Trial reportClinical cancer research : an official journal of the American Association for Cancer Research2025
Association between Locoregional Failure and NFE2L2/KEAP1/CUL3 Mutations in NRG/RTOG 9512: A Randomized Trial of Radiation Fractionation in T2N0 Glottic Cancer.
Trial report in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Role of molecular driver mutations in recurrence of early-stage laryngeal cancer following narrow field definitive radiotherapy.Oral oncology reports · 2026Article
- Nrf2 as a redox checkpoint in autoimmune joint inflammation: microenvironmental redox control across the arthritis spectrum.Frontiers in immunology · 2026Review
- Wise as a Serpent and Gentle as a Dove: Pharmacological Targeting of NRF2/KEAP1 Pathway from Treasure Trove of Mother Nature.Drug design, development and therapy · 2026Review
- Transoral laser microsurgery and open partial laryngectomy for limited-stage glottic cancer: a review of indications, oncologic and functional outcome, and prognosis.American journal of translational research · 2026Review
- Micro- and Nanoplastics and Functional Nutrients in Human Health: Epigenetic Mechanisms and Cellular Resilience Signaling in Brain Insulin Resistance and the Risk of Alzheimer's Disease.International journal of molecular sciences · 2025Review
- Effects of the Pharmacological Modulation of NRF2 in Cancer Progression.Medicina (Kaunas, Lithuania) · 2025Review
- Nrf2 Hyperactivation as a Driver of Radiotherapy Resistance and Suppressed Antitumor Immunity in Head and Neck Squamous Cell Carcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
Corrections and comments
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Authors and funding
28 authors.
Funding
Abstract
purposeNFE2L2/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
methodsWe 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 = 0.05) were used to evaluate the association with clinical outcomes, performed by an independent statistical team.
resultsNineteen 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 = 3.50; 95% confidence interval (CI), 1.56-7.89; P = 0.0025] and locoregional failure (HR = 3.80; 95% CI, 1.80-8.03; P = 0.0005). DFS was significantly worse for the mutated compared with the nonmutated group in the first 2 years (HR = 2.88; 95% CI, 1.46-5.66; P = 0.0022). The median DFS was shorter in the mutation group (10.3 months) versus those with intact NFE2L2/KEAP1/CUL3 (4.2 years).
conclusionsNFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer. See related commentary by Rao, p. 1563.
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