Association of low serum levels of transforming growth factor β1 (TGF-β1) and high levels of vascular endothelial growth factor-A (VEGF-A) following neoadjuvant chemoradiotherapy with poor outcome in esophageal cancer patients receiving combined modality therapy: A preliminary analysis using proximity ligation assay.

Abstract

80 Background: Currently, serum biomarkers do not influence the treatment of esophageal cancer. The purpose of this project is to investigate, using the proximity ligation assay (PLA), serum biomarkers that predict treatment response and survival outcome for patients with locally advanced esophageal cancer (LAEC) undergoing neoadjuvant concurrent chemoradiotherapy (CCRT) followed by radical esophagectomy. Methods: From 2004 to 2011, 79 patients with LAEC receiving CCRT of taxane-based chemotherapy and 40 Gy followed by curative surgery were enrolled in this study. Serum samples were collected before and within one month after CCRT. Fifteen biomarkers (Axl, BMP2/4, EGFR, FAM84B, Gas6, Her2, IGFBP3, MMP1, MMP13, OPN, PDGFR-α, Periostin, SPARC, TGF-β1, VEGF-A) were analyzed using PLA. Pathological responses were classified into complete response (CR), microscopic residual (MicroR), or macroscopic residual (MacroR). Associations between serum level of each biomarker and pathological response, disease-free survival (DFS), and overall survival (OS) were evaluated by ANOVA and Log-rank tests. Results: Of 79 patients, 30 had CR (38%), 37 had MicroR (47%) and 12 had MacroR (15%). With a median follow-up of 54.5 months, the median OS and DFS were 34 and 43 months, respectively. Among evaluated biomarkers, TGF-β1 was the most significant one associated with pathological response (p=0.009, two-way ANOVA), with higher post-CCRT TGF-β1 levels predicting better response (p=0.035, one-way ANOVA). Patients with higher post-CCRT TGF-β1 levels (≥3rd quartile) had significantly better DFS (median not reached vs. 27 months, p=0.03). Patients with both lower levels of post-CCRT TGF-β1 and higher levels of VEGF-A had significantly worse DFS (13 months, p=0.001) and OS (18 months, p=0.035). Conclusions: Post-CCRT serum TGF-β1 and VEGF-A levels by PLA may be used to predict pathological response and survival outcome for esophageal cancer patients receiving combined modality therapy.