Integrative Molecular Analysis to Predict Clinical Benefit of Everolimus in Patients With Gastro-Entero-Pancreatic...

IntroductionNeuroendocrine tumors (NETs) are rare and heterogeneous. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is widely used in gastrointestinal and pancreatic NETs (GEP-NETs). Owing to the lack of validated biomarkers, exploratory analyses of molecular pathways may help identify subgroups that derive clinical benefit from everolimus.MethodsWe conducted a retrospective observational cohort study of patients with GEP-NETs who received everolimus and underwent tumor next-generation sequencing (NGS). Genomic alterations were categorized into seven predefined signaling pathways (PI3K/AKT/mTOR, MAPK, DNA damage repair (DDR), developmental, epigenetic regulation, JAK-STAT, and cell-cycle regulation), and patients were classified as mutated (≥1 alteration) or wild-type. Clinical outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Associations between pathway alterations and outcomes were assessed.ResultsTwenty-eight patients were included. Median PFS was 26.4 months (95% CI, 17.3-37.1) and median OS was 41.0 months (95% CI, 36.6-not reached [NR]). Alterations in the PI3K/AKT/mTOR pathway were associated with more favorable treatment outcomes, including a higher ORR (47.6% vs. 14.3%; OR, 5.17; 95% CI, 0.49-275.05; p=0.191) and a significantly higher DCR (85.7% vs. 28.6%; OR, 13.0; 95% CI, 1.40-199.5; p=0.009). Survival outcomes also tended to be longer in this group compared with wild-type tumors, with median OS of 59.0 vs. 40.8 months (p=0.321) and median PFS of 26.4 vs. 18.6 months (p=0.858). In contrast, alterations in DDR-related genes were associated with lower ORR and DCR, while alterations in cell-cycle regulation pathways were associated with shorter OS and PFS and numerically lower response rates. No significant differences in survival or response outcomes were observed for MAPK, JAK-STAT, epigenetic, or developmental pathways.ConclusionsPathway-level genomic alterations were associated with differential clinical benefit from everolimus in GEP-NETs, with PI3K/AKT/mTOR alterations suggesting greater benefit, while DDR and cell-cycle alterations indicated reduced benefit. Despite the small cohort, these findings support the potential of pathway-based biomarkers and warrant prospective validation.