Concurrent TP53 Mutations Facilitate Resistance Evolution in EGFR-Mutant Lung Adenocarcinoma

Abstract

IntroductionPatients with EGFR-mutant NSCLC experience variable duration of benefit on EGFR tyrosine kinase inhibitors. The effect of concurrent genomic alterations on outcome has been incompletely described. MethodsIn this retrospective study, targeted next-generation sequencing data were collected from patients with EGFR-mutant lung cancer treated at the Dana-Farber Cancer Institute. Clinical data were collected and correlated with somatic mutation data. Associations between TP53 mutation status, genomic features, and mutational processes were analyzed. ResultsA total of 269 patients were identified for inclusion in the cohort. Among 185 response-assessable patients with pretreatment specimens, TP53 alterations were the most common event associated with decreased first-line progression-free survival and decreased overall survival, along with DNMT3A, KEAP1, and ASXL1 alterations. Reduced progression-free survival on later-line osimertinib in 33 patients was associated with MET, APC, and ERBB4 alterations. Further investigation of the effect of TP53 alterations revealed an association with worse outcomes even in patients with good initial radiographic response, and faster acquisition of T790M and other resistance mechanisms. TP53-mutated tumors had higher mutational burdens and increased mutagenesis with exposure to therapy and tobacco. Cell cycle alterations were not independently predictive, but portended worse OS in conjunction with TP53 alterations. ConclusionsTP53 alterations associate with faster resistance evolution independent of mechanism in EGFR-mutant NSCLC and may cooperate with other genomic events to mediate acquisition of resistance mutations to EGFR tyrosine kinase inhibitors.