Complete Surgical Resection Following Neoadjuvant Dabrafenib Plus Trametinib in BRAF V600E-Mutated Anaplastic Thyroid Carcinoma

Thyroid. 2019 Aug;29(8):1036-1043. doi: 10.1089/thy.2019.0133.

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 BRAFV600E-mutated ATC. Methods: Case series of six consecutive patients with BRAFV600E-mutated ATC diagnosed between January 2017 and February 2018. Pathologic confirmation of ATC was obtained before treatment. BRAFV600E 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 BRAFV600E-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.

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Chemoradiotherapy, Adjuvant
  • Disease-Free Survival
  • Female
  • Humans
  • Imidazoles / administration & dosage
  • Male
  • Middle Aged
  • Mutation
  • Neck Dissection
  • Neoadjuvant Therapy*
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Staging
  • Oximes / administration & dosage
  • Proto-Oncogene Proteins B-raf / genetics
  • Pyridones / administration & dosage
  • Pyrimidinones / administration & dosage
  • Survival
  • Thyroid Carcinoma, Anaplastic / diagnostic imaging
  • Thyroid Carcinoma, Anaplastic / genetics
  • Thyroid Carcinoma, Anaplastic / therapy*
  • Thyroid Neoplasms / diagnostic imaging
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / therapy*
  • Thyroidectomy*

Substances

  • Antibodies, Monoclonal, Humanized
  • Imidazoles
  • Oximes
  • Pyridones
  • Pyrimidinones
  • trametinib
  • pembrolizumab
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • dabrafenib