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 Bratman; Thomas J Galloway; Daniel J Ma; Sue S Yom; Mahesh Kudrimoti; Harold E Kim; Jonathan Harris; Quynh-Thu Le; D Neil Hayes

doi:10.1158/1078-0432.CCR-24-2334

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 Bratman

Thomas J Galloway, Daniel J Ma, Sue S Yom, Mahesh Kudrimoti, Harold E Kim, Jonathan Harris, Quynh-Thu Le, D Neil Hayes

Stanford University
National Cancer Institute
University of Tennessee Health Science Center
Washington University St. Louis
The Pittsburgh VA Medical Center and the University of Pittsburgh School of Medicine
Loyola University Medical Center
University of California
University of North Carolina at Chapel Hill
Juravinski Cancer Center at Hamilton Health Sciences
University of Texas MD Anderson Cancer Center
Medical College of Wisconsin
Moffitt Cancer Center
Sutter Sacramento Medical Center
Princess Margaret Cancer Centre
Mayo Clinic
University of Kentucky
Wayne State University
NRG Oncology
Univeristy of Tennessee Health Science Center

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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 = 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 = 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).

CONCLUSIONS: NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer. See related commentary by Rao, p. 1563.

Original language	English
Pages (from-to)	1615-1624
Number of pages	10
Journal	Clinical Cancer Research
Volume	31
Issue number	9
Early online date	Dec 10 2024
DOIs	https://doi.org/10.1158/1078-0432.CCR-24-2334
State	Published - May 1 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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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10.1158/1078-0432.CCR-24-2334

Cite this

Guan, L., Torres-Saavedra, P. A., Zhao, X., Major, M. B., Holmes, B. J., Nguyen, N. K., Kumaravelu, P., Hodge, T., Diehn, M., Zevallos, J. P., Holsinger, F. C., Emami, B., Jordan, R. C., Hayward, M. C., Sagar, S. M., Morrison, W., Schultz, C., Caudell, J. J., Jones, C. U., ... Hayes, D. N. (2025). Association between Locoregional Failure and NFE2L2/KEAP1/CUL3 Mutations in NRG/RTOG 9512: A Randomized Trial of Radiation Fractionation in T2N0 Glottic Cancer. Clinical Cancer Research, 31(9), 1615-1624. https://doi.org/10.1158/1078-0432.CCR-24-2334

@article{5b04af10b19140ee8555268c4c28e09d,

title = "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 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 = 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 = 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).CONCLUSIONS: NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer. See related commentary by Rao, p. 1563.",

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",

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

note = "{\textcopyright}2024 American Association for Cancer Research.",

year = "2025",

month = may,

day = "1",

doi = "10.1158/1078-0432.CCR-24-2334",

language = "English",

volume = "31",

pages = "1615--1624",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "9",

}

Guan, L, Torres-Saavedra, PA, Zhao, X, Major, MB, Holmes, BJ, Nguyen, NK, Kumaravelu, P, Hodge, T, Diehn, M, Zevallos, JP, Holsinger, FC, Emami, B, Jordan, RC, Hayward, MC, Sagar, SM, Morrison, W, Schultz, C, Caudell, JJ, Jones, CU, Bratman, SV, Galloway, TJ, Ma, DJ, Yom, SS, Kudrimoti, M, Kim, HE, Harris, J, Le, Q-T & Hayes, DN 2025, 'Association between Locoregional Failure and NFE2L2/KEAP1/CUL3 Mutations in NRG/RTOG 9512: A Randomized Trial of Radiation Fractionation in T2N0 Glottic Cancer', Clinical Cancer Research, vol. 31, no. 9, pp. 1615-1624. https://doi.org/10.1158/1078-0432.CCR-24-2334

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 - 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 = 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 = 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).CONCLUSIONS: NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer. See related commentary by Rao, p. 1563.

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 = 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 = 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).CONCLUSIONS: NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer. See related commentary by Rao, p. 1563.

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 - https://www.scopus.com/pages/publications/105004562552

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 -

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

Abstract

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Keywords

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