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. 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 aim to address this knowledge gap in a two-step process. Step 1 is a one year U34 planning grant during which we aim to develop the necessary study infrastructure, research protocols and documents in close collaboration with the NIDDK. Step 2 is a five year U01 multicenter randomized controlled trial to compare EET and endoscopic surveillance for the management of LGD. 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 defined patient-centered outcomes such as health-related quality of life between the two treatment groups. Specific Aim #3 will compare the performance of molecular (TissueCypher and p53 immunohistochemistry) and imaging (wide-area transepithelial sampling – WATS) biomarkers to conventional histologic assessment of dysplasia via forceps biopsy to improve risk-stratification in BE with LGD patients. Biological samples will also be obtained at study enrollment and during follow-up from all enrolled subjects 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, a cancer that has increased in incidence over the past four decades. Millions of dollars are spent yearly on the management of patients with BE and EAC. The impact of our innovative study will include identifying the best patient-centered treatment approach for BE patients with LGD, which will inform the care of thousands of patients annually.