Reference Detail

Ref Type

Journal Article

PMID

(38127829)

Authors

Hadoux J, Al Ghuzlan A, Lamartina L, Bani MA, Moog S, Attard M, Scoazec JY, Hartl D, Aldea M, Friboulet L, Jules-Clement G, Italiano A, Besse B, Lacroix L, Baudin E

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCO precision oncology	7		2023 Sep	e2300053	JCO Precis Oncol

URL

Abstract Text

Medullary thyroid cancer (MTC) harbors frequent mutations in RET oncogene. Selective RET inhibitors (RETi) have emerged as effective treatments. However, resistance almost invariably occurs.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.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.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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
RET	G810N	missense	unknown	RET G810N lies within the protein kinase domain of the Ret protein (UniProt.org). G810N has been associated with acquired resistance to RET inhibitors (PMID: 38127829), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET G810N RET M918T	medullary thyroid carcinoma	predicted - resistant	Selpercatinib	Case Reports/Case Series	Actionable	In a retrospective analysis, a medullary thyroid carcinoma patient harboring RET M918T progressed on treatment with Retevmo (selpercatinib) and was found to have acquired RET G810N (PMID: 38127829; NCT03157128, NCT03037385, NCT03780517).	38127829
RET Y806C RET M918T	medullary thyroid carcinoma	predicted - resistant	Selpercatinib	Case Reports/Case Series	Actionable	In a retrospective analysis, a medullary thyroid carcinoma patient harboring RET M918T progressed on treatment with Retevmo (selpercatinib) and was found to have acquired RET Y806C (PMID: 38127829; NCT03157128, NCT03037385, NCT03780517).	38127829
HRAS A59T RET A883F RET A883T	medullary thyroid carcinoma	predicted - resistant	Pralsetinib	Case Reports/Case Series	Actionable	In a retrospective analysis, a medullary thyroid carcinoma patient harboring RET A883T progressed on treatment with Gavreto (pralsetinib) and was found to have acquired RET A883F and HRAS A59T (PMID: 38127829; NCT03157128, NCT03037385, NCT03780517).	38127829
RET Y806C RET M918T	medullary thyroid carcinoma	predicted - resistant	Pralsetinib	Case Reports/Case Series	Actionable	In a retrospective analysis, a medullary thyroid carcinoma patient harboring RET M918T progressed on treatment with Gavreto (pralsetinib) and was found to have acquired RET Y806C (PMID: 38127829; NCT03157128, NCT03037385, NCT03780517).	38127829