Clinical, Pathological, and Molecular Profiling of Radioactive Iodine Refractory Differentiated Thyroid Cancer

Background: Six to 20% of thyroid cancer (TC) patients develop distant metastases, and one-third become radioiodine refractory (RAIR). Available targeted therapies increase progression-free survival but are associated with toxicities. This study aims to characterize clinical, pathological, and molecular profiles of patients with RAIR TC. Methods: Data of TC patients seen during 2013-2017 at two tertiary care centers were retrospectively analyzed. Patients were considered RAIR according to American Thyroid Association guidelines. The control cohort was sex matched and age matched and had either regression or stable disease (by Response Evaluation Criteria in Solid Tumors) on follow-up at least three years after initial therapy. Molecular profiles on a subset of RAIR patients were reviewed. Results: Compared with 22 matched controls, 54 RAIR patients had an average age of 57 years (standard deviation [SD] = 13), 56% were male (41% in the control group); the average tumor size was 4 cm (SD = 2.5); tumors were multifocal in 54%, with involved surgical margins in 42%, focal invasion in 79%, and extrathyroidal extension (ETE) in 61%. Sixty-six percent had distant metastases at initial presentation with metastases to the lungs in 85%, bone in 56%, both sites in 43%, brain in 9%, and liver in 4%. There were no statistically significant differences between RAIR and controls in tumor size, focal invasion, ETE, and histology. The RAIR group received a higher cumulative radioactive iodine (RAI) dose and number of therapies compared with the controls (518 mCi vs. 302 mCi, p = 0.002 and 2.2 vs. 1.3 treatments, p = 0.001). Overall, patients >46 years had 4.5 times higher odds ratio (OR) of being RAIR; white race/ethnicity was associated with a reduced OR of RAIR disease (OR 0.33, p = 0.079). Molecular profiling data in the RAIR subgroup indicated that 50% of patients harbored mutations in the RAS/RAF pathway (11/22). Among 19 patients with a more extensive molecular panel, median tumor mutational burden was 5 megabase (range 3-16) and 26% (5/19) exhibited strong PD-L1 positivity. Conclusion: Among patients with metastatic differentiated thyroid carcinomas, patients with RAIR have similar histopathological and clinical characteristics as patients with RAI avid cancer. The risk of having RAIR TC is increased at age ≥46 and reduced in Caucasians.