EGFR overexpression and macrophage infiltration correlate with poorer prognosis in HPV‐negative oropharyngeal cancer via STAT6 signaling

Background The prevalence of HPV‐negative oropharyngeal cancer (OPC) is higher in Asian countries. Patients with HPV‐negative OPC suffer poor outcomes. Multi‐omics analysis could provide researchers and clinicians with more treatment targets for this high‐risk group. We aimed to explore the prognostic significance of EGFR overexpression and macrophage infiltration in OPC, especially HPV‐negative OPC in this study. Methods EGFR alternation was evaluated with TCGA, PanCancer Atlas through cBioProtal. EGFR mRNA expression in HPV‐negative head and neck squamous cell carcinoma was analyzed using the Tumor Immune Estimation Resource (TIMER 2.0). We also examined EGFR/STAT6/MRC1 expression in paraffin‐embedded tissues from a p16‐negative OPC cohort. The correlation between EGFR expression and macrophage activation was explored using Person's correlation coefficient. The impact of biomarkers or macrophage infiltration on 5‐year overall survival and recurrence‐free survival were analyzed using Kaplan–Meier survival curves. Results EGFR alteration rate was 15%, 13%, and 0% for HPV‐negative HNSCC (excluding OPC), HPV‐negative OPC, and HPV‐positive OPC. High EGFR expression was associated with increased tumor infiltration of immune cells, such as macrophages. We observed positive correlations between EGFR, STAT6, and MRC1 expression in p16‐negative OPC. Higher MRC1 expression was associated with poorer survival rates. Conclusions There is strong correlation between EGFR overexpression and M2 polarization in patients with p16‐negative OPC. Immunotherapy with or without EGFR inhibitor could be considered in these high‐risk patients.