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

V600E and promoter mutations, particularly their genetic duet, are well known to be associated with poor clinical outcomes of papillary thyroid cancer (PTC). Loss of radioactive iodine (RAI) avidity in recurrent PTC is a major cause of treatment failure and hence poor clinical outcomes. This study investigated the role of mutation patterns in loss of RAI avidity in recurrent PTC. This was a retrospective study of the relationship between loss of RAI avidity in structural recurrent PTC and the genotype patterns of V600E and promoter mutations in 164 patients (104 women and 60 men) with a median age of 50 y (interquartile range, 35-62 y). The overall prevalence of RAI avidity loss in recurrent PTC was 62.8% (103/164). When the cohort was divided into mutation and wild-type groups, the RAI avidity loss was 80.4% versus 33.9% ( < 0.001) in V600E versus wild-type patients, with an adjusted odds ratio of 7.11 (95% confidence interval [CI], 3.24-16.27), and 89.4% versus 52.1% ( < 0.001) in mutation versus wild-type patients, with an adjusted odds ratio of 6.89 (95% CI, 2.28-25.66). When the cohort was divided into 4 genotypes, the RAI avidity loss was 70.3% (45/64), 55.6% (5/9), and 97.4% (37/38) in patients with V600E alone, mutation alone, and the genetic duet of coexisting and mutations, versus 30.2% (16/53) in patients with neither mutation ( < 0.001, = 0.251, and < 0.001, respectively). These corresponded to odds ratios of 5.39 (95% CI, 2.31-13.13), 2.84 (95% CI, 0.53-16.32), and 81.04 (95% CI, 11.67-3559.83), respectively. The synergy index was 13.28 (95% CI, 1.54-114.46; = 0.019) between V600E and mutation in cooperatively affecting RAI avidity. A similar genotype-associated expression pattern was observed for thyroid iodide-handling genes. V600E alone and, particularly, coexisting V600E and promoter mutations are strongly associated with 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.