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

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.