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Breast cancer is the most common cancer and the second most common cause of cancer death among women in the US.1 It is estimated that two-thirds of the invasive breast cancers will be hormone-receptor-positive and will require long-term adjuvant hormonal therapy.
Reducing the effect of oestrogen is the main aim of hormonal therapy in treating hormone-receptor-positive breast cancer. The effect of oestrogen is reduced in two ways – by blocking the oestrogen receptor or by inhibiting oestrogen biosynthesis. The mechanism of action of aromatase inhibitors (AIs) is to inhibit oestrogen biosynthesis. AIs have established their role in treating metastatic hormone-receptor-positive breast cancer in post-menopausal women through a number of clinical trials.2–5 In addition, multiple clinical trials have shown that AIs have superior efficacy compared with tamoxifen as an adjuvant hormonal therapy in post-menopausal women with hormone-receptor-positive breast cancer.6–11 AIs are therefore the recommended first-line adjuvant hormonal therapy in post-menopausal women with hormone-receptor-positive breast cancer, either as monotherapy or as sequential therapy after tamoxifen.
The recommended duration of adjuvant AI therapy is usually two to five years. With the recommended treatment period being up to five years in the adjuvant setting, it is important for physicians to understand the clinical pharmacology of some of the commonly used AIs.
Aromatase Inhibitor Development
AIs have been around for over 20 years. Aminoglutethimide was the first AI in general clinical use. Its use was limited by its intermediate efficacy in inhibiting aromatisation and its low specificity, which resulted in significant side effects.12,13 Roglethimide was the second glutethimide derivative, whose use was limited by its low potency and significant side effects.14,15 The second-generation AI fadrozole was then developed and was found to be more specific than aminoglutethimide. It still has significant side effects as it suppresses aldosterone synthesis.16,17 The third-generation AIs anastrozole, letrozole and exemestane have been developed most recently. They are superior in both their high oestrogen biosynthesis suppression and their specificity, resulting in very few side effects.18 Among them, anastrozole and letrozole are non-steroidal AIs, whereas exemestane is steroidal. Anastrozole was the first third-generation AI to be tested in clinical trials in treating metastatic and early-stage hormonereceptor- positive breast cancer in post-menopausal women.