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Title: KEAP1/NFE2L2 mutations of liquid biopsy as prognostic biomarkers in patients with advanced non-small cell lung cancer : results from two multicenter, randomized clinical trials
Authors: Zhu, H
Xie, D
Yu, Y
Yao, L
Xu, B
Huang, L
Wu, S
Li, F
Zheng, Y
Liu, X
Xie, W
Huang, M
Li, H
Zheng, S
Zhang, D
Qiao, G
Chan, LWC 
Zhou, H
Issue Date: Jul-2021
Source: Frontiers in oncology, July 2021, v. 11, 659200
Abstract: Purpose: The KEAP1-NFE2L2 (Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2)) mutations are associated with resistance to chemotherapy or immunotherapy in non-small cell lung cancer (NSCLC). Conversely, it has been reported that NFE2L2 mutations potentiate improved clinical outcome with immunotherapy. However, therapeutic benefits for patients with KEAP1/NFE2L2 mutations remain unclear. The purpose of this study was to investigate the association between KEAP1/NFE2L2 and NSCLC prognosis, and to explore whether immunotherapy can improve prognosis in populations with KEAP1/NFE2L2 mutations.
Experimental Design: The impact of KEAP1/NFE2L2 mutations on survival outcomes in NSCLC patients received immunotherapy and chemotherapy was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, POPLAR (n = 211) and OAK (n = 642)). The Cancer Genome Atlas (TCGA) NSCLC cohort (n=998) and an in-house Chinese NSCLC cohort (n=733) was used For the analysis of immune-related markers.
Results: Compared with KEAP1/NFE2L2 wild-type, patients with KEAP1/NFE2L2 mutations were significantly associated with poorer overall survival (OS, HR = 1.97, 95% CI 1.48–2.63, P < 0.001) on atezolizumab and docetaxel (HR = 1.66, 95% CI 1.28–2.16, P < 0.001). In KEAP1/NFE2L2 mutant group, there was no significant difference in median OS between atezolizumab and docetaxel (HR 0.74, 95% CI 0.53–1.03, P = 0.07). NFE2L2/KEAP1 mutations were significantly associated with higher TMB values and PD-L1 expression in the OAK/POPLAR and in-house Chinese NSCLC cohorts. GSEA revealed that KEAP1/NFE2L2mutant subgroup was associated with deficient infiltration of CD4+ T cells, NK T cells and natural Treg cells, and lower expression of DNA damage response genes in TCGA NSCLC cohort.
Conclusions: Our study revealed that patients with KEAP1/NFE2L2 mutations have a worse prognosis than wild-type patients, both on immunotherapy and chemotherapy. In addition, in patients with KEAP1/NFE2L2 mutations, immunotherapy did not significantly improve prognosis compared to chemotherapy.
Keywords: Chemotherapy
Immunotherapy
KEAP1/NFE2L2
Non-small cell lung cancer
Prognostic
Publisher: Frontiers Research Foundation
Journal: Frontiers in oncology 
EISSN: 2234-943X
DOI: 10.3389/fonc.2021.659200
Rights: © 2021 Zhu, Xie, Yu, Yao, Xu, Huang, Wu, Li, Zheng, Liu, Xie, Huang, Li, Zheng, Zhang, Qiao, Chan and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (https://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The following publication Zhu H, Xie D, Yu Y, Yao L, Xu B, Huang L, Wu S, Li F, Zheng Y, Liu X, Xie W, Huang M, Li H, Zheng S, Zhang D, Qiao G, Chan LWC and Zhou H (2021) KEAP1/NFE2L2 Mutations of Liquid Biopsy as Prognostic Biomarkers in Patients With Advanced Non-Small Cell Lung Cancer: Results From Two Multicenter, Randomized Clinical Trials. Front. Oncol. 11:659200 is available at https://doi.org/10.3389/fonc.2021.659200
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