In:
Frontiers in Oncology, Frontiers Media SA, Vol. 11 ( 2021-7-26)
Abstract:
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 & lt; 0.001) on atezolizumab and docetaxel (HR = 1.66, 95% CI 1.28–2.16, P & lt; 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.
Type of Medium:
Online Resource
ISSN:
2234-943X
DOI:
10.3389/fonc.2021.659200
DOI:
10.3389/fonc.2021.659200.s001
DOI:
10.3389/fonc.2021.659200.s002
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2021
detail.hit.zdb_id:
2649216-7
