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
PY - 2024/12/10
Y1 - 2024/12/10
N2 - 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.
AB - 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.
U2 - 10.1158/1078-0432.CCR-24-2334
DO - 10.1158/1078-0432.CCR-24-2334
M3 - Article
C2 - 39656603
SN - 1078-0432
JO - Clinical Cancer Research
JF - Clinical Cancer Research
ER -