Response to Targeted Therapy inBRAFMutant Anaplastic Thyroid Cancer

Abstract

Anaplastic thyroid cancer (ATC) is an aggressive uncommon malignancy with limited treatment. Traditional antineoplastic chemotherapy has not been successful in the management of metastatic ATC. As a result, the focus has shifted to the development of novel therapies for this disease. The availability of economical comprehensive genomic profiling (CGP) platforms with rapid turn-around to identify molecular aberrations in tumors that are potential therapeutic targets has increasingly changed the face of cancer therapy. Identification of targetable aberrations may help identify novel treatment options for ATC. Herein, we report our experience with a 47-year-old patient with metastatic ATC who experienced recurrent, progressive disease and rapid clinical deterioration despite surgery, radiation therapy, and treatment with 2 different chemotherapy regimens. She was found to have a BRAF V600E mutation on CGP, and was started on targeted therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. After 2 months of treatment, she showed a clinical and radiologic response. The patient remained on this combination for 9 months until evidence of disease progression. Discontinuation of these drugs was associated with rapid tumor growth. Through this case we want to emphasize the importance of early molecular sequencing and identification of genetic aberrations in patients with ATC, and using that information to develop therapies for ATC, an aggressive malignancy with limited therapy and a poor outcome.

Anaplastic thyroid carcinoma: review of treatment protocols

“…In single case reports, impressive response to BRAF inhibitors vemurafenib (Rosove et al 2013, Marten & Gudena 2015, Prager et al 2016, dabrafenib combined with MEK-Inhibitor trametinib (Agarwal et al 2016), ALK-inhibitor crizotinib (Godbert et al 2015) and the mTOR-Inhibitor everolimus (Wagle et al 2014) were reported. Very recently, a phase II trial including 16 BRAFV600E-positive ATC patients reported an overall response rate of 69% when patients were treated with the dabrafenib in combination with trametinib (Subbiah et al 2017).…”

Quantitation of Targetable Somatic Mutations Among Patients Evaluated by a Personalized Medicine Clinical Service: Considerations for Off‐Label Drug Use

“…Biologically, targeting BRAF ‐mutated cancers with inhibitors of the mitogen‐activated protein kinase signaling pathway appears to be a reasonable consideration. Indeed, utilization of BRAF inhibitors in BRAF ‐mutated NSCLC and thyroid cancer has shown promising results . However, limited responses to drugs such as vemurafenib or dabrafenib were observed in BRAF V600E metastatic colorectal cancer .…”

“…Indeed, utilization of BRAF inhibitors in BRAF-mutated NSCLC and thyroid cancer has shown promising results. 25,26 However, limited responses to drugs such as vemurafenib or dabrafenib were observed in BRAF V600E metastatic colorectal cancer. 27 A possible explanation is that colorectal cancer cell signaling differs from other cancer types, as BRAF inhibition in colorectal cancer may result in a feedback mechanism that activates EGFR signaling.…”

Juglone–ascorbic acid synergy inhibits metastasis and induces apoptotic cell death in poorly differentiated thyroid carcinoma by perturbing SOD and catalase activities

“…[9] The median overall survival in ATC is only 2-12 months, which improves with distinguished multiapproach treatment in 9-46% cases. [11] However, such Abbreviations: VEGF, Vascular endothelial growth factor; NAC, N-acetylcysteine; PARP, Poly (ADP-ribose) polymerase; COX-2, Cyclooxygenase-2; FITC, Fluorescein isothiocyanate; siRNA, Small interfering RNA and primary cell cultures and tumor-bearing mice. Their association with multiple noncancer targets is well known.…”

“…Their association with multiple noncancer targets is well known. [11] However, such Abbreviations: VEGF, Vascular endothelial growth factor; NAC, N-acetylcysteine; PARP, Poly (ADP-ribose) polymerase; COX-2, Cyclooxygenase-2; FITC, Fluorescein isothiocyanate; siRNA, Small interfering RNA and primary cell cultures and tumor-bearing mice. [22][23][24] Therefore, we studied juglone for its ability to alter intracellular redox potential in ARO, an ATC-derived cell line.…”