NF1-Mutant Cancer and Immune Checkpoint Inhibitors: A Large Database Analysis.
2021
PURPOSE/OBJECTIVE(S) Neurofibromin 1 (NF1) is a cancer suppressor gene which plays an important role in negatively regulates MAPK pathway. NF1 deficiency is associated with carcinogenesis, and NF1 mutations have been described in various cancers. Recently, several studies indicated that non-small-cell lung cancer (NSCLC) patients harboring NF1 mutations correlated with the inferior efficacy of target therapies, such as EGFR-tyrosine kinase inhibitors (TKIs), MET-TKIs and ROS1-TKIs, because of the MAPK pathway hyperactivation. However, the association between NF1 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. We aimed to assess the role of NF1 mutations in cancer patients undergoing ICIs therapy. MATERIALS/METHODS We analyzed the TMB and immunotherapy database to find the association between NF1 mutations and the responses of patients who received ICIs treatment. Genomic and survival data from 1661 patients sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay were included in this database. RESULTS A total of 185 patients (11%) with various cancer types harbored NF1 mutations. As for NSCLC subgroup, 35 patients (10%) had NF1 mutations, including 25 lung adenocarcinoma patients and five lung squamous cell carcinoma patients. At first, we performed TMB analysis in both entire group and NSCLC subgroup patients. Interestingly, the TMB was significantly higher in patients harboring NF1 mutations compared with their wild type counterparts both in the entire cohort (P < 0.001) and NSCLC subgroup (P < 0.001). Furthermore, we calculated the overall survival in both NF1-mutant and wild-type patients to evaluate the efficacy of ICIs. Corresponding to the TMB results, we found that patients who harbored NF1 mutations had significantly longer overall survival in the entire group (P = 0.025). However, we found that patients harboring NF1 mutations had comparable overall survival in the NSCLC subgroup (P = 0.460). CONCLUSION Our results suggested that NF1 mutation was associated with higher TMB and could serve as a favorable prognostic biomarker in various human cancers. Unfortunately, our results did not show the benefit from ICIs corresponding NF1 mutations in the NSCLC patients.
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