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.

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.

• Authors: D Generali, F M Buffa, S Deb, M Cummings, L E Reid, M Taylor, D Andreis, G Allevi, G Ferrero, D Byrne, M Martinotti, A Bottini, A L Harris, S R Lakhani, S B Fox
• Journal: British journal of cancer (Br J Cancer) Vol. 111 Issue 1 Pg. 46-54 (Jul 08 2014) ISSN: 1532-1827 [Electronic] England
• PMID: 24874483 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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