Epidemiology, Fusion Partners, and Preferred Testing Methods in ROS1-Positive Non-Small Cell Lung Cancer

ROS1 gene fusions occur in approximately 1% to 2% of advanced NSCLC cases, a small but clinically meaningful subset predominantly found in younger patients, women, light or never smokers, and those with non-squamous histology, most commonly adenocarcinoma. The CD74 fusion partner is the most common, accounting for approximately 44% to 64% of all identified ROS1 fusions.

Dr. Riedlinger explains that ROS1 fusions preserve the C-terminal kinase domain through fusion with N-terminal proteins, and that different breakpoints and fusion partners can influence responses to specific tyrosine kinase inhibitors. IHC detects ROS1 protein expression and is low-cost and accessible as a screening tool. FISH uses break-apart probes at the DNA level to detect rearrangements but typically evaluates only one analyte at a time. NGS, particularly comprehensive genomic profiling, allows simultaneous evaluation of all actionable alterations in NSCLC from a single assay.

RNA-based NGS is preferred over DNA-based NGS for fusion detection because RNA represents post-spliced mRNA, eliminating the need for DNA probes spanning the entire intron and improving sensitivity and reliability. Liquid biopsy (cell-free DNA) is valuable when tissue is unavailable, with high specificity; however, a negative result does not exclude an alteration, as tumor DNA shedding varies by disease volume and specimen handling. The panel uses a fishing analogy to counsel patients: a negative liquid biopsy result does not mean there are no fish in the lake.