Relations between mutant KRAS and TP53 subtypes and other co-mutations in pancreatic cancer.

e16294 Background: The most common mutations in pancreatic cancer are found in the KRAS, TP53, CDKN2A, or SMAD4 genes. Mutations in genes involved in the DNA damage repair (DDR) pathway are also frequently seen. Despite extensive research on the patho-genomic features of pancreatic cancer, the clinical significance of these recurring mutations remains poorly understood. Methods: We identified patients with pancreatic cancer treated at Yale Cancer Center between 2016 and 2021 who underwent Oncomine tumor profiling. The incidence and subtypes of KRAS and TP53, and their association with other genomic alterations and clinicopathological variables were measured. We compared the overall survival (OS) after the diagnosis of recurrent or metastatic disease using the Kaplan-Meier method and long-rank tests. Results: One hundred fifty-nine patients were identified and KRAS mutations were seen in 144 (90.6%) patients, including 64 G12D (44.4%), 48 G12V (33.3%), 19 G12R (13.2%), 6 Q61H (4.2%), and 7 others (4.9%). TP53 mutations were identified in 117 (73.6%) patients, including 80 loss-of-function (LOF) (68.4%), 24 gain-of-function (GOF) (20.5%), and 13 variants of unclear significance (VUS) (11.1%). TP53 LOF mutations were more common in tumors with KRAS WT (40.0%), G12D (56.3%), and G12V (56.3%), than in G12R (31.6%) and others KRAS mutation (30.1%). Conversely, TP53 GOF mutations were more common in tumors with G12R (26.3%) and other KRAS mutations (23.1%), than in KRAS WT (6.7%), G12D (14.1%), and G12V (12.5%). There was no difference in OS between KRAS subtypes (p=0.48) or TP53 subtypes (p=0.52). Patients with TP53 WT had a numerically longer but not statistically significant survival (median 1.65 years versus 1.16 years in patients with TP53 mutations, p=0.20). When each KRAS subtype was examined, patients with tumors with G12V but no TP53 mutation had longer OS (median 2.42 years) than those with WT KRAS or non-G12V mutation (median 1.38 years, p=0.02). Mutations in DDR genes were more frequently seen in the KRAS WT (33.3%) and G12D groups (15.6%), compared to that in the G12V (10.4%), G12R (10.5%) groups. Unique co-mutations were observed in certain KRAS subtypes but not others. Conclusions: In this retrospective study of comprehensive genomic and clinical data of pancreatic cancers, we found that KRAS or TP53 mutation subtypes had no significant impact on OS. Different KRAS subtypes have unique co-occurring genomic alterations, which may be clinically relevant as novel KRAS inhibitors continue clinical development.[Table: see text]