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Here we investigate <jats:italic>KRAS<\/jats:italic> ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS\/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy (\u201cPRINCE\u201d, NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p\u2009=\u20090.0010) but not G12V (p\u2009=\u20090.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p\u2009=\u20090.0002), but not G12V (p\u2009=\u20090.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.<\/jats:p>","DOI":"10.1038\/s41467-024-49915-5","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T21:01:36Z","timestamp":1720558896000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Circulating KRAS G12D but not G12V is associated with survival in metastatic pancreatic ductal adenocarcinoma"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2824-1282","authenticated-orcid":false,"given":"Jacob 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RHV reports he has received consulting fees from BMS, is an inventor on patents relating to cancer cellular immunotherapy, cancer vaccines, and KRAS immune epitopes (10286066, 9555105, 8722400, 7851591, 7754482, and 7385023), and receives royalties from Children\u2019s Hospital Boston for a licensed research-only monoclonal antibody. MHO report grants from the Parker Institute for Cancer Immunotherapy (PICI) during the conduct of this study as well as grants from BMS, Celldex, Psioxus, Genmab, Geistlich, Arcus, Elicio; grants and non-financial support from Stand Up To Cancer; and personal fees from Natera, Merus, and Alligator outside the submitted work. OER reports personal fees from Merck, Celgene, Five Prime Therapeutics, GlaxoSmithKline, Bayer, Roche\/Genentech, Puretech, Imvax and Sobi, as well as employment at and stock ownership of AstraZeneca outside the submitted work and has a patent pending (DFCI 2386.010) for methods that make use of pembrolizumab and trebananib. PFG reports stock ownership in Teiko.bio. TML reports Coherus Biosciences employment; stock ownership in AstraZenca and Coherus Biosciences. ZAW reports grants from PICI during the conduct of this study as well as research funding from BMS, Arcus, and Plexxikon and outside the submitted work and consulting\/DSMB from BMS, Pfizer, Merck, Eli Lilly, Daiichi, AstraZeneca, Arcus, Novartis, Ipsen, Seagen, Alligator, Boehringer Ingelheim, Astellas, Eisai and Genentech\/Roche. GAF reports personal fees from Merck, Roche\/Genentech and CytomX outside the submitted work; and his spouse owns stock in Seattle Genetics. JXY reports stock in and employment with Bristol Myers Squibb. CWA reports Personalis, Inc. employment. JET reports research funding from PICI during the conduct of this study. KAR reports research funding from Clovis Oncology, BMS, GSK, and Lilly Oncology, membership on advisory boards for Carisma Therapeutics (2021), Astrazenca (2022), BMS (2022 and 2024), Synovation (2024), Merus (2024), Guardant (2024), the Medical Affairs Advisory Council for FMI (2023\u20132025), and consultanting for MOMA (2024). LDM is a current employee of BillionToOne and former employee of Personalis, a company that PICI paid to produce sequence information for some samples reported in this paper as part of a collaboration. He reports stock ownership in Personalis. SSY reports employment with Century Therapeutics. NB reports employment by Prelude Therapeutics, Inc. DMD reports current employment by Sanofi US and no other competing interests related to the work presented. ELC reports research funding or non-financial support from PICI, AstraZeneca, GuardantHealth, United Healthcare Group (UHG), Tempus, C2i, Oncocyte, Merck, ChipDX, Becton Dickinson and NIH\/NCI. She received personal fees from BMS and Foundation Medicine. TBK reports grants from Bristol-Meyers Squibb, Eli Lilly Corporation, Genentech, Taiho, Xencor, Tempest Therapeutics, BioNTech, Boehringer Ingelheim, Replimune, Genfit, Totus Medicines, and PMV Pharma outside of the submitted work and personal fees from Incyte, AstraZeneca, Nucorion, Hepatitis B Foundation, Pfizer, Taiho, and Synnovation Therapeutics, all outside of the submitted work. SMB is an employee and shareholder of Personalis Inc, a company which performed genomic sequencing and joint research for the work in this publication. ROC is also an inventor on US patent number 09183496 issued to Personalis, which describes the genomic analyses in the Personalis sequencing platform used to sequence the samples in this study. He is also an employee of Personalis, a company which performed genomic sequencing and joint research for the work in this publication. LJP reports employment with Noetik, Inc. AHK reports research funding (paid directly to his institution) from Apexigen, Astellas, BMS, Celgene, Crystal Genomics, LEAP Therapeutics, Roche\/Genentech, Verastem, the Pancreatic Cancer Action Network (PanCAN), and Parker Institute for Cancer Immunotherapy (PICI); and consulting\/DSMB for Aadi, Arcus, Eisai, Fibrogen, Grail, Ipsen, Merus, and Roche\/Genentech. JRE reports research funding (institutional) from Oncolys, Gilead, Amgen, Hutchmed, Merck, Arcus and consulting\/advisory board fees from Merck, Oncolys, Exelixis, Daiichi Sanyko. Additionally, she reports employment and stock for her spouse at Janssen and Merus. PSW, DMM, SMP, CNS, ZW, MY, DB, WL, SC, CC, QL, AAA, URT, PJO, CJS, HS, RAW, JPL and CRC report no competing interests related to the work presented.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5763"}}