BACKGROUND: The standard treatment for patients with oral cavity cancer (OCC) with intermediate risk pathologic variables after surgery is adjuvant radiotherapy. Despite this, one-third of patients experience locoregional failure (LRF). Clinicopathologic prognostic models have not been able to identify subsets of patients at higher risk of failure in whom treatment intensification with the addition of systemic chemotherapy should be considered. We posited that gene expression-derived tumor taxonomies can predict treatment failures and therefore guide more nuanced clinical decision making. Herein, we report on a score model based on OCC gene expression characteristics that can be incorporated into risk stratification and treatment decisions.
METHODS: Formalin-fixed paraffin-embedded (FFPE) tissue samples from patients with intermediate risk OCC treated with surgery followed by radiation alone were subjected to quantitative nuclease protection and next-generation sequencing to measure gene expression (HTG Molecular EdgeSeq™). A subset of samples that had corresponding frozen tumor samples were profiled by RNAseq to validate the FFPE results. Patients were divided into two groups based on LRF. Differentially expressed genes were identified using the R limma package. 98 genes were selected on the basis of unadjusted P values and predicted biological impact, as measured by gene set enrichment results (GSEA) and resultant biological pathway scores. The Cancer Genome Atlas (TCGA) HNSCC dataset (n=521) was used to validate the prognostic performance of our gene set.
RESULTS: Of the 78 patients included in the study, 35% of patients had LRF. GSEA of the 98 genes demonstrated a role for DNA repair, oxidative phosphorylation, hypoxia and p53 pathways, indicating radiobiologic plausibility for a significant subset of the genes that constitute the score. The mean composite score was 0.42 for patients with LRF, and -0.19 for patients without LRF (P = 0.0002). The Kaplan-Meier estimates of progression free survival at 3 years for the 1st (high risk) and 4th quartile (low risk) groups were 0.65 (0.47 to 0.89; 95% CI) and 0.93 (0.82 to 1; 95% CI), respectively. On multivariate analysis, the composite score was the strongest predictor of LRF (P = 0.0073). Composite scores also strongly predicted for overall survival in the TCGA HNSCC dataset (P < 0.01) and the Kaplan-Meier estimates of overall survival at 2 years for the 1st and 4th quartile groups were 0.55 (0.45 to 0.68; 95% CI) and 0.73 (0.63 to 1; 84% CI), respectively. Composite scores performed the best in patients with OCC (P = 0.033).
CONCLUSIONS: We developed a gene signature that predicts LRF in patients with intermediate risk OCC treated with surgery and adjuvant radiotherapy. Further validation on larger datasets are needed. This biomarker can potentially identify higher risk patients who should be considered for intensification strategies with the addition of systemic therapy.
Citation Format: Elif I. Sarihan, Brian B. Burkey, Joseph Scharpf, Robert Lorenz, Eric D. Lamarre, Brandon Prendes, Jessica L. Geiger, David J. Adelstein, Shlomo A. Koyfman, Mohamed E. Abazeed. A biologic basis for locoregional failure in patients with oral cavity cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3681.