Identifying the genomic landscape of EGFR-mutant lung cancers with central nervous system metastases Journal Article
| Authors: | Wilcox, J. A.; Jeng, M. Y.; Tischfield, S.; Sui, J. S. Y.; Nemirovsky, D.; Heller, G.; Choudhury, N. J.; Ross, J. S.; Rudin, C. M.; Riely, G. J.; Kris, M. G.; Donoghue, M.; Boire, A. A.; Yu, H. A. |
| Article Title: | Identifying the genomic landscape of EGFR-mutant lung cancers with central nervous system metastases |
| Abstract: | Background: Despite the intracranial efficacy of osimertinib, central nervous system (CNS) metastases remain a major cause of morbidity and mortality in EGFR-mutant non-small-cell lung cancer (NSCLC). The genomic drivers of CNS dissemination are poorly understood. Patients and methods: We analyzed the clinicogenomic features of patients with EGFR-mutant NSCLC receiving first-line osimertinib with extracranial next generation sequencing (NGS) (n = 262) and individuals with intracranial NGS (n = 81). Paired extra- and intracranial NGS was available for 14 patients. Time-to-event analyses were conducted from time of metastatic diagnosis, except for time-to-treatment discontinuation (TTD), which began at treatment initiation. Results: Among 262 patients receiving first-line osimertinib, 53% developed CNS metastases (36% de novo, 16% acquired on treatment). The cumulative incidence of brain (BrM) and leptomeningeal metastases (LM) was 39% and 2% at 1 year, 49% and 6% at 3 years, and 54% and 12% at 5 years, respectively. CNS metastases correlated with a higher frequency of CARD11 amplifications (14% versus 3%, P = 0.031) and a lower frequency of MDM2 amplifications (1% versus 13%, P = 0.008) in extracranial NGS specimens, with otherwise similar genomic profiles. Patients who developed CNS metastases on treatment had worse overall survival (OS) [hazard ratio (HR) = 3.67, 95% confidence interval (CI) 2.41 to 5.59], followed by those with de novo (HR = 1.61, 95% CI 1.15 to 2.26), compared with those who never developed CNS metastases (P < 0.001). In multivariable Cox regression, atypical EGFR mutations were associated with shorter OS. Cell cycle pathway alterations were more frequent in BrM than LM samples (93% versus 47%, P = 0.003, q = 0.03). No other significant genomic differences were found between BrM and LM, or between paired CNS and systemic samples. Conclusions: Patients with atypical EGFR mutations or acquired CNS metastases on osimertinib have worse outcomes. Comparative NGS profiling of intra- and extracranial tumors suggest that CNS dissemination is driven by mechanisms beyond single-gene alterations. © 2025 European Society for Medical Oncology |
| Keywords: | genomics; non-small-cell lung cancer; brain metastases; leptomeningeal metastases; osimertinib; egfr-mutant |
| Journal Title: | Annals of Oncology |
| ISSN: | 0923-7534 |
| Publisher: | Oxford University Press |
| Publication status: | Online ahead of print |
| Date Published: | 2025-06-16 |
| Online Publication Date: | 2025-06-16 |
| Language: | English |
| DOI: | 10.1016/j.annonc.2025.06.001 |
| PUBMED: | 40532851 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding authors are Adrienne Boire and Helena Yu -- Source: Scopus |
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