIC cohort suggest that both BMI and abdominal obesity are important in EA development 
. Case-control studies of BE as an outcome generally indicate that measures of abdominal obesity outweigh BMI in terms of strength of association with BE 
. Similar results were observed in a nested case-control study within a large cohort with pre-diagnostic measures of abdominal diameter 
, and a small clinical study where visceral fat was measured using computerized tomography 
Thus the relative roles of increased weight per se
and abdominal obesity remain unclear. Overall, previous studies suggest that the effects of abdominal obesity are relatively strong with regard to the development of BE, and predominate over BMI. The present study suggests that, with regard to neoplastic progression to EA in persons with BE, the effects of abdominal obesity also predominate over BMI, but are more modest in their strength. There are several potential mechanisms which may be involved. First, deposition of abdominal fat may lead to increased intra-abdominal pressure which may directly cause gastro-esophageal reflux, a well-established risk factor for BE and EA 
. Second, adipose tissue is metabolically active, secreting pro-inflammatory cytokines and adipokines, which can promote cellular proliferation, reduce apoptosis, and trigger neoplastic transformation in the esophageal epithelium 
from the present report are consistent with a previous case-control study that suggested the relationship between obesity and EA may depend on the smoking status and age of the individual, with increased association between EA risk and obesity among non-smokers and younger individuals 
. It is notable that the gender differences in EA risk observed in this study are consistent with the known demographics of the disease and can partly be explained by the characteristic abdominal distribution of fat seen in males as well as increased prevalence of smoking among males.
Our study has several strengths, the most important one being its prospective design. Additionally, misclassification of exposure status was minimized by measurement of central adiposity by trained staff, in contrast to use of self-reported data limited to BMI in some previous studies. Comprehensive information on various parameters of smoking and alcohol consumption before occurrence of EA enabled us to characterize these behaviors adequately and limit confounding. In main analyses, we also excluded cases of EA that occurred within the first 5 months of follow-up, thus minimizing potential bias by reverse causation, contrary to some previous studies that were unable to account for this bias 
While substantially larger than other well-characterized prospective cohort studies with anthropometric measures, the relatively small number of incident cases is an important limitation, leading to imprecise estimates, especially for the evaluation of effect modification. Additionally, we will not have captured all the incident cases of EA that occurred among our participants as follow-up ended with cessation of active surveillance. As some of the cohort members were being followed prior to 1995 (baseline evaluation for the purposes of this manuscript), our analyses included a mix of prevalent and incident cases of BE. This is a limitation of most studies of BE, as BE is an endoscopic diagnosis and the exact date of disease is rarely known. Another potential limitation is the possibility of residual confounding due to measured or unmeasured risk factors. In particular, we lacked data on Helicobacter pylori
status, which could possibly confound the WHR-EA association. Not only has H.pylori
been shown to decrease body weight by suppressing appetite, but it is also been observed in multiple population-based studies to be inversely related to risk of EA 
. Finally, as our participants are from a specialized and relatively high-risk cohort of persons with histologically confirmed BE, the results presented in this report cannot necessarily be generalized to persons with BE in the general population or considered to be representative of the natural history of EA. Rather these estimates should be interpreted as describing the risk of progression to EA once diagnosed with BE.
In summary, we observed a statistically significant dose-response relationship with cigarette smoking pack-years as well as duration. We did not observe any association with alcohol intake or BMI. We also found that abdominal obesity, measured as WHR, may be modestly useful in predicting neoplastic progression to EA among Barrett's patients, especially among males. Further epidemiological studies with larger number of EA cases are required to validate these findings, especially among subgroups of people with BE in order to better understand the mechanisms by which tobacco and perhaps obesity increase the risk of neoplastic progression among Barrett's esophagus patients and their potential role in EA prevention.