Do Prognostic Differences Exist Among High-Risk RET Mutations? A Comparison of Outcomes Between the RET C634R and Other C634 Mutations in Hereditary Medullary Thyroid Carcinoma

Background: The American Thyroid Association has stratified RET C634 mutations as high risk. The association between RET C634R mutation and a more aggressive medullary thyroid carcinoma (MTC) behavior compared with other C634 mutations remains inconclusive, possibly due to the lack of large cohorts and long-term outcome data. This study aimed to evaluate the aggressiveness and long-term outcomes of hereditary MTC in patients with different RET codon 634 mutations. Methods: This study is an international, multicenter, retrospective cohort study. Data from patients with hereditary MTC carrying RET codon 634 mutations treated at three tertiary medical centers were retrospectively analyzed. Clinicopathological features and long-term outcomes were compared between patients with the C634R and those with other C634 mutations (C634F/G/S/W/Y). Results: The study cohort included 317 patients (C634R: 133; C634F/G/S/W/Y: 184) from 137 families with a median follow-up of 10.6 years (4.9–16.6 years). Patients with the C634R mutation were slightly younger at the time of initial surgery (27.8 ± 12.1 vs. 31.3 ± 14.9, p = 0.025). Meanwhile, the C634R group showed larger primary tumors (1.9 ± 1.2 vs. 1.5 ± 1.1, p = 0.006). Kaplan–Meier analysis revealed significantly higher cumulative rates and earlier occurrence of lymph node metastases ( p = 0.0003) and extrathyroidal extension (ETE; p < 0.0001) in the C634R group. The C634R mutation was significantly associated with distant metastases (hazard ratio [HR]: 2.545 [confidence interval (CI) 1.134–5.713]; p = 0.024). Moreover, multivariable analysis identified RET C634R genotype (HR: 6.488 [CI 1.364–30.862]; p = 0.019), increasing age (HR: 1.082 [CI 1.023–1.144]; p = 0.006), and ETE (HR: 9.695 [CI 2.344–40.105]; p = 0.002) to be significantly associated with worse disease-specific survival. Conclusions: Prognosis varied in hereditary MTC patients with RET C634 mutations. Our data highlight that the RET C634R mutation was associated with greater tumor aggressiveness in MTC and a poorer disease-specific survival.