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In Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

BACKGROUND : The prognosis of patients with HPV-negative advanced stage head and neck squamous cell carcinoma (HNSCC) remains poor. No prognostic markers other than TNM staging are routinely used in clinic. Epithelial-to-mesenchymal transition (EMT) has been shown to be a strong prognostic factor in other cancer types. The purpose of this study was to determine the role of EMT in HPV-negative HNSCC outcomes.

METHODS : Pretreatment tumor material from patients of two cohorts, totaling 174 cisplatin-based chemoradiotherapy treated HPV-negative HNSCC patients, was RNA-sequenced. Seven different EMT gene expression signatures were used for EMT status classification and generation of HNSCC-specific EMT models using Random Forest machine learning.

RESULTS : Mesenchymal classification by all EMT signatures consistently enriched for poor prognosis patients in both cohorts of 98 and 76 patients. Uni- and multivariate analyses show important HR of 1.6-5.8, thereby revealing EMT's role in HNSCC outcome. Discordant classification by these signatures prompted the generation of an HNSCC-specific EMT profile based on the concordantly classified samples in the first cohort (cross-validation AUC>0.98). The independent validation cohort confirmed the association of mesenchymal classification by the HNSCC-EMT model with poor overall survival (HR=3.39, p<0.005) and progression free survival (HR=3.01, p<0.005) in multivariate analysis with TNM. Analysis of an additional HNSCC cohort from PET-positive patients with metastatic disease prior to treatment further supports this relationship and reveals a strong link of EMT to the propensity to metastasize.

CONCLUSIONS : EMT in HPV-negative HNSCC co-defines patient outcome after chemoradiotherapy. The generated HNSCC-EMT prediction models can function as strong prognostic biomarkers.

van der Heijden Martijn, Essers Paul B M, Verhagen Caroline V M, Willems Stefan M, Sanders Joyce, de Roest Reinout H, Vossen David M, Leemans C René, Verheij Marcel, Brakenhoff Ruud H, van den Brekel Michiel W M, Vens Conchita


Chemoradiotherapy, Epithelial to mesenchymal transition, HNSCC, Head and neck cancer, Prognostic biomarkers, RNA-Seq