The Genetic Duet of BRAF V600E and TERT Promoter Mutations Robustly Predicts the Loss of Radioiodine Avidity in Recurrent Papillary Thyroid Cancer

Abstract

BRAF V600E and TERT promoter mutations, particularly their genetic duet, are well known to be associated with poor clinical outcomes of PTC. Loss of radioactive iodine (RAI) avidity in recurrent PTC is a major cause of treatment failure and hence poor clinical outcomes of PTC. This study investigated the role of the mutation patterns in the loss of RAI avidity in recurrent PTC. Methods: Retrospective study of the relationship between the loss of RAI avidity in structural recurrent PTC and the genotype patterns of BRAF V600E and TERT promoter mutations in 164 patients (104 females and 60 males) with a median age of 50 (interquartile, 35-62) years. Results: The overall prevalence of RAI avidity loss in recurrent PTC was 62.8% (103/164). When dividing the cohort into mutation and wild-type groups, RAI avidity loss was 80.4% vs. 33.9% (P<0.001) in BRAF V600E versus wild-type BRAF patients with an adjusted odds ratio (OR) of 7.11 (95% CI, 3.24-16.27) and was 89.4% vs. 52.1% (P<0.001) in TERT mutation versus wild-type patients with an adjusted OR of 6.89 (95% CI, 2.28-25.66). When dividing the cohort into four genotypes, RAI avidity loss was 70.3% (45/64), 55.6% (5/9), and 97.4% (37/38) in patients with BRAF V600E alone, TERT mutation alone, and the genetic duet of coexisting BRAF and TERT mutations versus 30.2% (16/53) in patients with neither mutation (P<0.001, 0.251, and <0.001, respectively). These corresponded to ORs (95% CI) of 5.39 (2.31-13.13), 2.84 (0.53-16.32), and 81.04 (11.67-3559.83), respectively. The synergy index was 13.28 (95% CI, 1.54-114.46; P = 0.019) between BRAF V600E and TERT mutation in cooperatively affecting the RAI avidity. A similar genotype-associated expression pattern was observed for thyroid iodide-handling genes. Conclusion: BRAF V600E alone and particularly coexisting BRAF V600E and TERT promoter mutations are strongly associated with the loss of RAI avidity and impairment of the iodide-metabolizing machinery in recurrent PTC, showing a robust predictive value for failure of RAI treatment of PTC.