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Review
. 2020 Mar 18;1(1):20190019.
doi: 10.1515/almed-2019-0019. eCollection 2020 Mar.

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

[Article in English, Spanish]
Estela Sánchez-Herrero  1 , Mariano Provencio  2 , Atocha Romero  2
Affiliations
Review

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

[Article in English, Spanish]
Estela Sánchez-Herrero et al. Adv Lab Med. .

Abstract

Background: Genomic 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.

Content: In 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 outlook: Non-invasive tumor molecular profiling is crucial to improve outcomes and quality of life of NSCLC patients whose tumors harbor a translocation involving ALK locus.

Keywords: anaplastic lymphoma kinase; circulating free DNA; exosomes; liquid biopsy; non-small-cell lung cancer; tyrosine kinase inhibitors.

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Conflict of interest statement

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Figures

Figure 1:
Figure 1:
EML4-ALK translocation. ALK (red) and EML4 (purple) genes are located in the short arm of chromosome 2 and they are oriented in opposite directions. Arrows indicate the orientation of the genes. The translocation occurs through a paracentric inversion [inv(2)(p21p23)] leading a fusion transcript that contains ALK catalytic domain and EML4 amino-terminal half. (Figure designed by https://app.biorender.com/).
Figure 2:
Figure 2:
Treatment of ALK+ NSCLC patients. Mechanisms of resistance to ALK-TKIs: ALK kinase domain mutations (such as G1202R, G1269A, F1174L or L1196M), ALK amplification, dysregulation of bypass signalling pathways (such as EGFR, c-KIT, RAS-MAPK or PI3K-Akt activation) and epithelial-mesenchymal transition (EMT). (Figure designed by https://app.biorender.com/).
Figure 3:
Figure 3:
Components of liquid biopsy sample. cfDNA and cfRNA in blood come from dying cells (necrosis or apoptosis). A small fraction of cfDNA is ctDNA. Wild type DNA from blood cells can dilute ctDNA and therefore pre-analytical conditions should avoid cell lysis. CTCs, platelets (TEPs) and exosomes can capture these molecules and others, such as miRNA or cancer cell proteins. This genetic information is better protected in these compartments than in the bloodstream. (Figure designed by https://app.biorender.com/).
See this image and copyright information in PMC

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