Somatostatin Analogues Do Not Improve Survival in Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: A Registry-Based Analysis with Ki-67 Stratification

Background/Objectives: The efficacy of somatostatin analogues (SSA) in Grade 3 (G3) neuroendocrine neoplasms (NEN) remains controversial, and registry data rarely permit a formal separation of NET G3 from neuroendocrine carcinoma (NEC). Methods: We analyzed 519 patients with G3 gastroenteropancreatic (GEP) NEN recorded in a national neuroendocrine tumor registry (data export 3 April 2025; 464 de novo G3, 55 transformed G3); bronchopulmonary primaries were excluded. A Ki-67 > 55%, entered as a time-varying indicator, served as a surrogate for NEC. Outcomes were compared using Kaplan–Meier and Cox proportional hazards models with all treatments and the Ki-67 > 55% indicator entered as time-varying covariates. Results: Among 410 patients with classifiable Ki-67, 256 (62.4%) ever had a Ki-67 > 55%. Ki-67 > 55% was associated with worse progression-free survival (PFS; HR 1.40, 95% CI 1.06–1.84; p = 0.016) and overall survival (OS; HR 1.65, 95% CI 1.15–2.37; p = 0.006). SSA use was not significantly associated with PFS (HR 1.32, 95% CI 0.85–2.04; p = 0.215) or OS (HR 0.91, 95% CI 0.54–1.56; p = 0.744). After adjustment for Ki-67, transformed G3 was associated with worse OS (HR 1.60, 95% CI 1.02–2.51; p = 0.040). Conclusions: SSA therapy was not associated with improved survival in G3 GEP-NEN. As this is an observational analysis subject to confounding by indication, these estimates do not establish a lack of biological efficacy of SSA. A Ki-67 threshold of 55% identified a prognostically distinct subgroup and explains why transformed G3 appears indolent: after adjustment, it was associated with worse overall survival. This finding rests on 55 patients with 29 deaths and is hypothesis-generating.