The role of distinct co-mutation patterns with TP53 mutation in immunotherapy for NSCLC
Shuhang Wang, Miaomiao Jiang, Zuozhen Yang, Xiaoyun Huang, Ning Li
Abstract
TP53 mutations was reported to be correlated to the efficacy of program death-1 (PD-1) and program death ligand-1 (PD-L1). The role of co-mutations of TP53 with other recurrently mutated genes in outcome of anti-PD-(L)1 treatment for non-small cell lung cancer (NSCLC) is unknown. Here we mined a previously generated dataset to address the effect of co-mutations on the progression free survival (PFS) of NSCLC patients. Non-synonymous mutations and clinical data of 240 NSCLC patients with anti-PD-(L)1 based therapy was downloaded from cBioPortal. Totally 206 patients received monotherapy and 34 patients received combination therapy. In 240 NSCLC patients, TP53 mutation rate was 59.2%. For the monotherapy cohort, TP53 mutated NSCLC patients have a significantly longer PFS (4.3 vs. 2.5 months, P = 0.0019) compared with TP53 wild type NSCLC patients. The same tendency was also observed in the combination therapy cohort, but the difference in PFS (6.3 vs. 5.4 months, P = 0.12) was not significant. Ever-smoker had a longer PFS compared to never-smokers (4.0 vs. 2.7 months). For further co-mutation analysis with TP53 including KEAP1 mutation (53/240, 22.1%), KMT3C mutation (26/240, 10.8%), STK11 mutation (56/240, 23.3%), EGFR mutation (28/240, 11.7%) and KRAS mutation (86/240, 35.8%). Patients with both TP53 plus KEAP1 mutations in all 240 patients had a longer PFS compared with co-wild population (PFS 9.2 vs. 4.2 months, P = 0.012) when treated with PD-1/PD-L1 inhibitors. TP53 might be the dominating mutation correlating with longer PFS in PD-1/PD-L1 monotherapy. Different genes displayed distinct effect when co-mutated with TP53 in NSCLC patients.