Driver Genes and Genomic Instability Predict the Incidence and Outcome of Brain Metastases.

Introduction: The incidence of brain metastases in patients diagnosed with ad-vanced lung cancer is high, drawing significant attention to the risk factors associated with this progression.

Methods: A total of 252 advanced non-small cell lung cancer (NSCLC) patients with brain metastases were enrolled in this study between July 2018 and December 2023 from our hos-pital. Additionally, driver genes, including EGFR, ALK, ROS1, KRAS, and RET, were doc-umented. Next-generation targeted sequencing of a 168-gene panel was conducted on all col-lected samples to explore the association between tumor genomic complexity and risk factors for NSCLC with brain metastases.

Results: Among 252 lung cancer patients with brain metastases enrolled in this research, the most prevalent driver gene was EGFR, accounting for 39.29% (99 patients). Other driver gene mutations, such as KRAS, ALK, ROS1, and RET, accounted for 3.57%, 7.14%, 2.78%, and 0.4%, respectively. Kaplan-Meier analysis showed that patients with EGFR mutations had a more favorable overall survival (OS) compared to those without the mutation (P < 0.0001). Additionally, patients with ALK fusions had longer survival times compared to those with wild-type genes (P = 0.0021). In this study, patients were divided into two groups based on the presence or absence of copy-number alterations. Further survival analysis revealed that patients with copy-number alterations experienced significantly shorter overall survival com-pared to the control group (P = 0.041).

Discussion: This study underscores the crucial role of driver mutations and genomic instability in advanced NSCLC with brain metastases, where EGFR and ALK alterations are linked to better survival. In contrast, high genomic complexity is associated with worse outcomes.

Conclusion: Driver gene mutations are present in more than half of the patients with central nervous system (CNS) failure. Genomic instability, characterized by the number of co-occur-ring mutated genes and copy-number alterations, is a risk factor associated with shorter sur-vival time.