Background: Pancreas adenocarcinoma (PC) is a challenging disease with overall single digit 5-year survivorship. Few validated biomarkers exist for directing treatment in PC. Only one targeted agent (erlotinib) is FDA-approved and was developed in an unselected population (Moore, et al, J Clin Oncol, 2007). Identification of individual PC genomic and phenotypic profiles may yield targets with novel therapeutic application. Methods: 2400 cases referred internationally to Caris Life Sciences were evaluated using a combination of sequencing (Sanger or next generation sequencing (NGS)), protein expression (immunohistochemistry), and/or gene amplification (CISH or FISH). Results: The published PC molecular profile (24 cases, Jones, et al, Science, 2008) is consistent with the 2400 cases evaluated; KRAS was the most common mutation N=1190/1460 (82%) followed by TP53, N=175/310 (56%), and SMAD4, N=39/324 (12%). Mutations in BRAF, EGFR, HER2, FLT3, HRAS, PDGFRA and PTEN were identified exclusively in KRAS WT cases. Conclusions: 18% of PC cases were KRAS WT, representing a significant minority of patients with PC. Aberrant signaling through the RAS/MAPK pathway through oncogenic mutations in HRAS, BRAF, EGFR, HER2 and PDGFR was found in a very small subset of KRAS WT cases (8%), and the likely benefit of anti-EGFR-based therapies is limited to those patients with KRAS wild-type tumors lacking downstream oncogenic activation of this pathway. IHC evaluation of certain markers, e.g., RRM1, SPARC, etc. may help select drugs and refine treatment decision making for certain patients. Evaluating these profiles with clinical outcomes will provide valuable insight into the clinical behavior in genomically defined subsets and will assist in developing rational combinations of targeted agents in PC.