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

Generali, D., Buffa, F. M., Deb, S., Cummings, M., Reid, L. E., Taylor, M., Andreis, D., Allevi, G., Ferrero, G., Byrne, D., Martinotti, M., Bottini, A., Harris, A. L., Lakhani, S. R. and Fox, S. B. (2014) 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. British Journal of Cancer, 111 1: 46-54. doi:10.1038/bjc.2014.236


Author Generali, D.
Buffa, F. M.
Deb, S.
Cummings, M.
Reid, L. E.
Taylor, M.
Andreis, D.
Allevi, G.
Ferrero, G.
Byrne, D.
Martinotti, M.
Bottini, A.
Harris, A. L.
Lakhani, S. R.
Fox, S. B.
Title 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
Formatted title
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
Journal name British Journal of Cancer   Check publisher's open access policy
ISSN 1532-1827
0007-0920
Publication date 2014-07-08
Year available 2014
Sub-type Article (original research)
DOI 10.1038/bjc.2014.236
Open Access Status DOI
Volume 111
Issue 1
Start page 46
End page 54
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2015
Language eng
Formatted 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.
Keyword DCIS
COX-2
Aromatase inhibitor
Breast cancer
Celecoxib
Exemestane
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2015 Collection
School of Medicine Publications
 
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