NGFR expression predicts tumor recurrence in radiotherapy/chemoradiotherapy-treated HPV-negative pharyngeal squamous cell carcinoma

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with high mortality rates, often exhibiting resistance to conventional treatments such as radiotherapy (RT) or a combination of chemotherapy and radiotherapy (CRT). The nerve growth factor receptor (NGFR, also known as p75NTR or CD271) is a well-established cancer stem cell marker in melanoma, where it has been linked to resistance to multiple therapies. In HNSCC, NGFR has been reported as a poor prognostic marker, with its overexpression associated with disease progression. However, its contribution to therapy resistance in HNSCC remains unknown. METHODS: NGFR expression was assessed by immunohistochemistry in pre-treatment biopsies from a cohort of RT/CRT-treated HPV-negative patients (n = 52), and NGFR staining intensity was classified as negative, low, or high. Associations with recurrence-free survival and post-treatment recurrence were analyzed, including multivariable models and subgroup analyses. RESULTS: NGFR expression showed considerable heterogeneity across tumors. High NGFR intensity was significantly associated with shorter recurrence‑free survival compared with NGFR‑negative or low‑expressing tumors, and this association remained robust in multivariable analyses. Elevated NGFR intensity was also significantly linked to an increased risk of post‑treatment recurrence, with a pronounced enrichment of both local and overall recurrences in NGFR‑high tumors relative to NGFR‑negative/low cases. CONCLUSIONS: These results indicate that NGFR contributes to therapy resistance in HNSCC. Altogether, our findings support NGFR intensity in diagnostic biopsies as a clinically relevant predictive biomarker of recurrence after RT/CRT in HPV-negative HNSCC.