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Tall cell variant (TCV) and columnar cell variant (CCV) are aggressive variants of papillary thyroid cancer (PTC) and they are overrepresented in radioactive iodine (RAI) refractory cases. Studies have reported using BRAF and/or MEK inhibitors to restore iodine avidity in patients with iodine refractory disease. There is much less experience of using targeted therapy pre-emptively to enhance iodine uptake for aggressive variants and advanced disease prior to the first RAI treatment (RAI-T). We present three patients with these variants and describe their responses to the first RAI-T after targeted therapy. Case 1: 64-year-old male with CCV-PTC and areas of poor differentiation (pT3aN1bM1) has somatic BRAF V600E, TERT and AJUBA mutations. Thyroglobulin (TG) 6 weeks post surgery was 21 ug/L, with negative TG antibodies (TGAb). PET-CT revealed FDG avid superior mediastinal lymphadenopathy and lung metastases. He received dabrafenib for 6 weeks followed by his first RAI -T(153 mCi) after thyroid hormone withdrawal (THW). Pre- and post-therapy scans showed uptake in the neck, right superior mediastinum and lung metastases. Three months post RAI, TG decreased to 5.1 ug/L. Chest CT revealed stable mediastinal lymphadenopathy and decreased size of lung metastases. Case 2: 41-year-old male with TCV-PTC containing areas of focal squamous differentiation and poor differentiation (pT4aN1bM1) has somatic BRAF V600E and TP53 mutations. PET-CT showed FDG avid neck lymph nodes and lung metastases. TG 8 weeks after surgery was 1.5 ug/L, TGAb 31.19 IU/L. He was treated with dabrafenib and trametinib for 4 weeks followed by his first RAI-T (150mCi) after THW. Pretreatment scan showed uptake in the thyroid bed and cervical lymph nodes. Post-therapy scan revealed additional uptake in the lung metastases. Chest CT 3 and 9 months after RAI-T revealed stable paratracheal lymph node and lung metastases. TGAb decreased to 7.04 IU/L; TG was 2.2 ug/L. Case 3: 33-year-old female with invasive TCV-PTC (pT3bN1aM1) has a somatic BRAF V600E mutation. CT chest showed multiple scattered lung nodules up to 4mm. Ten weeks post surgery, TG was 0.1 ug/L, TGAb 5.21 IU/ml. Patient received 1 month of dabrafenib and trametinib followed by his first RAI-T(125 mCi) after THW. Pre- and post-therapy scans revealed uptake in the neck and left supraclavicular areas, without uptake in lung nodules. Three months post RAI, chest CT revealed stable lung nodules. TG was 0.1 ug/L, and TGAb was 5.16 IU/L. Neck ultrasound showed no disease. Conclusion: These three patients with aggressive variants of PTC have advanced disease, and all were found to have a BRAFV600E mutation on genomic analysis. They tolerated BRAF targeted inhibition as an attempt to enhance iodine uptake preemptively with various responses to their first RAI-T. More studies will be needed to determine if this strategy will improve outcomes for these patients.

Responses to the First Radioactive Iodine Treatment After Targeted Therapy for Aggressive Papillary Thyroid Cancers