Female sex is associated with worse survival in laryngeal head and neck squamous cell carcinoma.

BACKGROUND: Despite treatment, approximately one-third of patients with head and neck squamous cell carcinoma (HNSCC) die within five years of diagnosis. Here, we assessed molecular and clinical features that correlate with biological sex and overall survival in HNSCC. METHODS: We analyzed HNSCC cases in the Cancer Genome Atlas (TCGA), which includes tumors from 382 males and 141 females. When possible, findings were validated with the National Cancer Institute's Surveillance, Epidemiology, and End Results dataset (November 2023 Submission, 1975-2021). RESULTS: Tumors from females had a significantly lower fraction of genome altered, along with fewer aneuploidy events. HNSCCs in females had increased expression of immune genes and higher overall immune infiltrate. Females showed worse overall survival in HNSCC compared to males (HR: 1.39). This disparity was statistically attributable to age at diagnosis as well as HPV status, as HNSCCs in females were less likely to be HPV-positive than in males. For laryngeal squamous cell carcinoma (L-HNSCC), females also had significantly worse outcomes (HR: 3.42), but here the disparity could not be attributed to available clinicogenomic features such as HPV or smoking status. The association of biological sex with outcome in L-HNSCC was also observed in the SEER database and was not present among patients diagnosed before the age of 50. CONCLUSION: Biological sex is associated with differences in survival and tumor genomic features in HNSCC. HPV infection status, diagnosis age, and tumor location contribute to a worse prognosis for females with HNSCC, particularly strong in L-HNSCC.