Breast cancer prevention—clinical trials strategies involving aromatase inhibitors

Abstract

Estrogens and their metabolites have been implicated in both the initiation and the prevention of breast cancer. The reduction in breast cancer incidence seen in the tamoxifen arms of the four prospective trials to date has established the proof of principle that antagonizing estrogen is a potential means of reducing breast cancer risk. However, the areas to improve on these results include: (a) enhanced efficacy, (b) reduction in the incidence of receptor-negative tumors, (c) improved overall and endocrinological side effects, and (d) improved function on end-organs other than the breast. The aromatase inhibitors offer the potential to achieve these goals in part in the following ways: (a) greater reduction in risk of disease as evidenced by superior efficacy in advanced breast cancer and by inhibition of both initiation and promotion of breast cancer, (b) reduction in receptor-negative tumors by synergy with COX-2 inhibitors resulting in growth factor inhibition, anti-angiogenesis and inhibition of tumor-associated aromatase expression, (c) fewer vasomotor and urogenital abnormalities, and (d) reduced thromboembolism and cardiovascular complications and satisfactory effects on bone metabolism. Important differences may exist between non-steroidal reversible inhibitors and steroidal irreversible inactivators in particular related to the androgenic/anabolic effects of the steroidal inactivators. Pilot studies of aromatase inhibitors described elsewhere in this session have begun in healthy women with dense mammography, or a high-risk genetic and/or histocytopathologic profile, to determine potential efficacy, as well as effects on end-organ function. A number of phase three trials with aromatase inhibitors are also underway or in planning. Among these are the BRCA 1 and 2 study of exemestane versus placebo in unaffected postmenopausal carriers, the International Breast Intervention Study 2 (IBIS 2) of anastrozole versus placebo in women with a high-risk profile, and the National Cancer Institute of Canada’s Clinical Trial Group (NCIC CTG) study of exemestane with or without celecoxib versus placebo in women at risk of the disease. For premenopausal women, combination strategies of gonadotrophin agonists and aromatase inhibitors are being investigated. The potential of using low doses of aromatase inhibitors to lower “in breast” estrogen levels without unduly perturbing plasma concentrations is also being explored. The potential of the aromatase gene functioning as an oncogene within the breast may be tied to breast density which in turn may represent both a selection tool for elevated risk and an intermediate marker of prevention. The strong link between postmenopausal estrogen levels and breast cancer risk suggests the possibility that plasma estrogen levels may be a useful intermediate marker of prevention. The aromatase inhibitors offer us the first ever tool to render women virtually free of estrogen and are potentially an exciting tool for the prevention of breast cancer.