Characterizing the prevalence and prognostic significance of MTAP loss in endemic nasopharyngeal cancer using immunohistochemistry (IHC) versus fluorescent in situ hybridization (FISH).

6052 Background: Methylthioadenosine phosphorylase (MTAP) loss has been associated with poor outcomes in various cancers, including nasopharyngeal carcinoma (NPC). Homozygous deletion of the MTAP locus is one of the most frequent somatic changes in NPC, creating opportunities for therapeutic targeting. However, the concordance between MTAP IHC and FISH for detecting MTAP loss, and the prognostic impact of partial MTAP loss, has not been fully explored. This study evaluated the prevalence of MTAP loss, correlation between IHC and FISH, and association of MTAP expression with time to progression (TTP), progression-free survival (PFS) and overall survival (OS). Methods: MTAP expression was analyzed by IHC, and locus loss was confirmed using FISH in tumors M0 (non-metastatic) NPC patients. Correlations between MTAP IHC and FISH results were analyzed to assess concordance, sensitivity, and specificity. Kaplan-Meier survival curves and log-rank tests compared survival distributions, while Cox proportional hazards models were applied for univariate and multivariate analyses. Subgroup analyses were performed by tumor, nodal and overall stage (AJCC 8th edition). Results: Among 175 patients, 65 (36.0%) exhibited IHC 0 and FISH-negative MTAP loss. Concordance rate between IHC 0 and FISH-negative was 94.9%. MTAP loss was significantly correlated with higher N2–3 and stage III–IVA disease (Pearson correlation coefficients: 0.81 and 0.73, respectively; p < 0.0001). Based on receiver operating curve (ROC) analysis, the optimal MTAP cutoff for progression was 110. Partial MTAP loss (MTAP 0–109) was significantly associated with shorter TTP compared to MTAP 110–300 (median TTP: 4.6 years vs. 15.8 years; p = 0.04). In multivariate analysis, MTAP <110 remained significant for TTP (HR = 0.65; CI 0.48-0.98 p = 0.04) after adjusting for grouped N stage. Subgroup analyses demonstrated that MTAP <110 was significantly associated with shorter PFS in N2–3 patients (HR 0.5 CI 0.28-0.9 p = 0.02) and shorter TTP in stage III–IVA patients (HR 0.61 CI 0.37-1.0 p = 0.05). Conclusions: Partial MTAP loss (IHC <110) is associated with worse outcomes in NPC, particularly shorter TTP and PFS, with significant prognostic value in advanced nodal and overall stage disease. High concordance between IHC and FISH supports IHC as a reliable diagnostic tool. These findings highlight MTAP expression as a potential prognostic biomarker for NPC, warranting further validation and exploration of targeted therapies.