Detection of ALK fusion variants by RNA-based NGS and clinical outcome correlation in NSCLC patients treated with ALK-TKI sequences

Tabbò, Fabrizio; Muscarella, Lucia Anna; Gobbini, Elisa; Trombetta, Domenico; Castellana, Stefano; Rigutto, Angelica; Galetta, Domenico; Maiello, Evaristo; Martelli, Olga; Tiseo, Marcello; Scotti, Vieri; Ghilardi, Laura; Sergi, Concetta; Pilotto, Sara; Conte, Alessandro Del; Cappuzzo, Federico; Cortinovis, Diego; Osman, Giorgia Amira; Bareggi, Claudia; Maïo, Massimo Di; Rossi, Antonio; Rossi, Giulio; Bria, Emilio; Volante, Marco; Scagliotti, Giorgio Vittorio; Graziano, Paolo; Novello, Silvia; Righi, Luisella

doi:10.1016/j.ejca.2022.07.026

Cited by 10 publications

(9 citation statements)

References 37 publications

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“…We analyzed a total of 210 NSCLC samples by FISH, and we succeeded in characterizing 200 of these samples (95%) by targeted RNA NGS and 198 samples (94%) by RT-PCR. The results of our analyses, together with already published data [ 17 , 18 , 19 , 20 ], showed an excellent concordance rate (91%) of the targeted RNA NGS results with the so-far considered gold standard FISH technique, underlining the essential role of the NGS testing approach in the molecular pathology diagnostics laboratory.…”

Section: Discussionsupporting

confidence: 74%

Gene Fusion Detection in NSCLC Routine Clinical Practice: Targeted-NGS or FISH?

Pecciarini

Brunetto

Grassini

et al. 2023

Cells

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The ability to identify the broadest range of targetable gene fusions is crucial to facilitate personalized therapy selection for advanced lung adenocarcinoma (LuADs) patients harboring targetable receptor tyrosine kinase (RTK) genomic alterations. In order to evaluate the most effective testing approach for LuAD targetable gene fusion detection, we analyzed 210 NSCLC selected clinical samples, comparing in situ (Fluorescence In Situ Hybridization, FISH, and ImmunoHistoChemistry, IHC) and molecular (targeted RNA Next-Generation Sequencing, NGS, and RealTime-PCR, RT-PCR) approaches. The overall concordance among these methods was high (>90%), and targeted RNA NGS was confirmed to be the most efficient technique for gene fusion identification in clinical practice, allowing the simultaneous analysis of a large set of genomic rearrangements at the RNA level. However, we observed that FISH was useful to detect targetable fusions in those samples with inadequate tissue material for molecular testing as well as in those few cases whose fusions were not identified by the RNA NGS panel. We conclude that the targeted RNA NGS analysis of LuADs allows accurate RTK fusion detection; nevertheless, standard methods such as FISH should not be dismissed, as they can crucially contribute to the completion of the molecular characterization of LuADs and, most importantly, the identification of patients as candidates for targeted therapies.

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Section: Discussionsupporting

confidence: 74%

Gene Fusion Detection in NSCLC Routine Clinical Practice: Targeted-NGS or FISH?

Pecciarini

Brunetto

Grassini

et al. 2023

Cells

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“…Clinical trial results suggest that ALK TKIs are most effective against tumors harboring the V2 variant fusion, while tumors harboring the V3 variant fusion exhibit a shorter duration of response to ALK TKIs. The E18:A20 variant identified in the patient described herein was categorized as the V5 subtype, representing 1.56% of all variants ( 35 , 36 ). Currently, there is no established evidence regarding the potential benefits of ALK -TKI treatment for tumors with the V5 variant fusion.…”

Section: Discussionmentioning

confidence: 96%

Primary lung adenocarcinoma with breast metastasis harboring the EML4‑ALK fusion: A case report

