[Effect of FBXW7 gene mutation on the prognosis of immunotherapy in patients with non-small cell lung cancer].

ABSTRACT

Objective: To explore the effect of F-box and WD-40 domain protein 7 (FBXW7) gene mutation on the prognosis of immunotherapy in patients with non-small cell lung cancer (NSCLC). Methods: (1) The clinical data of 125 patients with advanced NSCLC in the First Affiliated Hospital of Nanjing Medical University from January 2019 to June 2021 were collected. There were 70 males and 55 females, with a median age [M (Q1, Q3)] of 64(57, 70) years. The correlation of FBXW7 mutation with immunotherapy efficacy and prognosis was analyzed. (2) The Data set of NSCLC patients treated with immunotherapy from cBioPortal database was downloaded. A total of 261 patients were included as immunotherapy group. There were 120 males and 141 females, with a median age of 66(57, 73) years. The association of FBXW7 mutation with clinical characteristics and prognosis of NSCLC patients was investigated. (3) The data of patients with NSCLC from the cancer genome atlas (TCGA) database were downloaded. A total of 1 030 patients were included as TCGA group. There were 633 males and 397 females, with a median age of 67(60, 73) years. The effect of FBXW7 mutation on the efficacy of immunotherapy was analyzed. The key molecules and their biological functions were also determined Results: Among the 125 NSCLC patients, the FBXW7 mutation rate was 5.6% (7/125). All FBXW7 mutation types was truncating mutation. In these FBXW7 mutation patients who received immunotherapy, 4 had partial response, 2 had stable disease, and 1 had progressive disease. The objective response rate (ORR) and disease control rate (DCR) were 4/7 and 6/7, respectively. The median progression-free survival (PFS) was 13.0 months (95%CI 7.0-22.0 months) for patients with FBXW7 mutation and 4.0 months (95%CI 2.0-11.5 months) for patients with FBXW7 wild type, with a statistically significant difference (P=0.046). The bioinformatics analysis indicated that patients with FBXW7 mutation have higher clinical benefits from immunotherapy. Moreover, patients with FBXW7 mutation in immunotherapy group had higher tumor mutational burden (TMB) [M (Q1, Q3) 17.8 (11.5, 29.3)/Mb] than those with FBXW7 wild type [5.7 (3.0, 10.4)/Mb, P=0.001]. The TMB of patients with FBXW7 mutation in TCGA group was 15.9 (4.2, 28.1)/Mb, insertion-deletion (Indel) neoantigen was 192.5 (70.8, 535.0) and single nucleotide variant (SNV) neoantigen was 363.0 (194.8, 534.8), which were significantly higher than those of patients with FBXW7 wild type [5.6 (3.2, 8.9)/Mb, 53.0 (12.0, 131.0), 83.5 (34.0, 178.0), respectively] (P=0.002, P=0.008, P<0.001). The results indicated that FBXW7 mutated tumors had stronger immunogenicity, which might generate anti-tumor immunity. FBXW7 mutation was also related to the activation of T cells (T lymphocyte receptor complexes and signaling). In addition, FBXW7 mutation was correlated with increased infiltration of CD8+T cells and M1 macrophages. CD8+T cells and M1 macrophages infiltration level was significantly up-regulated in FBXW7 mutation group than wild-type group [10% (8%, 14%) vs 7%(4%, 12%), P=0.049; 8%(4%, 11%) vs 4%(1%, 8%), P=0.046]. Conclusions: NSCLC patients with FBXW7 mutant have higher clinical benefits from immunotherapy. FBXW7 mutation has the potential as a predictive marker for the efficacy of immunotherapy in NSCLC patients.