The study investigates the impact of KRAS mutation status and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (PDAC). Using data from 803 patients at MD Anderson Cancer Center, the researchers found that KRAS mutation status and subtypes were prognostic for overall survival (OS) (p < 0.001). Patients with KRAS wildtype tumors had a median OS of 38 months, while those with KRASG12R mutations had a similar median OS (34 months). Patients with KRASQ61 and KRASG12D mutations had shorter OS (median 20 months and 22 months, respectively). KRASG12D mutations were more prevalent in metastatic tumors (34% vs. 24%, p = 0.001), and KRASG12R mutations were more common in well- and moderately differentiated tumors (14% vs. 9%, p = 0.04). Similar findings were observed in an external validation cohort from the Pancreatic Cancer Action Network (PanCAN)’s Know Your Tumor® dataset (n = 408). The study also explored co-mutations, finding that TP53 was the most frequently detected co-mutation with KRAS, followed by CDKN2A and SMAD4. ARID1A mutation was associated with worse OS, while SMAD4 mutation was associated with better OS. These findings suggest that KRAS targeting and combination strategies may need to consider mutant allele-specific approaches and co-mutations to improve treatment outcomes in PDAC.The study investigates the impact of KRAS mutation status and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (PDAC). Using data from 803 patients at MD Anderson Cancer Center, the researchers found that KRAS mutation status and subtypes were prognostic for overall survival (OS) (p < 0.001). Patients with KRAS wildtype tumors had a median OS of 38 months, while those with KRASG12R mutations had a similar median OS (34 months). Patients with KRASQ61 and KRASG12D mutations had shorter OS (median 20 months and 22 months, respectively). KRASG12D mutations were more prevalent in metastatic tumors (34% vs. 24%, p = 0.001), and KRASG12R mutations were more common in well- and moderately differentiated tumors (14% vs. 9%, p = 0.04). Similar findings were observed in an external validation cohort from the Pancreatic Cancer Action Network (PanCAN)’s Know Your Tumor® dataset (n = 408). The study also explored co-mutations, finding that TP53 was the most frequently detected co-mutation with KRAS, followed by CDKN2A and SMAD4. ARID1A mutation was associated with worse OS, while SMAD4 mutation was associated with better OS. These findings suggest that KRAS targeting and combination strategies may need to consider mutant allele-specific approaches and co-mutations to improve treatment outcomes in PDAC.