Delta-Like Ligand 3 Expression and Functional Imaging in Gastroenteropancreatic Neuroendocrine Neoplasms.

Abstract

Delta-like ligand 3 (DLL3) is an emerging target across neuroendocrine cancers, but remains underexplored in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs), including poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP NECs) and well-differentiated neuroendocrine tumors (NETs). We aimed to define the landscape of DLL3 expression and feasibility of DLL3-targeted imaging in this population. We completed DLL3 immunohistochemistry (IHC) on 379 tumor samples from patients with GEP NENs, analyzing associations between DLL3 IHC positivity, clinicopathologic features, and outcomes. [⁸⁹Zr]Zr-DFO-SC16.56 DLL3 immuno-positron emission tomography-computed tomography (immunoPET-CT) imaging was performed in six patients with DLL3 IHC-positive advanced GEP NENs. Among GEP NECs, DLL3 expression was identified in 55/78 (71%) tumors, was enriched for small cell histology, and did not demonstrate prognostic significance. Among well-differentiated gastroenteropancreatic neuroendocrine tumors, DLL3 expression was identified in 5/235 (2%) of grade 1-2 and 25/66 (40%) grade 3 (G3) tumors, most commonly G3 pancreatic NETs (PanNETs; 22/52, 43%), with univariate analysis revealing increased mortality risk among patients with DLL3-positive advanced G3 PanNETs (hazard ratio 3.27 [95% CI, 1.09 to 9.78]). Between May 28, 2024, and February 10, 2025, six patients with DLL3 IHC-positive GEP NENs underwent [⁸⁹Zr]Zr-DFO-SC16.56 immunoPET-CT imaging, which delineated DLL3-avid tumor lesions in five of six patients (two of two GEP NECs, three of four G3 PanNETs). Tumor-specific uptake of [⁸⁹Zr]Zr-DFO-SC16.56 varied between patients, with maximum standard uptake values ranging from 7.4 to 36.7, with four of six cases demonstrating DLL3 avidity in ≥50% of tumor lesions. DLL3 is expressed on a majority of GEP NECs and on a subset of high-grade PanNETs marked by poor outcomes. Functional imaging suggests DLL3 as a promising therapeutic target in both GEP NECs and high-grade PanNETs.