Association between Locoregional Failure and NFE2L2/KEAP1/CUL3 Mutations in NRG/RTOG 9512: A Randomized Trial of Radiation Fractionation in T2N0 Glottic Cancer

Abstract

Purpose: NFE2L2/KEAP1/CUL3 mutations have been validated for radiation resistance in cell-based assays and animal models. However, clinical validation of these biomarkers has been challenging due to multimodality treatment regimens. This study aims to investigate the association between NFE2L2/KEAP1/CUL3 mutations and patient outcomes, including local failure (LF), locoregional failures (LRF), disease-free survival (DFS) and overall survival (OS), using samples from a phase III trial in which patients were treated with radiation monotherapy at 2 controlled doses. Experimental Design: We investigated NFE2L2/KEAP1/CUL3 mutations in 250 randomized patients with T2N0 glottic SCC receiving definitive RT in NRG/RTOG 9512 trial, 119 had available biospecimens that were subjected to amplicon-based next-generation sequencing to assess for presence of NFE2L2/KEAP1/CUL3 mutations without regard to outcomes. Mutations in NFE2L2/KEAP1/CUL3 were assessed blinded to clinical outcomes. Cox models (2-sided alpha = 0.05) were used to evaluate the association with clinical outcomes, performed by an independent statistical team. Results: Nineteen of 119 patients (16.0%) had NFE2L2/KEAP1/CUL3 mutations. Patient, treatment, and tumor characteristics were similar between those with and without mutations. Patients with mutation compared to those without had significantly more LF [HR 3.50 (95% CI 1.56, 7.89), p=0.0025] and LRF [HR 3.80 (95% CI 1.80, 8.03), p=0.0005]. DFS was significantly worse for the mutated compared to the non-mutated group in the first two years [HR 2.88 (95% CI 1.46, 5.66), p=0.0022]. Median DFS was shorter in the mutation group (10.3 months) versus those with intact NFE2L2/KEAP1/CUL3 (4.2 years). Conclusion: NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer.