Somatostatin Receptor Expression of Gastroenteropancreatic Neuroendocrine Tumors: A Comprehensive Analysis in the Era of Somatostatin Receptor PET Imaging

<b>Background</b><b>:</b> There is limited data on somatostatin receptor (SSTR) expression of metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) using modern imaging techniques and stratifying by primary site and tumor grade (G). Understanding patterns of SSTR expression and tumor heterogeneity is essential when determining the relevance of cold and radiolabeled somatostatin analog treatments. <b>Methods:</b> A single-institutional retrospective analysis of metastatic well-differentiated G1-3 GEP-NET patients who underwent Gallium-68 ([⁶⁸Ga])-DOTATATE or Copper-64 ([⁶⁴Cu])-DOTATATE positron emission tomography (PET) imaging from September 2016 to June 2024 was performed. <b>Results:</b> A total of 1192 patients were considered eligible for this study. Among them, 26 (2.2%) were completely negative on SSTR PET/computed tomography (CT), and 27 (2.3%) had weak uptake (less or equal to the normal liver). Up to 40 (3.4%) had heterogeneous SSTR expression on PET/CT: 26 (2.2%) displayed the coexistence of strongly avid lesions with the absence or near absence of SSTR uptake in measurable tumors (heterogeneous strong), while 14 (1.2%) had a combination of absent and weakly expressing SSTR tumors (heterogeneous low). An additional nine cases with prior homogeneous expression (0.8%) developed new SSTR-negative tumors along with disease progression, potentially indicating dedifferentiation. The absent or heterogeneous SSTR expression rates were greater in NET G3 than G1/G2 and in tumors originating outside the small bowel (midgut). Most NETs with absent or heterogeneous SSTR expression were fluorodeoxyglucose-F-18 ([¹⁸F]FDG)-avid. <b>Conclusions:</b> The large majority of metastatic GEP-NETs demonstrate strong and relatively uniform SSTR expression, but approximately 8% are SSTR-negative, weak or heterogeneous on PET/CT. Higher than average rates of absent/heterogeneous/weak SSTR expression occur in G3 NETs and lower rates among small intestine primaries.