Clinical Presentation of MTAP Deletions in Real-World Settings: Lessons for the Clinical Development of Novel Targeted Therapies

PURPOSE Homozygous deletions of methylthioadenosine phosphorylase ( MTAP ) enzyme are common across human cancers and are associated with poor prognoses. Currently, to our knowledge, there are no approved therapies targeting MTAP -deleted tumors, although there is significant ongoing research in this area. The aim of this study was to analyze the prevalence, clinical impacts, and comutational landscapes of patients with MTAP deletions in a network of community-based oncology clinics. METHODS We conducted retrospective analyses of clinicogenomic data from 21 community oncology practices in the Sarah Cannon Research Institute (SCRI) network. Clinical data from electronic health record systems, including drug administration dates, diagnosis dates, and molecular data from commercial next-generation sequencing vendors, were aggregated in SCRI's web-based precision medicine platform, Genospace. Overall survival (OS) and time to next therapy (TTNT) were analyzed using Kaplan-Meier plots and Cox proportional hazards regression. Patient data were deidentified before analysis. RESULTS Among 10,936 patients analyzed in this study, 9.4% had homozygous MTAP deletions ( MTAP -del). MTAP -del was prevalent in glioblastoma (58.2%) and mesothelioma (40.5%) and least common in breast (4.0%) and colorectal cancers (1.4%). Overall, MTAP -del patients had diminished OS (25.4 months v 52.1 months, P < .0001), with pronounced deficits in MTAP -del mesotheliomas (12.8 months v 23.0 months, P = .0478) and urothelial carcinomas (22.9 months v 36.0 months, P = .0549). MTAP -del patients receiving chemotherapy had shortened TTNT intervals overall (8.1 months v 10.1 months, P = .0002), and for urothelial (5.4 months v 6.4 months, P = .0195) and gastroesophageal carcinomas (7.2 months v 8.8 months, P = .0412). MTAP- del patients had distinct mutational landscapes, compared with MTAP- prof patients, including lower rates of TP53 mutation. CONCLUSION MTAP is a key biomarker in precision oncology; this work describes the clinical outlook for these patients within the community-oncology setting. These insights can inform future study design, as MTAP -directed therapies continue their development.