Current perspectives on the management of patients with advanced RET-driven thyroid cancer in Europe

Abstract

The incidence of thyroid cancer is increasing worldwide with the disease burden in Europe second only to that in Asia. In the last several decades, molecular pathways central to the pathogenesis of thyroid cancer have revealed a spectrum of targetable kinases/kinase receptors and oncogenic drivers characteristic of each histologic subtype, such as differentiated thyroid cancer, including papillary, follicular, and medullary thyroid cancer. Oncogenic alterations identified include B-Raf proto-oncogene (BRAF) fusions and mutations, neurotrophic tyrosine receptor kinase (NTRK) gene fusions, and rearranged during transfection (RET) receptor tyrosine kinase fusion and mutations. Multikinase inhibitors (MKIs) targeting RET in addition to multiple other kinases, such as sorafenib, lenvatinib and cabozantinib, have shown favourable activity in advanced radioiodine-refractory differentiated thyroid cancer or RET-altered medullary thyroid cancer; however, the clinical utility of MKI RET inhibition is limited by off-target toxicity resulting in high rates of dose reduction and drug discontinuation. Newer and selective RET inhibitors, selpercatinib and pralsetinib, have demonstrated potent efficacy and favourable toxicity profiles in clinical trials in the treatment of RET-driven advanced thyroid cancer and are now a therapeutic option in some clinical settings. Importantly, the optimal benefits of available specific targeted treatments for advanced RET-driven thyroid cancer require genetic testing. Prior to the initiation of systemic therapy, and in treatment-naïve patients, RET inhibitors may be offered as first-line therapy if a RET alteration is found, supported by a multidisciplinary team approach.

Update on Molecular Diagnostics in Thyroid Pathology: A Review

“…As the most frequent thyroid malignancy, papillary thyroid carcinoma (PTC) is most often classic PTC and is predominantly associated with BRAF p.V600E [7,8], although most prevalence studies were performed prior to a subset of PTC being relegated to other categories (non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), CMTC, well-differentiated tumor of uncertain malignant potential (WDT-UMP)) [8]. Following the publication of The Cancer Genome Atlas characterization of PTC in 2014 [9], which included a prominent subset of formerly classified follicular variant PTC, tumors were largely divided into those that were BRAF V600E -like and RAS-like [10].…”

Genomic and Transcriptomic Landscape of RET Wild-Type Medullary Thyroid Cancer and Potential Use of Mitogen-Activated Protein Kinase-Targeted Therapy

“…Hereditary syndromes predisposing a patient to MTC include multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B (more aggressive MTC at an earlier age, pheochromocytomas and neuromas), and familial (nonmultiple endocrine neoplasia) MTC. 2 Among sporadic MTC, 45% to 70% of cases have been attributed to an activating point mutation in the receptor tyrosine kinase gene RET , an oncogenic driver implicated in other cancers as well. 3 , 4 Although a majority of RET mutations in sporadic MTC affect codon 918 (M918T), followed by codon 634, other mutations have been identified as well.…”

“… 3 , 4 Although a majority of RET mutations in sporadic MTC affect codon 918 (M918T), followed by codon 634, other mutations have been identified as well. 2 , 5 - 12 …”