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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.

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Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel.
Department of Surgery and Transplantation, Sheba Medical Center, Ramat Gan, Israel.
Department of Surgery, Rabin Medical Center, Beilinson Hospital, Petach-Tikva, Israel.
Department of Surgery, Kaplan Medical Center, Rehovot, Israel.
Department of Pathology, Sheba Medical Center, Ramat Gan, Israel.
Department of Pathology, Rabin Medical Center, Petah Tikva, Israel.
Departments of Medicine and Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California.
Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel.


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.

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