A Review of Driver Genetic Alterations in Thyroid Cancers

Khatami, Fatemeh; Tavangar, Seyed Mohammad

doi:10.30699/ijp.13.2.125

Cited by 22 publications

(19 citation statements)

References 76 publications

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“…The most common driver genetic alterations observed in DTC include mutations in murine sarcoma viral oncogene homolog B (BRAF), rat sarcoma RAS, and RET (rearranged-during-transfection)/PTC rearrangements; in PDTC and ATC, TP53 (tumor protein p53) mutations are often observed; and in MTC, point mutations in RET oncogene and pathogenic RAS variants are common. These genetic alterations are affecting MAPK and PI3K signaling [8]. In this section, we discuss the molecular alterations that have been identified in different types of thyroid cancers, including DTC (PTC, FTC, and HTC), ATC, PDTC, and MTC.…”

Section: Molecular Landscape Of Thyroid Cancermentioning

confidence: 99%

Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review

Al-Jundi

Thakur

Gubbi

et al. 2020

Cancers

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The knowledge on thyroid cancer biology has grown over the past decade. Thus, diagnostic and therapeutic strategies to manage thyroid cancer are rapidly evolving. With new insights into tumor biology and cancer genetics, several novel therapies have been approved for the treatment of thyroid cancer. Tyrosine kinase inhibitors (TKIs), such as lenvatinib and sorafenib, have been successfully utilized for the treatment of radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC). In addition, pretreatment with mitogen-activated protein kinase (MAPK) inhibitors (trametinib and selumetinib) has been shown to restore RAI avidity in previously RAI-refractory DTCs. Local therapies, such as external beam radiation and radiofrequency/ethanol ablation, have also been employed for treatment of DTC. Vandetanib and cabozantinib are the two TKIs currently approved by the Food and Drug Administration (FDA) for the treatment of medullary thyroid cancer (MTC). Other novel therapies, such as peptide receptor radionuclide therapy and carcinoembryonic antigen (CEA) vaccine, have also been utilized in treating MTC. Ongoing trials on selective rearranged-during-transfection (RET) protooncogene inhibitors, such as LOXO-292 and BLU-667, have demonstrated promising results in the treatment of metastatic MTC resistant to non-selective TKIs. The FDA-approved BRAF/MEK inhibitor combination of dabrafenib and trametinib has revolutionized treatment of BRAFV600E mutation positive anaplastic thyroid cancer. Several other emerging classes of medications, such as gene fusion inhibitors and immune checkpoint inhibitors, are being actively investigated in several clinical trials. In this review, we describe the molecular landscape of thyroid cancer and novel targeted therapies and treatment combinations available for the treatment of metastatic thyroid cancer.

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Section: Molecular Landscape Of Thyroid Cancermentioning

confidence: 99%

Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review

Al-Jundi

Thakur

Gubbi

et al. 2020

Cancers

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“…Alternative transcripts were recurrently identified in EGFR (i.e., vIII, vIVb) within CNS tumors in AR (e.g., v7) within prostate tumors, and in MET (e.g., exon 14 skipping) within breast and lung (data not shown) tumors. Finally, point mutations in BRAF/NRAS/PTEN/TP53 are key driver events in Thyroid cancer, and were identified in approximately 80% of thyroid tumors in this study [ 27 , 28 ].…”

Section: Resultsmentioning

confidence: 99%

Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra®

et al. 2021

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We developed and analytically validated a comprehensive genomic profiling (CGP) assay, GEM ExTra, for patients with advanced solid tumors that uses Next Generation Sequencing (NGS) to characterize whole exomes employing a paired tumor-normal subtraction methodology. The assay detects single nucleotide variants (SNV), indels, focal copy number alterations (CNA), TERT promoter region, as well as tumor mutation burden (TMB) and microsatellite instability (MSI) status. Additionally, the assay incorporates whole transcriptome sequencing of the tumor sample that allows for the detection of gene fusions and select special transcripts, including AR-V7, EGFR vIII, EGFRvIV, and MET exon 14 skipping events. The assay has a mean target coverage of 180X for the normal (germline) and 400X for tumor DNA including enhanced probe design to facilitate the sequencing of difficult regions. Proprietary bioinformatics, paired with comprehensive clinical curation results in reporting that defines clinically actionable, FDA-approved, and clinical trial drug options for the management of the patient’s cancer. GEM ExTra demonstrated analytic specificity (PPV) of > 99.9% and analytic sensitivity of 98.8%. Application of GEM ExTra to 1,435 patient samples revealed clinically actionable alterations in 83.9% of reports, including 31 (2.5%) where therapeutic recommendations were based on RNA fusion findings only.

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“…Standard therapy for patients with thyroid cancer includes surgery and treatment with radioactive iodine [77,78]. The major driver mutations of thyroid cancer include BRAF and RAS mutations, and transfusion/papillary thyroid carcinoma (RET/PTC) rearrangements [79].…”

Section: Thyroid Cancermentioning

confidence: 99%

Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade

Shin

Kim

Lim

et al. 2020

IJMS

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The recent development of high-throughput genomics has revolutionized personalized medicine by identifying key pathways and molecular targets controlling tumor progression and survival. Mitogen-activated protein kinase (MAPK) pathways are examples of such targets, and inhibitors against these pathways have shown promising clinical responses in patients with melanoma, non-small-cell lung cancer, colorectal cancer, pancreatic cancer, and thyroid cancer. Although MAPK pathway-targeted therapies have resulted in significant clinical responses in a large proportion of cancer patients, the rate of tumor recurrence is high due to the development of resistance. Conversely, immunotherapies have shown limited clinical responses, but have led to durable tumor regression in patients, and complete responses. Recent evidence indicates that MAPK-targeted therapies may synergize with immune cells, thus providing rationale for the development of combination therapies. Here, we review the current status of ongoing clinical trials investigating MAPK pathway inhibitors, such as BRAF and MAPK/ERK kinase (MEK) inhibitors, in combination with checkpoint inhibitors targeting programmed death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T cell associated antigen-4 (CTLA-4). A better understanding of an individual drug’s mechanism of action, patterns of acquired resistance, and the influence on immune cells will be critical for the development of novel combination therapies.

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A Review of Driver Genetic Alterations in Thyroid Cancers

Cited by 22 publications

References 76 publications

Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review

Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review

Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra®

Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade

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