Characteristics of <i>KRAS</i> WT pancreatic adenocarcinomas: results of a large French multicentric cohort.

BackgroundGenome and transcriptome analysis has enhanced the characterisation of pancreatic ductal adenocarcinoma (PDAC), paving the way for targeted therapies. Tumours KRAS wild type (WT) represent a unique subgroup.ObjectivesCharacterise the population and molecular abnormalities present in KRAS WT PDAC.DesignClinical and molecular data from a large retrospective cohort of KRAS WT PDAC were analysed.MethodsNext-generation sequencing (NGS) was used to analyse DNAs and RNAs, allowing molecular and transcriptomic characterisation.ResultsWe identified 93/1059 (9%) KRAS WT PDAC, among which eight had druggable fusions (n = 8/30 contributive samples), six had BRAF mutations and 19 (n = 19/47) had mutations in homologous recombination (HR) pathway genes. Potential molecular targets in this series may be underestimated due to many non-contributive results. Clinical characteristics and survival did not differ between patients with KRAS WT and KRAS-mutated tumours. Transcriptomic data were available for 350 samples. Their analysis shows a difference in phenotype between mutated and WT tumours, with a molecular profile that appears to be better prognostic for KRAS WT tumours.ConclusionKRAS WT tumours are enriched with molecular abnormalities of therapeutic interest. These include oncogene driver alterations (gene fusions and mutations) and mutations in genes of the HR pathway. Targeted therapy strategies for PDAC rely on molecular testing beyond RAS, but further research is needed to identify new therapeutic approaches that improve outcomes in PDAC.