643 Background: The incidence of neuroendocrine tumors (NETs) has increased over the past few decades, especially among younger patients. While data from other gastrointestinal malignancies suggest early-onset may be associated with biological differences, this is yet to be investigated in NETs. We sought to characterize the molecular and immune landscape of early (EO)- versus average-onset (AO) pancreatic (pNETs) and small intestinal NETs (siNETs). Methods: Cases with metastatic pNETs and siNETs sequenced using the Tempus xT assay were included. DNA sequencing was performed to identify somatic alterations and whole transcriptome RNA-seq data were normalized to log2(TPM+1) with assay correction. Immune profiling analysis included tumor mutational burden (TMB), microsatellite instability (MSI), PD-L1 status, and immune infiltration estimated via quanTIseq. Differential expression between EO (50 years) was assessed using Wilcoxon rank sum tests with Benjamini–Hochberg correction, and pathway enrichment was assessed via GSEA (Gene Set Enrichment Analysis). Statistical significance was defined as p<0.05 and q<0.10 for GSEA. Results: A total of 502 patients were included, of which, 134 had EO-NETs (EO-pNETs=94, EO-siNETs=40). Compared to AO, EO-pNETs had a significantly lower prevalence of KRAS (2.1% vs 14%, p=0.001), TP53 (14% vs 25%, p=0.004), SMAD4 (3.2% vs 12%, p=0.01) and RB1 (6.4% vs 14%, p=0.04) and a higher prevalence of LRP1B (8.5% vs 1.3%, p=0.003) alterations. Among siNETs, EO cohort had a significantly higher prevalence of PAX5 (5% vs 0%, p=0.04) and HDAC2 (5% vs 0%, p=0.04) alterations. On GSEA, EO-pNETs had a significantly higher expression in the VEGF, apical junction, hedgehog signaling, and myogenesis pathways while AO-pNETs had higher expression in MYC, E2F, DNA repair and G2M checkpoint pathways. No significant differences in transcriptomic expression were noted between EO- and AO-siNETs. On immune profiling, EO-pNETs cases were enriched for M2 macrophages (p=0.004) while siNETs displayed no significant age-based differences. TMB-H, MSI-H, and PD-L1 expression did not differ by age in either group. Conclusions: This is the largest molecular analysis comparing EO and AO-enteropancreatic NETs. More age-based differences were seen in pNETs with some changes in EO cases predicting better response to immunotherapy while AO cases attained more alterations found in grade 3 NETs or NECs. Our results suggest that age at diagnosis may be an important determinant of tumor biology and clinical management options.
Grewal et al. (Sat,) studied this question.