The third generation lorlatinib, which is the only TKI able to target the ALK resistance mutation G1202R, has been approved both as a second and as a third line treatment after other ALK first or second generation TKIs. Different clinical trials demonstrated a better efficacy for the second generation drugs alectinib and brigatinib in comparison to crizotinib in the first line treatment of ALK-rearranged NSCLC. ĪLK rearrangements have a frequency of 2–7% among advanced lung ADC patients and five ALK inhibitors are currently available: the first generation crizotinib, the second generation alectinib, ceritinib and brigatinib and the third generation lorlatinib. In detail, patients with ADC harboring anaplastic lymphoma kinase ( ALK), ROS proto-oncogene 1 ( ROS1), rearranged during transfection proto-oncogene gene ( RET) and neurotrophin kinase ( NTRK) gene rearrangements can benefit from a treatment with tyrosine kinase inhibitors (TKIs), so an efficient and valued molecular testing is mandatory. Īmong targetable alterations with approved drugs in ADC there are different fusion proteins leading to constitutively activated kinases. Overall, whenever possible, the use of multigene testing panels, particularly next generation sequencing (NGS) ones, ensures a wider definition of the molecular landscape of lung tumors including all biomarker types, common and rare. Molecular characterization has then to be performed using highly sensitive, specific, adequate and validated tests allowing the analysis of samples with a low percentage of tumor cells (10–20%) and working both on histological and cytological specimens. According to the recent updated guidelines, molecular testing in NSCLC includes three classes of targets: the “must-test” biomarkers with approved targeted therapies (i.e., epidermal growth factor receptor ( EGFR)) “should-test” biomarkers (i.e., MET proto-oncogene, receptor tyrosine kinase ( MET)), crucial to eventually direct patients to ongoing clinical trials and “investigational” biomarkers, without a clear clinical value at the moment. Consequently, molecular testing guidelines are continuously updated on the basis of available clinical data, taking into account genetic discovery, new drug approval and new molecular techniques. Precision medicine in non-small cell lung cancer (NSCLC) and particularly in metastatic advanced lung adenocarcinoma (ADC), is evolving rapidly with an increased number of targetable alterations. Currently, more than 10,000 gene fusions have been identified in human cancers, many of which are strong driver alterations. There is not a perfect method for gene fusion analysis, but NGS approaches, though still needing a complete standardization and optimization, present several advantages for the clinical practice.įusion genes are hybrid genes generated by the juxtaposition of two previously independent genes, following structural rearrangements like deletions, inversions, translocations or duplications within the same chromosome or between different chromosomes. On liquid biopsy, satisfying data have been published on circulating tumor DNA hybrid-capture panels. RNA-based targeted approach analyses and quantifies directly fusion transcripts and is more accurate than DNA panels on tumor tissue, but it can be limited by RNA quality and quantity. DNA sequencing evaluates different alteration types simultaneously, but large introns and repetitive sequences can impact on the performance and it does not discriminate between expressed and unexpressed gene fusions. The analysis can be performed at DNA or RNA levels, using different target enrichment (hybrid-capture or amplicon-based) and sequencing chemistries, with both custom and commercially available panels. This is a PubMed-based narrative review aiming to summarize NGS approaches for gene fusion analysis and their performance on NSCLC clinical samples. Although several NGS panels are available, gene fusion testing presents more technical challenges than other variants. Several techniques can be used, from fluorescence in situ hybridization and immunohistochemistry to next generation sequencing (NGS). Gene fusions have a pivotal role in non-small cell lung cancer (NSCLC) precision medicine.
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