Zhang,

Zhou

et al. 2024

Oncol Lett

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Pulmonary adenocarcinoma with breast metastasis is rarely encountered in clinical practice. Therefore, precise clinical diagnosis of patients with this disease is crucial when selecting subsequent treatment modalities and for overall prognosis assessment. The present study reported on a case of lung cancer with breast metastasis harboring the EML4-ALK fusion. The patient was initially diagnosed with triple-negative breast cancer with lung metastasis, but comprehensive breast cancer treatment was ineffective. Reevaluation of the patient's condition via lung biopsy revealed primary lung adenocarcinoma. In addition, the results of genetic testing revealed the EML4-ALK fusion protein in both lung and breast tissues. After treatment with ALK inhibitors, the patient's symptoms improved rapidly. This case highlights the prolonged diagnostic journey from presentation with a breast mass to ultimately being diagnosed with lung cancer with breast metastasis, underscoring the critical need for heightened awareness among clinicians regarding the possibility of rare metastatic patterns. Timely identification of lung cancer with breast metastasis, facilitated by comprehensive genetic testing, not only refines treatment decisions but also emphasizes the importance of interdisciplinary collaboration in navigating complex clinical scenarios. Such insight contributes to the ongoing development of personalized cancer care that guides clinicians toward more effective and tailored therapeutic strategies for patients with similar diagnostic challenges.

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“…However, fusions associated with novel breakpoints may be missed by routine FISH (Peled et al., 2012 ). For example, rare ALK gene fusion variants with novel breakpoints that were detected by NGS but missed by FISH have been reported in non‐small cell lung cancer as well as IMT (Tabbò et al., 2022 ; Xia et al., 2021 ; Yao et al., 2022 ). Therefore, including testing with NGS targeted RNA‐sequencing in ROS1 inhibitor eligible patients may increase detection rate, especially in cases where IHC and FISH are negative.…”

Section: Discussionmentioning

confidence: 99%

Reclassification of a spindle cell sarcoma after identification of a TFG‐ROS1 fusion: A case demonstrating the clinical benefit of next‐generation sequencing in sarcoma

Lim,

Chen,

Schaub

et al. 2024

Molec Gen & Gen Med

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BackgroundInflammatory myofibroblastic tumors (IMTs) are rare mesenchymal soft tissue sarcomas that often present diagnostic challenges due to their wide and varied morphology. A subset of IMTs have fusions involving ALK or ROS1. The role of next‐generation sequencing (NGS) for classification of unselected sarcomas remains controversial.Methods and ResultsWe report a case of a metastatic sarcoma in a 34‐year‐old female originally diagnosed as an unclassified spindle cell sarcoma with myofibroblastic differentiation and later reclassified as IMT after NGS revealed a TFG‐ROS1 rearrangement. Histologically, the neoplasm had spindle cell morphology with a lobulated to focally infiltrative growth pattern with scant inflammatory cell infiltrate. Immunohistochemistry demonstrated focal desmin and variable smooth muscle actin staining but was negative for SOX10, S100, and CD34. Fluorescence in situ hybridization was negative for USP6 or ALK gene rearrangements. NGS revealed a TFG‐ROS1 rearrangement and the patient was treated with crizotinib with clinical benefit.ConclusionsWe discuss the role of NGS as well as its potential benefit in patients with unresectable, ALK‐negative metastatic disease. Considering this case and previous literature, we support the use of NGS for patients requiring systemic treatment.

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Detection of ALK fusion variants by RNA-based NGS and clinical outcome correlation in NSCLC patients treated with ALK-TKI sequences

Cited by 10 publications

References 37 publications

Gene Fusion Detection in NSCLC Routine Clinical Practice: Targeted-NGS or FISH?

Gene Fusion Detection in NSCLC Routine Clinical Practice: Targeted-NGS or FISH?

Primary lung adenocarcinoma with breast metastasis harboring the EML4‑ALK fusion: A case report

Reclassification of a spindle cell sarcoma after identification of a TFG‐ROS1 fusion: A case demonstrating the clinical benefit of next‐generation sequencing in sarcoma

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