The prognostic significance of uncoupled proliferation and EGFR expression in oral cancer treated with surgery and radiation.

Abstract

e21146 Background: Oral squamous cell cancer (OSCC) is characterized by poor prognosis, high morbidity and mortality. The epidermal growth factor receptor (EGFR) is overexpressed in most OSCCs; however, the association between EGFR and survival is inconsistent. Despite being linked to proliferation in normal tissue, few studies have examined the relationship between proliferation and EGFR expression, and OSCC outcomes. Methods: This retrospective study evaluated OSCC patients treated with surgery (n=17) or surgery and post-operative RT (n=47) between 1998-2005 at the Tom Baker Cancer Centre, Calgary, AB, Canada (median follow-up: 43 months). Tissue microarrays were assembled from pre-treatment formalin-fixed paraffin embedded tumor tissue. Clinico-pathologic data were obtained from chart review. EGFR and Ki67 expression were quantified using fluorescent IHC and AQUA technology. Regions of high and low EGFR expression were defined for each tumor core. We measured the ratio of Ki67 levels between high versus low EGFR expressing regions (Ki67EGFR-hi/Ki67EGFR-lo) to evaluate the relationship between proliferation and EGFR expression. Continuous variables were dichotomized using Xtile. Biomarker association with recurrence free survival (RFS) 5-year disease-specific survival (DSS) was analyzed using the Cox model. Results: In OSCC RFS and DSS associated with pathologic T-stage [RFS HR 2.8 (1.3-6.3), p=0.01; DSS HR 3.6 (1.5-8.4), p=0.004], and lymph node status [RFS HR 3.5 (1.6-7.7), p=0.002; DSS HR 6.4 (2.5-16.2), p<0.001]. Neither Ki67 nor EGFR alone significantly correlated with RFS or DSS. We observed a high Ki67EGFR-hi/Ki67EGFR-lo ratio in normal oral epithelium. In OSCC, a high Ki67EGFR-hi/Ki67EGFR-lo ratio (similar to normal epithelium) associated with improved survival [RFS HR 0.50 (0.23-1.08), p=0.076; DSS HR 0.46 (0.20-1.06), p=0.07]. The association with survival outcomes was more pronounced in patients who received RT [RFS HR 0.31 (0.12-0.83), p=0.02; DSS HR 0.40 (0.14-1.13), p=0.08]. Conclusions: Our results suggest that the uncoupling of proliferation and EGFR expression in OSCC represents a more aggressive and RT resistant tumor phenotype.