Association of Estrogen Receptor Alpha Expression With Survival in Oropharyngeal Cancer Following Chemoradiation Therapy

Background: Oropharyngeal squamous carcinoma (OPSC) continues to increase in incidence secondary to human papillomavirus (HPV) infection. Despite the good overall prognosis for these patients, treatment with chemoradiation is associated with morbidity and treatment failure. Better predictors for disease outcome are needed to guide de-intensification regimens. We hypothesized that estrogen receptor alpha (ER alpha), a prognostic biomarker in oncology with therapeutic implications, might have similar utility in OPSC. Methods: To investigate associations among ER alpha and demographics, HPV status, and survival, we analyzed ER alpha mRNA expression of head and neck squamous carcinomas (HNSC) from The Cancer Genome Atlas (TCGA) and immunohistochemistry (IHC) of pretreatment biopsy specimens from an independent group of 215 OPSC patients subsequently treated with primary chemoradiation (OPSC-CR). Associations among variables were evaluated with Fisher exact tests and logistic regression; associations with survival were evaluated with log-rank tests and Cox proportional hazards regression. Results: Among 515 patients in TCGA, ER alpha mRNA expression was highest in HPV-positive OPSC. High ER alpha mRNA expression was associated with improved survival among those receiving chemoradiation (hazard ratio adjusted for HPV status = 0.44, 95% confidence interval = 0.21 to 0.92). In OPSC-CR, ER alpha was positive by IHC in 51.6% of tumors and was associated with improved overall, disease-specific, progression-free, and relapse-free survival (log-rank tests: P<.001, P<.001, P = .002, P = .003, respectively); statistically significant associations of ER alpha positivity with improved survival were maintained after adjusting for clinical risk factors including HPV status. Conclusion: In two independent cohorts, ER alpha is a potential biomarker for improved survival that also may represent a therapeutic target in OPSC.