Aromatase inhibitors

The enzyme in the middle

After menopause, the ovaries stop producing oestrogen, but the hormone does not disappear. Aromatase, an enzyme encoded by the CYP19A1 gene, converts androgens into oestrogen in peripheral tissues — fat, muscle, the adrenal cortex — and, critically, in breast tumour tissue itself. Blocking aromatase rather than the oestrogen receptor therefore cuts the ligand supply at source. The result is a more complete oestrogen suppression in postmenopausal women than tamoxifen achieves, because tamoxifen occupies the receptor without abolishing circulating oestrogen.

Three third-generation aromatase inhibitors reached clinical use in the 1990s and early 2000s: anastrozole and letrozole are non-steroidal and reversible; exemestane is steroidal and binds the enzyme irreversibly. All three reduce circulating oestrogen levels by more than 95 percent, according to pharmacokinetic data compiled in reviews.

The ATAC trial — Arimidex, Tamoxifen, Alone or in Combination — enrolled more than 9,000 postmenopausal women with early hormone-receptor-positive breast cancer and reported in 2002 that anastrozole produced a longer disease-free interval than tamoxifen after five years of treatment. The Breast International Group 1-98 trial subsequently showed similar results for letrozole. The Early Breast Cancer Trialists' Collaborative Group's meta-analyses have since confirmed, across tens of thousands of women, that aromatase inhibitors reduce recurrence compared with tamoxifen in the postmenopausal setting.

The trade-off is in the side-effect profile. Because tamoxifen carries weak oestrogenic activity in bone, it partially preserves bone density; aromatase inhibitors do not. Accelerated bone loss and an increased fracture risk are the most clinically significant consequences of aromatase inhibition, and monitoring bone mineral density became standard practice once the drugs entered routine use. Joint pain and myalgia are also more common with aromatase inhibitors than with tamoxifen — a frequent reason for early discontinuation in practice.

The drugs are not useful in premenopausal women on their own, because intact ovarian function overwhelms the peripheral enzyme block. In premenopausal patients, ovarian suppression — pharmacological or surgical — must precede aromatase inhibitor therapy for the mechanism to work as intended.