[18F]DOPA PET Reveals Metabolically Active Transcriptomic States Associated with Clinical Outcome in Pancreatic Neuroendocrine Tumors.

[18F]fluorodihydroxyphenylalanine ([18F]DOPA) uptake is dependent on amino acid transport and decarboxylation pathways, including large neutral amino acid transporter 1, encoded by SLC7A5, which are linked to tumor aggressiveness. This study evaluated whether in vivo uptake of [18F]DOPA can serve as an imaging biomarker for pancreatic neuroendocrine tumors (panNETs), reflecting a tumor's transcriptional status and a patient's clinical course. Methods: This retrospective single-center study was based on a transcriptomic cohort of 74 primary panNETs. A subset of 22 panNETs from patients who underwent preoperative [18F]DOPA PET/CT constituted the discovery radiotranscriptomic cohort. [18F]DOPA tumor uptake was quantified using SUVmax and integrated with matched RNA-sequencing data. Unsupervised clustering, differential expression analysis, gene set enrichment, and tumor microenvironment deconvolution were performed to identify transcriptional programs associated with [18F]DOPA uptake. The prognostic value of SLC7A5 was evaluated in the discovery cohort, the full transcriptomic cohort (n = 74), and an independent external cohort (n = 33). Results: Unsupervised clustering of gene expression profiles identified 2 robust molecular subtypes: cluster 1 and cluster 2. Cluster 1 showed higher [18F]DOPA uptake than did cluster 2, with a median SUVmax of 24.3 versus 5.9, respectively (P = 0.030), and was associated with more advanced clinicopathologic features and shorter event-free survival. This subtype was also characterized by enrichment in extracellular matrix, stromal, vascular, and immune-related components, along with upregulation of amino acid transport and amine metabolism genes, including SLC7A5 As a mechanistic link between tracer uptake and tumor metabolism, SLC7A5 expression significantly stratified event-free survival in the discovery cohort and remained prognostic in the full cohort. Conclusion: [18F]DOPA PET uptake was associated with amino acid-driven metabolic programs in panNETs, including SLC7A5 expression, and adverse clinical features. These findings suggest that [18F]DOPA uptake may provide a noninvasive readout of tumor metabolic activity, although its value as an imaging biomarker requires independent validation.