ALK Rearrangement in ALK-Positive NSCLC Reflected in Circulating Tumour Cells

CTCs could represent a unique compartment to identify tumour clones to be targeted by personalised treatment

EML4–ALK fusion protein kinase is a potent oncogenic driver in 3–7% of patients with non-small cell lung cancer (NSCLC) and its discovery led to the development of the ALK inhibitor crizotinib. This agent and an accompanying companion diagnostic test were granted approval for the detection of ALK-rearrangements. The test is performed on tumour biopsies or fine-needle aspirates, but is hampered by the lack of available tumour tissue.

A group of researchers from the Institut Gustave Roissy, Villejuif, France, led by Dr Françoise Farace has evaluated whether circulating tumour cells (CTCs) might represent a non-invasive source of tumour material in NSCLC. The researchers isolated CTCs from 32 patients with metastatic NSCLC, 18 of whom had ALK-positive tumours.

ALK-rearranged CTCs and tumour specimens were characterized for epithelial (cytokeratins, E-cadherin) and mesenchymal (vimentin, N-cadherin) marker expression. ALK-rearranged CTCs were monitored in five patients treated with crizotinib.

Cell number is an essential criterion to exploit CTCs, therefore the researchers focused on the development of a fluorescence in situ hybridization (FISH) method on filters (Filter Adapted-FISH, FA-FISH) that takes into account the very fragile nature of CTCs and allows high cell recovery.

All ALK-positive patients had four or more ALK-rearranged CTCs per 1 mL of blood. No or only one ALK-rearranged CTC was detected in ALK-negative patients. The authors found ALK rearrangements in CTCs from all the patients with ALK-positive tumours. These CTCs had a unique ALK rearrangement and a mesenchymal phenotype, in contrast to the heterogeneous epithelial/mesenchymal phenotypes in the patient's tumours.

The researchers concluded that their results suggest that CTCs harbouring a unique ALK rearrangement and mesenchymal phenotype may arise from clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC. ALK-rearranged CTCs could result from a clonal selection process of tumour cells displaying migratory and invasive properties, and possibly a higher metastatic potential.

According to the research highlights commented by dr Farace in the Nature Review Clinical Oncology (full articles available upon log-in to the ESMO Scientific Journals Access program), “CTCs could represent a unique compartment to identify tumour clones that should be targeted by personalized treatments, as well as biomarkers that are more relevant for treatment prediction”.


1. Pailler, E. et al. Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive non–small-cell lung cancer. J Clin Oncol 2013; 31(18):2273-81.

2. Marchesi V. Lung cancer: ALK status of NSCLC reflected in CTCs. Nature Reviews Clinical Oncology 2013; 10 (7): 366.