Abstract PR-03: A prospective study of systemic markers of inflammation and risk of esophageal adenocarcinoma in a Barrett's esophagus cohort
Authors: Hardikar Sheetal , Onstad Lynn , Blount Patricia , Reid Brian , Vaughan Thomas 
Published: June 2012

Abstract
Background: A sustained increase in incidence of and mortality from esophageal adenocarcinoma (EA) has been observed over the past four decades in many developed countries. Persons diagnosed with Barrett's esophagus (BE), a metaplastic condition that confers a 30- to 100-fold increase in EA risk, are typically followed in a surveillance program involving periodic endoscopy with biopsies, with relatively few progressing to EA. No medical, surgical or lifestyle interventions have been proven to safely lower risk of EA. Recently studies have shown that prediagnostic serum inflammation markers may be predictive of cancers of the breast, colon, lung and prostate, but their role in predicting EA is unknown.
Methods: We investigated whether elevated serum markers of chronic inflammation, including C-reactive protein (CRP), Interleukin-6 (IL-6) and surface tumor necrosis factor receptors I and II (sTNF-RI & sTNF-RII) could predict progression to EA in a cohort of 411 BE patients followed prospectively. Participants underwent periodic endoscopy with multiple biopsies, personal interview and blood draw. Levels of CRP, IL-6 and sTNF receptors were measured in stored plasma samples using high-sensitivity nephelometry, ELISA and multiplex assay, respectively. For most individuals, two measurements were available - at baseline and the first follow up visit. Their mean was used as the primary predictor. CRP measurements over 10 mg/L were considered to be indicative of acute inflammation and were excluded from the analysis. Adjusted Hazard ratios (HR) were estimated using Cox proportional hazards regression.
Results: Median age of the cohort was 61.2 years and 81.3% were males. Median plasma concentrations of all markers were higher among cases (n=56) than among non-cases (CRP 2.65 vs. 1.85 mg/L; IL-6 1.94 vs. 1.87 pg/ml; sTNF-RI 1753 vs. 1378 pg/ml; sTNF-RII 6296 vs. 5337 pg/ml). The main analyses focused on 397 persons with at least 5 months of follow-up (median 78.6 months, 33,635 person-months), in whom 45 developed EA. Elevated CRP was significantly associated with an increased risk of EA after adjustment for age and gender. With CRP modeled as a continuous variable, the HR comparing the 75th%tile vs. 25th%tile was 1.62 (p-trend=0.01; 95% CI 1.12–2.34). Further adjustment for the effects of waist-to-hip ratio, smoking and NSAIDS intake attenuated the association only slightly. Although we found that persons with IL-6 levels above the median had a two-fold increased risk for EA (HR 1.95; 95% CI 1.03–3.72), we did not observe evidence of a trend with increasing concentrations. Increased sTNF receptor levels were not associated with EA risk and we did not observe any trend with increasing sTNF concentrations.
Conclusions: Prediagnostic plasma CRP concentrations are predictive of neoplastic progression to cancer in persons with BE. Although there is some suggestion of increased risk with IL-6, there was no significant trend with increasing concentrations. We did not observe any association between levels of sTNF receptors with EA risk. These data support the hypothesis that inflammation may play a significant role in EA development among BE patients, and suggest that serum CRP may be useful in identifying persons at higher risk of progression to cancer. Continued follow-up of this and other larger cohorts is needed to further evaluate CRP and potentially IL-6 as tools for clinical risk stratification among BE patients.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):PR-03.