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Drug regiment consisting of anti-inflammatories (COX-2) and anti-stress medications (β-Adrenergic Blockade) given before and after surgery could reduce cancer recurrence (biomarkers of metastatic processes)

Reporter: Aviva Lev-Ari, PhD, RN

“We found that the drugs were very efficient in reducing biomarkers of metastatic processes,” Prof. Ben-Eliyahu said. “For example, we found that the drug treatment reverses EMT — the process that tumor cells go through to slip out of the primary tumor and enter another organ. It is a crucially important step in the metastatic process. We also looked at indices related to the immune system and were able to improve immune competence and reduce inflammation with the drugs.”

The research team has conducted a similar study, which has not yet been published, on colorectal cancer patients and has found similar results.

The researchers are currently considering a larger-scale clinical trial to establish the clinical long-term beneficial effects of this treatment. “Positive outcomes should validate this treatment and lead to its becoming available for most cancer patients,” Prof. Ben-Eliyahu concluded.

Abstract

Purpose: Translational studies suggest that excess perioperative release of catecholamines and prostaglandins may facilitate metastasis and reduce disease-free survival. This trial tested the combined perioperative blockade of these pathways in breast cancer patients.

Experimental Design: In a randomized placebo-controlled biomarker trial, 38 early-stage breast cancer patients received 11 days of perioperative treatment with a β-adrenergic antagonist (propranolol) and a COX-2 inhibitor (etodolac), beginning 5 days before surgery. Excised tumors and sequential blood samples were assessed for prometastatic biomarkers.

Results: Drugs were well tolerated with adverse event rates comparable with placebo. Transcriptome profiling of the primary tumor tested a priori hypotheses and indicated that drug treatment significantly

(i) decreased epithelial-to-mesenchymal transition,

(ii) reduced activity of prometastatic/proinflammatory transcription factors (GATA-1, GATA-2, early-growth-response-3/EGR3, signal transducer and activator of transcription-3/STAT-3), and

(iii) decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells.

Drug treatment also significantly

• abrogated presurgical increases in serum IL6 and
• C-reactive protein levels,
• abrogated perioperative declines in stimulated IL12 and IFNγ production,
• abrogated postoperative mobilization of CD16⁻ “classical” monocytes, and
• enhanced expression of CD11a on circulating natural killer cells.

Conclusions: Perioperative inhibition of COX-2 and β-adrenergic signaling provides a safe and effective strategy for inhibiting multiple cellular and molecular pathways related to metastasis and disease recurrence in early-stage breast cancer. Clin Cancer Res; 1–11. ©2017 AACR.

SOURCES

“Anti-Inflammatory and Anti-Stress Drugs Taken Before Surgery May Reduce Metastatic Recurrence.” NeuroscienceNews. NeuroscienceNews, 7 August 2017.

Original Research: Abstract for

“Perioperative COX-2 and β-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial”

by Lee Shaashua, Maytal Shabat-Simon, Rita Haldar, Pini Matzner, Oded Zmora, Moshe Shabtai, Eran Sharon, Tanir Allweis, Iris Barshack, Lucile Hayman, Jesusa Arevalo, Jeffrey Ma, Maya Horowitz, Steven Cole and Shamgar Ben-Eliyahu in Clinical Cancer Research. Published online August 2017 doi:10.1158/1078-0432.CCR-17-0152