Therapeutically Targetable Mutational Landscape of Anaplastic Thyroid Cancer

PURPOSE Anaplastic thyroid cancer (ATC) is a rare and highly aggressive malignancy with limited treatment options. Currently, the only US Food and Drug Administration–approved targeted therapies for ATC are directed at BRAF V600E mutations and NTRK fusions. This study aimed to characterize the somatic pathogenic gene variant (PGV) landscape of ATC to identify additional potentially actionable pathways. METHODS We queried the American Association for Cancer Research Project GENIE database (v18.0) via cBioPortal for somatic PGVs in ATC tumors. This multi-institutional data set provides next-generation sequencing and clinical data across cancer types. Genes were grouped by pathway relevance: MAPK ( BRAF , KRAS , NRAS , EIF1AX ), PI3K/Akt/mTOR ( PIK3CA , PTEN , mTOR , AKT1/2/3 ), homologous recombination deficiency (HRD), and mismatch repair (MMR). RESULTS A total of 350 ATC tumor samples were analyzed. PGVs were identified in MAPK pathway genes in 57.7% of tumors, PI3K/Akt/mTOR pathway genes in 26.6%, HRD-associated genes in 8.0%, and MMR-associated genes in 3.7%. In total, 72.0% (252/350) of tumors harbored at least one PGV in one or more of these potentially targetable pathways. CONCLUSION Somatic PGVs in potentially targetable pathways were found in 72% of ATC tumors. Given the aggressiveness of ATC and the limited efficacy of current treatments, these findings support the rationale for biomarker-driven basket trials investigating the efficacy of targeted therapies in this population.