Aromatase Inhibitors for Treatment of Breast Cancer

John   R.   Benson; Oduru      Ravisekar

Abstract

Breast cancer remains the commonest malignancy amongst women and its incidence continues to increase worldwide. This inexorable rise in numbers of women suffering from the disease is particularly notable in those countries which previously had a relatively low incidence of breast cancer but have now adopted Western lifestyles with changes in reproductive behaviour and greater usage of the oral contraceptive pill. These epidemiological observations emphasize the hormone dependency of breast cancer and the importance of endocrine factors for tumour initiation and promotion. There has been a resurgence of interest in hormonal therapies with the advent of third generation aromatase inhibitors (AI) which represent the most significant advance in endocrine management of breast cancer since the introduction of tamoxifen 3 decades ago. This article will recount the historical development of endocrine therapies and the biological rationale for hormonal manipulation as a therapeutic goal. The application of AIs in the clinical setting will be critically discussed with citation of seminal studies. Like many novel agents for treatment of breast cancer, AIs were initially used in the advanced disease setting where they offered advantages over tamoxifen and progestins as first- and second-line therapies respectively. Aromatase inhibitors are widely used in the neoadjuvant setting for hormone sensitive tumours and can permit subsequent breast conservation surgery when mastectomy would otherwise have been indicated. However, it is in the adjuvant setting that AIs have stimulated much interest and generated an element of uncertainty in the optimum form of adjuvant hormonal therapy for post-menopausal women with oestrogen receptor positive tumours. It seems likely that any blanket policy is no longer appropriate and a selective strategy with tailoring of therapy based on risk of relapse is the preferred option. Those patients at greatest risk of relapse may benefit most from an upfront AI whilst those with lower hazard rates for relapse may be best treated with an early switch regimen involving tamoxifen for 2 - 3 years followed by an AI for a total duration of 5 years. Benefits in terms of disease-free and overall survival must be balanced against longer term adverse effects on bone health and cognitive function as well as cost. Some patients at very low risk of relapse may derive minimal additional benefit from incorporation of an AI into their treatment schedule and should receive tamoxifen only. The three oral AIs are of comparable efficacy and are potentially interchangeable. Longitudinal studies must be undertaken with gathering of longer term data on side-effect profiles before any definitive pronouncements on clinical utility. There are particular concerns about severe oestrogen depletion amongst women receiving an AI for chemoprevention and ongoing evaluation of treatment related morbidity is essential.

Keywords: Selective Oestrogen Receptor Modulators (SERMS), Anti-Oestrogens, GnRH, neoadjuvant chemotherapy, Tamoxifen

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