TY - JOUR
T1 - Association between Locoregional Failure and NFE2L2/KEAP1/CUL3 Mutations in NRG/RTOG 9512
T2 - A Randomized Trial of Radiation Fractionation in T2N0 Glottic Cancer
AU - Guan, Li
AU - Torres-Saavedra, Pedro A
AU - Zhao, Xiaobei
AU - Major, Michael B
AU - Holmes, Brittany J
AU - Nguyen, Ngan K
AU - Kumaravelu, Parasakthy
AU - Hodge, Tim
AU - Diehn, Maximilian
AU - Zevallos, Jose P
AU - Holsinger, F Christopher
AU - Emami, Bahman
AU - Jordan, Richard C
AU - Hayward, Michele C
AU - Sagar, Stephen M
AU - Morrison, William
AU - Schultz, Christopher
AU - Caudell, Jimmy J
AU - Jones, Christopher U
AU - Bratman, Scott V
AU - Galloway, Thomas J
AU - Ma, Daniel J
AU - Yom, Sue S
AU - Kudrimoti, Mahesh
AU - Kim, Harold E
AU - Harris, Jonathan
AU - Le, Quynh-Thu
AU - Hayes, D Neil
N1 - ©2024 American Association for Cancer Research.
PY - 2025/5/1
Y1 - 2025/5/1
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Biomarkers, Tumor/genetics
KW - Carcinoma, Squamous Cell/genetics
KW - Cullin Proteins/genetics
KW - Disease-Free Survival
KW - Dose Fractionation, Radiation
KW - Female
KW - Glottis/pathology
KW - Humans
KW - Kelch-Like ECH-Associated Protein 1/genetics
KW - Laryngeal Neoplasms/radiotherapy
KW - Male
KW - Middle Aged
KW - Mutation
KW - NF-E2-Related Factor 2/genetics
KW - Neoplasm Recurrence, Local/epidemiology
KW - Neoplasm Staging
KW - Prognosis
UR - http://www.scopus.com/inward/record.url?scp=105004562552&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-24-2334
DO - 10.1158/1078-0432.CCR-24-2334
M3 - Article
C2 - 39656603
SN - 1078-0432
VL - 31
SP - 1615
EP - 1624
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -