TERT Promoter Variants, Older Age, and Prognosis in Papillary Thyroid Carcinoma

Older age at diagnosis is associated with worse outcomes in papillary thyroid carcinoma (PTC). The current American Joint Committee on Cancer tumor-node-metastasis staging system incorporates an age of 55 years or older as staging criteria. TERT promoter variants are also associated with aggressive disease.

To evaluate the interplay between age, TERT promoter variants, and survival outcomes in PTC.

This multi-institutional retrospective cohort study was conducted from 1993 to 2020 at 3 academic centers in the US, with integration of publicly available cohorts from The Cancer Genome Atlas (TCGA) and American Association of Cancer Research's Project Genomics Evidence Neoplasia Information Exchange (AACR GENIE). The cohort included 169 patients with PTC from 3 US academic centers, who were integrated with TCGA and AACR GENIE, yielding a combined analytic population of 1555 patients with PTC. The association between age and TERT was examined across all patients. Within the multi-institutional cohort with long-term follow-up (n = 169), the association between TERT and survival was further examined.

Age at diagnosis and TERT promoter status.

The primary outcome was disease-specific survival (DSS), and the secondary outcome was progression-free survival (PFS).

Across all cohorts (N = 1555; 966 female individuals [62.1%] and 589 male individuals [37.9%]), the prevalence of TERT promoter variants increased progressively with age (r = 0.59; 95% CI, 0.54-0.63), being rare in patients younger than 30 years (<2%) and reaching 32% to 70% in those older than 65 years. For survival analyses, 169 patients were included (median follow-up, 13.7 years; 95% CI, 10.4-15.9 years). Among patients younger than 55 years without a TERT promoter variant, 10-year DSS was 100% and 10-year PFS was 83%. Among those 55 years or older, 10-year DSS was 91% for TERT wild-type tumors and 51% for TERT-variant tumors (91% vs 51%, respectively; difference, 40%; 95% CI, 4-68). A similar trend was observed for PFS (10-year PFS of 75% for TERT wild-type vs 23% for TERT variant; difference, 52%; 95% CI, 9-82). In multivariable analysis, TERT promoter variants remained independently associated with worse DSS after adjustment for age and pathologic tumor, node, and metastasis categories.

The findings of this cohort study suggest that the high prevalence of TERT promoter variants in older patients largely explains the association between age and worse prognosis in PTC. TERT promoter status offers more biologically grounded prognostic information than age and may improve risk stratification.