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. 2024 Feb 5:13:1288468.
doi: 10.3389/fonc.2023.1288468. eCollection 2023.

The prognosis of TP53 and EGFR co-mutation in patients with advanced lung adenocarcinoma and intracranial metastasis treated with EGFR-TKIs

Weiguo Gu #  1   2 , Penghui Liu #  1 , Jiaming Tang  2 , Jianfei Lai  1 , Siya Wang  1 , Jiaming Zhang  1 , Jinbiao Xu  2 , Jianxiong Deng  2 , Feng Yu #  1   2 , Chao Shi #  2   3 , Feng Qiu #  2   3
Affiliations

The prognosis of TP53 and EGFR co-mutation in patients with advanced lung adenocarcinoma and intracranial metastasis treated with EGFR-TKIs

Weiguo Gu et al. Front Oncol. .

Abstract

Background: TP53 mutation is a poor factor for non-small cell lung cancer (NSCLC), while the effect of TP53 on prognosis in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (LUAD) with brain metastasis remains elusive and needs further exploration.

Methods: We retrospectively analyzed 236 patients and tested for TP53- and EGFR-mutant status in metastasis LUAD patients who had received first-line EGFR-tyrosine kinase inhibitor (TKI) treatment. Survival rates were calculated by the Kaplan-Meier method. Furthermore, univariate and multivariate Cox analyses were performed to identify the independent prognostic factors.

Results: There were 114 patients with confirmed non-brain metastasis (NBM), 74 patients with preliminary diagnosis early brain metastasis (EBM), and 48 patients with late brain metastasis (LBM). TP53 and EGFR co-mutations were found in 35/236 patients (14.8%). The median progression-free survival (PFS) and overall survival (OS) in the EGFR mutation and TP53 wild-type group were significantly longer than those in the EGFR and TP53 co-mutation group in all advanced LUAD or NBM. Concurrently, PFS and OS were found to be not significant in EBM and LBM patients. Subgroup analysis revealed longer median PFS and OS in the TP53 wild-type group compared to the TP53 mutant group in L858R patients and not significant in EGFR Exon 19 deletion patients. In LBM patients, the time to brain metastasis in the EGFR mutation and TP53 wild-type group was longer than that in the EGFR and TP53 co-mutation group, and TP53 mutant status was an independent prognostic factor for brain metastasis. The TP53 wild-type group exhibited a higher objective remission rate (ORR) and disease control rate (DCR) than the TP53 mutant group in NBM, EBM, and LBM patients, irrespective of primary lung and brain metastatic lesions.

Conclusion: TP53/EGFR co-mutation patients receiving first-line EGFR-TKI treatment had poor prognoses in advanced LUAD, especially with L858R mutation. Moreover, TP53/EGFR co-mutation patients treated with EGFR-TKIs may more easy developed intracranial metastasis.

Keywords: EGFR; TP53; brain metastasis; lung cancer; prognosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
A flowchart for the study to enrolled the patients.
Figure 2
Figure 2
The relation between TP53 and EGFR-TKI therapy in EGFR-mutant advanced LUAD. (A) The number of LUAD patients in NBM, EBM, and LBM. (B) Pie chart about TP53 missense mutant status. (C, D) The TP53 wild-type group had a high median PFS and OS than the TP53 mutant group in all advanced LUAD patients. (E, F) The TP53 mutant group had no effect on PFS and OS compared to the TP53 wild-type group in EGFR Exon 19 deletion patients. (G, H) Subgroup analysis revealed longer median PFS and OS in the TP53 wild-type group compared to the TP53 mutant group in L858R patients. EBM, early brain metastasis; LBM, late brain metastasis; and NBM, non-brain metastasis.
Figure 3
Figure 3
Correlation between TP53 mutation and brain metastasis in advanced LUAD first line treated with EGFR-TKIs. In all advanced LUAD patients, the median of PFS in the EBM group was insignificant compared to the NBM and LBM groups (A), while the median of OS in the NBM group was the longest among all groups (B). (C, D) The TP53 wild-type group had a higher median PFS and OS than the TP53 mutant group in NBM patients. (E–H) In EBM and LBM patients, the TP53 wild-type group did not affect PFS and OS compared to the TP53 mutant group. EBM, early brain metastasis; LBM, late brain metastasis; and NBM, non-brain metastasis.
Figure 4
Figure 4
Relationship between clinical–pathological features and time to brain metastasis in EGFR-mutant advanced lung adenocarcinoma with EGFR-TKI therapy. (A) The TP53 wild-type group exhibited a significantly longer time to brain metastasis than the TP53 mutant group. (B) The IIIB–C group had a significantly shorter time to brain metastasis than the local recurrence and IV stage group. (C, D) The low PLR and NLR groups took significantly longer time to brain metastasis than the high PLR and NLR groups. (E) The univariate Cox analysis showed that gender, smoking index, and Ki-67 expression were correlated with time to brain metastasis in advanced lung adenocarcinoma (p < 0.05); these factors were drawn using a forest map. (F, G) The number of brain metastasis in the TP53 wild-type group was insignificant compared to the TP53 mutant group in EBM and LBM patients. The diameter of brain metastasis in the TP53 wild-type group was insignificant compared to the TP53 mutant group in EBM (H), while the TP53 wild-type group was greater than the TP53 mutant group in LBM (I).
Figure 5
Figure 5
Anti-tumor activity and TP53 mutant status and EGFR-TKIs in four patients with EGFR-mutant advanced LUAD. PR, partial response; PD, progressive disease.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the First Affiliated hospital of Nanchang University of Youth Talent Research and Cultivation Fund (YFYPY202244 to WG), Jiangxi Provincial Chinese Medicine Science (2023B0049 to WG), by Jiangxi Provincial Natural Science Foundation (20232BAB216086 to WG) and Nanchang Key Laboratory of Tumor Gene Diagnosis and Innovative Treatment Research (2021-NCZDSY-009).