Metastatic patterns plus clinical and molecular characteristics of ROS1 aberrations in non-small cell lung cancer patients without rearrangements.

e21117 Background: Fusions in the ROS1 proto-oncogene are among the best treatable genetic aberrations in Non-small cell lung cancer (NSCLC). Besides the occurrence of solvent-front mutations (SFM) in acquired resistance to targeted therapy, little is known about ROS1 aberrations other than fusions. We analyzed molecular and clinical characteristics and metastatic patterns of ROS1 mutations in NSCLC patients without activating ROS1 fusions or SFMs. Methods: Next-generation sequencing (NGS) was performed on tissue samples from NSCLC patients within the National Network Genomic Medicine (nNGM). Patients with activating ROS1 fusions detected by fluorescence in-situ hybridization (FISH) were excluded. Staging and restaging procedures were performed following local standards from each partner. We analyzed the mutations’ characteristics, co-occurring mutations and metastatic patterns. Results: Of 8072 patients analyzed by NGS between 2018 and 2021, 118 (1.5%) patients harbored ROS1 mutations. Most patients were male (76.3%) and had adenocarcinoma histology (57.6%). The median age at diagnosis amounted to 68 years. Nearly all of the patients (96.5%) had a smoking history, amassing 40 pack-years on average. Besides TP53 mutations (61.0%), KRAS (25.4%), EGFR (7.6%), PIK3CA and FGFR1-4 mutations (5.9% each) co-occurred most frequently. In 12 (10.2%) patients, ROS1 mutation was the only detected aberration. The majority (59.3%) of patients had UICC stage IV whereby 27.2% of patients featured Stage III; about 7% fall upon stage I and II. The metastatic pattern of all stage IV patients shows that 22.9% of metastasis is allotted to cerebral, 12.5% to lung, 16.7% to subdiaphragmatic, 14.9% to bone and 6.3% to skin metastasis. Thereby, the patients’ subgroup with mutually exclusive ROS1 mutations (10.2%) resembles this trend: about a half of these patients had UICC stage IV, too, and the metastasis distribution featured similar characteristics. Conclusions: The cohort contrasts the clinical characteristics of patients with ROS1 fusion regarding sex, age, and histology. This evidence implies a basic clinical impact exerted by this molecular subtype. We warrant further research on the detected mutations to characterize the biological impact and the potential to act as a drug target.