Clinical characteristics and therapeutic implications of MTAP deletion in pancreatic cancer: A nationwide genomic analysis

BACKGROUND: Methylthioadenosine phosphorylase (MTAP) deletion is a frequent genomic alteration in several cancers and a potential therapeutic vulnerability. However, its prevalence and clinical significance in pancreatic cancer remain insufficiently characterized. METHODS: We retrospectively analyzed 8834 patients with pancreatic cancer profiled by FoundationOne® CDx in a nationwide genomic cohort. MTAP-deleted and non-deleted groups were compared for clinicopathological characteristics, co-occurring genomic alterations, tumor mutational burden (TMB), microsatellite instability (MSI), overall survival (OS), and treatment response to first- and second-line chemotherapies. RESULTS: MTAP deletion was identified in 27.3% of pancreatic cancers, with high frequencies in pancreatic ductal adenocarcinoma (PDAC) (28.0%) and adenosquamous carcinoma (35.0%). MTAP deletion strongly co-occurred with CDKN2A/2B deletion and was associated with major driver alterations (KRAS, TP53, SMAD4), while showing no association with high TMB or MSI. In PDAC, the median OS was significantly shorter in the MTAP-deleted group compared with the non-deleted group (24.3 vs. 29.9 months; P < 0.0001). However, CDKN2A-deleted subcohort analysis revealed that MTAP deletion was not associated with OS (HR: 0.96; 95% CI: 0.85-1.08). Furthermore, the objective response and disease control rates to gemcitabine plus nab-paclitaxel or FOLFIRINOX were comparable between the groups. CONCLUSIONS: MTAP deletion is a frequent genomic alteration in pancreatic cancer. Although it was not an independent prognostic or chemotherapy-predictive biomarker, our comprehensive clinicogenomic findings provide a foundation for future evaluation of MTAP-focused therapeutic strategies in pancreatic cancer.