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. 2020 Jun;25(6):e955-e963.
doi: 10.1634/theoncologist.2019-0885. Epub 2020 Apr 28.

NFE2L2/KEAP1 Mutations Correlate with Higher Tumor Mutational Burden Value/PD-L1 Expression and Potentiate Improved Clinical Outcome with Immunotherapy

Xian Xu #  1 , Yang Yang #  2 , Xiaoyan Liu #  3 , Na Cao  3 , Peng Zhang  3 , Songhui Zhao  3 , Donglin Chen  3 , Li Li  4 , Yong He  4 , Xiaowei Dong  3 , Kai Wang  3   5 , Hanqing Lin  3 , Naiquan Mao  6 , Lingxiang Liu  7
Affiliations

NFE2L2/KEAP1 Mutations Correlate with Higher Tumor Mutational Burden Value/PD-L1 Expression and Potentiate Improved Clinical Outcome with Immunotherapy

Xian Xu et al. Oncologist. 2020 Jun.

Abstract

Background: Abnormalities in the KEPA1-NRF2 pathway have a role in cancer progression, metastasis, and resistance to chemo- and radiotherapies. Persistent activation of NRF2 associates with poor prognosis across different cancer types. However, the beneficial therapeutic strategy to harness this pathway in cancer remains unclear. This study aimed to investigate the clinical outcome with immunotherapy in NFE2L2/KEAP1 mutant population.

Materials and methods: We investigated the correlation between NFE2L2/KEAP1 mutations and tumor mutational burden (TMB) and programmed death-ligand 1 (PD-L1) expression status to identify the therapeutic vulnerability. For this purpose, relevance analysis with TMB value was performed in 9,040 patients with cancer, and relevance analysis with PD-L1 expression was performed in 3,457 patients. The Memorial Sloan Kettering Cancer Center (MSKCC) database and real-world evidence were used to assess the immunotherapy response in NFE2L2/KEAP1 mutant subsets.

Results: NFE2L2/KEAP1 mutations occurred in various cancers, and the highest mutation incidences occurred in lung squamous cell carcinoma (LUSC) at 19.16% (NFE2L2) and 10.31% (KEAP1). We confirmed that higher TMB value and PD-L1 expression were associated with NFE2L2/KEAP1 mutations compared with wild-type, especially in non-small lung cancer. MSKCC database analysis showed the improved survival of patients with NFE2L2/KEAP1 mutant with immunotherapy compared with other treatments (median overall survival 22.52 VS 12.89, p = .0034). Real-world evidence further confirmed the efficacy of immunotherapy in the mutant population.

Conclusion: Our study revealed that patients with NFE2L2/KEAP1 mutant could achieve improved outcomes from immunotherapy than the other treatments. These findings may broaden the application of immune checkpoint blockade to patients harboring NFE2L2/KEAP1 mutations.

Implications for practice: NFE2L2/KEAP1 alterations occur frequently in multiple cancer types and are associated with poor prognosis; however, the efficacious strategy to inhibit this pathway in cancer is poorly understood. This study was designed to analyze the mutational characteristics of NFE2L2/KEAP1 alterations in 9,243 Chinese patients. The highest mutation incidences occurred in lung squamous cell carcinoma at 19.16% (NFE2L2) and 10.31% (KEAP1). Relevance analysis showed the NFE2L2/KEAP1 mutant subsets were associated with higher tumor mutational burden value and programmed death-ligand 1 expression. Clinical data further confirmed NFE2L2/KEAP1 mutations correlate with improved outcome with immunotherapy. These findings suggest the clinical application of immunotherapy in the NFE2L2/KEAP1 mutant population.

Keywords: KEAP1; NFE2L2; Immunotherapy; PD-L1; TMB.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1
Figure 1
The prevalence and distribution of NFE2L2/KEAP1 mutations with different cancer types. (A): The prevalence of NFE2L2 and KEAP1 mutation patients with different cancer types. (B): The distribution of NFE2L2 and KEAP1 mutations is shown on protein schematics. Symbols indicate the type and location of the mutations. Abbreviations: COADREAD, colorectal adenocarcinoma; CSCC, cervical squamous cell carcinoma; EAC, endometrioid adenocarcinoma; ESCA, esophageal squamous cell carcinoma; GBAC, gallbladder adenocarcinoma; LIHC, hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; STAD, gastric adenocarcinoma.
Figure 2
Figure 2
NFE2L2/KEAP1 mutations correlate with higher TMB value. Violin plots show the distribution of TMB in WT versus NFE2L2 mutations versus KEAP1 mutations in pan‐cancer (A), LUSC (B), LUAD (C), COADREAD (D), GBAC (E), STAD (F), LIHC (G), and ESCA (H). No significance (NS), p ˃ .05, *p ≤ .05, **p ≤ .01, ***p ≤ .001, ****p ≤ .0001. Abbreviations: COADREAD, colorectal adenocarcinoma; ESCA, esophageal squamous cell carcinoma; GBAC, gallbladder adenocarcinoma; LIHC, hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; STAD, gastric adenocarcinoma; TMB, tumor mutational burden; WT, wild type.
Figure 3
Figure 3
NFE2L2/KEAP1 mutations correlate with increased PD‐L1 expression. PD‐L1 expression level in WT versus NFE2L2 mutations versus KEAP1 mutations in pan‐cancer (A), LUSC (B), LUAD (C), LIHC (D), and ESCA (E). No significance (NS), p ˃ .05, *p ≤ .05, **p ≤ .01, ***p ≤ .001, ****p ≤ .0001. Abbreviations: ESCA, esophageal squamous cell carcinoma; LIHC, hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; WT, wild type.
Figure 4
Figure 4
Immunotherapy is effective in NFE2L2/KEAP1 mutant patients. (A): Overall survival of pan‐cancer patients with NFE2L2‐WT and NFE2L2‐Mut tumors (WT, n = 7,441; Mut, n = 133). (B): Overall survival of NFE2L2‐Mut patient received ICI and other treatments (ICI, n = 20; other treatments, n = 113). (C): Overall survival of pan‐cancer patients with KEAP1‐WT and KEAP1‐Mut tumors (WT, n = 7,239; Mut, n = 335). (D): Overall survival of KEAP1‐Mut patient received ICI and other treatments (ICI, n = 61; other treatments, n = 274). (E): Overall survival of pan‐cancer patients with NFE2L2/KEAP1‐WT and NFE2L2/KEAP1‐Mut tumor (WT, n = 7,114; Mut, n = 460). (F): Overall survival of NFE2L2/KEAP1‐Mut patients received ICI and other treatments (ICI, n = 81; other treatments, n = 379). Abbreviations: ICI, immune checkpoint inhibitor; Mut, mutant; WT, wild type.
Figure 5
Figure 5
Immunotherapy is effective in NFE2L2/KEAP1 mutated NSCLC. (A): Overall survival of patients with NSCLC with NFE2L2/KEAP1‐WT and NFE2L2/KEAP1‐Mut tumor (WT, n = 1,169; Mut, n = 274). (B): Overall survival of NFE2L2/KEAP1‐Mut patients received ICI and other treatments (ICI, n = 61; other treatments, n = 213). (C): Computed tomography imaging of patient OM_6 before and after immunotherapy treatment, which showed the decreasing tumor size at indicated time points. Red arrows indicate the lesion position. Abbreviations: ICI, immune checkpoint inhibitor; Mut, mutant; WT, wild type.
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