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Understanding progression mechanisms and developing new targeted therapies is imperative in pancreatic ductal adenocarcinoma (PDAC). In this study, 80 metastatic PDAC patients were prospectively recruited and divided into discovery (n=37) and validation (n=43) cohorts. Tumor and plasma samples taken at diagnosis were pair analyzed using whole exome sequencing (WES) in patients belonging to the discovery cohort alone. The variant allele frequency (VAF) of KRAS mutations was measured by ddPCR in plasma at baseline and response assessment in all patients. Plasma WES identified at least one pathogenic variant across the cohort, uncovering oncogenic mechanisms, DNA repair, microsatellite instability, and alterations in the TGFb pathway. Interestingly, actionable mutations were mostly found in plasma rather than tissue. Patients with shorter survival showed enrichment in cellular organization regulatory pathways. Through WES we could identify a specific molecular profile of patients with liver metastasis, which exhibited exclusive mutations in genes related to the adaptive immune response pathway, highlighting the importance of the immune system in liver metastasis development. Moreover, KRAS mutations in plasma (both at diagnosis and persistent at follow-up) correlated with shorter progression free survival (PFS). Patients presenting a reduction of over 84.75 % in KRAS VAF at response assessment had similar PFS to KRAS-negative patients. Overall, plasma WES reveals molecular profiles indicative of rapid progression, potentially actionable targets, and associations between adaptive immune response pathway alterations and liver tropism., Competing Interests: Declaration of competing interest AC declares institutional research funding from Genentech, Merck Serono, BMS, MSD, Roche, Beigene, Bayer, Servier, Lilly, Natera, Novartis, Takeda, Astellas and Fibrogen and advisory board or speaker fees from Merck Serono, Roche, Servier, Takeda and Astellas. NT declares advisory board or speaker fees from Merck Serono, Servier, Pfizer, Natera and Guardant Health. MH declares advisory board and speaker fees from Servier. TF declares institutional research funding from Genentech, Adapt immune, Roche, Beigene, Astelas, BMS, Daichii Sanyo, Amgen and speaker fees from Astrazeneca, Amgen, Bayer, BMS, Lilly, MSD and Servier. VG declares advisory board fees from Boehringer Ingelheim and institutional research funding from Bayer, Boehringer, Roche, Genentech, Merck Serono, Beigene, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Natera, Sierra Oncology, AstraZeneca, Medimmune, BMS, MSD. SR declares personal fees as an invited speaker from Amgen, MSD and Servier. Advisory board fees from Amgen, Servier and Sirtex and institutional funding from Ability Pharmaceuticals, Astellas, G1 Therapeutics, Hutchinson, Menarini, Mirati, Novartis, Pfizer, Pierre Fabre, Roche and Seagen. LS declares advisory board or speaker fees from Johnson and Johnson, Medtronic, Baxter, Cella Medical Solutions. The remaining authors declare no competing interests. All authors have read the journal's policy on disclosure of potential conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.) more...