Clinical utility of liquid biopsy for the diagnosis and monitoring of EML4-ALK NSCLC patients

Abstract

BackgroundGenomic rearrangement in anaplastic lymphoma kinase (ALK) gene occurs in 3−7% of patients with non-small-cell lung cancer (NSCLC). The detection of this alteration is crucial as ALK positive NSCLC patients benefit from ALK inhibitors, which improve both the patient's quality of life and overall survival (OS) compared to traditional chemotherapy.ContentIn routine clinical practice, ALK rearrangements are detected using tissue biopsy. Nevertheless, the availability of tumor tissue is compromised in NSCLC patients due to surgical complications or difficult access to the cancer lesion. In addition, DNA quality and heterogeneity may impair tumor biopsies testing. These limitations can be overcome by liquid biopsy, which refers to non-invasive approaches for tumor molecular profiling. In this paper we review currently available technology for non-invasive ALK testing, in NSCLC patients, based on the analysis of circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), circulating tumor cells (CTCs), tumor-educated platelets (TEPs) and extracellular vesicles (EVs) such as exosomes.Summary and outlookNon-invasive tumor molecular profiling is crucial to improve outcomes and quality of life of NSCLC patients whose tumors harbor a translocation involving ALK locus.

Liquid First Is “Solid” in Naïve Non-Small Cell Lung Cancer Patients: Faster Turnaround Time With High Concordance to Solid Next-Generation Sequencing

“…It is established, however, that the sensitivity of analyzing cfDNA for rearrangements is lower than that for SNVs or indels because the cfDNA is highly fragmented resulting in lower amounts of mappable sequence to detect the fusion. It is also estimated that ALK rearrangements are more easily detectable utilizing cfRNA than cfDNA techniques ( 15 , 16 ).…”

One-Step Polymerase Chain Reaction-Free Nanowire-Based Plasma Cell-Free DNA Assay to Detect EML4-ALK Fusion and to Monitor Resistance in Lung Cancer

“…NGS using cfDNA has proved to be useful for detecting EML4‐ALK fusions with high sensitivity and specificity of 80% and 100%, respectively [35]. However, the needs for specialized equipment, slow processing times (2 to 3 weeks), and bioinformatics support for data interpretation often limit the wide application.…”

“…As an optical sensing platform, the NW‐based method makes it an attractive alternative for clinical sample analysis because of its relatively low cost, small sample volume, and fast turnaround time (1 hour). Nevertheless, ALK fusion testing using cfDNA is rather challenging because genomic breakpoints are usually unknown, and the rearrangement usually involves thousands of base pairs [35]. Thus, further large‐scale study is required to find an appropriate and optimal balance of threshold levels between false positives and false negatives.…”

MagPure chip: an immunomagnetic-based microfluidic device for high purification of circulating tumor cells from liquid biopsies

“…In particular, the anaplastic lymphoma kinase (ALK) genetic abnormality, located on the short arm of chromosome 2, is a key oncogenic driver, especially in nonsmall cell lung cancer 64 . Thus, FISH is routinely performed on lung cancer tissues to detect EML4 and ALK gene fusion which occurs in 3−7% of NSCLC patients 65 . This detection is crucial since specific tyrosine kinase inhibitors (ALK inhibition) is recommended as the first-line standard therapy for these patients (according to the US FDA), improving both the patient's quality of life and overall survival compared to traditional chemotherapy 66,67 .…”