The role of plasma genotyping in ALK- and ROS1-rearranged lung cancer

Several subsets of non-small cell lung cancer (NSCLC) are defined by the presence of oncogenic rearrangements that result in constitutive activation of a chimeric fusion protein. In NSCLCs that harbor ALK or ROS1 rearrangements, aberrant signaling from these fusion proteins can be overcome by potent and selective tyrosine kinase inhibitors (TKIs). These targeted therapies can induce durable responses and significantly improve prognostic outcomes. Historically, analysis of tissue biopsies was the primary approach to identifying key activating rearrangements. In recent years, non-invasive genotyping of tumor-derived nucleic acids in the circulation has gained ground as a strategy for determining the genetic composition of NSCLCs at diagnosis and throughout the disease course based on prospective and retrospective studies validating the utility of plasma analysis in heterogeneous populations of patients with metastatic NSCLC. Notably, these practice-changing studies predominantly included patients with NSCLCs with oncogenic mutations. Compared to other types of molecular alterations such as mutations and insertions/deletions, oncogenic rearrangements are more complex as they incorporate a variety of fusion partners and diverse breakpoints. Because of this structural complexity, detecting oncogenic rearrangements with plasma assays is more challenging than identifying disease-defining point mutations. In this review, we discuss technical aspects of plasma genotyping strategies and summarize findings from studies exploring plasma genotyping (including ctDNA analysis and profiling of nucleic acids contained in other plasma components) in two rearrangement-driven NSCLC subsets (ALK-rearranged and ROS1-rearranged).