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
PurposeThe 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 potentiat...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.659200/full |
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| author | Hongyuan Zhu Hongyuan Zhu Daipeng Xie Yunfang Yu Lintong Yao Bin Xu Luyu Huang Shaowei Wu Fasheng Li Yating Zheng Xinyi Liu Wenzhuan Xie Mengli Huang Hao Li Shaopeng Zheng Dongkun Zhang Guibin Qiao Lawrence W. C. Chan Haiyu Zhou |
| author_facet | Hongyuan Zhu Hongyuan Zhu Daipeng Xie Yunfang Yu Lintong Yao Bin Xu Luyu Huang Shaowei Wu Fasheng Li Yating Zheng Xinyi Liu Wenzhuan Xie Mengli Huang Hao Li Shaopeng Zheng Dongkun Zhang Guibin Qiao Lawrence W. C. Chan Haiyu Zhou |
| author_sort | Hongyuan Zhu |
| collection | DOAJ |
| description | PurposeThe 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 DesignThe 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.ResultsCompared 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.ConclusionsOur 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. |
| first_indexed | 2024-12-22T11:59:56Z |
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| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-22T11:59:56Z |
| publishDate | 2021-07-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-14f46ce745294216873daeea1119f9a62022-12-21T18:26:39ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-07-011110.3389/fonc.2021.659200659200KEAP1/NFE2L2 Mutations of Liquid Biopsy as Prognostic Biomarkers in Patients With Advanced Non-Small Cell Lung Cancer: Results From Two Multicenter, Randomized Clinical TrialsHongyuan Zhu0Hongyuan Zhu1Daipeng Xie2Yunfang Yu3Lintong Yao4Bin Xu5Luyu Huang6Shaowei Wu7Fasheng Li8Yating Zheng9Xinyi Liu10Wenzhuan Xie11Mengli Huang12Hao Li13Shaopeng Zheng14Dongkun Zhang15Guibin Qiao16Lawrence W. C. Chan17Haiyu Zhou18Division of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Southern Medical University, Guangzhou, ChinaDivision of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, ChinaDivision of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDivision of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Southern Medical University, Guangzhou, ChinaDivision of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Southern Medical University, Guangzhou, ChinaDivision of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Southern Medical University, Guangzhou, ChinaDivision of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Southern Medical University, Guangzhou, ChinaDivision of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Southern Medical University, Guangzhou, ChinaThe Medical Department, 3D Medicines Inc., Shanghai, ChinaThe Medical Department, 3D Medicines Inc., Shanghai, ChinaThe Medical Department, 3D Medicines Inc., Shanghai, ChinaThe Medical Department, 3D Medicines Inc., Shanghai, ChinaDivision of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Southern Medical University, Guangzhou, ChinaDivision of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, Shantou, ChinaDivision of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Southern Medical University, Guangzhou, ChinaDivision of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Southern Medical University, Guangzhou, ChinaDepartment of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, ChinaDivision of Thoracic Surgery, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Southern Medical University, Guangzhou, ChinaPurposeThe 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 DesignThe 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.ResultsCompared 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.ConclusionsOur 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.https://www.frontiersin.org/articles/10.3389/fonc.2021.659200/fullprognosticKEAP1/NFE2L2non-small cell lung cancerimmunotherapychemotherapy |
| spellingShingle | Hongyuan Zhu Hongyuan Zhu Daipeng Xie Yunfang Yu Lintong Yao Bin Xu Luyu Huang Shaowei Wu Fasheng Li Yating Zheng Xinyi Liu Wenzhuan Xie Mengli Huang Hao Li Shaopeng Zheng Dongkun Zhang Guibin Qiao Lawrence W. C. Chan Haiyu Zhou 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 Frontiers in Oncology prognostic KEAP1/NFE2L2 non-small cell lung cancer immunotherapy chemotherapy |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | prognostic KEAP1/NFE2L2 non-small cell lung cancer immunotherapy chemotherapy |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.659200/full |
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