The Genomic Landscape of Thyroid Nodules in Patients ≥75 Years Old

Introduction

• Thyroid nodules are increasingly common in older adults; most are benign.¹
• In patients “>=”75 years, malignant nodules often behave more aggressively, making accurate risk stratification essential.
• The Afirma Genomic Sequencing Classifier (GSC) is an exome-enriched RNA-seq assay validated in adults “>=”21 years that refines malignancy risk in Bethesda III/IV nodules, potentially avoiding unnecessary surgery.²
• Limited data exist on the genomic and transcriptomic landscape of thyroid nodules in patients “>=”75 years.
• The goal of this study was to characterize the molecular and transcriptomic profiles of thyroid nodules in patients “>=”75 years compared with younger cohorts.

Methods

• The Afirma GSC database was queried from August 2017 – June 2024.
• Nodules that had adequate genomic material from follicular cells were identified to analyze expressed variants and fusions among Afirma GSC-(S)uspicious and nodules with Bethesda V/VI cytology.
• Nodules from patients <20 yrs were excluded.
• TERT promoter mutations were analyzed from March 2023 – June 2024.
• A subset of samples with available transcriptomic were analyzed for ERK and EMT signaling expression, the BRAF-RAS (BRS) score, and expression of the Human Molecular Signatures Database (MSigDB) hallmarks of cancer pathways.
• Patients were stratified into the following age cohorts:
  • 20-54 yrs
  • 55-74 yrs
  • “>=”75 yrs

Results

250,200 were included in the analysis. Expressed variants and fusions are reported amongst nodules that were Afirma GSC-(S)uspicious or that had Bethesda V/VI cytology.

• 8,627 samples with TERT promoter mutation testing were analyzed.
• A subset of 17,000 GSC-S or B V/VI samples with available transcriptomic were analyzed for ERK and EMT signaling expression, the BRAF-RAS (BRS) score, and expression of the Human Molecular Signatures Database (MSigDB) hallmarks of cancer pathways.

Patients “>=”75 years had a higher Afirma GSC-(B)enign rate compared to younger age groups (Table 2a).

Females had a higher rate of Afirma GSC-B than males in all age groups (Table 2b).

Conclusion

• Molecularly tested nodules from patients “>=”75 years have an overall higher benign call rate and generally favorable variant/fusion profiles.
• In BV/VI nodules, there are higher levels of alterations suggestive of aggressive thyroid cancer (e.g. TERTp).
• Differential gene expression analysis suggests nodules in patients “>=”75 years have increased inflammatory changes, while younger patients demonstrate more neoplastic pathways.
• Future studies should be done with histopathology detail and longer-term oncologic outcomes to see if improved prognostic features from the above-described expression analysis can personalize treatment for thyroid cancer in older patients.
• These data suggest one can increase confidence in more conservative management in older patients and may decrease the need for unnecessary surgery in this population.