NRG/RTOG 9512 uncovers a subset of radiation resistant tumors driven by NRF2 mutations, providing opportunities for rational treatment stratification in early laryngeal squamous cell carcinoma

By Neil Hayes, MD, FASCO, MS, MPH
Vice Chair, NRG Oncology Head & Neck Cancer Committee; Co-Chair, NRG Oncology H&N Translational Working Group
Director, University of Tennessee Health Sciences, Center for Cancer Research

And Sidharth Puram, MD, PhD, FACS
Co-Chair, NRG Oncology H&N Translational Working Group; Lindburg Professor & Chair, Department of Otolaryngology – Head & Neck Surgery Director, Robert Ebert & Greg Stubblefield Head & Neck Tumor Center | Washington University

Recent analysis of the NRG/RTOG 9512 phase III trial provides important new insight into the biologic determinants of radiation response in early-stage laryngeal cancer. In this study of patients with T2N0 glottic squamous cell carcinoma treated uniformly with definitive radiotherapy, activating mutations in the NRF2 pathway genes (NFE2L2, KEAP1, and CUL3) were identified in approximately 16% of tumors and were strongly associated with treatment failure.

Patients harboring these mutations experienced significantly higher rates of local and locoregional failure, with hazard ratios of 3.5 and 3.8, respectively. Notably, disease-free survival was markedly shorter in the first two years among mutation-positive patients, highlighting a clinically meaningful radioresistant phenotype.

These findings are particularly impactful given the lack of validated biomarkers to guide treatment selection in early-stage laryngeal cancer, where both radiation and surgery are considered standard options. The results suggest that NRF2 pathway alterations may serve as the first molecular biomarker to inform this decision, identifying patients at high risk for radiation failure who may benefit from alternative strategies such as upfront surgery or treatment intensification.

Beyond laryngeal cancer, NRF2 pathway activation is common across multiple tobacco-associated malignancies, raising the broader possibility that this biomarker could inform radiation sensitivity in other disease sites. Prospective validation will be essential, but this work represents a significant step toward biomarker-driven, personalized radiation therapy within NRG Oncology. This study and other works by the Head and Neck Cancer Committee’s translational scientists illustrate the important discoveries enabled by biospecimens and other components collected on NRG Oncology trials.