Perioperative beta-adrenergic blockade and COX2 inhibition in colorectal cancer patients improves pro-metastatic indices in the excised tumor: EMT, tumor infiltrating lymphocytes (TILs), and gene regulatory pathways

Abstract

Excess release of catecholamines and prostaglandins was shown to mediate pro-metastatic processes during the perioperative period. Here, in a randomized controlled biomarker clinical trial in colorectal cancer patients (CRCP) (n = 34), we tested the combined perioperative use of the β-blocker, propranolol, and the COX2-inhibitor, etodolac, scheduled for 20 perioperative days, starting 5 days before surgery. Tumor samples were subjected to whole genome mRNA profiling and transcriptional control pathways analyses. Recurrence-free survival (RFS) is currently monitored. Drugs were well tolerated. Whole genome mRNA profiling indicated that drug treatment significantly reduced (i) markers of epithelial-to-mesenchymal- transition (EMT), (ii) tumor infiltrating CD14 + monocytes, and (iii) tumor infiltrating CD19 + B-cells, which are associated with tumor progression and metastatic disease in CRCP. Drug treatment increased tumor infiltrating CD56 + NK-cells, potentially improving anti-metastatic immunity, as the majority of colorectal tumors are susceptible to NK cytotoxicity. Lastly, drug treatment reduced the indicated activity of several pro-metastatic transcription factors (GATA1/GATA2, IRF1/ISRE, OCT1, c-MYB, HSF1, CREB), but increased the potentially tumor-promoting STAT1 activity. Two-year recurrence rates are 7% (1/15 patients) in the drug-treated group and 27% (5/19 patients) in the placebo group (p=0.35 – underpowered study for this index). Overall, CRCP undergoing curative surgery may benefit from the combined drug treatment through reduction of stress-mediated pro-metastatic pathways in the primary tumor and potentially residual disease. Long-term cancer outcomes should be studied to test clinical ramifications.