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Concurrent TP53 mutations facilitate resistance evolution in EGFR mutant lung adenocarcinoma

*March 2022*


Patients with EGFR-mutant non-small cell lung cancer (NSCLC) experience variable duration of benefit on EGFR tyrosine kinase inhibitors (TKI). The effect of concurrent genomic alterations on outcome has been incompletely described.


In this retrospective study, targeted next-generation sequencing data was 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.


269 patients were identified for inclusion in the cohort. Among 185 response-evaluable patients with pre-treatment specimens, TP53 alterations were the most common event associated with decreased first-line progression-free survival (PFS), and associated with decreased overall survival along with DNMT3AKEAP1 and ASXL1 alterations. Reduced PFS on later-line osimertinib in 33 patients was associated with METAPC and ERBB4 alterations. Further investigation of the effect of TP53 alterations demonstrated 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.


TP53 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 TKIs. Read more.