Critical issues in the clinical application of liquid biopsy in non-small cell lung cancer.

Current therapeutic options for non-small cell lung cancer (NSCLC) patients are chemotherapy and targeted therapy directed mainly against epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. Targeted therapy relies on the availability of tumor biopsies for molecular profiling at diagnosis and to longitudinally monitor treatment response and resistance development. Unfortunately, tumor biopsy might be invasive, recover poor material of suboptimal quality, and cause sample bias due to tumor heterogeneity. Many studies have illustrated the potential of liquid biopsy as minimal invasive approach to respond to the urgent need for real time monitoring, stratification, and personalized optimized treatment in NSCLC patients. In principle, the liquid biopsy could provide the genetic landscape of primary and metastatic cancerous lesions, detecting "druggable" genomic alterations or associated with treatment resistance. Moreover, it would guarantee the prognostic/predictive biomarkers evaluation in patients for whom biopsies are inaccessible or difficult to repeat. At this regard, the prognostic value of circulating tumor cells (CTCs) in NSCLC patients has been largely investigated, but still their clinical utility as tumor biomarker is hampered by the lack of a consensus on the criteria necessary and sufficient to define them and on the standard operating procedures (SOPs) for their assessment. This review will summarize current developments on liquid biopsy in NSCLC, addressing the technology issues that contribute to the poor ability to track CTCs in the blood of NSCLC patients, thus limiting their extensive use in the clinical practice, and analyzing the solutions adopted to overcome such limits, on the road towards the clinical validation.