Comprehensive genomic profiling (CGP) in KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC).

271Background: Mutations in oncogenic KRAS have been widely accepted as the signature genomic alteration (GA) in sporadic PDAC, but therapeutic efforts aimed at targeting constitutively activated KRAS have been disappointing. We examined somatic GAs in KRAS WT PDAC utilizing a CGP platform to identify actionable targets. Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) PDAC clinical specimens and CGP was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 unique reads. Alterations in the RAS/RAF/MEK pathway genes (KRAS, NRAS, HRAS, ARF, BRAF, EGFR, MAP2K2, MAP2K1, MAPK1) and DNA Damage Repair (DDR) pathway genes (BRCA1/2, ATM, ATR, BRIP1, RAD50, RAD51, RAD52, PALB2, CHEK1, CHEK2) were examined. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. TMB was categorized based on mutations(m)/Mbp of DNA - high (H; > 20), Intermediate (I; 8-20) and low (L; < 8)....