Abstract Context The predictive role of mutational status in the response to lenvatinib in advanced radioiodine-refractory thyroid cancer (RAIR-TC) is not yet defined. Objective To identify a molecular signature of RAIR-TC treated with lenvatinib and its impact on clinical response to lenvatinib. Design This is a retrospective study including 49 RAIR-TC patients treated with first-line lenvatinib and followed at least 1 year median follow-up 9.2 years (interquartile range 6-14.1). Next-generation sequencing on tissues was used to detect genetic alterations. Setting The study was performed in a referral center for the treatment of thyroid cancer. Results Among 49 cases, BRAF (38.7%) and RAS (22.4%) were the most frequent driver mutations, while TERT and TP53 were mutated in 57.1% and 6.1%. No driver mutations were found in 34.6%. Driver mutations co-occurred with TERT or TP53 in 44.9%. In 10/49 (20.4%), no mutations were found. Cases with ≥1 mutation had longer progression-free survival (PFS) than cases negative for any mutation (P = .004). Both BRAF-mutated and RAS-mutated cases showed better PFS and overall survival (OS), although this was not statistically significant with respect to wild-type cases. Cases with a single driver mutation (group 1) showed longer PFS than cases without driver mutations (group 3) (P = .04) but no difference with cases with driver + TERT or TP53 (group 2) (P = .13). Group 1 showed longer OS than group 2 (P = .026) and group 3 (P = .034). Conclusions The RAIR-TC molecular profile is heterogeneous with TERT being the most frequent mutation. Cases negative for all mutations and cases presenting the coexistence of TERT + driver mutation had a worse response to lenvatinib. Conversely, the presence of 1 driver mutation correlated with a better response to lenvatinib.
Minaldi et al. (2026) studied this question.