Elisei Rossella, Grande Enrique, Kreissl Michael C, Leboulleux Sophie, Puri Tarun, Fasnacht Nicolas, Capdevila Jaume
Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Medical Oncology Department, MD Anderson Cancer Center Madrid, Madrid, Spain.
Front Oncol. 2023 May 3;13:1141314. doi: 10.3389/fonc.2023.1141314. eCollection 2023.
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 () fusions and mutations, neurotrophic tyrosine receptor kinase () gene fusions, and rearranged during transfection () 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 -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 -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 -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 alteration is found, supported by a multidisciplinary team approach.
全球范围内甲状腺癌的发病率正在上升，欧洲的疾病负担仅次于亚洲。在过去几十年中，甲状腺癌发病机制的核心分子通路揭示了一系列可靶向的激酶/激酶受体以及每种组织学亚型特有的致癌驱动因素，如分化型甲状腺癌，包括乳头状、滤泡状和髓样甲状腺癌。已确定的致癌改变包括B-Raf原癌基因（）融合和突变、神经营养酪氨酸受体激酶（）基因融合以及转染期间重排（）受体酪氨酸激酶融合和突变。除了索拉非尼、仑伐替尼和卡博替尼等多种其他激酶外，靶向RET的多激酶抑制剂（MKIs）在晚期放射性碘难治性分化型甲状腺癌或改变的髓样甲状腺癌中显示出良好的活性；然而，MKI对RET的抑制作用在临床应用中受到脱靶毒性的限制，导致剂量降低和停药率较高。新型选择性RET抑制剂selpercatinib和pralsetinib在治疗驱动的晚期甲状腺癌的临床试验中已显示出强效疗效和良好的毒性特征，目前在某些临床环境中是一种治疗选择。重要的是，对于晚期驱动的甲状腺癌，现有特定靶向治疗的最佳益处需要进行基因检测。在开始全身治疗之前，对于未接受过治疗的患者，如果发现改变，在多学科团队方法的支持下，RET抑制剂可作为一线治疗药物。
