Therapeutically Targetable Mutational Landscape of Anaplastic Thyroid Cancer

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Anaplastic thyroid cancer (ATC) is a rare, aggressive malignancy with few effective treatments.
• Current targeted therapies for ATC are limited to BRAF V600E mutations and NTRK fusions.
• Identifying additional therapeutic targets is crucial for improving patient outcomes.

Purpose of the Study:

• To characterize the landscape of somatic pathogenic gene variants (PGVs) in ATC.
• To identify potentially actionable molecular targets beyond BRAF and NTRK.
• To inform the development of targeted therapies for ATC.

Main Methods:

• Somatic PGVs in 350 ATC tumors were analyzed using data from the American Association for Cancer Research Project GENIE database.
• Genes were categorized into relevant pathways: MAPK, PI3K/Akt/mTOR, homologous recombination deficiency (HRD), and mismatch repair (MMR).
• Next-generation sequencing and clinical data were utilized for variant identification and pathway analysis.

Main Results:

• Pathogenic gene variants were detected in 57.7% of tumors within the MAPK pathway.
• The PI3K/Akt/mTOR pathway showed PGVs in 26.6% of ATC samples.
• Overall, 72.0% of ATC tumors harbored at least one PGV in the investigated potentially targetable pathways.

Conclusions:

• A significant majority (72%) of anaplastic thyroid cancer cases possess somatic PGVs in actionable pathways.
• These findings provide a strong rationale for biomarker-driven basket trials.
• Investigating targeted therapies in ATC patients based on identified PGVs may improve treatment efficacy.