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

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. 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. 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. TP53 GOF mutations define a biologically and clinically distinct subtype of EGFR-mutant NSCLC characterized by early resistance to osimertinib.