Abnormal TP53 predicts risk of progression in patients with Barrett’s esophagus regardless of a diagnosis of dysplasia

Abstract

ABSTRACTBarrett’s esophagus is the precursor to esophageal adenocarcinomas, which are deadly cancers with a rapidly rising incidence. A major challenge is identifying the small group with Barrett’s esophagus who will progress to advanced disease from the many who will not. Assessment of p53 status has promise as a predictive biomarker, but analytic limitations and lack of validation in large, definitive studies have precluded its use. In this study, criteria for abnormal immunohistochemical expression of p53 were developed in non-dysplastic Barrett’s biopsies and validated with sequencing to assess TP53 mutations. The utility of p53 expression as a biomarker for progression of Barrett’s esophagus was tested retrospectively in 561 Barrett’s patients with or without known progression. The findings were prospectively validated in a clinical practice setting in 1487 Barrett’s patients. Abnormal p53 expression highly correlated with TP53 mutation status (90.6% agreement) and strongly associated with neoplastic progression in the retrospective cohorts, regardless of histologic diagnosis (P<0.001). In patients with non-dysplastic Barrett’s esophagus at baseline, 89/179 (49.7%) of those with subsequent progression to high grade dysplasia/cancer and 3/179 (1.7%) of non-progressors had abnormal p53 (sensitivity: 49.7,% specificity: 98.3%, Odds ratio: 58 (95% CI 17.9-188.5, P<0.0001) for identifying progressors). In the prospective validation cohort, p53 immunohistochemistry predicted progression among non-dysplastic Barrett’s, indefinite for dysplasia, and low-grade dysplasia (P<0.001). p53 immunohistochemistry can successfully identify Barrett’s esophagus patients at high risk of progression, including in patients without evidence of dysplasia. p53 immunohistochemistry is inexpensive, easily integrated into routine practice, and should be considered in biopsies from all Barrett’s patients without high grade dysplasia or cancer.