Liquid Biopsy and Nonendoscopic Biomarkers for Precision Early Detection of Esophageal Cancer: Evidence, Risk Stratification and Translational Challenges.

Esophageal cancer remains one of the most lethal malignancies worldwide, largely because most tumors are detected after symptoms develop. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) differ in epidemiology, precursor lesions and molecular biology, and therefore require subtype-specific early-detection pathways. This narrative critical review used a structured PubMed/MEDLINE search and classifies evidence by intended use: population risk triage for ESCC in high-incidence regions; targeted case finding for previously undiagnosed Barrett esophagus; surveillance and progression prediction in established Barrett esophagus; diagnostic evaluation of symptomatic or referred patients; and multicancer early-detection studies as indirect contextual evidence. We evaluate nonendoscopic cell-collection devices, cfDNA methylation and fragmentomics, mutation-based circulating tumor DNA assays, circulating RNA and extracellular vesicles, autoantibodies, metabolomic and microbiome signals, and clinical risk models. Although many clinically diagnosed or case-control series report high AUROC values, such estimates often overstate performance in asymptomatic populations, where low prevalence sharply limits positive predictive value. The most credible near-term role is calibrated, risk-stratified triage that concentrates endoscopy on individuals most likely to harbor early cancer or high-grade precursors. Increased detection yield, favorable modeling and implementation feasibility are not equivalent to clinical utility; utility requires evidence that biomarker-guided care improves meaningful outcomes at acceptable cost and harm. Integrated multiomic testing remains a proposed future strategy rather than a prospectively validated esophageal-cancer screening platform.