A randomised controlled phase II trial of pre-operative celecoxib treatment reveals anti-tumour transcriptional response in primary breast cancer
- Equal contributors
1 Department of Clinical Genetics, Unit of Clinical Genomics, Maastricht University Medical Centre+, P. Debyelaan 25, Maastricht, 6229 HX, The Netherlands
2 GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre+, P. Debyelaan 25, Maastricht, 6202 AZ, The Netherlands
3 Department of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Centre+, P. Debyelaan 25, Maastricht, 6229 HX, The Netherlands
4 Department of Pathology, Maastricht University Medical Centre+, P. Debyelaan 25, Maastricht, 6229 HX, The Netherlands
5 Institute of Pathology, RWTH Aachen University Hospital, Pauwelsstr. 30, Aachen, 52074, Germany
6 Department of Internal Medicine, Division of Haematology, Maastricht University Medical Centre+, P. Debyelaan 25, Maastricht, 6229 HX, The Netherlands
7 Pharmacell BV, Oxfordlaan 70, Maastricht, 6229 EV, The Netherlands
8 Department of Surgery, Maastricht University Medical Centre+, P. Debyelaan 25, Maastricht, 6202 AZ, The Netherlands
9 Saint James School of Medicine, Basic Science and Premedical Faculty, Kralendijk, Bonaire, Netherlands Antilles
Breast Cancer Research 2013, 15:R29 doi:10.1186/bcr3409Published: 8 April 2013
Cyclooxygenase-2 (COX-2) is frequently over-expressed in primary breast cancer. In transgenic breast cancer models, over-expression of COX-2 leads to tumour formation while COX-2 inhibition exerts anti-tumour effects in breast cancer cell lines. To further determine the effect of COX-2 inhibition in primary breast cancer, we aimed to identify transcriptional changes in breast cancer tissues of patients treated with the selective COX-2 inhibitor celecoxib.
In a single-centre double-blind phase II study, thirty-seven breast cancer patients were randomised to receive either pre-operative celecoxib (400 mg) twice daily for two to three weeks (n = 22) or a placebo according to the same schedule (n = 15). Gene expression in fresh-frozen pre-surgical biopsies (before treatment) and surgical excision specimens (after treatment) was profiled by using Affymetrix arrays. Differentially expressed genes and altered pathways were bioinformatically identified. Expression of selected genes was validated by quantitative PCR (qPCR). Immunohistochemical protein expression analyses of the proliferation marker Ki-67, the apoptosis marker cleaved caspase-3 and the neo-angiogenesis marker CD34 served to evaluate biological response.
We identified 972 and 586 significantly up- and down-regulated genes, respectively, in celecoxib-treated specimens. Significant expression changes in six out of eight genes could be validated by qPCR. Pathway analyses revealed over-representation of deregulated genes in the networks of proliferation, cell cycle, extracellular matrix biology, and inflammatory immune response. The Ki-67 mean change relative to baseline was -29.1% (P = 0.019) and -8.2% (P = 0.384) in the treatment and control arm, respectively. Between treatment groups, the change in Ki-67 was statistically significant (P = 0.029). Cleaved caspase-3 and CD34 expression were not significantly different between the celecoxib-treated and placebo-treated groups.
Short-term COX-2 inhibition by celecoxib induces transcriptional programs supporting anti-tumour activity in primary breast cancer tissue. The impact on proliferation-associated genes is reflected by a reduction of Ki-67 positive cells. Therefore, COX-2 inhibition should be considered as a treatment strategy for further clinical testing in primary breast cancer.