RET Fusion-Positive Papillary Thyroid Cancers are Associated with a More Aggressive Phenotype.

Background: It is unclear if different genetic drivers in papillary thyroid cancer (PTC) confer different phenotypic tumor behavior leading to more aggressive disease. We hypothesized that RET-driven cancers are more aggressive.

Patients And Methods: We reviewed records of consecutive patients treated for newly diagnosed PTC at this single institution from 2015 to 2016. Tumor samples from these patients were genotyped to identify RET-translocated, BRAF mutant, and HRAS, KRAS, and NRAS mutant tumors. Patient demographic, clinicopathologic, and outcomes data were compared to identify genotype-specific patterns of disease.

Results: Of the 327 patients who underwent initial surgery for PTC during the study period, 192 (58.7%) had BRAF mutant tumors (BRAF), 14 (4.3%) had RET-rearranged tumors (RET), 46 (14.1%) had RAS mutant tumors (RAS), and 75 (22.9%) had BRAF, RET, and RAS wildtype tumors. RET-driven tumors were more likely to have extrathyroidal extension (50.0% versus 27.0% for BRAF and 2.2% for RAS, P < 0.001), multifocal disease (85.7% versus 60.3%, and 44.4%, respectively, P = 0.017), and distant metastases (14.3% versus 1.1%, and 0%, respectively, P = 0.019). RET and BRAF patients also had worse disease-free survival than RAS patients (Kaplan-Meier log rank, P = 0.027).

Conclusions: Patients with RET-driven PTCs had higher rates of extrathyroidal extension, multifocal disease, and distant metastases than patients whose tumors had BRAF or RAS mutations. Patients with RET-rearranged tumors had similar disease-free survival to patients with BRAF mutant tumors. RET rearrangement may confer an aggressive phenotype in PTC.