Male Sex, Age, and Tumor Genetics Linked to Thyroid Cancer Mortality

Male sex was associated with higher papillary thyroid cancer (PTC)-specific mortality among patients aged 45 years or older whose tumors harbored concurrent BRAF V600E and TERT promoter (TERTp) mutations, according to an international multicenter cohort study published in JAMA Network Open.¹

Among patients aged 45 years or older with both mutations, male sex was associated with a 3-fold higher risk of PTC-specific mortality after adjustment for clinicopathologic factors (adjusted HR, 3.07; 95% CI, 1.35-6.97; P =.007). This group also had the highest observed mortality rate, at 37.07 deaths per 1000 person-years, highlighting the prognostic relevance of evaluating these biological factors together.

Study Design and Patient Characteristics

The retrospective cohort study included 4746 patients with PTC treated at 15 medical centers across 10 countries between 1979 and 2023. The median patient age was 48 years (IQR, 37-59), and 3612 patients (76.1%) were women. Median follow-up was 51.0 months (IQR, 26.4-109.1).

The investigators assessed PTC-specific mortality according to sex, age, and tumor mutation status, focusing on BRAF V600E and TERTp mutations. They also examined whether the association between sex and mortality differed among patients with neither mutation, either mutation alone, or both mutations.

Tumor Characteristics, Age, and Mortality

Overall, PTC-specific mortality was higher among male patients than female patients, at 3.7% (42 of 1134) and 1.7% (60 of 3612), respectively (P <.001). Male patients also had a higher prevalence of adverse clinicopathologic characteristics, including lymph node metastases (54.1% vs 38.3%), distant metastases (5.7% vs 3.5%), and stage III or IV disease (8.2% vs 5.0%).

The prevalence of concurrent BRAF V600E and TERTp mutations was higher among male patients than female patients (9.0% vs 5.0%; P <.001). Within this dual-mutation subgroup, PTC-specific mortality was 22.8% among male patients and 11.9% among female patients (P = .02). After adjustment for clinicopathologic characteristics, male sex remained associated with higher mortality (HR, 2.63; 95% CI, 1.74-9.00; P =.01).

The investigators also found that TERTp mutations became more prevalent with increasing age among patients with BRAF V600E, particularly among male patients. Male patients with BRAF V600E had nearly twice the odds of harboring a TERTp mutation compared with female patients (odds ratio, 1.83; 95% CI, 1.41-2.38; P <.001).

By contrast, when patients were stratified by age and mutation status, no significant sex-associated mortality difference was observed among those with neither mutation, BRAF V600E alone, or TERTp mutations alone.

Implications for Risk Stratification

The findings suggest that the association between male sex and PTC-specific mortality is not uniform across patients but varies according to age and tumor genetics. Based on the observed association, the authors suggested prioritizing BRAF V600E and TERTp testing in male patients aged 45 years or older and considering more intensive management when both mutations are present.

The 2025 American Thyroid Association guidelines discuss the association between concurrent BRAF V600E and TERT promoter mutations and more aggressive disease, although sex is not included as an independent factor in the ATA recurrence risk stratification system.² These proposals require further evaluation before being incorporated into routine clinical practice.

“This study reconciled previous inconsistent findings on the prognostic value of patient sex in thyroid cancer and supported its formal integration as a cardinal component, in conjunction with patient age and tumor genetics, into the risk stratification systems for PTC,” Wu et al, study authors, concluded.

The study's retrospective design and differences in patient characteristics and clinical practices across participating centers may limit the generalizability of the findings. The investigators also did not evaluate other potentially relevant genetic alterations, including TP53 mutations. Further research is needed to determine how sex, age, and tumor genotype should inform PTC risk stratification and management.

REFERENCES

1. Wu L, Wang Z, Lin S, et al. Sex and Mortality Among Patients with Papillary Thyroid Cancer. JAMA Netw Open. 2026;9(9):e2635582. doi:10.1001/jamanetworkopen.2026.35582

2. Ringel MD, Sosa JA, Baloch Z, et al. 2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer. Thyroid. 2025;35(8):841-985. doi:10.1177/10507256251363120