Complete Surgical Resection Following Neoadjuvant Dabrafenib Plus Trametinib inBRAF^V600E-Mutated Anaplastic Thyroid Carcinoma

Abstract

Background: When achieved, complete surgical resection improves outcomes in anaplastic thyroid carcinoma (ATC). However, most ATC patients present with advanced inoperable disease, often with impending airway obstruction, increased hemorrhage risk, and significant dysphagia. Novel treatment strategies are critically needed to improve disease control and decrease locoregional morbidity. The objective of this study was to determine the feasibility and effectiveness of a neoadjuvant regimen by using dabrafenib with trametinib followed by surgical resection in patients with initially unresectable BRAF V600E -mutated ATC. Methods: Case series of six consecutive patients with BRAF V600E -mutated ATC diagnosed between January 2017 and February 2018. Pathologic confirmation of ATC was obtained before treatment. BRAF V600E status was ascertained via immunohistochemistry or sequencing of circulating tumor DNA. All patients received dabrafenib and trametinib (DT) followed by surgical resection and adjuvant chemoradiation. Three patients also received pembrolizumab. Results: Complete surgical resection was achieved in all patients. Histopathologic analyses of resected specimens showed high pathologic response rates with significantly decreased ATC viability and residual papillary thyroid carcinoma components. Overall survival at six months and one year was 100% and 83%, respectively. Locoregional control rate was 100%. Two patients died of distant metastases without evidence of locoregional disease at 8 and 14 months from diagnosis. The remaining four patients had no evidence of disease at the last follow-up. Conclusions: We report the first series in the literature of BRAF V600E -mutated ATC patients with locoregionally advanced disease treated with DT followed by surgical resection. We demonstrated feasibility of complete resection, decreased need for tracheostomy, high pathologic response rates, and durable locoregional control with symptom amelioration.

Evaluation of the 8th Edition TNM Classification for Anaplastic Thyroid Carcinoma

“…Although multimodal treatment with surgery, radiation, and chemotherapy is the standard therapy of choice for ATC [2,3,17,18], no effective method has been identified to prevent recurrence. Novel therapeutic agents have been developed to control the systemic or inoperable disease of ATC, including paclitaxel [19], fosbretabulin [20], vascular endothelial growth factor receptor inhibitors: sorafenib [21] and lenvatinib (approved for ATC in Japan only) [22], selective tyrosine kinase inhibitors of V600E mutated BRAF gene: dabrafenib in combination with selective MEK (Mitogen-activated protein kinase/ Extracellular signal related kinase Kinase) inhibitor: trametinib (approved for ATC by the US Food and Drug Administration) [23,24], and immune checkpoint inhibitors [25,26]. In addition, successful neoadjuvant treatment with those agents followed by complete surgical resection as a novel multimodal therapeutic strategy was reported [24].…”

“…Novel therapeutic agents have been developed to control the systemic or inoperable disease of ATC, including paclitaxel [19], fosbretabulin [20], vascular endothelial growth factor receptor inhibitors: sorafenib [21] and lenvatinib (approved for ATC in Japan only) [22], selective tyrosine kinase inhibitors of V600E mutated BRAF gene: dabrafenib in combination with selective MEK (Mitogen-activated protein kinase/ Extracellular signal related kinase Kinase) inhibitor: trametinib (approved for ATC by the US Food and Drug Administration) [23,24], and immune checkpoint inhibitors [25,26]. In addition, successful neoadjuvant treatment with those agents followed by complete surgical resection as a novel multimodal therapeutic strategy was reported [24]. The prognoses of ATC patients will depend to some degree on the efficacies of these anticancer agents; in other words, the genetic alteration status of the tumor and/or the immune status of the patient may largely influence the patient's prognosis.…”

Histological features of BRAF V600E‐mutant anaplastic thyroid carcinoma

“…19 Promising results have been reported for selective BRAF inhibitors alone or in combination with a MEK inhibitor in patients with BRAF-mutant ATC. [20][21][22][23][24] Moreover, in 2018 the Food and Drug Administration (FDA) approved dabrafenib and trametinib (a BRAF and a MEK inhibitor, respectively) for the treatment of BRAF V600E-mutant ATC. BRAF mutation status can be determined by molecular techniques or by IHC.…”

Thyroid Follicular Cell Loss of Differentiation Induced by MicroRNA miR-17-92 Cluster Is Attenuated by CRISPR/Cas9n Gene Silencing in Anaplastic Thyroid Cancer

“…Thyroid oncogenesis is mediated mainly by genetic alterations in MAPK signaling, with RET/papillary thyroid cancer (PTC) rearrangements, as well as RAS and BRAF mutations as the most prevalent alterations in PTC (2,3). Anaplastic thyroid cancer (ATC) is the most aggressive histotype of thyroid malignancy, and its pathogenesis remains incompletely un-inhibitors (dabrafenib + trametinib) and immunotherapy that turned the tumor resectable, and treatable with chemoradiation and sustained control with BRAF therapy in combination with immunotherapy (9,10). Indeed, the combined therapy of dabrafenib + trametinib has been recently approved by the Food and Drug Administration for the treatment of patients with locally advanced or metastatic ATC positive for the BRAF V600E mutation and with no satisfactory locoregional treatment options.…”