Polymorphisms in epidermal growth factor (EGF) and proteinase activated receptor 1 (PAR-1) associated with tumor recurrence in localized adenocarcinoma (EA) of the esophagus treated with surgery alone

Abstract

4564 Background: Tumor angiogenesis is a well-recognized aspect of human cancer biology and is mediated at least in part by EGF and PAR-1, which in turn may impact the process of tumor growth and progression. Systemic tumor recurrence after curative resection continues to be a significant problem in the management of patients with localized EA. Further, it is being increasingly recognized that esophageal squamous cell carcinoma and EA are separate and distinct disease groups and need to be considered individually. We therefore designed a large retrospective study of EA patients to identify novel molecular markers of prognosis to better define tumor stage and progression, and help to define novel targets, as well as surrogate-endpoints of disease progression and response to therapy. Methods: Between 1992 and 2005 normal esophageal tissue samples from 239 patients with localized EA treated with surgery alone were obtained at University of Southern California medical facilities. The median follow-up was 3.2 years. 114 out of 239 (48%) patients had tumor recurrence, with a probability of 5-year recurrence of 0.62 ± 0.04. DNA was isolated from formalin-fixed paraffin-embedded specimens and 10 angiogenesis related and functional gene polymorphisms were analyzed using a PCR-RFLP and 5´-end [γ-33P] ATP-labeled PCR method. Results: PAR-1 -506 ins/del (p-value=0.003; log-rank test) and EGF +61 A>G (p-value=0.034; log-rank test) are adverse prognostic markers in univariate analysis. After adjusting for covariates (gender, T1-, N-category, type of surgery) in the multivariable model, "high-expression" variants of PAR-1 (any insertion allele) (RR: 1.81; adjusted p-value = 0.011) and EGF (A/A) (RR: 1; adjusted p-value=0.035) remained significantly associated with time to recurrence, compared to other genotype combinations of PAR-1 (RR: 1) and EGF (RR: 0.65). Conclusions: This study supports the role of functional EGF and PAR-1 polymorphisms as independent prognostic markers in localized EA and may therefore help to identify patient subgroups at high risk for tumor recurrence. Prospective and biomarker-embedded clinical trials are needed to validate our findings. [Table: see text]