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

Li Guan, Pedro A Torres-Saavedra, Xiaobei Zhao, Michael B Major, Brittany J Holmes, Ngan K Nguyen, Parasakthy Kumaravelu, Tim Hodge, Maximilian Diehn, Jose P Zevallos, F Christopher Holsinger, Bahman Emami, Richard C Jordan, Michele C Hayward, Stephen M Sagar, William Morrison, Christopher Schultz, Jimmy J Caudell, Christopher U Jones, Scott V BratmanThomas J Galloway, Daniel J Ma, Sue S Yom, Mahesh Kudrimoti, Harold E Kim, Jonathan Harris, Quynh-Thu Le, D Neil Hayes

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Abstract

Purpose: NFE2L2/KEAP1/CUL3 mutations have been validated for radioresistance in cell-based assays and animal models. However, clinical validation of these biomarkers has been challenging because of multimodality treatment regimens. This study aims to investigate the association between NFE2L2/KEAP1/ CUL3 mutations and patient outcomes, including local failure, locoregional failure, disease-free survival (DFS), and overall survival, using samples from a phase III trial in which patients were treated with radiation monotherapy at two controlled doses. Patients and Methods: We investigated NFE2L2/KEAP1/ CUL3 mutations in 250 randomized patients with T2N0 glottic squamous cell carcinoma receiving definitive radiotherapy in the NRG/RTOG 9512 trial. A total of 119 patients had available biospecimens that were subjected to amplicon-based next-generation sequencing to assess for the presence of NFE2L2/ KEAP1/CUL3 mutations without regard to outcomes. Mutations in NFE2L2/KEAP1/CUL3 were assessed blinded to clinical outcomes. Cox models (two-sided α ¼ 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 with those without had significantly more local failure [HR ¼ 3.50; 95% confidence interval (CI), 1.56–7.89; P ¼ 0.0025] and locoregional failure (HR ¼ 3.80; 95% CI, 1.80–8.03; P ¼ 0.0005). DFS was significantly worse for the mutated compared with the nonmutated group in the first 2 years (HR ¼ 2.88; 95% CI, 1.46–5.66; P ¼ 0.0022). The median DFS was shorter in the mutation group (10.3 months) versus those with intact NFE2L2/KEAP1/CUL3 (4.2 years). Conclusions: NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer. See related commentary by Rao, p.

Original languageEnglish
Pages (from-to)1615-1624
Number of pages10
JournalClinical Cancer Research
Volume31
Issue number9
Early online dateDec 10 2024
DOIs
StatePublished - May 1 2025

Keywords

  • Adult
  • Aged
  • Biomarkers, Tumor/genetics
  • Carcinoma, Squamous Cell/genetics
  • Cullin Proteins/genetics
  • Disease-Free Survival
  • Dose Fractionation, Radiation
  • Female
  • Glottis/pathology
  • Humans
  • Kelch-Like ECH-Associated Protein 1/genetics
  • Laryngeal Neoplasms/radiotherapy
  • Male
  • Middle Aged
  • Mutation
  • NF-E2-Related Factor 2/genetics
  • Neoplasm Recurrence, Local/epidemiology
  • Neoplasm Staging
  • Prognosis

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