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Acquired Secondary RAS Mutation in BRAF^V600E-Mutated Thyroid Cancer Patients Treated with BRAF Inhibitors.

ABSTRACT: Background: The BRAF^V600E mutation is the most common driver mutation in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC). This mutation is considered actionable and, for BRAF^V600E-mutated ATC, a BRAF inhibitor (dabrafenib) in combination with an MEK inhibitor (trametinib) is FDA approved. BRAF inhibitors have also shown efficacy in BRAF^V600E-mutated PTC. However, as with all targeted therapies, resistance to these drugs eventually develops. It is essential that we understand the mechanisms of resistance to the BRAF inhibitors in thyroid cancer to develop future strategies to effectively treat these patients and improve survival. Patients: Herein, we describe four patients with thyroid cancer treated with selective BRAF inhibitors, who developed a RAS mutation in addition to the BRAF^V600E mutation at progression. Results: Patients 1 and 3 acquired a KRAS^G12V mutation in the progressive tumor, patient 2 acquired a NRAS^Q61K mutation in a progressive lymph node, and patient 4 acquired NRAS^G13D mutation on liquid biopsy performed at the time of radiographic disease progression. Conclusion: Similar to the melanoma experience, the emergence of RAS mutations appears to act as a mechanism of resistance to BRAF inhibitors in thyroid cancers.

SUBMITTER: Cabanillas ME

PROVIDER: S-EPMC7869871 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Acquired Secondary RAS Mutation in BRAFV600E-Mutated Thyroid Cancer Patients Treated with BRAF Inhibitors.

Cabanillas Maria E ME Dadu Ramona R Iyer Pryianka P Wanland Kacey B KB Busaidy Naifa L NL Ying Anita A Gule-Monroe Maria M Wang Jennifer R JR Zafereo Mark M Hofmann Marie-Claude MC

Thyroid : official journal of the American Thyroid Association 20200507 9

Background: The BRAFV600E mutation is the most common driver mutation in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC). This mutation is considered actionable and, for BRAFV600E-mutated ATC, a BRAF inhibitor (dabrafenib) in combination with an MEK inhibitor (trametinib) is FDA approved. BRAF inhibitors have also shown efficacy in BRAFV600E-mutated PTC. However, as with all targeted therapies, resistance to these drugs eventually ...[more]

PMID: 32216548

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Project description:BackgroundThe BRAFV600E mutation is valuable for the diagnosis, prognosis, and therapy of papillary thyroid cancer (PTC). However, studies related to this mutation have involved only a small number of patients. Therefore, we performed a large-scale analysis from a single institute to evaluate the accuracy of combined fine-needle aspiration (FNA) and BRAFV600E mutation tests for PTC diagnosis.MethodsA total of 4600 patients with thyroid nodules who underwent both FNA cytology and BRAFV600E mutation analysis on FNA specimens were enrolled. The association between the BRAFV600E mutation and clinicopathological features was analyzed. A separate analysis was performed for the 311 patients who underwent repeated FNA for comparison of cytological evaluation and BRAFV600E mutation results. The diagnostic efficacy of the BRAFV600E mutation test and cytologic diagnoses was evaluated for 516 patients who underwent preoperative FNA tests in comparison with conclusive postoperative histopathologic results.ResultsThe cytology results of all 4600 FNA samples were categorized according to The Bethesda System for Reporting Thyroid Cytology (TBSRTC) stages I-VI, which accounted for 11.76%, 60.02%, 6.46%, 3.61%, 6.71%, and 11.43% of the samples, respectively. The BRAFV600E mutation was detected in 762 (16.57%) FNA samples, with rates of 1.48%, 0.87%, 20.20%, 3.01%, 66.02%, and 87.81% for TBSRTC I-VI lesions, respectively. Among the 311 repeat FNA cases, 81.0% of the BRAFV600E -positive and 4.3% of the BRAFV600E -negative specimens with an initial indication of cytological non-malignancy were ultimately diagnosed as malignant by repeat FNA (p < 0.001). Among the 516 patients who underwent thyroidectomy, the sensitivity and specificity of the BRAFV600E mutation test alone for PTC diagnosis were 76.71% and 100.0%, respectively, which increased to 96.62% and 88.03%, respectively, when combining the BRAFV600E mutation test with cytology. BRAFV600E mutation was significantly associated with lymph node metastasis (p < 0.001), but not with age, gender, or tumor size.ConclusionsThe BRAFV600E mutation test in FNA samples has potential to reduce false negatives in PTC diagnosis, and therefore plays an important role in the diagnosis of thyroid nodules, especially those with an indeterminate or nondiagnostic cytology, which should be considered for repeat FNA.

Dataset Information

Acquired Secondary RAS Mutation in BRAF^V600E-Mutated Thyroid Cancer Patients Treated with BRAF Inhibitors.

Publications

Acquired Secondary RAS Mutation in BRAF<sup>V600E</sup>-Mutated Thyroid Cancer Patients Treated with BRAF Inhibitors.

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