Prognostic gene expression signatures for HPV-negative head and neck squamous cell carcinoma

Background: Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths worldwide, with HPV-negative cases being particularly aggressive. These cases often show poor prognosis and low responsiveness to radiotherapy. Improved prognostic tools and treatment strategies are needed to enhance outcomes. Aim: To evaluate the prognostic value of various gene expression signatures in predicting survival outcomes in HPV-negative HNSCC patients receiving radiotherapy and to compare their accuracy against the current TNM staging system. Methods: This observational cohort study used data from the European BD2Decide project, systematically analyzing gene expression in loco-regionally advanced, non-metastatic HPV-negative HNSCC patients (stage III-IVa/b) treated with curative radiotherapy (post-operative or definitive) between 2008 and 2017. The primary outcome was overall survival (OS), with secondary outcomes including disease-free survival (DFS), distant metastasis-free survival (DMFS), and loco-regional recurrence-free survival (LRRFS). The prognostic performance of selected gene expression signatures was evaluated using receiver operating characteristic (ROC) curves and hazard ratios (HR) from Cox models. Results: The study included 783 patients, with a median age of 63 years, mostly male (68 %), with significant tobacco (84 %) and alcohol (69 %) exposure. The 172-gene signature (172GS) showed the highest prognostic accuracy, outperforming the TNM system in predicting OS, DFS, DMFS, and LRRFS. Multivariable analysis confirmed its independent prognostic value. Conclusions: The 172GS gene signature offers superior prognostic information compared to TNM staging, supporting its potential use for better risk stratification and personalized treatment planning in HPV-negative HNSCC. Future trials should consider tumor biology and gene signatures for better patient selection. Trial Registration: NCT02832102.