The impact of RET fusions on radioiodine avidity and prognosis in patients with distant metastatic papillary thyroid cancer.

BACKGROUND

RET gene fusion is one of the key oncogenic drivers in papillary thyroid cancer (PTC). However, the impact of different RET fusion subtypes on clinicopathological features and radioiodine (RAI) avidity in metastatic PTC remains unclear.

METHODS

We retrospectively analyzed clinicopathological data, RAI avidity, and progression-free survival (PFS) in RET-driven metastatic PTC. Initial RAI avidity status was classified as initially RAI-avid (all or partial lesions showing uptake in the first therapy) or initially RAI-non-avid (all lesions with no uptake in the first therapy). The definition of RAI refractory (RAIR) was based on the 2025 ATA guidelines.

RESULTS

Among 65 enrolled patients, 25 (38.5%) harbored CCDC6-RET, 24 (36.9%) NCOA4-RET, and 16 (24.6%) other RET fusions. Older age was associated with the other RET fusion group (P = 0.011). NCOA4-RET patients were more likely to be initially RAI-avid (P = 0.017). Overall, 46.8% (29/62) of evaluable patients were classified as RAIR (CCDC6: 56.0%, NCOA4: 27.3%, other RET fusions: 60.0%; P = 0.072). TERT promoter mutation (18.2%, 8/44) in RET-fusion PTC was associated with older age (P < 0.001), larger metastatic lesions (P = 0.012) and metastatic sites beyond lungs (P = 0.002). RAIA patients demonstrated a longer median PFS compared with RAIR patients (86 vs. 33 months), but this association was not statistically significant (P = 0.402).

CONCLUSION

In this metastatic RET-driven PTC cohort, 46.8% of evaluable patients eventually develop RAIR status. While the specific RET subtypes are associated with initial RAI avidity status, no significant differences in RAIR status or PFS were observed across distinct RET subtypes, warranting further exploration in larger sample sizes.