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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.

Original publication

DOI

10.1038/bjc.2014.236

Type

Journal article

Journal

Br J Cancer

Publication Date

08/07/2014

Volume

111

Pages

46 - 54

Keywords

Androstadienes, Antineoplastic Combined Chemotherapy Protocols, Aromatase Inhibitors, Breast Neoplasms, Carcinoma, Intraductal, Noninfiltrating, Celecoxib, Cohort Studies, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Drug Resistance, Neoplasm, Female, Humans, Middle Aged, Neoadjuvant Therapy, Neoplasm Recurrence, Local, Prognosis, Pyrazoles, Sulfonamides, Survival Analysis