Guan Li, Torres-Saavedra Pedro A, Zhao Xiaobei, Major Michael B, Holmes Brittany J, Nguyen Ngan K, Kumaravelu Parasakthy, Hodge Tim, Diehn Maximilian, Zevallos Jose, Holsinger F Christopher, Emami Bahman, Jordan Richard C, Hayward Michele C, Sagar Stephen M, Morrison William, Schultz Christopher, Caudell Jimmy J, Jones Christopher U, Bratman Scott V, Galloway Thomas J, Ma Daniel J, Yom Sue S, Kudrimoti Mahesh, Kim Harold E, Harris Jonathan, Le Quynh-Thu, Hayes D Neil
School of Medicine, Stanford University, Stanford, California.
NRG Oncology Statistics and Data Management Center, American College of Radiology, Philadelphia, Pennsylvania.
Clin Cancer Res. 2025 May 1;31(9):1615-1624. doi: 10.1158/1078-0432.CCR-24-2334.
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.
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.
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).
NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer. See related commentary by Rao, p. 1563.
NFE2L2/KEAP1/CUL3突变已在细胞实验和动物模型中被证实与放射抗性相关。然而，由于多模式治疗方案，这些生物标志物的临床验证一直具有挑战性。本研究旨在利用一项III期试验的样本，调查NFE2L2/KEAP1/CUL3突变与患者预后之间的关联，包括局部失败、区域局部失败、无病生存期（DFS）和总生存期，该试验中患者接受了两种控制剂量的单纯放疗。
我们在NRG/RTOG 9512试验中，对250例接受根治性放疗的T2N0声门鳞状细胞癌随机患者的NFE2L2/KEAP1/CUL3突变进行了调查。共有119例患者有可用的生物标本，对其进行基于扩增子的下一代测序，以评估NFE2L2/KEAP1/CUL3突变的存在，而不考虑结果。在不了解临床结果的情况下评估NFE2L2/KEAP1/CUL3的突变情况。由独立的统计团队使用Cox模型（双侧α = 0.05）评估与临床结果的关联。
119例患者中有19例（16.0%）存在NFE2L2/KEAP1/CUL3突变。有突变和无突变患者的患者、治疗和肿瘤特征相似。与无突变患者相比，有突变的患者局部失败显著更多[风险比（HR）= 3.50；95%置信区间（CI），1.56 - 7.89；P = 0.0025]，区域局部失败也更多（HR = 3.80；95% CI，1.80 - 8.03；P = 0.0005）。在前两年中，突变组的DFS明显比未突变组差（HR = 2.88；95% CI，1.46 - 5.66；P = 0.0022）。突变组的中位DFS较短（10.3个月），而NFE2L2/KEAP1/CUL3完整的患者为4.2年。
NFE2L2/KEAP1/CUL3突变可能预测T2N0声门癌的放射治疗失败。见Rao的相关评论，第1563页。
