Prognostic Implications of Codon-Specific KRAS Mutations in Localized and Advanced Stages of Pancreatic Cancer.

PURPOSE: Although KRAS mutations represent the primary oncogenic driver in pancreatic ductal adenocarcinoma (PDAC), the association between codon-specific alterations and patient outcomes remains poorly elucidated, largely because of a lack of data sets coupling genomic profiling with rich clinical annotations across disease stages. MATERIALS AND METHODS: We used American Association for Cancer Research's GENIE Biopharma Consortium Pancreas v1.2 data set to test the association of codon-specific KRAS mutations with clinicogenomic features and patient outcomes in patients with PDAC diagnosed with localized (stages I to III) and advanced disease (stage IV). Overall survival (OS) was compared using Kaplan-Meier and multivariable Cox proportional hazards methods. RESULTS: Among 1,032 eligible patients, 949 (92%) exhibited mutant KRAS. These mutations were predominantly observed at G12D (n = 390, 41%), G12V (n = 305, 32%), and G12R (n = 149, 16%). In the group of patients who presented with localized disease, those with G12V mutation had notably longer survival compared with G12D mutation (P = .03). By contrast, patients with G12V mutation who presented with metastatic disease experienced shorter OS compared with those with G12R (P = .04) and G12D mutations (P = .04). Furthermore, no significant differences were observed in the frequencies of coaltered driver genes, including TP53, CDKN2A, and SMAD4, across the different KRAS mutations. CONCLUSION: These findings demonstrated that codon-specific KRAS mutations affect PDAC outcomes differently based on disease stage at diagnosis. As studies testing KRAS inhibitors continue to emerge and mature, the prognostic variability of individual KRAS mutations must be carefully considered to avoid confounding and ensure accurate evaluation of therapeutic efficacy in early-phase studies.

Duke Scholars

Author Bruce W Rogers Surgery, Surgical Sciences

Author Clark Howell  

Author Shannon Jones McCall Pathology

Author Donna Niedzwiecki Biostatistics & Bioinformatics, Division of Biostatistics

Author Daniel Philip Nussbaum Surgical Oncology

Author Zahra Kabiri Surgery, Surgical Sciences