Breath- and blood-based molecular assessment for gastroesophageal cancer

Gastroesophageal cancer remains a significant health care problem characterized by diagnosis at advanced stages, rendering a significant proportion of patients ineligible for curative treatment. Conversely, early diagnosis and treatment of gastroesophageal cancer demonstrates markedly improved outcomes, with 5-year overall survival rates ranging from 83% to 96%. To date, gastroesophageal cancer surveillance primarily focuses on patients with Barrett's esophagus, relying on invasive upper endoscopy. However, despite its high specificity, upper endoscopy demonstrates a suboptimal cancer yield and moderate missed rates, compromising its cost-effectiveness for screening in the general population. Moreover, screening strategies for gastroesophageal cancer are still lacking, in part owing to the invasiveness of current diagnostic methods. To overcome these challenges, innovative minimally invasive technologies have emerged, including metabolomics of exhaled breath, and detection of circulating tumor DNA or proteomics in blood. Promising results from phase I diagnostic trials emphasize the potential of these approaches to advance early detection and monitoring of gastroesophageal cancer. As these methods further refine and consistently demonstrate adequate sensitivity and specificity, they are poised to challenge existing diagnostic modalities. This progress may prompt reconsideration of current one-size-fits-all paradigms, facilitating the evolution toward a patient-tailored management of gastroesophageal cancer. In this article, we review the current minimally invasive breath- and blood-based diagnostic approaches for gastroesophageal cancer, elucidating the underlying biologic basis of identifiable biomarkers. As these approaches will become an integral part of future diagnostic paradigms, understanding the operational mechanisms, strengths, and limitations of these approaches is crucial for optimizing their implementation and interpretability in clinical practice.