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

Abstract

Background 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. Methods In a randomized placebo-controlled biomarker trial, 38 early-stage breast cancer patients received 11 days of perioperative treatment with a beta-adrenergic antagonist (propranolol) and a cyclooxygenase-2 (COX-2) inhibitor (etodolac), beginning five days before surgery. Excised tumors and sequential blood samples were assessed for pro-metastatic biomarkers. Results Drugs were well tolerated with adverse event rates comparable to 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 pro-metastatic/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 interleukin-6 (IL-6) and C-reactive protein levels, abrogated perioperative declines in stimulated interleukin-12 and interferon-gamma 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.

Reducing the Risk of Post-Surgical Cancer Recurrence: A Perioperative Anti-Inflammatory Anti-Stress Approach

“…In both of our Phase II clinical studies [18,21], drugs were well tolerated, with minor adverse event rates equivalent to placebo group. To ascertain the long-term safety of the drug regiment, in the CRC clinical trial we also recorded 3-year recurrence rates.…”

“…These outcomes were supported with corresponding effects on both the intracellular mRNA expression levels and the transcriptional activity related to those cytokines [23]. Additionally, drug treatment also blocked a post-operative influx of circulating CD14 ++ CD16 -monocytes, and enhanced the expression of the activation marker CD11a (LFA-1) on circulating NK cells [18]. The numerous indices positively affected by the drug treatment in these two Phase II clinical trials establish an empirical basis and provide medical justification for large clinical trials to assess the impact of this treatment on disease recurrence and overall survival.…”

“…Noteworthy, for patients without contraindications, the safety profiles of propranolol and etodolac are well established, especially for the short duration employed in our clinical studies (elaborately discussed in the Supplementary of [18]). In both of our Phase II clinical studies [18,21], drugs were well tolerated, with minor adverse event rates equivalent to placebo group.…”

“…In both studies, transcriptome profiling of the PT, based on a priori hypotheses, indicated that drug treatment decreased tumor epithelial-to-mesenchymal transition, reduced activity of pro-metastatic and pro-inflammatory transcription factors associated with malignant progression, and decreased tumor-infiltrating monocytes, together suggesting reduced metastatic potential of the malignant tissue [18,21]. In CRC patients, there was an increase in tumor-infiltrating NK cells, which seem to be of special interest, as tumor-infiltrating NK cells were reported to be associated with improved survival [22].…”

“…Additionally, concerns were raised regarding the safety of the perioperative use of the β1-selective antagonist, metoprolol, in the POISE trial [17], yet no evidence indicates a risk associated with use of non-selective β-adrenergic antagonists, such as propranolol. Furthermore, propranolol use was associated with reduced post-operative cardiac complications (elaborately discussed in the Supplementary of [18]) and reduced risk of cancer development, especially after prolonged use [19]. Similarly, a recent meta-analysis has identified a protective effect of COX-2 inhibitors against BC [20].…”