Monitoring therapeutic response and resistance with liquid biopsy

Lung cancer is the leading cause of cancer-related death in industrialized countries and one of the most common cancers in the world. The most common type of lung cancer is non-small cell lung cancer (NSCLC), which accounts for 80–90%. Approximately 3–7% of NSCLC patients have a genomic rearrangement of the anaplastic lymphoma kinase (ALK) gene. Tyrosine kinase inhibitors (TKIs) of the ALK have significantly improved the quality of life and survival of ALK-positive NSCLC. The therapeutic arsenal includes first-generation ALK-TKI: crizotinib and more recently second-generation ALK-TKI: ceritinib, ensartinib, alectinib and brigatinib and third-generation ALK-TKI: lorlatinib. Second-generation ALKTKIs have become the new standard of care in first-line setting in advanced ALK-positive NSCLC patients. However, most of these patients relapse as the tumor acquires resistance mutations. Although the rebiopsy at the time of ALK-TKI progression is not always feasible, liquid biopsy at progression is a potential alternative tool. Circulating tumor cells (CTCs), circulating free tumor DNA (cfDNA), exosomes and tumor-educated platelets (TEPs) in body fluid could be used to monitor response to treatments and resistance mechanisms, this may provide relevant information to define genomic-driven therapeutic sequences. Even though, the use of ALK-TKI according to the resistance mechanism, at the time of progression, seems the most appropriate, blinded treatment decisions are the most common in the clinic.