Central Nervous System Metastases from Primary Lung Carcinoma: Significance of RNA Fusion Testing and Early Versus...

Background/Objectives: While the genomic landscape of primary lung carcinomas is well characterized, there is a relative scarcity of fusion data on corresponding central nervous system (CNS) metastases. This study aimed to elucidate the molecular profiles of CNS metastases to (1) assess the significance of a combined DNA-reflex RNA fusion testing approach and (2) compare the mutational landscape between patients who present initially [early (≤2 months)] with CNS metastases and those who develop CNS metastases thereafter [late (>2 months)]. Methods: We performed a retrospective search of CNS metastases of adenocarcinoma of probable lung origin interrogated by targeted DNA-reflex RNA next-generation sequencing (NGS). The DNA NGS panel included the driver mutations EGFR, BRAF, KRAS, MET, and ERBB2. RNA NGS included ALK, RET, ROS1, and MET. Additionally, mutational profiles were examined between those with early versus late CNS metastases. Results: Of the 58 patients, 44 (75.9%) had mutations or alterations, including 34 identified by DNA NGS [EGFR (n = 17; 50.0%), KRAS (n = 15; 44.1%), MET (n = 2; 5.9%)] and 10/24 by RNA NGS [ALK (n = 7; 70%), MET (n = 2; 20%), ROS1 (n = 1; 10%)]. Of all patients, 32 (55%) presented with early and 26 (45%) with late CNS metastases. Although patients with early metastases had worse survival compared to those with late metastases (p < 0.001), there were no statistically significant differences in the mutational profiles between the two cohorts. Conclusions: A significant proportion of CNS metastases without driver mutations identified by DNA NGS had targetable alterations identified by RNA NGS (10/24, 41.7%). In summary, a combined DNA with reflex RNA fusion testing approach plays a significant role in detecting and potentially managing CNS metastases. Comprehensive prospective studies are essential to elucidate the differences between early and late CNS metastases.