MON-349 A challenging case of co-occurring TERT/RAS mutations in metastatic papillary thyroid carcinoma

Abstract Disclosure: S. Htoo: None. S. Kalik: None. A. Busta: None. Background: Most differentiated thyroid cancers demonstrate good prognosis. Distant metastases of differentiated thyroid cancer can occur in 1-9% of thyroid cancer cases. TERT promoter mutations are found in aggressive thyroid cancer with distant metastases, in the form of anaplastic and poorly differentiated carcinomas. Case: A 65-year-old woman with metastatic thyroid cancer came to our clinic for an evaluation of radiographic bone lesions. She was diagnosed with thyroid cancer at age of 47, when she presented with a 2.5 cm left anterior mediastinal mass that showed Papillary Thyroid Cancer (PTC) on biopsy. She underwent total thyroidectomy and mediastinal mass resection. Pathology showed PTC in left thyroid lobe, follicular variant of PTC in the mediastinal mass and one positive lymph node. The cancer was categorized as a stage 1 T2N1 tumor. She was then treated with radioactive iodine (RAI). She was placed on suppressive levothyroxine (LT4) replacement therapy and monitored yearly. 13 years later, she had a structural recurrence in her thyroid bed along with metastases to the lungs. RAI uptake scan was negative. She again was treated with thyroidectomy and wedge lobe resection of two lung lesions. Genetic testing revealed mutations in NRAS and TERT genes. She chose to forgo targeted therapy at that time and was kept under active surveillance. She demonstrated persistent biochemical incomplete response with thyroglobulin levels ranging 18 - 20 ng/mL (0.9 -77.3 ng/mL) however had negative yearly PET/CT imaging during the next 4 years. At the present-day visit, PET/CT showed FDG avid lytic lesions in the left 5th rib and L5 vertebral body. RAI scan again was negative. Thyroglobulin levels rose to >200 ng/mL with TSH 0.04 uIU/mL (0.27- 4.2 uIU/mL) on LT4. Past literature had shown benefits of neoadjuvant debrafenib and trametinib (DT) therapy on BRAF/TERT thyroid tumors, but the data on RAS/TERT thyroid tumors was limited. Due to patient’s preference to receive external beam radiation therapy (EBRT) over trial of neoadjuvant therapy, patient was treated with radiation to thoracic and lumbar spine. 6 months follow-up imaging was negative for structural recurrence and thyroglobulin levels improved to 70 ng/mL. Discussion: This is a challenging case of non-RAI avid PTC with distant metastases to lung and spine, driven by RAS/TERT mutation. Our case demonstrates benefits of early gene testing even in presumed low-risk cancers. RAS mutations are common in the follicular-pattern thyroid tumors, whereas TERT mutations are common in invasive tumors with high risk of distant metastases and rather rare in PTCs. Co-occurence of RAS and TERT mutations in PTC is even rarer and the past evidence is limited on the superiority of the use of kinase inhibitors over EBRT for metastatic bone lesions. Therefore, more large-scale molecular studies are needed on the therapeutic options for these rare tumors. Presentation: Monday, July 14, 2025