Male Sex Ups Mortality Risk in BRAF V600E Papillary Thyroid Cancer

Male sex is a predictor of poorer disease-specific survival in patients with BRAF V600E papillary thyroid cancer (PTC), according to a recent article published in the Journal of Clinical Oncology.

“A prominent but controversial mortality risk factor of PTC is male sex,” wrote senior author Mingzhao Xing, MD, PhD, of Johns Hopkins Thyroid Tumor Center, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, in Baltimore, Maryland. “Some early studies did not show a significant effect of male sex on PTC-specific patient survival, but others did.”

PTC accounts for between 85% and 90% of thyroid cancers, with conventional PTC (CPTC) the main histologic subtype. Although mostly indolent, PTC can result in high mortality among certain populations; thus, prognostic risk stratification with clinicopathologic risk factors, such as patient age, tumor size, metastases, and extrathyroidal extension, is key to clinical management.

As expected, genetics play an important role in PTC, and BRAF V600E is the most frequent oncogenic mutation, found in an average of 45% of patients. This mutation is correlated with aggressive tumor behaviors, disease recurrence, and disease-specific mortality of PTC.

Wang et al hypothesized that the “BRAF V600E mutation might constitute a genetic background conferring male sex mortality risk and that BRAF status could thus differentiate the prognostic risk of male sex in PTC, reconciling the controversial clinical results from recent decades.”

Researchers retrospectively assessed the relationship between male sex and clinicopathologic outcomes among 2,638 PTC patients (623 men; median age, 46 years) treated with total or near-total thyroidectomy and therapeutic neck dissection. The team focused on mortality with a median follow-up of 58 months. Cox regression and Cox proportional hazards analyses were utilized to compare the univariable and multivariable effects on disease recurrence and mortality and to determine hazard ratios (HRs) and 95% confidence intervals (CIs).

Regardless of BRAF status, a significant correlation was found between male sex and poor clinicopathologic characteristics of PTC. Furthermore, male sex exerted an adverse effect on disease recurrence and disease-specific mortality, but this effect on disease-specific mortality was not independent. Of note, the investigators observed similar effects in CPTC.

“These results were consistent with some previous reports, providing further evidence suggesting that male sex is a risk factor for poor clinical outcomes of PTC, but it may be so only under certain circumstances,” the investigators wrote.

A significant mortality difference was found in patients with BRAF V600E PTC. Specifically, mortality was 6.6% in men vs 2.9% in women (P = .006), with an HR of 2.43 (95% CI, 1.30-4.53) that remained significant following multivariable adjustment (HR, 2.74; 95% CI, 1.38-5.43). Similar results were seen in CPTC patients. No significant difference in mortality was observed in patients with wild-type BRAF V600E PTC.

“The study demonstrates that male sex of [the] patient is associated with a higher thyroid cancer-related mortality risk than female sex in BRAF mutation-positive cases but not in wild-type BRAF cases,” said Xing. “This provides a molecular/genetic explanation for the half century-recognized mysterious phenomenon of the higher thyroid cancer-related mortality risk in male patients than female patients. When applying the male sex as a mortality risk in the risk stratification of thyroid cancer, it is important to know the BRAF genetic status, as male sex is a mortality risk only in patients with BRAF mutation-positive disease.”