Lung-molGPA may stratify the prognostic impact of TP53 co-mutation in EGFR-mutant lung adenocarcinoma with brain metastases: a multi-center retrospective analysis.

BACKGROUND: The optimal approach to treatment intensification for epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma with brain metastases remains a topic of debate, especially in the context of high-risk molecular features such as TP53 co-mutation. The extent to which baseline clinical risk influences treatment efficacy is yet to be determined. OBJECTIVES: We aim to systematically evaluate the prognostic significance of EGFR/TP53 co-mutations in treatment-naïve patients with lung adenocarcinoma and newly diagnosed brain metastases. DESIGN: This study enrolled 218 treatment-naïve patients with EGFR-mutant lung adenocarcinoma and brain metastases who received first-line third-generation EGFR-tyrosine kinase inhibitors (TKIs). Treatment effects were evaluated using interaction models stratified by Lung-molGPA scores. Stratification: Group A (Lung-molGPA 1-2) versus Group B (Lung-molGPA 2.5-4). METHODS: Within each group, the influence of TP53 co-mutations on survival was analyzed. Additionally, among patients with TP53 co-mutations, the effects of cranial radiotherapy (CRT) and treatment with either third-generation EGFR-TKIs monotherapy or third-generation EGFR-TKIs combined with chemotherapy on overall survival (OS) were further investigated, taking into account the Lung-molGPA scores. RESULTS: The Lung-molGPA significantly influenced the prognostic impact of TP53 mutations and the survival benefits of treatment intensification strategies (log-rank test p = 0.044, hazard ratio (HR) = 2.1832, 95% confidence interval (CI): 1.023-4.661). In patients with low Lung-molGPA scores, intensification with CRT did not correlate with a survival advantage (32.2 vs 28.0 m, log-rank test p = 0.5088, HR = 1.417, 95% CI: 0.4768-4.211). Conversely, in patients with high Lung-molGPA scores, both CRT and systemic intensification were associated with improved outcomes (44.0 vs 26.3 m, log-rank test p = 0.0054, HR = 0.3199, 95% CI: 0.1585-0.6456; 20.1 vs 32.3 m, log-rank test p = 0.0074, HR = 2.547, 95% CI: 1.113-5.831). CONCLUSION: Baseline clinical risk, as delineated by the Lung-molGPA, serves as a crucial determinant of therapeutic benefit in cases of EGFR-mutant lung adenocarcinoma with cerebral metastases. Implementing risk-adapted treatment intensification strategies could potentially prevent overtreatment in patients classified as low-risk, while simultaneously optimizing clinical outcomes in high-risk cohorts.