Patterns of Treatment Failure After Selective Rearranged During Transfection (RET) Inhibitors in Patients With Metastatic Medullary Thyroid Carcinoma

JCO Precis Oncol. 2023 Sep:7:e2300053. doi: 10.1200/PO.23.00053.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Medullary* / genetics
  • Carcinoma, Medullary* / pathology
  • Carcinoma, Medullary* / surgery
  • Humans
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-ret / genetics
  • Thyroid Neoplasms* / drug therapy
  • Thyroid Neoplasms* / genetics
  • Transfection
  • Treatment Failure


  • Proto-Oncogene Proteins c-ret
  • Protein Kinase Inhibitors
  • RET protein, human

Supplementary concepts

  • Thyroid cancer, medullary