Journal Article

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

Taylor, M, Andreis, D, Cummings, M, Ferrero, G, Martinotti, M, Lakhani, S R, Allevi, G, Fox, S B, Bottini, A, Deb, S, Buffa, F M, Byrne, D, Harris, A L, Generali, D, Reid, L E

2014

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/53/2422 / 692/699/67/1059/2326 / 692/699/67/1059/602 / 692/699/67/1347 / Androstadienes - administration & dosage / Androstadienes - therapeutic use / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Aromatase Inhibitors - therapeutic use / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - enzymology / Breast Neoplasms - pathology / Cancer Research / Carcinoma, Intraductal, Noninfiltrating - drug therapy / Carcinoma, Intraductal, Noninfiltrating - enzymology / Carcinoma, Intraductal, Noninfiltrating - pathology / Celecoxib / Clinical Study / Cohort Studies / Cyclooxygenase 2 - biosynthesis / Cyclooxygenase 2 - genetics / Cyclooxygenase 2 Inhibitors - therapeutic use / Drug Resistance / Drug Resistance, Neoplasm / Epidemiology / Female / Growth factors / Gynecology. Andrology. Obstetrics / Hospitals / Humans / Hypoxia / Mammary gland diseases / Medical research / Medical sciences / Metastasis / Middle Aged / Molecular Medicine / Multiple tumors. Solid tumors. Tumors in childhood (general aspects) / Neoadjuvant Therapy / Neoplasm Recurrence, Local - enzymology / Neoplasm Recurrence, Local - pathology / Oncology / Pathology / Prognosis / Pyrazoles - administration & dosage / Radiation therapy / Sulfonamides - administration & dosage / Surgery / Survival Analysis / Tumors