In the present study, we selected patients with EGFR and TP53 co-mutation and retrospectively analyzed the PFS in patients with different treatment options. To the best of our knowledge, this study was the first to analyze optimal treatment options for EGFR and TP53 co-mutant NSCLC patients in a relatively large case series. We found that for patients with concomitant concurrence of EGFR and TP53 mutations, the duration of PFS was significantly longer with EGFR-TKI treatment combined with antiangiogenic drugs or chemotherapy than with EGFR-TKIs only, regardless of whether first-, second-, or third-generation EGFR-TKI was used. These data were even more significant for patients with TP53 exon 4 or 7 mutations.
The p53 protein regulates cellular responses to various cellular stress signals by inducing cell-cycle arrest, senescence, or apoptosis [18]. The complete loss of TP53 function can accelerate the transformation potential of driver oncogenes in lung cancers [19]. TP53 mutations play a role in predicting poor prognosis of patients with advanced NSCLC [20, 21]. TP53 mutations is an unfavorable prognostic factor in patients receiving first-, second-, and third-generation EGFR-TKI therapy with EGFR mutant advanced NSCLC [7, 11, 22, 23]. TP53 mutation status can be used to select treatment for patients with EGFR mutated lung cancer. In the present study, we also compared the PFS of patients treated with first-, second-, and third-generation EGFR-TKIs and found comparable PFS among the treatments with lower PFS compared with the efficacy of EGFR TKIs reported in the literature.
The role of TP53 in angiogenesis has also been established, and multiple studies have shown that the presence of TP53 mutation is associated with the upregulation of the VEGF pathway and may predict clinical sensitivity to antiangiogenic therapies in several tumor types [24, 25]. Clinical studies have also shown that for patients with concomitant TP53 mutation, the combination regimen of EGFR-TKIs and antiangiogenic drugs improved the PFS compared with TKI only [16, 26]. The combination of chemotherapy and EGFR-TKIs also eliminated this heterogeneity of TP53 co-mutation [17]. In our study, PFS was significantly longer with EGFR-TKI treatment combined with antiangiogenic drugs or chemotherapy than with EGFR-TKIs only. We also compared the PFS of patients treated with antiangiogenic drugs or chemotherapy and found that the efficacy of the two regimens is comparable.
EGFR mutation types exhibit different biology after treatment with EGFR-TKIs therapy, with improved outcomes in patients harboring exon 19 deletions compared with L858R [27–29]. For patients with EGFR/TP53 co-mutation, higher ORR and PFS was observed in the subgroup of patients with exon 19 deletion with respect to patients with L585R mutation [16, 23]. In the present study, patients with 19 deletion or L858R mutations both achieved a significant PFS benefit after combination therapy compared with EGFR-TKI alone, but no difference was observed between 19 deletion and L858R. The survival advantage of 19 deletion may be neutralized by the negative effects of TP53 mutations.
Classifying TP53 mutations has become increasingly important, because mutants in different exons exhibit different biological effects and clinical implications [9, 11, 16, 23]. Potential optimization strategies for certain subgroups of patients with baseline EGFR/TP53 co-mutated status must be explored. Mutations in the exon 4 or 7 of TP53 in patients with NSCLC were correlated with worse PFS than in patients with other exons [9]. We compared the PFS of patients with 4 or 7 of TP53 mutations and other TP53 mutations and found PFS benefits tended to favor the combination group in the subgroup of exon 4 or 7 mutations. Canale and Zhao H [11, 16, 23] reported a shorter median PFS in patients with EGFR mutant NSCLC with TP53 exon 8 mutations compared with other exon subsets. In the present study, patients with exon 8 of TP53 mutations achieved a similar PFS benefit in the EGFR-TKIs group and the combination group, and had similar median PFS to the overall patient population with the same therapy group..
Co-occurring genomic alterations such as RB1 mutation, PTEN mutation, and MDM2 and CDK4/6 amplification are associated with worse PFS in patients with EGFR mutation-positive NSCLC [30, 31]. However, in our EGFR and TP53 co-mutation cohort, these alternations were not associated with PFS. BRAC1 mutation and MYC amplification predicted poor prognosis for EGFR-TKI therapy or combination therapy. The amplification and overexpression of MYC were found in approximately 10% NSCLC [32]. MYC amplification was correlated with chemotherapy resistance in lung cancers [33]. The enforced expression of ectopic MYC partially protects sensitive EGFR mutant cells from undergoing osimertinib-induced apoptosis and decreases cell survival [34]. APC alternations are also associated with shorter PFS in patients treated with gefitinib [26], which was consistent with our study. Low BRCA1 expression levels were associated with increased PFS after platinum-based chemotherapy [35]. Our study was the first to report that BRCA1 was associated with unfavorable PFS after EGFR-TKI treatment or combination therapy. Nevertheless, considering the small number of BRAC1 and MYC mutated patients, the study was not powered for subgroup analysis. Thus, the results of the analysis of BRAC1 and MYC alternations should be interpreted with caution.
The present study was limited by its retrospective nature, the use of a single accrual center, and lack of data validation from external multicenter, which restricted our ability to investigate other sources of potential bias. Considering that we included patients that received different first-, second-, third-generation EGFR-TKIs treatment and different combination regimens, and the TP53 mutations in six patients were only recorded based on medical records without detailed information, the generalizability of our study findings must be considered. In addition, this study did not include the analysis of adverse effects because of the incomplete medical records. Therefore, further prospective studies conducted in larger cohorts are required to validate the efficacy of combination therapy observed in the study.