Synapse - Vemurafenib redifferentiation of BRAF mutant, RAI-refractory thyroid cancers

Vemurafenib redifferentiation of BRAF mutant, RAI-refractory thyroid cancers Journal Article

Authors:	Dunn, L. A.; Sherman, E. J.; Baxi, S. S.; Tchekmedyian, V.; Grewal, R. K.; Larson, S. M.; Pentlow, K. S.; Haque, S.; Tuttle, R. M.; Sabra, M. M.; Fish, S.; Boucai, L.; Walters, J.; Ghossein, R. A.; Seshan, V. E.; Ni, A.; Li, D.; Knauf, J. A.; Pfister, D. G.; Fagin, J. A.; Ho, A. L.
Article Title:	Vemurafenib redifferentiation of BRAF mutant, RAI-refractory thyroid cancers
Abstract:	Context: BRAF(V600E) mutant thyroid cancers are often refractory to radioiodine (RAI). Objectives: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). Design: This was a pilot trial that enrolled from June 2014 to January 2016. Setting: Academic cancer center. Patients: Patients with RAIR, BRAF mutant thyroid cancer. Intervention: Patients underwent thyrotropin-stimulated iodine-124 (I-124) positron emission tomography scans before and after similar to 4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (I-124 responders) were treated with iodine-131 (I-131). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogenactivated protein kinase (MAPK) signaling and thyroid differentiation. Main Outcome Measure: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant I-131. Results: Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were I-124 responders on vemurafenib and treated with I-131, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among I-124 responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). Conclusions: Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.
Keywords:	radioactive iodine; carcinoma; therapy; papillary; cells; inhibition; dedifferentiation; multicenter; i-124; lenvatinib
Journal Title:	Journal of Clinical Endocrinology and Metabolism
Volume:	104
Issue:	5
ISSN:	0021-972X
Publisher:	Oxford University Press
Date Published:	2019-05-01
Start Page:	1417
End Page:	1428
Language:	English
ACCESSION:	WOS:000473692100009
DOI:	10.1210/jc.2018-01478
PROVIDER:	wos
PMCID:	PMC6435099
PUBMED:	30256977
Notes:	Source: Wos