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      A narrative review of methods for the identification of ALK fusions in patients with non-small cell lung carcinoma

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          Abstract

          Background and Objective

          This narrative review is intended to provide pragmatic knowledge of current methods for the search of anaplastic lymphoma kinase ( ALK) fusions in patients with non-small cell lung carcinoma (NSCLC). This information is very timely, because a recent survey has identified that almost 50% of patients with advanced NSCLC were not candidates for targeted therapies because of biomarker testing issues.

          Methods

          PubMed was searched from January 1 st, 2012 to February 28 th, 2023 using the following keywords: “ ALK” and “lung”, including reviews and our own work.

          Key Content and Findings

          Testing rates have not reached 85% among patients’ candidates to ALK inhibition. The advantages and disadvantages of the different analytical options [immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), real-time polymerase chain reaction and next-generation sequencing (NGS)] are discussed. The key factor for success in ALK testing is a deep understanding of the concept of “molecular redundancy”. This notion has been recommended and endorsed by all the major professional organizations in the field and can be summarized as follows: “laboratories should ensure that test results that are unexpected, discordant, equivocal, or otherwise of low confidence are confirmed or resolved using an alternative method or sample”. In-depth knowledge of the different ALK testing methodologies can help clinical and molecular tumor boards implement and maintain sensible algorithms for a rapid and effective detection of predictive biomarkers in patients with NSCLC.

          Conclusions

          Multimodality testing has the potential to increase both the testing rate and the accuracy of ALK fusion identification.

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          Most cited references76

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          Lung cancer

          Alesha Thai, Benjamin Solomon, Lecia V. Sequist … (2021)
          Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide with an estimated 2 million new cases and 1·76 million deaths per year. Substantial improvements in our understanding of disease biology, application of predictive biomarkers, and refinements in treatment have led to remarkable progress in the past two decades and transformed outcomes for many patients. This seminar provides an overview of advances in the screening, diagnosis, and treatment of non-small-cell lung cancer and small-cell lung cancer, with a particular focus on targeted therapies and immune checkpoint inhibitors.
          Article 0 comments Cited 626 times – based on 0 reviews     Review now
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            Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.

            Manabu Soda, Young Choi, Munehiro Enomoto … (2007)
            Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.
            Article 0 comments Cited 569 times – based on 0 reviews     Review now
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              Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-positive Advanced Non-small-cell Lung Cancer in the Global Phase III ALEX Study

              D. Ross Camidge, Rafal Dziadziuszko, Solange Peters … (2019)
              At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34-0.65, p < 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' follow-up (cutoff December 1, 2017).
              Article 0 comments Cited 180 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Transl Lung Cancer Res
                Journal ID (iso-abbrev): Transl Lung Cancer Res
                Journal ID (publisher-id): TLCR
                Title: Translational Lung Cancer Research
                Publisher: AME Publishing Company
                ISSN (Print): 2218-6751
                ISSN (Electronic): 2226-4477
                Publication date (Electronic): 11 July 2023
                Publication date (Print): 31 July 2023
                Volume: 12
                Issue: 7
                Pages: 1549-1562
                Affiliations
                [1 ]Pathology Department , Hospital Universitario 12 de Octubre, Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain;
                [2 ]Pathology Department , Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid , Research Institute Hospital 12 de Octubre (i+12), Ciberonc, Madrid, Spain;
                [3 ]Pathology Department , Hospital Universitario 12 de Octubre, Madrid, Spain;
                [4 ]Oncology Department , Hospital Universitario 12 de Octubre, H12O-CNIO Lung Cancer Clinical Research Unit , Research Institute Hospital 12 de Octubre (i+12)/Spanish National Cancer Research Center (CNIO), Madrid, Spain;
                [5 ]Oncology Department , Hospital Universitario 12 de Octubre, H12O-CNIO Lung Cancer Clinical Research Unit , Research Institute Hospital 12 de Octubre (i+12)/Spanish National Cancer Research Center (CNIO), Ciberonc, Madrid, Spain;
                [6 ]Oncology Department , Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, H12O-CNIO Lung Cancer Clinical Research Unit , Research Institute Hospital 12 de Octubre (i+12)/Spanish National Cancer Research Center (CNIO), Ciberonc, Madrid, Spain
                Author notes

                Contributions: (I) Conception and design: S Hernandez, E Conde, F Lopez-Rios; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: S Hernandez, E Conde; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

                [#]

                These authors contributed equally to this work and should be considered as co-first authors.

                Correspondence to: Fernando Lopez-Rios, MD, PhD. Pathology Department, Hospital Universitario 12 de Octubre, Research Institute Hospital 12 de Octubre (i+12), CIBERONC, Av. de Cordoba s/n, 28041, Madrid, Spain. Email: fernandolopezriosmoreno@ 123456gmail.com .
                [^]

                ORCID: Susana Hernandez, 0000-0003-0833-1114; Esther Conde, 0000-0002-0914-0988; Fernando Lopez-Rios, 0000-0001-6813-0395.

                Article
                Publisher ID: tlcr-12-07-1549
                DOI: 10.21037/tlcr-22-855
                PMC ID: 10413037
                PubMed ID: 37577307
                SO-VID: 9f6ee738-3512-49d5-95ed-6045b2d94fc1
                Copyright © 2023 Translational Lung Cancer Research. All rights reserved.
                License:

                Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

                History
                Date received : 01 March 2023
                Date accepted : 25 June 2023
                Funding
                Funded by: Instituto de Salud Carlos III, Fondos FEDER and Plan Estatal I+D+I 2008–2011
                Award ID: No. PI11-02866
                Award ID: Nos. PI14-01176, PI17-01001
                Award ID: No. PI22-01700
                Funded by: INGENIO
                Award ID: No. PMP21/00107
                Funded by: the Next Generation EU funds; Comunidad de Madrid iLUNG Program
                Award ID: Nos. B2017-BMD-3884, S2022-BMD-7437
                Funded by: Fundacion Mutua Madrileña
                Award ID: No. AP18051-2022
                Categories
                Subject: Review Article

                Keywords: anaplastic lymphoma kinase (alk),fluorescence in situ hybridization (fish),immunohistochemistry (ihc),next-generation sequencing (ngs),non-small cell lung carcinoma (nsclc)
                Data availability:
                Keywords: anaplastic lymphoma kinase (alk), fluorescence in situ hybridization (fish), immunohistochemistry (ihc), next-generation sequencing (ngs), non-small cell lung carcinoma (nsclc)

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