MTAP-deficient pancreatic adenocarcinoma: Clinical and molecular features.

742 Background: KRAS, TP53, CDKN2, and SMAD4 mutations are implicated in PDAC development and progression. Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway, and its loss may be associated with a shorter overall survival (OS). Early clinical trials in patients with MTAP-deficient malignancies are currently underway with encouraging results. However, there are only few studies characterizing patients with MTAP-deficient PDAC. Our study is a retrospective case series interrogating the molecular profiles, demographics, and clinical courses of patients diagnosed with MTAP-deficient PDAC in 3 institutions. Methods: This is a multi-center retrospective cohort study of patients with metastatic PDAC from January 2019 to August 2025. MTAP gene loss and associated genomic changes were determined by next generation sequencing (NGS) of tumor tissue. Patient demographics, tumor characteristics, treatment history, and survival data were collected. Plasma ctDNA based NGS was done for select patients. Results: 21 patients were identified. 85% of patients were white, 10% African American, 5% Asian. 57% of patients were female. The median age at diagnosis was 63 years, with a range of 49 to 81 years of age. Liver metastasis was present in 80% of patients. TP53 and SMAD4 mutations were present in 95%, and 25% of patients, respectively. CDKN2A and B mutations were present in 80% and 85% of patients, respectively. 10% of patients had neither CDKN2A nor B mutation. All patients had KRAS mutations; G12D and Q61H/R mutations were each present in 29% of patients, while G12V and G12R mutations were seen in 20% and 15% of patients, respectively. MTAP deletion was not detected by plasma ctDNA analysis undergone by 9 patients. Five patients (25%) were initially diagnosed with localized disease and underwent surgical resection prior to developing metastatic disease. Three patients (15%) had rapidly progressive disease and died before starting treatment. Two patients recently began treatment and are yet to be assessed for response. Of the 16 patients with an evaluable treatment response, 25% experienced disease progression on first-line therapy and 75% experienced disease stability or partial response by RECIST criteria. Mean response duration was 8.5 months. Median survival of the entire cohort was 15.5 months. Conclusions: Patient demographics and clinical courses did not vary significantly from the general metastatic PDAC population. KRAS mutation subtype frequency is different than expected, with the higher frequency of Q61H/R mutations. Further study of the relationship between MTAP deletion and specific KRAS mutation subtypes may influence treatment decision-making and future clinical trial designs. Lack of detection in liquid biopsy may relate to type of assay used.