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Cancer Prevention Clinical Trials

	Paul E. Goss, MD, PhD

Paul E. Goss, MD, PhD
Professor of Medicine, University of Toronto
Director, Breast Cancer Prevention Program
Princess Margaret Hospital, University Health Network
Toronto, Canada

The many years required for breast cancer to progress from initiation to an invasive tumor affords ample opportunity for prevention. Estrogen is a central player in tumor promotion and possibly initiation.(1) Although the median age of onset of breast cancer in the Western world is about 63 years, epidemiological data suggest that events in early childhood, at puberty, during reproductive life, and in menopause may contribute to tumor formation. The optimal timing and duration of any preventative measures are therefore likely to be difficult to ascertain.

Tamoxifen interacts with the estrogen receptor and antagonizes estrogen's action. Evidence for its preventative effects came from preclinical models and clinically from its inhibition of advanced hormone-dependent breast cancer and the reduction in the incidence of contralateral new primary breast cancers when given to women with early stage disease.(2) The National Surgical Breast and Bowel Project prevention trial (NSABP P1) led to Food and Drug Administration (FDA) approval of tamoxifen "for reducing the incidence of breast cancer" in 1998.(3) However, due to its mixed antagonist/agonist action, tamoxifen's efficacy is in part self-defeating, and estrogen agonist-related thromboembolism and endometrial cancer reduce the therapeutic index of the drug.(3)

Estrogen is synthesized in the ovary, peripheral organs, and in both pre-invasive and invasive breast tumors. Aromatase (estrogen synthetase) inhibitors (AI) almost completely block peripheral and tumor estrogen synthesis but require additional ovarian function suppression in premenopausal women.(4) The AI's have shown preventative effects in the MNU- and DMBA-carcinogen-induced mammary tumor models (5--7) as well as the ability to block or reduce preneoplastic changes of the breast caused by aromatase overexpression in the aromatase-transgenic mouse model (int-5/aromatase).(8) Clinically, superiority of the AI's over tamoxifen has been demonstrated in advanced disease, (9--11) in early stage breast cancer, (12) and as preoperative therapy.(13) In the Arimidex, Tamoxifen, Alone, or in Combination (ATAC) trial, the incidence of contralateral new primary breast cancer was significantly lower when anastrozole was compared to tamoxifen (OR 0.42, P = .0068). In the recently published National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.17 adjuvant trial, letrozole halved the risk of contralateral breast cancer (26 vs. 14 cases) compared to placebo.(14) Estrogen and its metabolites may initiate breast cancer and act via non-estrogen receptor pathways.(1) Hence, removing estrogen with the AI's may prove to be superior to tamoxifen in breast cancer prevention.

Pre-invasive and invasive breast lesions frequently have elevated levels of cyclooxygenase (COX), which catalyses the synthesis of prostaglandin E2. This in turn stimulates a number of tumor-promoting pathways including anti-apoptosis, angiogenesis, the epithelial growth factor receptor (EGFR), and upregulation of aromatase.(15) Thus, celecoxib, a selective COX-2 inhibitor, is a putative aromatase inhibitor and, when given alone, prevents DMBA-induced tumors in the rat, as well as having additive or synergistic effects in combination with the AI exemestane.(15)

Two processes are underway to investigate the role of AI's as breast cancer preventatives. Proof-of-principle studies are being conducted in women with clinical markers of life-long cumulative estrogen exposure that have been linked to breast cancer risk. Three examples are elevated plasma estrogen levels, upper tertile bone density in menopausal women, and increased mammographic breast density (NCIC CTG MAP.1 and MAP.2). Similarly, the effects of celecoxib are being examined in cells obtained by duct lavage or needle aspiration from women at elevated risk. In addition, two definitive phase III randomized trials examining the role of AI's are being conducted in postmenopausal women. The International Breast Intervention Study 2 (IBIS 2) is evaluating anastrozole versus placebo in 6,000 postmenopausal women at increased risk of breast cancer.

The nonsteroidal AI's anastrozole and letrozole have been shown to enhance bone resorption, reduce bone mineral density (BMD), and thereby increase the risk of osteoporosis. The steroidal inhibitor exemestane, by virtue of its additional androgenic action, protects bone and lipid metabolism in the castrated menopausal rat model (16) and in postmenopausal volunteers.(17) Thus, the NCIC CTG MAP.3 breast cancer prevention trial (n = 5,100) currently being launched in North America and Europe is a placebo controlled trial of exemestane with or without celecoxib (Figure 1).

The AI's promise to be more effective than tamoxifen at reducing breast cancer occurrence. Limitation of long-term end-organ toxicities may be achieved with the steroidal inhibitor exemestane. Prospective validation of traditional risk factors, markers of cumulative estrogen exposure, and genetic risk profiling (including polymorphisms that affect estrogen synthesis and catabolism) is being undertaken in the NCIC MAP.3 trial. This will assist in better selection of women for prevention therapy in the future. Optimal duration and timing of AI therapy also will need to be determined by future research.

Figure 1: National Cancer Institute of Canada Clinical Trials Group MAP.3 Breast Cancer Prevention Trial: Celecoxib 400mg daily for three years; Exemestane 25 mg daily for five years.

References:

1. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344:276-285.
2. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet. 1998;351:1451-1467.
3. Fisher B, Costantino JP, Wickerham L, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388.
4. Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol. 2001;19:881-894.
5. Lubet RA, Steele VE, Casebolt TL, et al. Chemopreventive effects of the aromatase inhibitors vorozole (R-83842) and 4-hydroxyandrostenedione in the methylnitrosourea (MNU)-induced mammary tumor model in Sprague-Dawley rats. Carcinogenesis. 1994;15:2775-2780.
6. Schieweck K, Bhatnagar AS, Matter A. CGS 16949A, a new nonsteroidal aromatase inhibitor: effects on hormone-dependent and -independent tumors in vivo. Cancer Res. 1988;48:834-838.
7. Schieweck K, Bhatnagar AS, Batzl C, et al. Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors. J Steroid Biochem Mol Biol. 1993;44:633-636.
8. Tekmal RR, Kirma N, Gill K, et al. Aromatase overexpression and breast hyperplasia, an in vivo model - continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands. Endocr-Relat Cancer 1999;6:307-314.
9. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol. 2000;18:3758-3767.
10. Bonneterre J, Buzdar A, Nabholtz JM, et al.; Arimidex Writing Committee; Investigators Committee Members. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer. 2001;92:2247-2258.
11. Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001;19:2596-2606.
12. The ATAC Trialists' Group. Arimidex, tamoxifen alone or in combination. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359:2131-2139.
13. Eiermann W, Paepke S, Appfelstaedt J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol. 2001;12:1527-1532.
14. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793-1802.
15. Arun B, Goss P. Role of COX-2 Inhibition in Breast Cancer Treatment & Prevention. Sem Oncol. 2004;(suppl). In press.
16. Goss PE, Qi S, Josse RG, et al. The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone. 2004. In press.
17. Goss PE, Thomsen T, Banke-Bochita J, Hadji P. Effects of steroidal and nonsteroidal aromatase inhibitors on markers of bone turnover and lipid metabolism in healthy volunteers. Breast Cancer Res Treat. 2003;82(suppl 1):S101, A427.