641 Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus has shown efficacy, particularly in GEP-NETs. However, predictive markers of treatment response are lacking. With the increasing use of next-generation sequencing (NGS), pathway-level genomic alterations have emerged as potential candidates to guide patient selection. Methods: We conducted a molecular analysis of patients with GEP-NETs who received everolimus and underwent tumor NGS. Genomic alterations were grouped into seven predefined signaling pathways: PI3K/AKT/mTOR, MAPK, DNA damage repair (DDR), Developmental (NOTCH/WNT/TGF-β), Epigenetic regulation, JAK–STAT, and Cell cycle regulation (p53–CDKN1A–RB). Patients were categorized as mutated (≥1 alteration) or wild-type for each pathway. Clinical benefit was assessed by objective response rate (ORR) and disease control rate (DCR; complete or partial response, or stable disease), and their associations with pathway alterations were evaluated. Results: A total of 28 patients with GEP-NETs were included in the analysis. In the overall cohort, the median progression-free survival (PFS) was 26.4 months (95% CI, 17.3–37.1). The median overall survival (OS) was 41.0 months (95% CI, 36.6–not reached). Among the 7 canonical signaling pathways, alterations in the PI3K/AKT/mTOR pathway were associated with a numerically greater ORR compared with wild-type (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 1.40–199.53; p=0.009). In contrast, DDR alterations showed a lower ORR (34.6% vs. 100.0%; OR 0.00, 95% CI 0.00–3.34; p=0.146) and DCR (69.2% vs. 100.0%; OR 0.00, 95% CI 0.00–13.66; p=1.000), while cell-cycle regulation alterations were associated with reduced ORR (20.0% vs. 50.0%; OR 0.26, 95% CI 0.02–1.86; p=0.226) and DCR (60.0% vs. 77.8%; OR 0.44, 95% CI 0.06–3.24; p=0.400). Other pathways, including MAPK, JAK–STAT, Epigenetic regulation, and Developmental, showed no notable differences. Conclusions: Alterations in canonical pathways showed exploratory trends of differential association with everolimus clinical benefit, with PI3K/AKT/mTOR alterations suggesting possible sensitivity and DNA damage repair and cell-cycle regulation pathways indicating reduced response. Although limited by small sample size, these hypothesis-generating findings underscore the need for prospective validation of pathway-based biomarkers to refine patient selection for everolimus in GEP-NETs.
Han et al. (Sat,) studied this question.