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Clin Cancer Res. 2017 Aug 15;23(16):4651-4661. doi: 10.1158/1078-0432.CCR-17-0152. Epub 2017 May 10.

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

Author information

1
Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel.
2
Department of Surgery and Transplantation, Sheba Medical Center, Ramat Gan, Israel.
3
Department of Surgery, Rabin Medical Center, Beilinson Hospital, Petach-Tikva, Israel.
4
Department of Surgery, Kaplan Medical Center, Rehovot, Israel.
5
Department of Pathology, Sheba Medical Center, Ramat Gan, Israel.
6
Department of Pathology, Rabin Medical Center, Petah Tikva, Israel.
7
Departments of Medicine and Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California.
8
Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel. shamgar@post.tau.ac.il.

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; 23(16); 4651-61. ©2017 AACR.

PMID:
28490464
PMCID:
PMC5559335
DOI:
10.1158/1078-0432.CCR-17-0152
[Indexed for MEDLINE]
Free PMC Article

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