Stratification of Cancer Risk in Patients with Non-Dysplastic Barrett's Esophagus using TissueCypher: The SCRiBE study - Project Summary Barrett’s esophagus (BE), the condition in which an abnormal columnar mucosa replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease (GERD), is the only known precursor of esophageal adenocarcinoma (EAC), a deadly cancer whose incidence has increased more than eight-fold over the past 50 years. During this time, our primary strategy for preventing EAC deaths has remained essentially unchanged - using endoscopy to screen GERD patients for BE, and enrolling BE patients in a program of endoscopic surveillance. This stagnant strategy has failed to stem the rising frequency of EAC because current screening practices are inadequate, and because surveillance relies on finding dysplasia, a biomarker with considerable shortcomings, to trigger a cancer-preventive intervention. New screening tests are available that could profoundly increase identification of BE patients, but it makes little sense to expand screening efforts merely to enter more patients into expensive, ineffective surveillance programs. The TissueCypher BE Assay, which can detect precancerous molecular and cellular changes in BE biopsies without dysplasia, has the potential to be a precision risk-stratification test that could change the practice paradigm for BE patients. Retrospective, case-control studies, heavily enriched with patients who developed dysplasia and EAC, have shown that TissueCypher can identify BE patients at high and low risk for neoplastic progression. However, if TissueCypher is to be used clinically for risk stratification, then the promising results of these studies in a “cherry-picked” population of BE patients will need validation in a general population of patients with non- dysplastic BE (NDBE). Ideally, validation would be in the form of a randomized, controlled trial (RCT), but the large sample size and lengthy follow-up durations required for such a study on NDBE have been deemed untenable. Our proposed study utilizes an alternative, innovative design to assess TissueCypher’s predictive performance accurately without the untenable requirements of an RCT. We will use biopsy specimens already available in a large community GI practice to establish an unbiased study cohort of 2,000 consecutive patients who had baseline endoscopies with biopsies showing NDBE in 2008-2011, and who had ≥1 follow-up endoscopies performed up to December 2021. TissueCypher will be run on baseline biopsy specimens, and we will assess its performance in predicting neoplastic progression as identified in subsequent endoscopic biopsies. We also will determine if TissueCypher’s predictive performance can be improved by incorporating clinical variables and enhanced image analysis features. Validation of TissueCypher’s ability to risk-stratify BE patients could shift the BE clinical practice paradigm from one of expensive and ineffective endoscopic surveillance to one of precision medicine test-guided management with early intervention for high-risk patients and reduced surveillance for low-risk patients. This would justify expanding BE screening efforts, and could stem the rising frequency of EAC in a cost-effective manner.
