Role of liquid biopsy in the multimodal assessment and treatment of esophageal cancer: a surgical perspective

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Abstract Esophageal cancer (EC) remains a highly lethal malignancy, characterized by late diagnosis, early systemic dissemination, and high recurrence rates. Conventional diagnostic and surveillance strategies have limited sensitivity for early disease detection and minimal residual disease. Liquid biopsy technologies have emerged as promising minimally invasive tools for diagnosis, prognostication, and longitudinal monitoring. This scoping review summarizes current evidence on the clinical utilization of liquid biopsies in esophageal squamous cell and adenocarcinoma. PubMed, EMBASE and Cochrane Library were queried. Inclusion criteria encompassed studies investigating the use of liquid biopsy for EC diagnosis, treatment response evaluation, and prognosis definition. A total of 73 studies reported the role of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), or microRNAs (miRNA). The majority (59%) focused on ctDNA while CTC and miRNA were assessed in 12 and 14 studies, respectively. The reported pooled diagnostic sensitivity and specificity was 71% and 98.6%, respectively, with superior performance in advanced stages (III-IV). Serial ctDNA measurements during neoadjuvant therapy have been reported useful for assessing tumor burden reduction. Additionally, comprehensive ctDNA profiling proved valuable for analysis of tumor heterogeneity and actionable genetic alterations suitable for targeted treatment therapies. Elevated preoperative ctDNA levels correlated with an increased risk of nodal metastasis and postoperative cancer recurrence. ctDNA was also identified as a useful prognostic marker, demonstrating sensitivity and specificity of 49% and 95%, respectively, for survival prediction. Despite limitations related to the various methodologies employed and the lack of laboratory standardization, liquid biopsy constitutes a promising frontier in the surgical management of EC, offering minimally invasive, real-time tool for assessing tumor genetics, genomic heterogeneity, and dynamics of tumor progression. It might enhance early diagnosis, inform neoadjuvant treatment response, and enable postoperative surveillance for residual or recurrent cancer.