TPS659 Background: Neuroendocrine neoplasms (NENs) are a rare spectrum of malignant neoplasms originating from neuroendocrine cells, most commonly affecting the gastrointestinal tract, pancreas, and lungs. Tumors may vary from low grade neuroendocrine tumors (NET) to high grade neuroendocrine carcinomas (NEC). The annual occurrence of NENs is increasing worldwide and currently the incidence in the US is about 6 cases per 100,000 people per year. A variety of therapeutic options are available for advanced NENs, however, when to apply a given option, what combination therapeutic approach should be used, how long treatment should be continued is unclear and controversial. Moreover, unlike common cancers, pre-clinical models for NENs are sorely limited. Without robust pre-clinical models our understanding of tumor pathophysiology and novel drug development can be challenging. Methods: A prospective study to evaluate the natural history and sample acquisition of NENs comprehensively and longitudinally. Patients ≥ 18 years old with histological confirmation of NENs, biochemical evidence of NENs, or by imaging studies of NENs are eligible. Participants are invited to NIH for biannual evaluations or as clinically indicated. Patients complete individual medical history, family history, and laboratory assessments including blood, saliva, and tumor for RNA/DNA analysis. A tumor analysis via a 500+ gene panel (Illumina TruSight Oncology 500 Panel) is performed for comprehensive genomic and epigenomic analysis. When feasible, fresh tissue is collected to develop pre-clinical models for drug testing. If clinically indicated, anatomic and functional imaging is performed. We aim to 1) create a repository of biological samples and conduct future investigations to understand the basic biology of NENs with the goal to develop novel treatment approaches, biomarkers of treatment response, and new prognostic and diagnostic models, 2) acquire clinical data so that the overall genomic, proteomic, and metabolomic alternations can be correlated to clinical parameters, 3) establish organoid cultures, cell line models, and xenograft models corresponding to NENs of various grades for drug screening. This protocol will evaluate the natural history of NENs, allow tissue acquisition, and study this heterogenous group of neoplasms with unique tumor biology, and current clinical management to stabilize correlations with clinical outcomes and develop novel therapies. Clinical trial information: NCT05237934 .