REVIEW article
Front. Oncol.
Sec. Gastrointestinal Cancers: Gastric and Esophageal Cancers
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1622984
This article is part of the Research TopicReal-World Clinical and Translational Research in Gastrointestinal CancersView all 12 articles
Multi-Analyte Liquid Biopsy Approaches for Early Detection of Esophageal Cancer: The Expanding Role of ctDNA
Provisionally accepted
Derek Tai1
Kareem Latif1
Pranati Shah1Daniel Park2
Christiana Crook3Sofia Guzman3Gagandeep Brar3Daneng Li3*
Dani Castillo3*- 1Department of Internal Medicine, Loma Linda University Medical Center (LLUMC), Loma Linda, United States
- 2Department of Medicine, University of California, San Francisco Fresno, Fresno, United States
- 3Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, United States
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Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for the early detection of esophageal cancer (EC), offering a minimally invasive means to assess tumor-derived genomic and epigenomic alterations. This review synthesizes current data on ctDNA biology, detection technologies, diagnostic performance, and clinical applicability in both esophageal adenocarcinoma and squamous cell carcinoma. We conducted a comprehensive literature review of PubMed-indexed studies on ctDNA in EC, emphasizing recent (January 1, 2019– December 31, 2024) findings, systematic reviews, and meta-analyses. Key data on ctDNA characteristics, diagnostic performance in both early-stage esophageal adenocarcinoma and squamous cell carcinoma, and clinical outcomes were extracted. We also discuss technical and clinical challenges in ctDNA assays and future perspectives for integrating ctDNA evaluation into clinical practice. We highlight technological innovations such as methylation profiling, fragmentomics, and ultrasensitive sequencing, and compare ctDNA-based approaches to alternative non-endoscopic modalities. While early studies report encouraging sensitivity and specificity for ctDNA in high-risk populations, specifically with methylation assays, current data remain limited by small sample sizes, retrospective design, low tumor DNA abundance, and heterogeneity in assay methodology. Furthermore, the clinical implementation of ctDNA-based screening must address population-level feasibility, cost-effectiveness, and health equity. We conclude that ctDNA holds significant potential for early EC detection but remains investigational pending validation in large prospective cohorts.
Keywords: CtDNA, esophageal cancer, Early detection, liquid biopsy, biomarker, Esophageal adenocarcinoma, esophageal squamous cell carcinoma, surveillance
Received: 05 May 2025; Accepted: 31 Jul 2025.
Copyright: © 2025 Tai, Latif, Shah, Park, Crook, Guzman, Brar, Li and Castillo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Daneng Li, Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, United States
Dani Castillo, Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, United States
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.