Treatment of patients with well-differentiated thyroid cancer (WDTC; papillary and follicular histologies) includes thyroidectomy, with adjuvant radioactive iodine (RAI) ablation reserved for moderate to high-risk patients.¹⁾ However, some patients present with locally advanced disease making surgical resection challenging and cure unlikely.

Tyrosine kinase inhibitors (TKI) have shown favourable clinical results and are employed in the management of advanced/metastatic WDTC. Lenvatinib is the most commonly used TKI in advanced WDTC. Compared to placebo, patients with RAI refractory unresectable disease treated with Lenvatinib showed a response rate of 65% and had a significantly better progression free survival (median PFS 18.3 months vs. 3.6 months).²⁾

Molecular studies have shown a high prevalence of activating somatic alterations in genes encoding mitogen-activated protein kinase (MAPK) pathways in thyroid cancer.³⁾ The BRAF^V600E mutation occurs in approximately 50% of WDTC and represents >90% of all BRAF gene mutations detected.^4-8) Papillary thyroid cancers with these mutations exhibit overactivated RAF/ERK pathway with downstream effects on thyroid-specific genes. These mutations correlate with more aggressive clinical phenotypes leading to shorter disease-free and overall survival along with higher chances of recurrence.^9-11) BRAF^V600E mutations also lead to poor response to RAI therapy via the impairment in iodine metabolism, making it difficult for cells to uptake and incorporate radioiodine. The BRAF inhibitor dabrafenib, along with MEK inhibitor trametinib have been used in differentiated thyroid cancers with response rates ranging from 26% to 54%.⁵⁾

Although their efficacy in the treatment of metastatic and RAI resistant WDTC has been established, no data is available for their use in reducing disease burden to allow resection. Herein, we describe a case of a previously unresectable BRAF mutated WDTC, treated with dabrafenib and trametinib in the neo-adjuvant setting ultimately leading to resection and subsequent definitive treatment with RAI.

A 60-year-old female presented with a large WDTC which had been in-situ for seven years. She was initially diagnosed in 2012 with a 3×2.2×2.5 cm right sided papillary thyroid carcinoma with a BRAF^V600E mutation but declined against definitive management. Although the patient had inconsistent follow-up, in 2015, an ultrasound showed an enlarging mass measuring 4.5×3.5×2.6 cm. At that time, the patient elected to use naturopathic therapies and refused a thyroidectomy.

In September of 2019, due to significant enlargement of the mass, she sought surgical reassessment. A CT demonstrated a heterogeneous 5.3×6×7.6 cm mass with a large enhancing central component and peripheral septate cystic areas. The mass was abutting the right external carotid artery with effacement of more than 180 degrees of its circumference with adherence to the adventitia (Fig. 1A). Metastatic lymph nodes were noted in the midline pre-tracheal location, the tracheoesophageal grove on the right, and at level IV in the neck.

Use of targeted therapies in WDTC is a relatively new topic. Recent studies looking at TKI and BRAF inhibitors have shown promise particularly in the RAI refractory palliative setting. However, no studies have selectively looked at BRAF inhibitors in the neoadjuvant setting to facilitate locoregional disease control.

Clinical trials in BRAF mutated differentiated thyroid cancers are quite scarce and upfront targeted treatment is still not common practice. Some studies have shown the efficacy of dabrafenib in anaplastic thyroid cancers and the available results are quite encouraging. In one case series, dabrafenib and trametinib was given to six unresectable BRAF^V600E positive patients with anaplastic thyroid carcinoma. R0 surgical resection was achieved in four of the patients with the other two having microscopically positive margins. Despite this, five patients received adjuvant chemoradiation and three had treatment with pembrolizumab. All patients had at least a component of papillary thyroid cancer. Overall, survival at six months and at one year was 100% and 83%, respectively with two patients passing away from metastases.⁶⁾

Significant partial response was also documented in the RAI refractory settings for WDTC.^12,13) In an open label, phase II trial, RAI refractory patients were treated with vemurafenib either as first line treatment or after VEGF inhibitors. Vemurafenib showed a partial response in 10 out of 26 patients without prior exposure to VEGF inhibitors versus 6 out of 22 patients responding after prior treatment with VEGF inhibitor. This achieved a PFS of 18.2 months and 35% of patients achieved stable disease for at least six months. Similarly, in a phase I study, dabrafenib achieved partial responses in 29% of cases and stable disease in 45% of patients. The median PFS was 11.3 months and 50% of cases showed a lack of progression for the entire study duration.¹⁰⁾ Combination treatments with dabrafenib and trametinib also showed a complete response in one out of 16 patients and partial response in 10 out of 16¹⁴⁾ patients. Interim data of single agent dabrafenib versus dabrafenib/trametinib combination showed that partial response rates were approximately 50% in both arms.¹⁴⁾ These studies strongly indicate that use of BRAF/MEK inhibitors can induce significant tumor response, and it is feasible to use them in a pre-operative setting (Table 1).

No potential conflict of interest relevant to this article was reported.