Potential use of COX-2-aromatase inhibitor combinations in breast cancer

Abstract

Cyclooxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer. Cyclooxygenase-2-positive tumours tend to be larger, higher grade, node-positive and HER-2/neu-positive. High COX-2 expression is associated with poor prognosis. Cyclooxygenase-2 inhibition reduces the incidence of tumours in animal models, inhibits the development of invasive cancer in colorectal cancer and reduces the frequency of polyps in familial adenomatous polyposis (FAP). These effects may be as a result of increased apoptosis, reduced angiogenesis and/or proliferation. Studies of COX-2 inhibitors in breast cancer are underway both alone and in combination with other agents. There is evidence to suggest that combining COX-2 inhibitors with aromatase inhibitors, growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective. Preliminary results from combination therapy with celecoxib and exemestane in postmenopausal women with advanced breast cancer showed that the combination increased the time to recurrence. Up to 80% of ductal carcinomas in situ (DCISs) express COX-2, therefore COX-2 inhibition may be of particular use in this situation. Cyclooxygenase-2 expression correlates strongly with expression of HER-2/neu. As aromatase inhibitors appear particularly effective in patients with HER-2/neu-positive tumours, the combination of aromatase inhibitors and COX-2 inhibitors may be particularly useful in both DCIS and invasive cancer.

Figure 1

COX-2 is strongly expressed in the cell cytoplasm in (A) ductal carcinoma in situ and (B) invasive breast cancer. For comparison, (C) shows COX-2 as negatively expressed in a ductal carcinoma in situ with little staining.

Figure 2

Celecoxib, a COX-2 inhibitor, slows growth of cancer cell lines derived from (A) lung, (B) colon and (C) breast when xenografted into mice (Masferrer et al, 2000; Barnes et al, 2003). (C) Median tumour growth, bars=interquartile range. Figures (A) and (B) reproduced with permission from Masferrer et al (2000).

Figure 3

Combined celecoxib (CXB) and exemestane (EXE), reduces mammary tumour growth in a rodent model more effectively than either therapy alone (Pesenti et al, 2001).