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.