Characterization of thyroid cancer driven by known and novel ALK fusions

Panebianco, Federica; Nikitski, Alyaksandr V.; Nikiforova, Marina N.; Kaya, Cihan; Yip, Linwah; Condello, Vincenzo; Wald, Abigail I.; Chiosea, Simion I.

doi:10.1530/erc-19-0325

Cited by 41 publications

(39 citation statements)

References 43 publications

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“…ALK rearrangement is common in PDTCs with a prevalence of 16%; striatin ( STRN )- ALK rearrangement is the commonest and rarely EMAP like 4 ( EML4 )- ALK [ 95 , 96 ]. Neurotrophic tyrosine kinase receptor ( NTRK ) fusion oncogenes ( NTRK3 / ETV6 , NTRK1 - TPR and NTRK1 - LMNA and NTRK1 - TMP3 ) are recognised in up to 26% of PTCs.…”

Section: Tumour Progressionmentioning

confidence: 99%

The Genomic Landscape of Thyroid Cancer Tumourigenesis and Implications for Immunotherapy

Singh

Ham

et al. 2021

Cells

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Thyroid cancer is the most prevalent endocrine malignancy that comprises mostly indolent differentiated cancers (DTCs) and less frequently aggressive poorly differentiated (PDTC) or anaplastic cancers (ATCs) with high mortality. Utilisation of next-generation sequencing (NGS) and advanced sequencing data analysis can aid in understanding the multi-step progression model in the development of thyroid cancers and their metastatic potential at a molecular level, promoting a targeted approach to further research and development of targeted treatment options including immunotherapy, especially for the aggressive variants. Tumour initiation and progression in thyroid cancer occurs through constitutional activation of the mitogen-activated protein kinase (MAPK) pathway through mutations in BRAF, RAS, mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway and/or receptor tyrosine kinase fusions/translocations, and other genetic aberrations acquired in a stepwise manner. This review provides a summary of the recent genetic aberrations implicated in the development and progression of thyroid cancer and implications for immunotherapy.

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Section: Tumour Progressionmentioning

confidence: 99%

The Genomic Landscape of Thyroid Cancer Tumourigenesis and Implications for Immunotherapy

Singh

Ham

et al. 2021

Cells

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“…Only one other ITSN2 (exon 29)- ALK (exon 18) fusion has been reported so far, specifically in a patient with thyroid cancer. 33 In that case, RNA-Seq showed overexpression of ALK exons 18-29 downstream of the fusion point; however, neither IHC results nor the therapeutic effects of ALK-TKIs were reported.…”

Section: Discussionmentioning

confidence: 90%

Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors

Takeyasu

Okuma²,

Kojima³

et al. 2021

JCO Precision Oncology

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PURPOSE Anaplastic lymphoma kinase ( ALK) rearrangement is a well-known driver oncogene in non–small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare ALK-rearranged tumors. PATIENTS AND METHODS Between April 2012 and April 2019, clinical outcomes and characteristics of patients with ALK-rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression. RESULTS We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-ALK and ITSN2-ALK, were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib. CONCLUSION This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK-rearranged nonlung solid tumors.

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“…All 5 PDTCs carried the STRN-ALK fusion. Compared to EML4-ALK, STRN-ALK may be more common in PDTC, and ∼10% of ALK fusions involve rare gene partners [ 17 ]. In the same study, Panebianco et al showed that all 19 resected thyroid nodules with ALK fusions identified preoperatively by fine-needle aspiration were malignant [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Aggressive Differentiated Thyroid Cancer due to EML4e13-ALKe20 Fusion: A Case Presentation and Review of the Literature

Khthir

Shaheen

Santhanam

et al. 2021

Case Reports in Endocrinology

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Background. Differentiated thyroid cancer (DTC) is an indolent malignancy. It rarely presents with aggressive local invasion and/or distant metastatic disease. Patient findings. We describe a case of a 30-year-old man with a locally aggressive form of papillary thyroid cancer with EML4e13-ALKe20 fusion (EML4: echinoderm microtubule-associated protein-like 4; ALK: anaplastic lymphoma kinase). He presented with right-side cervical lymphadenopathy with a highly suspicious right-side thyroid nodule. Total thyroidectomy and level IV lymph node resection showed extensive bilateral disease, with extrathyroidal and extranodal extension. FDG-PET CT scan following surgery confirmed the presence of significant residual disease in the neck area. He underwent bilateral lateral lymph node dissection followed by radioactive iodine treatment. Somatic mutation testing showed EML4e13-ALKe20 fusion. Summary. This case represents an aggressive form of DTC with EML4e13-ALKe20 fusion. The rapid progression of clinical signs and symptoms and the local extension beyond the thyroid and lymph nodes with the persistence of high-volume local disease after thyroidectomy highlight the aggressive nature of this mutation and the importance of performing genetic analysis to guide future treatments and determine prognosis. Conclusion. This case highlights the importance of using molecular diagnostics in patient care, especially if the presentation is unusual for DTC. A thorough evaluation of the tumor pathology and the somatic mutational profile analysis are important for obtaining vital therapeutic and prognostic guidance.

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Characterization of thyroid cancer driven by known and novel ALK fusions

Cited by 41 publications

References 43 publications

The Genomic Landscape of Thyroid Cancer Tumourigenesis and Implications for Immunotherapy

The Genomic Landscape of Thyroid Cancer Tumourigenesis and Implications for Immunotherapy

Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors

Aggressive Differentiated Thyroid Cancer due to EML4e13-ALKe20 Fusion: A Case Presentation and Review of the Literature

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