The Effect Of Concurrent TP53 Mutations On Clinical Efficacy Of First-generation EGFR-TKIs In Patients With EGFR-mutated Advanced NSCLC

Purpose: Tumor suppressor gene TP53 is the most frequently mutated gene(>50%)in human cancers.TP53 gene mutations can be found in 35%-60% of patients with NSCLC.In the past two years,several studies published in foreign countries have suggested that TP53 mutation was a potential negative prognostic factor among patients with EGFR-mutated advanced NSCLC and received first-generation EGFR-TKIs treatments.and might be involved in the development of acquired resistance to first-generation EGFR-TKIs.However,the prognostic and predictive value of EGFR/TP53 concurrent mutations on the efficacy of first-generation EGFR-TKIs in Chinese patients with advanced NSCLC remain largely unknown.The study investigated the impact of TP53 mutations on the clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors(TKIs)in Chinese patients with advanced or recurrent non-small-cell lung cancer(NSCLC).Methods: Electronic medical records of patients who were diagnosed with EGFR-mutated advanced/metastatic NSCLC by pathologic examination and next-generation sequencing(NGS)and received targeted treatment with first-generation TKIs at the Affiliated Hospital of Qingdao University from Sep,2017 to Dec,2018 were screened.Basic clinical pathological information,treatment history and patients' outcomes were collected by medical records screening and patients following up.The primary endpoints of our study were progression-free survival [PFS] and overall survival[OS];the secondary endpoints of our study were objective response rate [ORR] and disease control rate [DCR].All statistical analyses were performed with SPSS version24.0.The two-tailed level of significance was set at 0.05.Results: The Electronic medical records of 334 patients with advanced/metastatic NSCLC were screened,and 147 cases were identified as EGFR-mutant and received EGFR-TKIs treatment.Among the 147 patients,71 patients with detailed NGS sequencing results and meeting the criteria of our study were included.The frequency of pathogenic TP53 mutations of the 71 patients were was 60.6%(43/71),Markedly shorter median PFS(m PFS)(6.5 versus 14.0 months,P=0.025)and median OS(m OS)(28.0 versus 52.0 months,P=0.023)were observed in TP53-mut patients than in TP53-wt controls.The overall DCR and ORR of TP53-mutant patients were both lower than those of the TP53-wt cases(DCR: 76.7% versus 89.3%,P=0.160;ORR: 25% versus 28%,P=0.374).Differences in prognosis were significant,especially in the subgroup of patients with TP53 non-missense mutations((m PFS: 6.3 versus 14 months,P=0.041;m OS: 21.2versus 52.5 months,P=0.001),non-disruptive mutations(PFS: 6.3 versus 14.0 months,P=0.028;OS: 35.0 versus52.5 months,P=0.008),mutations in exon 6(m PFS: 6.5 versus14.0 months,P=0.211;m OS: 39.0 versus 52.5 months,P=0.036),mutations in exon7(m PFS: 5.0 versus 14.0 months,P=0.002;m OS: 14.0 versus 52.5 months,P=0.008)and mutations in the non-DBD region(m PFS: 4.0 versus 14.0 months,P=0.007;m OS: 14.6versus 52.5 months,P=0.002)among all TP53 mutations.Conclusion: TP53 mutations reduce responsiveness to TKIs and worsen the prognosis of EGFR-mutant NSCLC patients,especially for those with non-missense mutations and nondisruptive mutations,as well as mutations in exon 6,exon 7 and non-DBD region,thus acting as an independent predictor of poor outcome in advanced NSCLC patients treated with first-generation EGFR-TKIs.Our study also suggests that TP53 mutation might be involved in development of primary resistance to EGFR-TKIs in Chinese NSCLC patients.