[al from Canada]

O.14

COX-2 inhibitors and breast cancer

D.J. Richel,

Amsterdam Medical Center, Medical Oncology, Meibergdreef 9 1105 AZ Amsterdam, the

Netherlands

Email: d.j.richel@amc.uva.nl

The cyclooxygenase enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid into different

prostaglandins. The function and pattern of expression of COX-1 and COX-2 is substantially different.

Whereas COX-1 is constitutively expressed in a wide range of tissues, and functions as a housekeeping

gene by the production of prostaglandins involved in several physiological functions like gastric mucosa

protection, platelet aggregation, and renal blood flow, The COX-2 enzyme is induced during inflammation,

wound repair, and carcinogenesis. Preclinical and clinical evidence shows that COX-2 induced

prostaglandins play an important role in the growth and development of cancer.

A large number of studies demonstrated an elevated expression of COX-2 mRNA and protein in several

cancer types, including breast cancer. COX-2 is raised in both ductal carcinoma in situ and in invasive breast

cancer and appears to be associated with higher proliferation, lower apoptosis, and increased new blood

vessel formation (1). In several studies the extent of COX-2 expression was correlated with invasion, tumor

size, metastasis, HER-2/neu positivity (2), and survival. In a large study of 1576 patients with invasive breast

cancer high COX-2 expression was found in over 50% of the patients and these patients demonstrated a

significantly worse disease free survival compared with patients whose tumors expressed low levels of, or

absent, COX-2 (3).

Numerous observational epidemiological studies in the general population have been performed to analyze

risk factors for cancer. Regular use of aspirin or other NSAIDs is associated with a considerable decreased

incidence of adenomatous polyps and CRC. Besides for CRC, a reduced risk estimate is found for other

types of cancer which is most evident for esophageal, gastric cancers, pancreatic cancer and breast cancer

(4).

Several studies with selective COX-2 inhibitors have been performed in animal models.

Celecoxib, a selective COX-2 inhibitor, was able to inhibit the PGE

2 levels by 50% resulting in a lower

incidence of mammary tumors in a HER-2/neu induced breast cancer model in transgenic mice (5). This

potential benefit of COX-2 inhibitors has also been demonstrated in other tumor models.

With preclinical studies demonstrating an effect of COX-2 inhibition on tumor growth in animal models and

COX-2 being involved in breast carcinogenesis, COX-2 inhibition is being considered for inclusion into breast

cancer therapy. Recently several reports pointed to the increased cardiovascular risk of COX-2 inhibitors

(especially for RofecoxibR). These risks limit the use of COX-2 inhibitors in cancer prevention, but in patients

(without a history of ischemic heart disease) with poor prognostic indicators and in patients with metastatic

disease, COX-2 inhibition is still a potential way of treatment. It is likely that COX-2 inhibitors will be used as

combination therapy with hormonal agents, such as aromatase inhibitors and growth factor receptor

blockers, such as trastuzumab (HerceptinR). In addition, COX-2 inhibition has been shown to make tumors

significantly more chemo- and radio-sensitive. Therefore, several combinations are being explored in current

clinical trials.

Prostaglandins are able to increase aromatase activity in breast stromal tissue and studies with selective

agonists and antagonists showed that that this regulation of signaling pathways occurs through the

prostanoid receptors EP1 and EP2 receptor subtypes (6). Cox-2 expression correlates strongly with

expression of HER-2/neu, whereas in preclinical models a positive loop has been described between the

expression of COX-2 and HER-2/neu (7). Therefore, inhibition of PGE2 by COX-2 inhibitors may interfere

with aromatase activity and HER-2/neu expression and combination therapy with aromatase inhibitors and

HER-2/neu blockers is an attractive option to treat ER and HER-2/neu positive breast cancer.

1. Kirkpatrick K, et al. The association between cyclooxygenase-2 expression and cell proliferation

and angiogenesis in human breast cancer. Breast Cancer Res 2001, 3, (suppl 1): A37.

2. Subbaramaiah K, et al. Cyclooxygenase-2 is overexpressed in HER-2/neu positive breast cancer:

evidence for involvement of AP-1 and PEA-3. J Biol Chem 2002;277:18649-57.

3. Ristimaki A, et al. Prognostic significance of elevated cyclooxygenase-2 expression in breast

cancer. Cancer Res 2002; 62: 632-35.

4. Swede H, et al. Association of regular aspirin use and breast cancer risk. Oncology 2005;68:40-

47.

5. Lanza-Jacoby S, et al. The cyclooxygenase-2 inhibitor, celecoxib, prevents the development of

mammary tumors in HER-2/neu mice. Cancer Epidemiol Biomarkers Prev 2003;12: 1486-91.

6. Bundred NJ, et al. Potential use of COX-2 aromatase inhibitor combinations in breast cancer.

British J Cancer 2005;93 (suppl 1): S10-S15.

7. Benoit V, et al. Regulation of HER-2 oncogene expression by cyclooxygenase-2 and prostaglandin

E2. Oncogene 2004; 23: 1631-35