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Background: Chemotherapies have limited efficacy in pancreatic cancer (PC) and biliary tract cancer (BTC), underscoring the need for new regimens. Recently, tumor-agnostic approaches have been developed for some targeted therapies in advanced solid tumors; however, the frequency of alterations by clinical and genomic background is unclear in PC and BTC.Methods: To assess the frequencies of druggable gene alterations and investigate new potential therapeutic targetable genomic alterations, advanced PC and BTC patients were tested with comprehensive genomic profiling at Foundation Medicine during the course of clinical care.Results: A total of 16 913 PC patients and 3031 BTC patients were available for analyses, and frequencies of genomic alterations were stratified by age (≥40 years or <40 years), microsatellite instability status, tumor mutational burden status (high ≥10 or low <10 Muts/Mb), and select genomic alterations. Alterations in BRCA2, BRAF, ERBB2, CDK12, PIK3CA, FGFR2, EGFR, and other potential targets were seen across cohorts, with enrichment observed within particular subsets such as in PC patients lacking a KRAS mutation. In BTC patients, the rate of ERBB2 amplification was statistically significantly higher in the tumor mutational burden-high population (23.3% vs 13.7%). Interestingly, CDK12 rearrangement was observed in BTC patients with ERBB2 amplification tumors. In patients younger than 40 years, FGFR2 rearrangement (4%) was observed in PC: GATA6 amplification (11.1%) and rearrangement of BRAF (2.8%)FGFR2 (5.6%) was observed in BTC patients.Conclusions: We identified an appreciable frequency of immunotherapy biomarkers and targetable gene alterations in both PC and BTC, with notable frequencies in PC samples lacking KRAS mutations and children or adolescent and young adult populations, that should encourage comprehensive genomic profiling testing. [ABSTRACT FROM AUTHOR]