AI Article Synopsis
- Medullary thyroid cancer (MTC) often has mutations in the RET gene, and while selective RET inhibitors (RETi) are effective treatments, most patients eventually develop resistance to these drugs.
- A study analyzed 46 MTC patients treated with RETi from 2018 to 2022, finding that 26 discontinued treatment due to progression, death, or toxicity; resistance mechanisms included mutations in RAS genes and others in 75% of cases, and specific RET mutations explained resistance in the remaining 25%.
- The research revealed that patients' tumors became more aggressive after treatment, indicated by increased Ki 67-index levels and a more poorly differentiated histology, highlighting the need
Article Abstract
Purpose: Medullary thyroid cancer (MTC) harbors frequent mutations in RET oncogene. Selective RET inhibitors (RETi) have emerged as effective treatments. However, resistance almost invariably occurs.
Methods: MTC patients who were initiated on RETi between 2018 and 2022 were included. Baseline characteristics, RET mutational status, RETi response, available tumor tissue and molecular profiles sampled pre- and post-RETi were analyzed.
Results: Among 46 MTC patients on RETi during the study period, 26 patients had discontinued at data cut-off because of progression (n = 16), death (n = 4), and toxicity (n = 6). The most frequent RET mutations at baseline were p.M918T (n = 29), and p.C634X (n = 6). Pre- and post-RETi molecular profiles were available in 14 patients. There was no primary resistance on pre-RETi samples. Post-RETi profiles revealed a bypass mechanism of resistance in 75% of the cases including RAS genes mutations (50%), FGFR2 and ALK fusions and and MYC p.P44L. RET solvent from and hinge region mutations was the only resistance mechanisms in 25% of the cases. Tumor samples from initial thyroidectomy, pre- and post-RETi, from six patients, showed an increase of the mean Ki 67-index of 7%, 17% and 40% respectively (P = 0.037) and a more aggressive poorly differentiated histology in three patients.
Discussion: Bypass resistance may be the most frequent mechanism of progression under RETi. A more aggressive histology may arise following RETi and warrants further investigation.
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| http://dx.doi.org/10.1200/PO.23.00053 | DOI Listing |
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Article Synopsis
- Medullary thyroid cancer (MTC) often has mutations in the RET gene, and while selective RET inhibitors (RETi) are effective treatments, most patients eventually develop resistance to these drugs.
- A study analyzed 46 MTC patients treated with RETi from 2018 to 2022, finding that 26 discontinued treatment due to progression, death, or toxicity; resistance mechanisms included mutations in RAS genes and others in 75% of cases, and specific RET mutations explained resistance in the remaining 25%.
- The research revealed that patients' tumors became more aggressive after treatment, indicated by increased Ki 67-index levels and a more poorly differentiated histology, highlighting the need
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