Hemangiogenic response after pre-operative COX2 inhibition predicts recurrence in esophageal cancer

Abstract

15077 Background: Growth of esophageal cancer involves a proliferative hemangiogenic component. Biomarkers that predict this propensity in esophageal cancer and the impact of anti-angiogenic strategy on their levels as well as clinical response remain unknown. Methods: A multimodular approach was devised to assess hemangiogenic parameters in a cohort of chemotherapy naïve patients with locally advanced (T2-T3N0, T1-T3N1M0M1a) esophageal cancer pre- and 4 days post-celecoxib neoadjuvant treatment. Patients went on to receive neoadjuvant therapy with celecoxib, paclitaxel and carboplatin for 3 cycles, followed by surgical resection. This bioassay panel consists of 5 components: i) HUVEC-based angiogenic scale for functional plasma angiogenic activity, ii) flow cytometry to quantify CD133+VEGFR2+ circulating endothelial progenitors (CEPs), iii) hematopoietic colony-forming assay to quantify circulating hematopoietic progenitors (CHPs), iv) plasma SDF-1 level, and v) platelet VEGF-A level. Results: The cohort consists of 8 consecutive patients (6 men, 2 women) with median age of 58. After 18 months of followup, 6 patients remained alive and without evidence of recurrence, while 2 had tumor recurrence and metastasis. Analysis of the positive responders (pre-celecoxib baseline versus 4 days post treatment) revealed a global suppression of hemangiogenic parameters with reduction of the functional HUVEC-based angiogenic scale (mean score of 3.3 versus 1.8; p<0.05), 2.2-fold decrease in CEPs (p<0.05), and 3-fold decrease in CHPs (p<0.05). This trend also correlated with decreased plasma SDF-1 and platelet VEGF-A levels . However, in the 2 cases of tumor recurrence, the initial hemangiogenic response was blunted with no significant difference in all parameters tested during the celecoxib monotherapy period. Conclusion: Esophageal cancer development involved a hemangiogenic switch toward increased CEPs, CHPs, and functional plasma pro-angiogenic activity. COX2 inhibition with celecoxib normalized the hemangiogenic profile. Collective assessment of hemangiogenic biomarkers during neoadjuvant setting may be a promising tool in predicting clinical outcomes, recurrence, and for validating impact of anti-angiogenic therapy on esophageal cancer. No significant financial relationships to disclose.