Molecular and clinicopathological characteristics ofROS1-rearranged non-small-cell lung cancers identified by next-generation sequencing

ROS1gene rearrangements have been reported in diverse cancer types including non-small-cell lung cancer (NSCLC), and with a notably higher prevalence in lung adenocarcinoma. The tyrosine kinase inhibitors, crizotinib, lorlatinib, and entrectinib, have demonstrated favorable efficacy in treatingROS1-rearranged NSCLCs. Herein, we retrospectively reviewed 17 158 NSCLC patients whose tumor specimen and/or circulating cell-free DNA underwent comprehensive genomic profiling. A total of 258 unique patients were identified withROS1rearrangements, representing an overall prevalence of approximately 1.5% ofROS1fusions in newly diagnosed and relapsed NSCLC patients.CD74(38%) was the most common fusion partner ofROS1, followed byEZR(13%),SDC4(13%),SLC34A2(10%), and other recurrent fusion partners with lower frequencies, includingTPM3,MYH9, andCCDC6. Variant breakpoints occurred inROS1introns 33 (37%), 31 (25%), 32 (17%), and 34 (11%) with no obvious hotspots.CD74(63%) andEZR(50%) were more frequently fused toROS1intron 33 than other introns, whileROS1intron 31 was most frequently fused withSDC4(79%) andSLC34A2(81%). Crizotinib progression-free survival (PFS) was not significantly different between fusion variants involving breakpoints in differentROS1introns, nor was there a significant difference in PFS betweenCD74-ROS1and non-CD74-ROS1groups of patients. Furthermore,TP53was most frequently mutated in patients who progressed on crizotinib, andTP53mutations were significantly associated with shorter crizotinib PFS.ROS1mutations, including G2032R, were observed in approximately 33% of post-crizotinib samples. Collectively, we report the prevalence ofROS1fusions in a large-scale NSCLC population and the efficacy of crizotinib in treating patients withROS1-rearranged NSCLC.