Complete Surgical Resection Following Neoadjuvant Dabrafenib Plus Trametinib in BRAFV600E-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.

Keywords: anaplastic thyroid cancer; chemotherapy; dabrafenib; dedifferentiated; pembrolizumab; sarcomatoid; squamous; surgery; targeted therapy; trametinib; undifferentiated.

FIG. 1.

Summary of treatment course and representative imaging. Swimmer's plot of patients' treatment course (A); representative PET/CT images before and after neoadjuvant treatment, before surgical resection (B). PET/CT, positron emission tomography–computed tomography.

FIG. 2.

Representative histopathology of pre- and post-BRAF/MEK-treated anaplastic thyroid carcinomas. Residual tumor viability and representative histopathology. (A, B) Show representative histologic slides from Patient 2. (C–E) Show representative slides from Patient 5. (A) Pretreatment biopsy showing pleomorphic cells with eosinophilic cytoplasm with squamoid features growing in cords. The background is desmoplastic with scattered inflammatory infiltrate (hematoxylin and eosin stain, 400 × magnification). (B) Post-treatment surgical resection at low power magnification (hematoxylin and eosin stain, 40 × magnification) shows large fibrotic areas of the treated tumor bed with scattered viable tumor nests (left side); the inset shows a viable tumor area with desmoplastic stroma (100 × magnification). (C) Diagnostic core biopsy shows irregular squamoid tumor cells in a fibrotic stroma (hematoxylin and eosin stain, 100 × magnification). (D) Post-treatment, the surgical resection shows large areas of fibrosis with scattered follicles of residual well-differentiated papillary thyroid carcinoma that retain BRAF^V600E expression by immunohistochemistry (inset) (100 × magnification); (E) Post-treatment area that showed progression in the scalp shows viable anaplastic thyroid carcinoma growing in squamoid nests similar to the pretreatment biopsy (hematoxylin and eosin stain, 100 × magnification). This tumor also retains BRAF^V600E immmunoexpression (immunoslide not shown).