Polymorphisms in epidermal growth factor (EGF) and proteinase activated receptor 1 (PAR-1)

1. 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. G. Lurje1, J.M. Leers2, A. Pohl1, A. Oezcelik2, W. Zhang1, D. Yang1, J.A. Hagen2, S.R. DeMeester2, T.R. DeMeester2, and H.J. Lenz1 1Department of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 2Department of Surgery, University Hospital, University of Southern California, Los Angeles, CA Introduction Methods Results Tumor recurrence after curative resection continues to impose a significant problem in the management of patients with localized esophageal adenocarcinoma (EA). The identification of molecular markers of prognosis is critical in better defining tumor stage- and progression, and may also help to define novel targets, as well surrogate endpoints of disease progression and response to therapy. Proteinase-activated-receptor 1 (PAR-1) and epidermal-growth-factor (EGF) have been shown to mediate the regulation of early-onset angiogenesis and in turn may impact the process of tumor growth and disease progression. Tissue samples from 239 patients (median age of 64 years; range: 25-91) were obtained at the University of Southern California University Hospital. All patients were diagnosed with locally advanced esophageal adenocarcinoma (pT1-4, pN1-2, pM0) and were uniformly treated with surgery alone. The median time to recurrence was 2.8 years (95% CI: 1.9-4.2). Within the first 3 years after surgery, 101 out of 114 (89%) patients showed recurrent disease. DNA was isolated from formalin-fixed paraffin-embedded normal esophageal tissue samples and polymorphisms were analyzed using PCR-based protocols. PAR-1 -506 ins/del (adjusted p-value = 0.011) and EGF +61 A>G (adjusted p-value = 0.035) showed to be adverse prognostic markers, in both univariate and multivariable analysis (adjusted by type of surgery, T1- and N-category and race). In combined analysis, grouping alleles into favorable vs. non-favorable alleles, high expression variants of PAR-1 -506 ins/del (any insertion allele) and EGF +61 A>G (A/A) were associated with a higher likelihood of developing tumor recurrence (adjusted p-value < 0.001). Conclusions This study supports the role of functional PAR-1 and EGF polymorphisms as independent prognostic markers in localized EA and may therefore help to identify patient subgroups at high risk for tumor recurrence. As such, the assessment of the patients’ individuals risk may be optimized on the basis of tumor-stage specific genotypes. Larger prospective and biomarker embedded clinical trials are needed to validate these preliminary data. * Greenwood SE + Estimates were not reached † Based on log-rank test § For two patients information of tumor differentiation was not available ‡ Grouped together for the estimates of relative risk and probability ± SE of 5-year recurrence and overall survival