Gil-Bernabé Sara, García-DeLaFuente Lucía, García-Álvarez Alejandro, García-Rostán Ginesa, Capdevila Jaume, Hernando Jorge
Pathology Department, Faculty of Medicine, Valladolid University, Valladoli, Spain.
Group Pathobiology of Cancer: Inter-, Intra-Tumor Heterogeneity and Molecular Targets, Institute of Molecular Genetics and Biomedicine (IBGM), Valladoli, Spain.
Am J Med Genet C Semin Med Genet. 2025 Jan 4:e32127. doi: 10.1002/ajmg.c.32127.
RET gene is a driver of thyroid cancer (TC) tumorigenesis. The incidence of TC has increased worldwide in the last few decades, both in medullary and follicular-derived subtypes. Several drugs, including multikinase and selective inhibitors, have been explored. Selpercatinib and pralsetinib are selective RET inhibitors that have shown clear clinical benefits for patients in the LIBRETTO and ARROW trials, respectively. Currently, their development and application in clinical practice are ongoing. However, its efficacy in different RET pathogenic variants has not yet been well established. Although selpercatinib and pralsetinib achieved a high ORR, no data are available regarding the differences in tumor responses of both TC groups according to RET pathogenic variants. Clinical trials and literature have analyzed the efficacy of selective RET inhibitors with a special interest in the most common variants. A review of LIBRETTO and ARROW trials was made regarding the change in tumor size depending on the pathogenic variants. M918T pathogenic variant resulted in a higher complete response rate. Patients who underwent fusion had the highest ORR (objective response rate). MKi-treated patients did not exhibit significant differences from untreated patients. Different RET pathogenic variants are not biomarkers of RETi response in TC. Selpercatinib showed a tendency to achieve a complete response. All patients with RET pathogenic variants should receive treatment with selpercatinib or pralsetinib at any moment of the therapeutic schedule owing to off-target inhibition and toxicity. Therefore, new targets for drug sensitivity and resistance should be explored.
RET基因是甲状腺癌（TC）肿瘤发生的驱动因素。在过去几十年中，TC的发病率在全球范围内有所上升，包括髓样和滤泡来源的亚型。已经探索了几种药物，包括多激酶抑制剂和选择性抑制剂。塞尔帕替尼和普拉替尼是选择性RET抑制剂，分别在LIBRETTO和ARROW试验中对患者显示出明显的临床益处。目前，它们在临床实践中的开发和应用正在进行中。然而，其在不同RET致病变体中的疗效尚未得到充分证实。尽管塞尔帕替尼和普拉替尼实现了高客观缓解率（ORR），但尚无关于根据RET致病变体划分的两组TC肿瘤反应差异的数据。临床试验和文献分析了选择性RET抑制剂的疗效，特别关注最常见的变体。对LIBRETTO和ARROW试验进行了回顾，以了解根据致病变体肿瘤大小的变化。M918T致病变体导致更高的完全缓解率。发生融合的患者客观缓解率最高。接受多激酶抑制剂（MKi）治疗的患者与未治疗的患者没有显著差异。不同的RET致病变体不是TC中RET抑制剂（RETi）反应的生物标志物。塞尔帕替尼显示出实现完全缓解的趋势。由于脱靶抑制和毒性，所有携带RET致病变体的患者在治疗过程中的任何时候都应接受塞尔帕替尼或普拉替尼治疗。因此，应探索药物敏感性和耐药性的新靶点。
