Aromatase inhibitors and their use in the adjuvant setting.

Over the past decade several novel aromatase inhibitors have been introduced into clinical practice. The discovery of these drugs followed on from the observation that the main mechanism of action of aminoglutethemide was via inhibition of the enzyme aromatase, thereby reducing peripheral levels of estradiol in post-menopausal patients. The second-generation drug 4-hydroxyandrostenedione was introduced in 1990, and although its use was limited by its need to be given parenterally, it was found to be a well-tolerated form of endocrine therapy. The third-generation inhibitors include vorozole, letrozole, anastrozole and exemestane, the former three being non-steroidal inhibitors, the latter being a steroidal inhibitor. All these compounds are capable of reducing estrogen levels to within 5%-10% of baseline levels compared with 20%-30% base line levels in the case of 4-hydroxyandrostenedione. Studies are currently in progress to determine the value of these third-generation aromatase inhibitors in the adjuvant setting. These studies include head-to-head comparison of aromatase inhibitor with tamoxifen, sequential aromatase inhibitor after tamoxifen and first-line aromatase inhibitor followed by adjuvant tamoxifen. Current issues revolve around the toxicity of these compounds in terms of effects on the cardiovascular system and bone.