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

<b><i>Background:</i></b> The American Thyroid Association has stratified <i>RET</i> C634 mutations as high risk. The association between <i>RET</i> 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 <i>RET</i> codon 634 mutations. <b><i>Methods:</i></b> This study is an international, multicenter, retrospective cohort study. Data from patients with hereditary MTC carrying <i>RET</i> 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). <b><i>Results:</i></b> 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, <i>p</i> = 0.025). Meanwhile, the C634R group showed larger primary tumors (1.9 ± 1.2 vs. 1.5 ± 1.1, <i>p</i> = 0.006). Kaplan-Meier analysis revealed significantly higher cumulative rates and earlier occurrence of lymph node metastases (<i>p</i> = 0.0003) and extrathyroidal extension (ETE; <i>p</i> < 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]; <i>p</i> = 0.024). Moreover, multivariable analysis identified <i>RET</i> C634R genotype (HR: 6.488 [CI 1.364-30.862]; <i>p</i> = 0.019), increasing age (HR: 1.082 [CI 1.023-1.144]; <i>p</i> = 0.006), and ETE (HR: 9.695 [CI 2.344-40.105]; <i>p</i> = 0.002) to be significantly associated with worse disease-specific survival. <b><i>Conclusions:</i></b> Prognosis varied in hereditary MTC patients with <i>RET</i> C634 mutations. Our data highlight that the <i>RET</i> C634R mutation was associated with greater tumor aggressiveness in MTC and a poorer disease-specific survival.