The history of anastrozole's creation

Today anastrozole is one of the basic drugs of hormonal therapy for breast cancer. But the road to it took several decades: from an anticonvulsant with dangerous side effects to a selective molecule taken as a single tablet a day. The editors have reconstructed the chronology of this story and explain why it matters for understanding the modern drug.

Background: estrogens and breast cancer

The link between the ovaries and breast cancer was noticed as early as the end of the 19th century: the Scottish surgeon George Beatson described the shrinking of tumors after removal of the ovaries in premenopausal women. Thus arose the idea that breast cancer might depend on hormones, although estrogens themselves were discovered much later.

By the middle of the 20th century it became clear that after menopause estrogens do not disappear completely. The ovaries stop producing them, but in fat tissue, muscles, skin and the tumor itself, adrenal androgens are converted into estrogens. The key enzyme of this conversion is aromatase, the product of the CYP19A1 gene.

For postmenopausal women this meant that surgical removal of the ovaries would not help: the source of estrogens is peripheral. Doctors resorted to radical operations — removal of the adrenal glands or pituitary — which carried high mortality and severe consequences. The need for a "pharmacological" alternative was obvious.

In parallel, in the 1970s tamoxifen appeared — the first widely used antiestrogen that blocks receptors. However, scientists were also looking for another route: not to block the receptor, but to stop the very formation of estrogens. It was precisely this idea that led to the class of aromatase inhibitors.

The first aromatase inhibitors

The first drug to inhibit aromatase in the clinic was aminoglutethimide. It was created as an anticonvulsant, but it turned out to disrupt the synthesis of steroid hormones in the adrenal glands, causing adrenal cortical insufficiency. This "side effect" was put to use: in the 1970s aminoglutethimide began to be used as a "medical adrenalectomy" in breast cancer.

The drug worked, but non-selectively: it blocked a number of enzymes of steroid synthesis, so patients had to take hydrocortisone at the same time. Side effects — drowsiness, rash, dizziness — were common. Nevertheless, aminoglutethimide proved the main point: inhibiting aromatase produces a clinical effect in postmenopausal women.

A key role in developing the concept was played by the biochemists Angela and Harry Brodie. In the 1970s they deliberately searched for steroid compounds that selectively inactivate aromatase, and created 4-hydroxyandrostenedione — later known as formestane. It was the first selective aromatase inhibitor to reach the clinic, but it was administered only intramuscularly.

Thus formed the "generations" of aromatase inhibitors, still used today in educational literature for classification.

The birth of anastrozole

Anastrozole was created at the British company ICI Pharmaceuticals, whose pharmaceutical division later became Zeneca and, after the merger with the Swedish Astra, AstraZeneca. The same company had earlier brought tamoxifen to market, so it had extensive experience in hormonal therapy of breast cancer. In early publications the compound appeared under the code ZD1033.

The chemists chose a non-steroidal structure with a triazole ring. The nitrogen atom of the triazole reversibly binds to the iron atom in the heme of aromatase, blocking the active site. Unlike formestane or the later exemestane, anastrozole does not destroy the enzyme but competitively occupies it, so the effect is maintained by the constant presence of the drug in the blood.

An important advantage was selectivity: at therapeutic doses anastrozole has almost no effect on the synthesis of cortisol and aldosterone, so no additional hormonal "cover" is needed. Its long half-life allowed the drug to be taken once a day; the registered dose is 1 mg.

In 1995 the FDA approved anastrozole under the trade name Arimidex for the treatment of advanced breast cancer in postmenopausal women with progression after tamoxifen. Soon the third-generation class was joined by letrozole (1997) and exemestane (1999), and competition unfolded between the drugs for earlier lines of therapy.

ATAC and IBIS-II: from treatment to prevention

A turning point was the ATAC trial ("Arimidex, Tamoxifen, Alone or in Combination"), which enrolled more than 9 thousand postmenopausal women with early breast cancer. The first results, published in The Lancet in 2002, showed that anastrozole in the adjuvant setting is superior to tamoxifen in time to recurrence, while the combination of the two drugs provides no advantage.

The safety profile was also important: on anastrozole, endometrial cancer, venous thromboses and strokes occurred less often, but joint pain and fractures due to bone loss occurred more often. These findings still determine how doctors choose between SERMs and aromatase inhibitors. Ten-year follow-up (Cuzick et al., 2010) confirmed the durability of the advantage in recurrences.

The next step was prevention. In the IBIS-II trial (Cuzick et al., 2014), postmenopausal women at increased risk of breast cancer received anastrozole or placebo over five years. The incidence of cancer in the anastrozole group turned out to be roughly half as high. On the basis of these data, a number of clinical guidelines included anastrozole among the options for pharmacological risk reduction.

Thus, over two decades the drug traveled from a "second line" in advanced disease to first-line adjuvant therapy and prevention in healthy women at high risk.

Anastrozole outside oncology and in sport

After the appearance of selective aromatase inhibitors, researchers began to study them beyond oncology as well. Among the directions that appeared in the scientific literature:

• treatment of short stature in boys — an attempt to slow the closure of growth plates (studies by Mauras et al.);
• elderly men with low testosterone — effect on hormones and bones;
• rare conditions with an excess of estrogens, such as McCune-Albright syndrome;
• gynecomastia in adolescents — with predominantly negative results.

The results were mixed. For example, in the study by Burnett-Bowie et al. (2009) in older men, anastrozole raised testosterone but lowered bone mineral density — another confirmation that estradiol is critically important for the male skeleton.

In parallel, aromatase inhibitors entered the arsenal of athletes who use anabolic steroids — to control estrogenic effects. Accordingly, they are classified as class S4 "Hormone and metabolic modulators" of the WADA Prohibited List and are banned both in and out of competition.

The history of anastrozole reminds us that each expansion of use required separate studies, and transferring results from one group of patients to another often proved mistaken.

Editorial conclusions

Anastrozole is the result of half a century of developing the idea of aromatase inhibition: from the non-selective aminoglutethimide and the injectable formestane to an oral, highly selective molecule.

Its 1995 approval and the results of the ATAC and IBIS-II trials made it the standard of adjuvant therapy and prevention of breast cancer in postmenopausal women.

Attempts to use it outside oncology showed that estrogens in the body are not a "superfluous" hormone, and suppressing them comes at a price, above all for the bones.

We also recommend reading "Anastrozole: mechanism of action", "Anastrozole in women: medical indications" and "Anastrozole or letrozole: what is the difference".

References

1. Santen RJ, Brodie H, Simpson ER, et al. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr Rev. 2009;30(4):343–375.
2. Baum M, Buzdar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359(9324):2131–2139.
3. Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11(12):1135–1141.
4. Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014;383(9922):1041–1048.
5. Burnett-Bowie SA, McKay EA, Lee H, Leder BZ. Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels. J Clin Endocrinol Metab. 2009;94(12):4785–4792.
6. Arimidex (anastrozole) tablets. Prescribing information. U.S. Food and Drug Administration.
7. World Anti-Doping Agency. Prohibited List. Montreal: WADA (актуальна редакція).