Targeted Therapy in Advanced Thyroid Cancer to Resensitize Tumors to Radioactive Iodine

Tania Jaber; Steven G. Waguespack; Maria E. Cabanillas; Mohamed Elbanan; Thinh Vu; Ramona Dadu; Steven I. Sherman; Moran Amit; Elmer B. Santos; Mark Zafereo; Naifa L. Busaidy

Disclosures

J Clin Endocrinol Metab. 2018;103(10):3698-3705. 

In This Article

Abstract and Introduction

Abstract

Context: Many differentiated thyroid cancers (DTC) dedifferentiate and become radioactive iodine (RAI)–refractory (RAIR) with worse outcomes. Targeted therapy (TTx) may downregulate MAPK signaling and sensitize tumors to RAI.

Objective: We describe patients with RAIR DTC receiving TTx with demonstrated RAI uptake allowing for iodine-131 (I131) administration.

Design: Charts of patients with metastatic, progressive, RAIR DTC in whom TTx increased RAI uptake on a diagnostic whole-body scan (WBS), were reviewed. Results of WBS, I131 administration, thyroglobulin (TG) panels, and cross-sectional studies were recorded.

Setting: Thirteen patients [median age (range), 56 (45 to 75) years; seven men] were included; 11 (85%) had DTC, two (15%) had poorly DTC. Nine (69%) had BRAF mutations, three (23%) had RAS mutations, and one (8%) was wild type. Selective BRAF or an MEK inhibitor TTx was continued for a median (range) of 14.3 (1 to 76.4) months before diagnostic WBS.

Results: Nine (69%) patients were treated with I131 [median (range) activity, 204.4 (150 to 253) mCi], after which TTx was discontinued. Median (range) follow-up was 8.3 (0 to 17.4) months after I131 therapy. All nine patients had durable disease control (three had partial response, six had stable disease). TG and TG antibody levels increased in patients who demonstrated uptake before TTx, and declined in eight of the nine patients after I131 treatment. Adverse events included pneumonitis and sialadenitis.

Conclusion: TTx in BRAF−/RAS–mutated RAIR DTC resensitizes tumors to iodine. Subsequent I131 administration results in meaningful responses. Patient selection, adverse events, response duration, and survival impact require additional study.

Introduction

Differentiated thyroid cancer (DTC) makes up ~90% of all thyroid cancers.[1] A three-pronged treatment approach of surgery with or without radioactive iodine (RAI) therapy and thyrotropin-suppressive thyroid hormone provides an excellent prognosis for most localized, well-differentiated disease. The prognosis for distantly metastatic disease drops significantly, however, with an estimated 10-year survival rate of 42%.[2] Radioiodine refractory (RAIR) disease has an even more dismal prognosis, with an estimated 10-year survival of just 10%.[3] Management options in that subset of patients include active surveillance, local therapy for metastatic sites, or multikinase inhibitor therapy for rapidly progressing, symptomatic, or life-threatening disease.[1,4–6]

Multiple agents to attempt to restore RAI avidity in patients with RAIR DTC have been studied. The use of retinoids,[7–9] romidpesin,[10] rosiglitazone,[11] and even the multikinase inhibitor sorafenib[12] unfortunately proved to be of little clinical value. Understanding the biological pathways implicated in thyroid cancer has allowed us to define therapeutic targets. Specifically, gain-of-function mutations in the MAPK signaling pathway, in particular the BRAF V600E mutation, have been implicated in loss of the sodium-iodine symporter that mediates iodine uptake.[13,14] In one study, BRAF-mutant tumors had reduced expression of all thyroid-specific genes involved in iodine metabolism.[13] In another study, targeted inhibition of the MAPK pathway with a MEK inhibitor restored the expression of iodide-metabolizing genes in normal and malignant thyroid cells.[14] In a series of very elegant experiments, Chakravarty et al.[15] showed that activation of BRAF V600E transformed thyroid follicular cells into poorly DTC with inability to incorporate RAI, and that inactivation of this mutation with a MEK or BRAF inhibitor restored normal architecture and RAI sensitivity.

This work laid the foundation for more recent trials that showed promising results with use of the MEK inhibitor selumetinib[16] and the BRAF inhibitor dabrafenib.[17] Of 12 patients treated with selumetinib, eight had a clinically meaningful uptake to warrant treatment with RAI, of whom five had objective response and three had durable stable disease.[16] Of the 10 patients treated with dabrafenib, six had a clinically meaningful uptake on diagnostic RAI scans to warrant treatment and two had objective response as well.[17] Long-term outcomes of these patients, however, are not known. In this article, we describe the experience from a tertiary cancer center of using targeted therapy (TTx) in restoring RAI avidity in patients with previously RAIR, advanced thyroid cancer.

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