Influence of TP53 mutation on efficacy and survival in advanced EGFR-mutant non-small cell lung cancer patients treated with third-generation EGFR tyrosine kinase inhibitors

TP53 comutation is related to poor prognosis of non-small cell lung cancer. However, there is limited study focusing on the structural influence of TP53 mutation on third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. We retrospectively analyzed the clinical and molecular data of patients treated with third-generation EGFR-TKIs in two independent cohorts. A total of 117 patients from the Sun Yat-sen University Cancer Center (SYSUCC) and 141 patients from the American Association for Cancer Research Project GENIE database were included. In the SYSUCC cohort, TP53 comutations were found in 59 patients (50.4%) and were associated with poor median progress-free survival (mPFS) and median overall survival (mOS). The additional subtype analysis found that TP53 mutation in the alpha-helix region had shorter mOS compared with those with TP53 mutations in other regions in the SYSUCC cohort (mOS, 12.2 vs. 21.7 months; p = 0.027). Similar findings were confirmed in the GENIE cohort. Specifically, the presence of TP53 mutation in the alpha-helix region was an independent negative predictive factor for PFS [hazard ratio (HR) 2.05(1.01-4.18), p = 0.048] and OS [HR 3.62(1.60-8.17), p = 0.002] in the SYSUCC cohort. TP53 mutation in alpha-helix region was related to inferior clinical outcomes in patients treated with third-generation EGFR-TKIs. TP53 comutation was associated with poor outcomes in non-small cell lung cancer patients treated with third-generation epidermal growth factor receptor tyrosine kinase inhibitors. Notably, subgroup analysis has revealed that patients with TP53 mutations in the alpha helix region had shorter median OS compared with those with TP53 mutations in other structural regions. Similar findings were confirmed in another GENIE cohort. image