During the last decades the knowledge on follicular cell-derived thyroid cancer (TC) molecular biology has led to the evolution of a number of novel therapies for these tumors, mainly tyrosine kinase inhibitors (TKIs). Lenvantinib, sorafenib and recently cabozantinib have been approved for differentiated thyroid cancer (DTC), while larotrectinib and entrectinib for NTRK-fusion thyroid cancer. For radioiodine (RAI) refractory DTCs ongoing research aims to identify agents that may restore RAI avidity via redifferentiation protocols (vemurafenib or dabrafenib and trametinib) or combination treatments. These treatments are based on the tumor molecular signature. The treatment with targeted therapies has changed the therapeutic strategies and the disease prognosis, however drug resistance remains the main reason for treatment failure. Thus, the understanding not only of the molecular pathways implicated in tumorigenesis but also of the underlying tumoral escape mechanisms are of paramount significance for the development of new therapies for DTC. The present review focuses on the molecular landscape of DTC, the approved targeted therapies as well as the mechanisms of drug resistance. Furthermore, it points to the ongoing research and the future perspectives for the development of more efficient drugs for DTC.
Background: Medullary thyroid carcinoma (MTC) has varying clinical course with familial cases (fMTC) diagnosed earlier than sporadic MTC (spMTC). Methods: A total of 273 MTCs (familial: n = 110 [40.3%], males: 38.5%) were followed for 1-35 years (median 5.0 years). Fifty one of the familial cases were operated because of positive findings at genetic screening. Disease extent at diagnosis and follow-up was recorded. Results: Mean age at diagnosis was: fMTC = 33.85 AE 16.5 years (range 4-74) and spMTC = 52.6 AE 14.0 years (range 16-81, P < .001). This difference remained when genetic screening cases were excluded. fMTCs had more frequently multifocality, smaller size, and more favorable stage at diagnosis (stages I and II: 60.9% vs 47.9%, stage III: 30.0% vs 23.9%, stage IV: 9.1% vs 28.9%, P = .01). fMTC had lower preoperative and postoperative calcitonin, more frequently remission (59.1% vs 47.2%) and less frequently progressive disease (8.2% vs 35.0%, P < .001). After excluding genetic screening cases, no difference in stage at diagnosis was observed. Outcome was more favorable in fMTC compared to sporadic (P = .002); the 10-year probability of lack of progression of disease differed significantly between fMTCs and spMTCs (86.4% vs 65.0%, P < .001). Conclusion: After excluding genetic screening cases, although stage at diagnosis is similar, disease outcome remains worse in sporadic compared to fMTCs. K E Y W O R D Sfamilial, hereditary, medullary thyroid cancer, outcome, sporadic
Context Although the majority of RET alterations are single nucleotide variants (SNV), small deletions and/or insertions have been reported at variable prevalence. No information about the efficacy of RET specific inhibitors in patients harboring RET indels, has been provided. Objective To present an update on the prevalence of RET indels in MTC and describe the efficacy of selpercatinib in patients with advanced RET indels MTC. Patients and Methods MTC tissues of 287 patients were analyzed using an Ion S5 targeted sequencing. The functional role of the reported indels have been evaluated by Mutation-Taster. Clinical and pathological data of MTC patients harboring a RET indel were collected and analyzed. Two patients with a RET indel have been treated with selpercatinib. Results Among 178 RET positive cases, 147 (82.6%) harbored a SNV and 31 (17.4%) a RET in-frame indel. Nine indels were not previously reported and were found to be disease causing by Mutation-Taster. Patients harboring an indel were found to have an aggressive disease and 2 of them were treated with selpercatinib, experiencing a good response to the treatment. Conclusions These data show that RET indels are not infrequent and correlate with an aggressive disease. Two RET indels positive patients showed a partial response to the treatment with highly selective RET inhibitor thus these RET indels can be considered actionable mutations. In order to not miss these alterations, the analysis of the full gene is recommended.
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