Background: Targeted therapy has a minimal role in PC, partly because PC has not yet been well molecularly characterized. Little is known about the molecular characteristics of the subset of PC that doesn’t carry KRAS mutations. Better knowledge would enhance our ability to develop targeted therapies. Methods: PC tumors submitted to Caris Life Sciences for IHC (protein expression), ISH (gene amplification), and NGS sequencing between 2009 and 2015 were studied. Chi-square tests determined differences. Results: A total of 2426 PC tumors were examined. KRAS mutations (85%) were the most frequent genetic alteration. Other commonly mutated genes were TP53 (63%), SMAD4 (13%), BRCA2 (12%), ATM/APC/NTRK1 (5% each), BRCA1 (4%) and cMET/PIK3CA (3% each). BRAF mutations were seen in 6% of the RAS WT tumors. When compared with KRAS MT, KRAS WT tumors had a greater frequency of BRCA1 (9% vs. 3%, p = 0.05), CTNNB1 (5% vs. 0.2%; p < 0.01), GNAS (4% vs. 1.5%, p = 0.02), and FGFR2 (1.2% vs. 0.1%, p < 0.01) mutations, whereas SMAD4 and TP53 mutations were higher in KRAS MT tumors (15% vs. 5%, p = 0.02; 68% vs. 28%, p < 0.01, respectively). KRAS MT tumors had higher expression (66% vs. 49%, p < 0.01) and amplification (2.5% vs. 0%, p = 0.04) of cMET, and higher expression of EGFR (90% vs. 82%, p = 0.04), whereas KRAS WT tumors had higher HER2 expression (2% vs. 0.4%, p < 0.01) and amplification (6% vs. 0.7%, p < 0.01). Comparing 1^o (n = 1099) with Met (n = 1327) PC, 1^o tumors had a higher frequency of “low” ERCC1 (81% vs. 63%, p < 0.01) and “low” RRM1 (87% vs. 77%, p < 0.01), and higher PD1+ TILs (45% vs. 34%, p < 0.01). Conversely, cMET (62% vs. 51%, p = 0.006), PDL1 (10% vs. 5%, p = 0.01), and TOPO1 (65 vs. 33, p < 0.01) were overexpressed at higher rates in Met PC. Lung Mets, had a higher expression of HER2 (2.3% vs. 0.5%; < 0.01), and PD1 TILs (50% vs. 33%; p = 0.03) than liver Mets, whereas, the PIK3CA mutation rate was higher in liver Mets (4% vs. 0%; p = 0.03). Conclusions: Genomic differences between KRAS WT vs. MT tumors suggest different carcinogenic pathways and tumor biology. 1^o tumors may carry genetic alterations that are distinct from distant Mets. Mutations in druggable genes (e.g., HER-2, PIK3CA, BRCA2) may provide therapeutic opportunities.