Aromtase Inhibitors in Breast Cancer

Abstract

Breast cancer is now the second most cancer in women after stomach cancer in Korea, and is increasing continuously. In the year 2000, the crude incidence of breast cancer in Korea was estimated about 23 per 100,000 people.(1) For the process of inducing breast cancer, estrogens appear to play a predominant role. These sex steroids are believed to initiate and to promote the process of the breast carcinogenesis by enhancing the rate of cell division and reducing time available for DNA repair. A new concept is that estrogens can be metabolized to catechol-estrogens and then to quinines that directly damage DNA. These two process-estrogen receptor mediated, genomic effects on proliferation and receptor independent, genotoxic effects of estrogen metabolites-can act in an additive or synergistic fashion to cause breast cancer.(2) Breast cancers that arise in patients can be divided into hormone dependent and hormone independent subtypes.(3) The role of estrogens as modulators of mitogenesis override the influence of other factors in the hormone dependent subtype. These sex steroids stimulate cell proliferation directly by increasing the rate of transcription of early response genes such as c-myc and indirectly through stimulation of growth factors which are produced largely in response to estrogenic regulation.(4) Based upon the concept that estrogen is the proximate regulator of cell proliferation, two general strategies were developed for treatment of hormone dependent breast cancer: blockade of estrogen receptor (ER) action and inhibition of estradiol biosynthesis. Antiestrogens such as tamoxifen bind to ER and interfere with transcription of estrogen induced genes involved in regulating cell proliferation. Clinical trials showed tamoxifen to be effective in inducing objective tumor regressions and to be associated with minimal side effects and toxicity. The second strategy, blockade of estradiol biosynthesis, was demonstrated to be feasible using the steroidogenesis inhibitor, aminoglutethimide, which produced tumor regressions equivalent to those observed with tamoxifen.(3) However, side effects from aminoglutethimide were considerable and its effects on several steroidogenic enzymes required concomitant use of a glucocorticoid. Consequently, tamoxifen became the preferred, first line endocrine agent with which to treat ER-positive advanced breast cancer. However, the clinical efficacy of aminoglutethimide focused attention upon the need to develop more potent, better tolerated, and more specific inhibitors of estrogen biosynthesis.