Abstract Background: While blood-based next-generation sequencing is increasingly integral to clinical practice across various malignancies, the routine assessment of circulating tumor DNA (ctDNA) in head and neck cancer remains underexplored, with limited supportive data. Methods: This study focused on head and neck cancer patients enrolled in the Gustave Roussy precision medicine program (STING, NCT04932525), undergoing liquid biopsy (LB) with the FoundationOne Liquid CDX panel. The Molecular Tumor Board discussed cases, calculating Tumor Fraction (TF) based on aneuploidy, categorizing it as high or low with a 10% cutoff. Results: The analysis encompassed 239 LBs from 214 patients with relapsed or metastatic head and neck cancers. Of these, 59 LBs were from 57 patients showing stability or positive response (SD/R), while 180 were from 167 patients at diagnosis or disease progression (BL/PD). Notably, 156 (73%) were male, with a median age of 61 years. Within the cohort, 65% of LBs were from patients with squamous cell carcinomas (SCC), 15% adenoid cystic carcinomas (ACC), and 20% other histologies mainly adenocarcinomas. The anatomical distribution included 59 LBs from salivary gland (SG) cancers, 49 oropharynx (OP), 48 oral cavity (OC), and others including larynx, hypopharynx, sinus and nasopharynx. Among LBs performed at BL/PD, 72% were informative, while only 36% were so at SD/R. The proportion of informative biopsies varied across anatomical sites. For SCC, TP53 mutations were most prevalent (71%), followed by TERT and PIK3CA variants, and FGF19 and FGF3 amplifications. ACCs showed NOTCH1 mutations (6/19, 32%) as the most common, followed by TP53 and various other variants. In the entire cohort, clonal hematopoiesis-related variants were identified, with 40% showing at least one of DNMT3A, CHEK2, or ASXL1. Patients with low TF at BL/PD exhibited significantly improved overall survival (21.6 vs. 7.6 months, HR 0.35, 95% CI 0.23 - 0.53, p < 0.0001), consistent across subgroups except for OP.Conclusion: This study demonstrates the feasibility of liquid biopsy in HNSCC and rare head and neck tumors, providing valuable therapeutic and prognostic insights. The findings underscore the potential of liquid biopsy as a valuable tool in clinical decision-making for head and neck cancer patients. Citation Format: Filippo Gustavo Dall'Olio, Damien Vasseur, Lea Loriguet, Francois Regis Ferrand, Antoine Moya-Plana, Yungan Tao, Mariana Iacob, Karim Benihoud, Odile CASIRAGHI, Catherine Brenner, Pierre Busson, Philippe Gorphe, Santiago Ponce, Pierre Blanchard, Etienne Rouleau, Yohann Loriot, Ludovic Lacroix, Antoine Italiano, Ingrid Breuskin, Caroline Even. Feasibility and clinical utility of blood based NGS in head and neck carcinomas: A single center experience from precision medicine program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2414.