Molecular stratification of esophageal adenocarcinoma: implications for prognosis and treatment strategy

Genome-wide molecular profiling has emerged as a promising approach for advancing the clinical management of esophageal adenocarcinoma (EAC), with the potential to improve prognostic accuracy and enable more personalized treatment strategies. In this review, we summarize current evidence from genomic and epigenomic EAC stratification studies, highlighting the proposed molecular subtypes and evaluating their clinical relevance. We discuss how these subclassifications may inform disease outcomes, refine patient selection for specific therapies and uncover new treatment opportunities aligned with tumor molecular profiles. Additionally, we explore molecular subtypes associated with Barrett's esophagus, a precursor lesion of EAC, and consider how these insights can help elucidate the mechanisms underlying EAC development. Such understanding may inform improved strategies for early tumor detection, risk stratification and prevention, ultimately aiming to reduce the burden of EAC. We also address the current challenges limiting the clinical application of these molecular classifiers, including restricted sample availability, insufficient validation and the difficulty of translating genome-wide findings into practical and clinical useful biomarkers. Integrating molecular subtyping into clinical workflows is a key step toward precision medicine in EAC, with the goal of enhancing treatment response rates and patient outcomes. Future advances will require collaborative efforts and robust clinical validation in large prospective studies to ensure that molecular stratification strategies can be effectively translated into improved management of EAC.