Bone metastases identify a high-risk subgroup in metastatic neuroendocrine tumors with particular relevance in NETs of unknown primary

Background Bone metastases (BM) are an increasingly recognized manifestation of advanced neuroendocrine tumors (NETs), but their prevalence and association with survival in NETs of unknown primary (CUP NET) remain insufficiently characterized. We assessed the prevalence of BM and their association with overall survival (OS) in patients with metastatic pancreatic NETs (PanNETs), small intestinal NETs (siNETs), and CUP NETs. Methods We conducted a retrospective analysis of 642 patients with histologically confirmed metastatic well-differentiated NETs who were treated at the European Neuroendocrine Tumour Society (ENETS) Center Essen between 2009 and 2023 using somatostatin-receptor (SSTR)- based hybrid imaging with 68Ga-DOTATOC PET/CT. The patients included 171 with PanNETs, 305 with siNETs, and 166 with CUP NETs. The primary outcome was OS, defined as the time from date of initial NET diagnosis to death from any cause. Secondary outcomes included BM prevalence, entity-specific survival according to BM status, BM morphology and timing, and skeletal-related events. Results BM were detected in 238 patients (37.1%) and were most frequent in CUP NETs (42.8%), followed by PanNETs (36.3%) and siNETs (34.4%). Median OS in the overall cohort was 77 months (95% confidence interval [CI], 64–89) in patients with BM and 141 months (95% CI, 119–186) in metastatic patients without BM (log-rank p < 0.001). In CUP NETs, median OS was 30 months in patients with BM and 66 months in metastatic patients without BM (log-rank p = 0.021). In multivariable Cox regression adjusted for age, sex, tumor grade, functioning status, and tumor entity, BM remained associated with shorter OS (hazard ratio [HR], 1.45; 95% CI, 1.13–1.85; p = 0.0034). In an entity-stratified model BM remained associated with OS (HR, 1.43; 95% CI, 1.09–1.89; p = 0.011). In the CUP NET subgroup, the adjusted HR associated with BM was 1.83 (95% CI, 1.17–2.85; p = 0.008). Conclusion BM were common in patients with metastatic NETs and are particularly prevalent and clinically relevant in CUP NET.