HPV status fully mediates sex-related survival differences in oropharyngeal cancer: a population-based analysis with formal interaction testing

Objectives To determine whether sex independently predicts survival in oropharyngeal squamous cell carcinoma and whether human papillomavirus status mediates apparent sex-related survival differences at the population level. Methods Population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database (17 Registries, 2018–2021). Multivariable Cox regression and a formal sex–human papillomavirus interaction test (likelihood ratio test) were performed in 19,716 patients with known p16/HPV status. Results p16-positive disease was more prevalent in males (73.6 per cent vs. 56.2 per cent; p < 0.001). Within human papillomavirus subgroups, survival did not differ significantly between sexes (all p > 0.30). After full adjustment, female sex was not independently associated with overall survival (hazard ratio 0.98; 95 per cent confidence interval 0.91–1.05; p = 0.52) or disease-specific survival (hazard ratio 1.01; p = 0.80). The sex–human papillomavirus interaction was non-significant (hazard ratio 1.057; p = 0.459), confirming human papillomavirus status fully mediates the apparent female survival disadvantage. Conclusion Sex is not an independent prognostic variable in oropharyngeal squamous cell carcinoma. HPV/p16-based stratification remains the primary prognostic framework.