Background: Pancreatic adenocarcinoma (PC) is the fourth leading cause of cancer deaths, with increased incidence among patients (pts) younger than 50 years old (y.o). Small cohort studies suggest early-onset PC (EOPC, diagnosis at <50 yrs old) tumors may have a unique biology, harboring a higher proportion of KRAS wild-type status (KRAS WT) and an enrichment of targetable mutations/fusions compared to non-EOPC. In addition, therapy targeted towards oncogenic fusions in KRAS WT tumors has shown meaningful clinical responses in PC patients. Here, we investigate the prevalence of fusions, mutations, and homologous recombination deficiency (HRD) in KRAS WT PC to identify potential targets for therapeutic intervention, and compare EOPC to non-EOPC to better characterize EOPC differences.

Methods: De-identified records from 4,956 PC pts with formalin-fixed, paraffin-embedded tumor biopsies sequenced using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; full transcriptome RNA-seq) were retrospectively reviewed. Fusions were detected from RNA-seq data via the Tempus bioinformatics pipeline. Mutations identified included germline and/or somatic single-nucleotide variants and insertions/deletions. HRD status was determined from RNA-seq data by the Tempus HRD test. Significance was determined as FDR-corrected p-values <0.05.

Results: Across the entire cohort, 21% tumors were KRAS WT. HRD was more frequent in KRAS WT (7.9%) compared to KRAS MUT (3.1%) (P<0.001). Significant somatic mutational differences between the KRAS WT and KRAS MUT cohorts included BRAF (5.0% vs 0.2%), CDKN2A (5.4% vs 25%), ARID1A (3.6% vs 8.6%), CTNNB1 (1.3% vs 0.3%), and TSC2 (1.2% vs 0.1%) (all P<0.001). Actionable rearrangements were enriched to the KRAS WT cohort (10% vs 2.1%, P<0.001); the most common fusion partners include NRG1, MET, RAF1, BRAF, NTRK1-3, FGFR 1-4, and RET. TMB-high (10 muts/Mb) and MSI high were more common in KRAS WT (2.9% and 1.0%) compared to KRAS MUT (1.7% and 0.4%) tumors (P=0.015) . Additionally, 382 patients were classified as EOPC. KRAS WT tumors comprised 30% of EOPCs, 22% of the 50-70 y.o. cohort, and 17% of the >70 y.o. cohort. Germline (pathogenic/likely pathogenic) alterations in BRCA1 and BRCA2 were more frequent in EOPCs (2.0% and 4.5%) compared to the 50-70 y.o. (0.4% and 1.7%) and >70 y.o. (0.4% and 0.8%) cohorts (P=0.015 and <0.001, for BRCA1 and BRCA2 respectively). There were no statistical differences in actionable genes detected in EOPC vs non EOPC. HRD was found in higher frequency in EOPC (5.4%) and decreased in age cohorts 50-70 y.o. (4.7%) and >70 y.o. (2.5%) P=0.047.

Conclusions: HRD, TMB-H/MSI-H and oncogenic rearrangements are more prevalent in KRAS
WT PCwhen compared with KRAS MUT. These molecular analyses may provide additional targeted therapy options for patients, warranting increased comprehensive genomic profiling for this population.

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