COX-2 expression is predictive for early relapse and aromatase inhibitor resistance in patients with ductal carcinoma in situ of the breast, and is a target for treatment

Br J Cancer. 2014 Jul 8;111(1):46-54. doi: 10.1038/bjc.2014.236. Epub 2014 May 29.

Abstract

Background: Stratification of patients for treatment of ductal carcinoma in situ (DCIS) is suboptimal, with high systemic overtreatment rates.

Methods: A training set of 95 tumours from women with pure DCIS were immunostained for proteins involved in cell survival, hypoxia, growth factor and hormone signalling. A generalised linear regression with regularisation and variable selection was applied to a multiple covariate Cox survival analysis with recurrence-free survival 10-fold cross-validation and leave-one-out iterative approach were used to build and test the model that was validated using an independent cohort of 58 patients with pure DCIS. The clinical role of a COX-2-targeting agent was then tested in a proof-of-concept neoadjuvant randomised trial in ER-positive DCIS treated with exemestane 25 mg day(-1)± celecoxib 800 mg day(-1).

Results: The COX-2 expression was an independent prognostic factor for early relapse in the training (HR 37.47 (95% CI: 5.56-252.74) P=0.0001) and independent validation cohort (HR 3.9 (95% CI: 1.8-8.3) P=0.002). There was no significant interaction with other clinicopathological variables. A statistically significant reduction of Ki-67 expression after treatment with exemestane ± celecoxib was observed (P<0.02) with greater reduction in the combination arm (P<0.004). Concomitant reduction in COX-2 expression was statistically significant in the exemestane and celecoxib arm (P<0.03) only.

Conclusions: In patients with DCIS, COX-2 may predict recurrence, aiding clinical decision making. A combination of an aromatase inhibitor and celecoxib has significant biological effect and may be integrated into treatment of COX2-positive DCIS at high risk of recurrence.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / administration & dosage
  • Androstadienes / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Aromatase Inhibitors / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology
  • Carcinoma, Intraductal, Noninfiltrating / drug therapy*
  • Carcinoma, Intraductal, Noninfiltrating / enzymology*
  • Carcinoma, Intraductal, Noninfiltrating / pathology
  • Celecoxib
  • Cohort Studies
  • Cyclooxygenase 2 / biosynthesis*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 Inhibitors / therapeutic use
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Middle Aged
  • Neoadjuvant Therapy
  • Neoplasm Recurrence, Local / enzymology
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Pyrazoles / administration & dosage
  • Sulfonamides / administration & dosage
  • Survival Analysis

Substances

  • Androstadienes
  • Aromatase Inhibitors
  • Cyclooxygenase 2 Inhibitors
  • Pyrazoles
  • Sulfonamides
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Celecoxib
  • exemestane