Abstract # 1731 Perioperative COX-2 inhibition and beta-adrenoceptor blockade in breast cancer patients improve markers of immunity and reduce inflammation and primary tumor epithelial-to-mesenchymal transition (EMT)

Abstract

Preclinical research has implicated excess perioperative release of catecholamines and prostaglandins in mediating the metastasis-promoting effects of stress and surgery. This study reports the first clinical test of combined blockade of these pathways using the beta-adrenergic blocker, propranolol, and the COX-2 inhibitor, etodolac. In a double-blind placebo-controlled clinical trial, 36 breast cancer patients were randomized to an 11-day oral drug treatment beginning five days before surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4), and excised tumors were collected. No adverse effects of drug treatment were reported. Among other findings, in the placebo group, (i) serum IL-6 and CRP levels increased before surgery (T2), and (ii) stimulated IL-12 and IFN γ levels were reduced by stress and surgery (T2&T3). Both effects were blocked and further reversed by the drug treatment. Transcriptome analyses of excised tumor tissue identified 368 genes showing >1.20-fold differential expression as a function of drug treatment. Bioinformatics analyses based on a priory hypotheses indicated decreased tumor expression of several pro-metastatic gene programs, including inflammatory and epithelial-to-mesenchymal transition (EMT). Flow cytometry showed that drug treatment also abolished a postoperative (T3) circulating influx of immature-proinflammatory monocytes (CD14++CD16-), and enhanced perioperative (T2&T3) expression levels of CD11a on NK cells. These findings suggest pro-immune, anti-inflammatory, and potential anti-metastatic effects of this novel and safe therapy.