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Ref Type Journal Article
PMID (31085763)
Authors Owen DH, Konda B, Sipos J, Liu T, Webb A, Ringel MD, Timmers CD, Shah MH
Title KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid Cancer.
Journal Journal of the National Comprehensive Cancer Network : JNCCN
Vol 17
Issue 5
Date 2019 May 01
URL
Abstract Text BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS. This case report describes a patient with radioactive iodine-refractory metastatic PTC treated in a clinical trial with combination BRAF and MEK inhibition who achieved a durable PR. At time of progression, biopsy revealed an acquired KRAS G12V-activating mutation. The patient subsequently went on to have a PR to cabozantinib therapy in the clinical trial. This is the first reported case of an acquired KRAS-activating mutation that developed during treatment with BRAF and MEK inhibition in a patient with BRAF-mutated PTC. The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.ClinicalTrials.gov identifier: NCT01723202.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E thyroid gland papillary carcinoma predicted - sensitive Dabrafenib + Trametinib Case Reports/Case Series Actionable In a clinical case study, a papillary thyroid carcinoma patient who progressed on Lenvima (lenvatinib) was found to harbor BRAF V600E and was treated with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) on a clinical trial, resulting in partial response in the thyroid bed, cervical and intrathoracic lymph nodes, and pulmonary lesions, with a decrease in target lesion size of 67%, and the patient remained on treatment for 18 months before stopping due to progression (PMID: 31085763). 31085763