Liquid biopsy for monitoring anaplastic lymphoma kinase inhibitors in non-small cell lung cancer: Two cases compared

Three to seven percent of non-small cell lung cancer (NSCLC) patients show anaplastic lymphoma kinase (ALK)-translocation and could be treated with ALK-inhibitors. However, under crizotinib, a first-generation ALK-inhibitor, patients develop drug resistance after a median of 12 months. To overcome crizotinib resistance, several next-generation ALK inhibitors have been developed. In NSCLC, liquid biopsy allowed important improvements in the detection of the epidermal growth factor receptor (EGFR) mutation. The ability of liquid biopsy to detect oncogenic gene/protein fusions is a newly investigated field, and is not routinely applied yet. We here present two NSCLC patients, both rearranged for echinoderm microtubule associated-protein like 4-anaplastic lymphoma kinase (EML4-ALK) and treated accordingly, who differed in the clinical outcome. We analyzed the predictive value of the liquid biopsy components, namely epithelial cellular adhesion molecule (EpCAM)+ circulating tumor cells (CTCs), EpCAM low/neg CTCs, EML4-ALK rearranged CTCs, and cell-free mRNA (cfmRNA), during ALK-inhibitors treatment. This analysis showed a potential association between the liquid biopsy biomarkers, patients' outcome and response to treatment, thus suggesting their combined use in the clinical practice, as proposed here. This approach would allow longitudinal monitoring and consequent identification of putative drug-resistance mechanisms, in the light of improving high-risk patient management.