Clinical and Molecular Characteristics of KRAS Codon-Specific Mutations in Advanced Pancreatic Ductal Adenocarcinoma with Prognostic and Therapeutic Implications

<i>KRAS</i> mutations occur in over 90% of pancreatic ductal adenocarcinomas (PDACs), most commonly at codon 12, but the clinical implications of codon-specific subtypes in advanced disease remain unclear. We retrospectively analyzed 269 patients with advanced PDAC who underwent next-generation sequencing between 2020 and 2024 at a single tertiary cancer center. Clinical features, co-mutations, treatment outcomes, and survival were evaluated. <i>KRAS</i> mutations were detected in 92% of patients, most frequently G12V (36%) and G12D (34%), followed by G12R (10%) and non-G12 variants (9%). <i>TP53</i> was the most frequent co-mutation (67%) and was significantly enriched in G12D tumors compared with wild type (74.2% vs. 31.8%). Mutations in homologous recombination and DNA damage response genes were more common in non-G12 and wild-type tumors, although not statistically significant. Serum CA 19-9 was elevated in most G12-mutant tumors, whereas approximately 40% of non-G12 and wild-type patients showed normal levels despite advanced disease. No significant survival differences were observed among <i>KRAS</i> subtypes in the overall or treated cohorts. However, patients with G12V mutations achieved significantly longer survival with fluorouracil-based than gemcitabine-based chemotherapy. These findings suggest that, while <i>KRAS</i> subtyping alone lacks prognostic value, the G12V subtype may inform chemotherapy selection and warrants further prospective validation.