Biomarkers and Emerging Approaches in Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NEN): Current Evidence and Future Directions

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) comprise a biologically and clinically heterogeneous spectrum of tumors with substantial inter- and intratumoral variability. Despite advances in molecular classification, imaging, and treatment, accurate diagnosis, prognostication, and disease monitoring remain challenging. Established biomarkers, including chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA), provide limited and context-dependent information, highlighting the need for more biologically informative approaches. Recent advances in liquid biopsy, transcriptomic and genomic profiling, spatial technologies, molecular imaging, radiomics, and artificial intelligence are expanding the ability to characterize tumor biology and evolution. However, biological association and analytical validity do not necessarily translate into clinical utility. This narrative review critically evaluates established and emerging biomarkers according to the biological information they provide, with particular emphasis on molecular heterogeneity, tumor evolution, and the distinction between validated and investigational applications. We further discuss how complementary molecular, circulating, spatial, imaging, and clinical information may be integrated through multimodal and artificial intelligence-based approaches to advance tumor characterization and support precision oncology in GEP-NENs.