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PurposeThis study investigated the relationship between BRAFV600E mutation of the primary tumor and radioiodine avidity in lung metastases (LMs) and then further evaluated the impact of BRAFV600E mutation and radioiodine avidity status on the prognosis of papillary thyroid cancer (PTC) with LMs.MethodsNinety-four PTC patients with LMs after total thyroidectomy and cervical lymph node dissection between January 2012 and September 2021 were retrospectively included. All patients received BRAFV600E mutation examination of primary tumors and radioactive iodine (RAI) therapy. The therapeutic response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) assessments (version 1.1). For patients with target lesions, the response was divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD); for patients without target lesions, the response was divided into CR, non-CR/non-PD, and PD. In therapeutic response, PR and SD were classified as non-CR/non-PD for analysis. The chi-square test and logistic regression were used to analyze the impact factor on PD and mortality. Progression-free survival (PFS) and overall survival (OS) curves were constructed by the Kaplan–Meier method.ResultsIt was found that 21.2% (7/33) of patients with positive BRAFV600E mutation and 62.3% (38/61) of patients with negative BRAFV600E mutation had radioiodine-avid LMs (χ2 = 14.484, p = 0.000). Patients with positive BRAFV600E mutation are more likely to lose radioiodine avidity; the odds ratios (ORs) were 5.323 (95% CI: 1.953–14.514, p = 0.001). Finally, 25 patients had PD, and six patients died; loss of radioiodine avidity was the independent predictor for PD, and the ORs were 10.207 (95% CI: 2.629–39.643, p = 0.001); BRAFV600E mutation status was not correlated with PD (p = 0.602), whether in the radioiodine avidity group (p = 1.000) or the non-radioiodine avidity group (p = 0.867). Similarly, BRAFV600E mutation status was not correlated with mortality; only loss of radioiodine avidity was the unfavorable factor associated with mortality in univariate analyses (p = 0.030).ConclusionPatients with LMs of PTC were more likely to lose radioiodine avidity when their primary tumor had positive BRAFV600E mutation; however, only radioiodine avidity and not BRAFV600E mutation status affected the clinical outcome of patients with lung metastatic PTC.