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

Overview

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.

authors

  • Shaashua Berger, Lee
  • Shabat-Simon, Maytal
  • Haldar, Rita
  • Matzner, Pini
  • Zmora, Oded
  • Shabtai, Moshe
  • Sharon, Eran
  • Allweis, Tanir
  • Barshack, Iris
  • Hayman, Lucile
  • Arevalo, Jesusa
  • Ma, Jeffrey
  • Horowitz, Maya
  • Cole, Steven
  • Ben-Eliyahu, Shamgar

publication date

  • May 10, 2017

Research

keywords

  • Antineoplastic Combined Chemotherapy Protocols
  • Biomarkers, Tumor
  • Breast Neoplasms
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic

Identity

PubMed Central ID

  • PMC5559335

Scopus Document Identifier

  • 85027548181

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-09-3141

PubMed ID

  • 28490464

Additional Document Info

volume

  • 23

issue

  • 16