Project Summary/Abstract Barrett's esophagus (BE), a metaplastic change of the esophageal lining associated with chronic gastroesophageal reflux disease, is the only known precursor to esophageal adenocarcinoma (EAC). EAC is one of the most rapidly increasing cancers in the United States, frequently presenting at an advanced stage and associated with a dismal 5-year survival rate. Endoscopic eradication therapy (EET) is the standard of care for patients with BE and high-grade dysplasia (HGD) or mucosal EAC. However, a central unresolved issue is whether BE patients with low-grade dysplasia (LGD) benefit from EET. The diagnosis of LGD is far more common than HGD and is associated with a lower risk of EAC, so it is unclear whether the costs and complications of EET are justified in this group of patients or whether they should simply continue with periodic surveillance endoscopy. The presence of clinical equipoise and the importance of this question indicates that a trial of endoscopic surveillance versus EET in this patient population is an urgent, unmet gap in our current knowledge regarding treatment of this common condition. We are uniquely positioned to address this significant gap in knowledge as we have assembled a multidisciplinary team with the requisite expertise in the conduct of clinical trials and biomarker research to ensure successful design and high-quality execution of the SURVENT trial (Surveillance versus Endoscopic Therapy for BE with LGD). This multicenter randomized controlled trial (n=530) will compare endoscopic surveillance and EET for the management of LGD using uniform inclusion criteria, design and endpoints. This trial will also include an observational cohort arm for those who decline randomization but are otherwise eligible (up to 150 subjects). Following our achievements during the U34 grant period, we propose the following aims for the U01: Specific Aim #1 will compare the two approaches using the primary endpoint of neoplastic progression rate (progression to HGD or mucosal or invasive EAC). Specific Aim #2 will compare patient-centered outcomes such as health-related quality of life between the two treatment groups. Specific Aim #3 will determine the utility of molecular (TissueCypher and p53 immunohistochemistry) and imaging (wide-area transepithelial sampling – WATS) biomarkers to improve risk-stratification in BE with LGD patients undergoing surveillance and EET. Biological samples will also be obtained at pre-specified time points to establish a biorepository for future translational research initiatives. The relevance of this work to the public health is high. BE is a common condition, affecting 2-3% of adult US population and LGD is seen in up to 40% of BE patients. This is a precursor for EAC and millions of dollars are spent yearly on the management of BE and EAC patients. The impact of our innovative study will include identifying the best patient-centered treatment approach for BE patients with LGD, whic...