Unmet needs beyond precision in gastrointestinal cancers

Gastrointestinal (GI) cancers account for a substantial proportion of global cancer mortality and remain a major focus of translational and clinical oncology. Over the past decade, advances in molecular profiling, biomarker development, and systemic therapies—including liquid biopsy and circulating tumor DNA (ctDNA) for minimal residual disease (MRD) detection and longitudinal monitoring—have substantially enhanced biological resolution. Precision oncology has already produced major clinical successes in selected molecularly defined subsets, although the magnitude and breadth of benefit remain heterogeneous across tumor types and disease settings. Yet, increasing biological precision has not always translated proportionally into predictable and actionable clinical decisions for individual patients. In this critical narrative review, we examine major GI cancers—including colorectal, gastric, esophageal, pancreatic, biliary tract cancers (BTCs), and hepatocellular carcinoma (HCC)—through the lens of conceptual limitations and unmet clinical needs. Across these malignancies, although with important tumor-specific exceptions and different levels of supporting evidence, recurring themes emerge: the gap between precise prognostication and actionable treatments, exemplified by settings in which ctDNA identifies high-risk patients without providing an effective strategy to modify that risk; the limitations of static models applied to dynamic disease processes; and the persistence of empirically driven decision-making despite increasingly detailed molecular information. By framing uncertainty as an intrinsic feature of cancer biology rather than simply a failure of evidence, this review argues for more adaptive clinical frameworks integrating longitudinal molecular, genetic, and clinical information, allowing therapeutic and surveillance strategies to be reassessed as disease evolves rather than relying exclusively on single-time-point characterization. Such frameworks should complement, rather than replace, the established achievements of precision oncology and be tailored to the distinct biological and evidentiary context of each GI cancer type.