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Primary radiation therapy with or without chemotherapy (RT/CRT) is the most common treatment for oropharyngeal squamous cell carcinomas (OPSCC), but there has been an increase in transoral surgery (TOS) for T1-2 tumors. Because only a subset of T1-2 tumors are TOS-favorable, nonrandomized comparisons between RT/CRT and TOS could be confounded by indication. We aimed to compare outcomes of potential TOS-candidates versus non-TOS candidates, among patients who underwent RT/CRT for early T-stage OPSCC.For patients treated with RT/CRT for early-stage human papilloma virus positive OPSCC between 2014 and 2018, pretreatment imaging was reviewed by 3 head and neck surgeons, blinded to outcomes, to assess primary-site appropriateness for TOS, and extracapsular extension (ECE) was scored by a head and neck neuroradiologist. We compared outcomes based on surgical favorability pertaining to (1) the primary site tumor alone and (2) the primary site and an absence of ECE. Kaplan-Meier estimates for overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were compared using the log-rank test, with Cox regression used for multivariable modeling.One hundred and forty-three patients were evaluated, of which 121 were male (84.6%), the median age was 59.4 years, and all of them were p16 positive (100%). The primary site was TOS-favorable in 115 of 143 (80.4%). Patients with TOS-favorable primary site experienced superior 5-year OS (89.8% vs 71.2%, P = .017), DSS (90.4% vs 63.4%, P = .022), and RFS (83% vs 49.4%, P = .04) compared with TOS-unfavorable patients. Similarly, patients with a TOS-favorable primary site and no ECE on imaging 101 of 143 (70.6%), had improved OS, DSS, and RFS (P.05) compared with TOS-unfavorable patients.In this first study to assess surgical favorability as a prognostic factor among patients with T1/2 p16+ OPSCC, patients with TOS-favorable early-stage OPSCC have better outcomes than TOS-unfavorable patients. This provides valuable prognostic information for patients, and also suggests the risk of confounding by indication in nonrandomized comparisons of treatment modalities.

Objectives Survival in head and neck squamous cell carcinoma (HNSCC) has been associated with patient sex, typically with males experiencing poorer outcomes. It is unclear if this disparity is based in divergent tumor biology. We analyzed the TCGA HNSCC cohort to uncover disparities in the somatic single nucleotide variation (SNV), copy number alteration (CNA) and mRNA abundance profiles between males and females. Critically, we stratified our results by tumor HPV status to control for this significant confounder. Methods SNV, CNA and mRNA abundance differences between males and females were compared separately for the HPV-positive (n = 67) and negative (n = 431) TCGA HNSCC cohorts. Overall survival outcomes were compared in males and females in both HPV-positive and HPV-negative subsets of patients. Results Females were found to have poorer overall survival than males (p = 0.048), largely due to higher rates of HPV-positive disease among men. SNV analysis revealed that in HPV-positive disease, there were no differences by sex after accounting for the false discovery rate (FDR). In HPV-negative tumors, BRWD3 mutations occurred more frequently in the tumors of female patients compared to males after adjusting for the FDR (p = 0.02). Further, HPV-negative BRWD3 mutant tumors were found to have significantly worse 5-year overall survival compared to wildtype on multivariate analysis (p = 0.02). There were 88 heterozygous deletions and 14 amplifications that were differentially altered between male and female HPV-negative tumors and associated with expression changes. Pathway analysis of these genes revealed that tumors from males were enriched in five pathways including chemokine and phosphophatidylinositol signaling. Conclusions Reanalysis of the TCGA HNSCC dataset stratified by sex revealed that males in this cohort had a significant survival advantage, due to a higher proportion of HPV-positive disease. Mutations in BRWD3 were more frequent in HPV-negative tumors of females and were associated with poorer overall survival. BRWD3 may represent a novel biomarker of patient outcomes, but will require additional validation.