Characterization of Advanced RAS -driven Follicular-derived Thyroid Cancers and Review of Future Therapeutic Avenues

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CONTEXT: With novel RAS-targeted therapies emerging, better understanding of RAS-driven differentiated (DTC) and anaplastic (ATC) thyroid cancers is warranted. OBJECTIVE: Characterize the genotypic and phenotypic landscape of RAS-driven DTC and ATC and review current and future therapeutic avenues. DESIGN: Retrospective chart review between January 2015 and June 2023. Median follow-up duration 8.4 years in DTC cohort and 36.4 months in ATC cohort. SETTING: Single-center study at MD Anderson Cancer Center. PATIENTS: Individuals with RAS-altered DTC or ATC identified before kinase inhibitor exposure. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Primary objective was to describe clinical and molecular characteristics. Secondary objectives included identifying prognostic factors and assessing survival outcomes with available therapies. RESULTS: Among 120 RAS-driven DTC and 71 RAS-driven ATC, NRAS was the most common alteration (69% of DTC, 70% of ATC), mainly at residue Q61. Brain metastases were found in 22% of patients undergoing brain imaging (19% in DTC, 25% in ATC). Median overall survival (OS) was 15.2 years in DTC, with 49% of patients receiving at least 1 line of systemic therapy, most commonly lenvatinib (66%). Median time to systemic therapy was 3.5 years from diagnosis, and median OS from therapy initiation was 6.0 years. In ATC, median OS was 7.5 months. Stage IVC [hazard ratio (HR) = 6.78)], neck surgery (HR = 0.29), and exposure to immunotherapy (HR = 0.13) were significantly associated with mortality. CONCLUSION: Advanced RAS-driven follicular-derived thyroid cancers seem to exhibit an aggressive behavior, particularly in ATC, in which prognosis remains poor despite expert multidisciplinary care. Advances in RAS-targeted therapies offer hope for improved therapeutic options.

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