Associations Between OPN-CD44 Axis Genetic Variability, Plasma Osteopontin, and Treatment Outcomes in Head and Neck Squamous Cell Carcinoma

Inter-individual variability in outcomes following radiotherapy-based treatment remains a major challenge in head and neck squamous cell carcinoma (HNSCC). Osteopontin (OPN) and its receptor CD44 are key mediators of tumor progression, hypoxia-related treatment resistance, and metastatic dissemination. In this exploratory, hypothesis-generating study, we investigated selected functional polymorphisms in OPN (SPP1) and CD44 genes, together with pretreatment plasma OPN levels, in relation to overall survival (OS), locoregional recurrence-free survival (LRFS), and metastasis-free survival (MFS) in 242 HNSCC patients treated with curative-intent radiotherapy alone (RT) or combined with chemotherapy (RT + CT). In individual multivariable models, the OPN rs11730582 C and CD44 rs13347 T variants were associated with improved survival outcomes, while elevated OPN levels correlated with shorter OS. In full multivariable models, rs11730582 C and high OPN levels remained independent predictors of OS in the entire cohort. In the RT + CT subgroup, high OPN independently predicted worse OS, whereas rs13347 T was associated with better MFS. In the RT subset, rs11730582 CC independently predicted longer OS. These findings suggest that both germline variability within the OPN-CD44 signaling axis and circulating OPN levels are associated with treatment outcomes in HNSCC patients receiving radiotherapy-based regimens. Given the exploratory design, further validation in independent cohorts is warranted.