Association of TP53 gain-of-function mutations with early osimertinib resistance in epidermal growth factor receptor-mutant lung adenocarcinoma

BACKGROUND: The aim of this study was to investigate the clinical and biological impact of TP53 gain-of-function (GOF) mutations in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Although concurrent TP53 mutations are associated with poor outcomes in EGFR-mutant NSCLC, the specific impact of TP53 GOF mutations on resistance to EGFR tyrosine kinase inhibitors has remained unknown. MATERIALS AND METHODS: Genomic profiling was performed for pretreatment tumor samples from 140 individuals with advanced or recurrent EGFR-mutant NSCLC who received first-line osimertinib monotherapy. TP53 mutations were functionally classified into GOF and non-GOF mutations. Progression-free survival (PFS) was evaluated according to TP53 status. Underlying biological characteristics of tumors positive for TP53 mutations were explored by transcriptome analysis in 53 patients. RESULTS: TP53 mutations were detected in 64 (45.7%) of 140 patients, with GOF and non-GOF mutations being identified in 19 (13.6%) and 45 (32.1%) patients, respectively. PFS was significantly shorter in individuals with TP53 GOF mutations than in those wild type for TP53 (median of 12.0 versus 31.4 months, P = 0.0016) or those with TP53 non-GOF mutations (median of 12.0 versus 21.9 months, P = 0.038). The GOF mutations were not associated with baseline clinical features or a reduced objective response rate, suggestive of a role in early development of osimertinib resistance. Transcriptomic analysis revealed upregulation of the ephrin signaling pathway in TP53 GOF-mutant NSCLC. CONCLUSIONS: TP53 GOF mutations define a biologically and clinically distinct subtype of EGFR-mutant NSCLC characterized by early resistance to osimertinib.