Prognostic Role of MTAP Loss in Cholangiocarcinoma

Methylthioadenosine phosphorylase (MTAP) loss is a common genomic event in cancer and is associated with an immunologically cold phenotype. Recent research has highlighted a synthetic lethality of MTAP loss when combined with PMRT5 or MAT2A inhibition. Although contemporary somatic genomic testing now routinely includes MTAP status, the clinicogenomic characteristics of MTAP loss in cholangiocarcinoma (CCA) remain largely undefined. In this study, we examine the genomic profiles, clinical features, and survival outcomes of MTAP loss CCA.

This is a single-center retrospective cohort study of patients with CCA from December 2017 to January 2024. Somatic genomics alterations were assessed using targeted next-generational sequencing with FoundationOne CDx. Patient demographics, tumor characteristics, treatment history, and overall survival (OS) were retrospectively collected. Genomics coalterations were assessed using the Fisher exact test. Multivariate Cox proportional hazards regression analysis was used to assess the relationship between MTAP status and OS.

Among 94 CCA samples, 89 were successfully sequenced, uncovering 339 genomic alterations, with MTAP loss identified in 16% of cases. It commonly co-occurred with CDKN2A and B loss (93% and 86%, respectively) and was not associated with FGF2R rearrangement, IDH1 mutation, or human epidermal growth factor receptor 2 (ERBB2) amplification. Tumor mutational burden were similar between MTAP status. MTAP loss was associated with lower OS (hazard ratio, 3.95 [95% CI, 1.43 to 10.9]; P = .008) after adjustment for key covariates including age, Eastern Cooperative Oncology Group performance status, nodal stage, metastatic spread, resectability, histologic, and line of therapy.

MTAP loss is common CCA, co-occurred with CDKN2A and CDKN2B loss, and was associated with poor OS. Future effort to exploit this therapeutic vulnerability in MTAP-loss CCA is critical to improve the care of this population.