PO-024 Perioperative blockade of stress-inflammatory responses improves biomarkers of metastasis in excised tumours and blood samples: phase ii clinical trials in colorectal and breast cancer patients

Abstract

ABSTRACT Introduction Excess release of catecholamines and prostaglandins has been shown to mediate pro-metastatic processes of stress and surgery, specifically during the critical perioperative period. Material and methods Here, in two randomised placebo controlled clinical trials in colorectal (CRC, n=34) and in breast cancer patients (BC, n=38), we tested the combined 20 day perioperative use of the b-blocker, propranolol, and the COX2-inhibitor, etodolac, initiated 5 days before surgery. Tumour samples were collected during surgery, and were subjected to histological analyses, whole genome mRNA profiling, and transcriptional control pathways analyses. In BC patients, four blood samples were also collected perioperatively. Results and discussions Drugs were well tolerated, with adverse effects equivalent to placebo. In blood samples, treatment reduced serum IL-6 and CRP levels even before surgery, improved markers of NK cytotoxicity, and enhanced induced production of IFNg and IL-12, without affecting anti-inflammatory soluble factors (cortisol and IL-10). In both studies, whole genome mRNA profiling of excised tumours showed decreased epithelial-to-mesenchymal transition (EMT); down-regulation of the transcriptional activity of CREB, NFkB, GATA family, and STAT3; reduced presence of tumor-associated monocytes; and increased presence of NK cells in CRC and B cells in BC tissue. The tumour proliferation marker Ki67 was tested in BC patients, and was significantly reduced by drug treatment. In CRC patients, three-year follow-up showed large but statistically insignificant improvement in disease free survival (DFS) in the treatment group (1/15 vs 5/19), further suggesting the safety of the paradigm. Conclusion These findings suggest a critical impact to the short pre-operative period, clearly indicate the efficacy of this combined drug regimen, and suggest its metastatic-reducing impact, which should be tested in larger clinical trials. Such a stress-inflammatory-reducing approach can be exploited during the critical perioperative period, potentially improving long-term survival rates.