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

<b>Background/Objectives:</b> 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)]. <b>Methods</b>: 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 <i>EGFR</i>, <i>BRAF</i>, <i>KRAS</i>, <i>MET</i>, and <i>ERBB2</i>. RNA NGS included <i>ALK</i>, <i>RET</i>, <i>ROS1</i>, and <i>MET</i>. Additionally, mutational profiles were examined between those with early versus late CNS metastases. <b>Results:</b> Of the 58 patients, 44 (75.9%) had mutations or alterations, including 34 identified by DNA NGS [<i>EGFR</i> (<i>n</i> = 17; 50.0%), <i>KRAS</i> (<i>n</i> = 15; 44.1%), <i>MET</i> (<i>n</i> = 2; 5.9%)] and 10/24 by RNA NGS [<i>ALK</i> (<i>n</i> = 7; 70%), <i>MET</i> (<i>n</i> = 2; 20%), <i>ROS1</i> (<i>n</i> = 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 (<i>p</i> < 0.001), there were no statistically significant differences in the mutational profiles between the two cohorts. <b>Conclusions</b>: 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.