Simple SummaryThere is a need to identify new translational prognostic biomarkers in head and neck cancer. Metabolomics, the study of small molecules resulting from cellular metabolism, is an emerging and promising field regarding head and neck cancer. We performed metabolomics on patients’ blood prior to treatment and found that it can divide patients into high-risk and low-risk groups based on their cancer progression and survival. We believe our study provides compelling results to consider metabolomics as a translational prognostic biomarker and that it may offer novel information for patient risk stratification. With continued research, we hope to gain a fuller understanding of how metabolomics may aid in the early detection, prognosis, treatment monitoring, and targeted therapies of head and neck cancer.AbstractThere is growing evidence that the metabolism is deeply intertwined with head and neck squamous cell carcinoma (HNSCC) progression and survival but little is known about circulating metabolite patterns and their clinical potential. We performed unsupervised hierarchical clustering of 209 HNSCC patients via pre-treatment plasma metabolomics to identify metabolic subtypes. We annotated the subtypes via pathway enrichment analysis and investigated their association with overall and progression-free survival. We stratified the survival analyses by smoking history. High-resolution metabolomics extracted 186 laboratory-confirmed metabolites. The optimal model created two patient clusters, of subtypes A and B, corresponding to 41% and 59% of the study population, respectively. Fatty acid biosynthesis, acetyl-CoA transport, arginine and proline, as well as the galactose metabolism pathways differentiated the subtypes. Relative to subtype B, subtype A patients experienced significantly worse overall and progression-free survival but only among ever-smokers. The estimated three-year overall survival was 61% for subtype A and 86% for subtype B; log-rankp= 0.001. The association with survival was independent of HPV status and other HNSCC risk factors (adjusted hazard ratio = 3.58, 95% CI: 1.46, 8.78). Our findings suggest that a non-invasive metabolomic biomarker would add crucial information to clinical risk stratification and raise translational research questions about testing such a biomarker in clinical trials.