Next Generation Sequencing-Based Profiling of Cell Free DNA in Patients with Advanced Non-Small Cell Lung Cancer: Advantages and Pitfalls

SIMPLE SUMMARY: Genomic profiling of non-small cell lung cancer (NSCLC) patients offers the possibility of therapeutic intervention with target-based agents. The analysis of circulating free DNA (cfDNA) through next generation sequencing (NGS) technologies is emerging as a powerful tool to assess the whole tumor molecular landscape of NSCLC patients and characterize spatial and temporal tumor heterogeneity. Moreover, cfDNA NGS testing allows the monitoring of therapy response and the early identification of resistance mechanisms. In this review, we describe the importance of implementation of cfDNA NGS testing in routine clinical practice to improve targeted diagnostic procedures and personalized therapies in NSCLC patients. ABSTRACT: Lung cancer (LC) is the main cause of death for cancer worldwide and non-small cell lung cancer (NSCLC) represents the most common histology. The discovery of genomic alterations in driver genes that offer the possibility of therapeutic intervention has completely changed the approach to the diagnosis and therapy of advanced NSCLC patients, and tumor molecular profiling has become mandatory for the choice of the most appropriate therapeutic strategy. However, in approximately 30% of NSCLC patients tumor tissue is inadequate for biomarker analysis. The development of highly sensitive next generation sequencing (NGS) technologies for the analysis of circulating cell-free DNA (cfDNA) is emerging as a valuable alternative to assess tumor molecular landscape in case of tissue unavailability. Additionally, cfDNA NGS testing can better recapitulate NSCLC heterogeneity as compared with tissue testing. In this review we describe the main advantages and limits of using NGS-based cfDNA analysis to guide the therapeutic decision-making process in advanced NSCLC patients, to monitor the response to therapy and to identify mechanisms of resistance early. Therefore, we provide evidence that the implementation of cfDNA NGS testing in clinical research and in the clinical practice can significantly improve precision medicine approaches in patients with advanced NSCLC.