Multicenter Validation of the Sensitivity of Theranostic ALK Rearrangement Detection by FISH Analysis and Prevalence of Escaping Mutations in Circulating Tumor Cells for the Non-invasive Management of Lung Cancer Patients

Patients eligibility to targeted therapies relies on a molecular test performed on a tumor sample collected by biopsy. This invasive procedure is associated with a relative high risk of morbidity and requires the intervention of a costly and important technical platform. Thus, inoperable patients can be deprived from potentially more efficient therapies. A "liquid biopsy" of Circulating Tumor Cells (CTCs) present in the blood and their molecular characterization is an appealing alternative to meet an urgent need for these patients. Moreover no CTC-based molecular test is currently routinely available. The 5-year survival rate of patients with non-small cell lung carcinoma (NSCLC) is low. Recent reports demonstrated that the detection of an ALK rearrangement in the tumor tissue allows patients with late-stages NSCLC to benefit from crizotinib treatment. However, 1) the detection of an ALK rearrangement is currently performed on small biopsies or fine-needle aspirates and can be hindered by the limited tissue quantities available. Tumor tissue is difficult to obtain in patients with advanced/metastatic lung cancer for whom surgery is rarely a component of treatment. Finding alternative and more effective means of diagnosing an ALK rearrangement are critical issues for identifying patients who may benefit from treatment with crizotinib; 2) some patients develop resistance to crizotinib due to de novo ALK mutations. In this setting, circulating tumor cells (CTCs), which have been shown to be detectable by ISET (Isolation by Size of Epithelial Tumor Cells) method in 80% to 100 % of late stages lung cancer patients represent a non-invasive and easily accessible source of tumor material for assessing ALK rearrangement and escaping mutations in a kinetic manner. The ISET method was first published in 2000 and several independent teams have now established its high sensitivity and specificity of ISET for NSCLC. With ISET, specificity can be achieved using the same methods