Aromatase inhibitors

Aromatase inhibitors are used as targeted tumour therapeutics with anti-oestrogenic and antitumour properties for the treatment of breast cancer in postmenopausal women.

The selective aromatase inhibitors suppress the synthesis of estradiol from adrostendione and testosterone and drastically reduce estradiol levels by preventing the conversion of androgens to estrogens by the enzyme aromatase in muscle and fat tissue ("aromatization"). This is where the biosynthesis of oestrogen takes place after menopause. A distinction is made between steroidal and non-steroidal aromatase inhibitors.

• The non-steroidal aromatase inhibitors - anastrozole and letrozole - bind competitively to the heme portion of the aromatase.
• The steroidal aromatase inhibitor Exemestan, on the other hand, irreversibly inactivates the enzyme.

The reduction of the estradiol level exceeds the physiologically observed decrease after menopause, since androgens of adrenal origin are also no longer aromatized to estradiol. The decrease in estradiol levels slows down the growth of estrogen-dependent (ER-positive, see below estrogen receptors) tumors. The aromatase inhibitors are metabolically eliminated. CYP3A4 (see below cytochrome P450 enzymes) is involved in the breakdown of Exemestan and Letrozole.

However, aromatase inhibitors do not sufficiently reduce ovarian oestradiol production. By blocking peripheral oestrogen production, the gonadotropin axis may even be activated during premenopause and ovarian hyperstimulation may follow. In this respect, aromatase inhibitors were primarily used in postmenopausal patients with advanced or metastasized breast cancer. However, since the publication of data from two phase III studies (TEXT and SOFT), aromatase inhibitors can also be used in premenopause, but only in combination with ovarian suppression.

The preparations are approved for use in metastatic breast cancer. Aromatase inhibitors and tamoxifen are available as adjuvant treatment options for postmenopausal women. In addition to an "upfront" therapy (five years of aromatase inhibitors), a so-called switch therapy with a change of medication (tamoxifen aromatase inhibitors or aromatase inhibitors → tamoxifen) is also possible.

Due to their long half-life, the drugs only need to be taken once a day. The side effects are comparable to menopausal symptoms. They are due to the lack of estradiol and include hot flushes, dry vagina, osteoporosis with spontaneous fractures, arthralgia, myalgia, fatigue, sweating and headaches.

Arthralgia: As the occurrence of joint pain is the most common reason for discontinuing treatment, both education and effective management of the condition are important.

Osteoporosis: The current S3 guideline Osteoporosis(www.dv-osteologie.org) recommends that additional risk factors (e.g. co-medication with corticosteroids, immobility) should be assessed before starting aromatase inhibitor treatment and, if necessary, a basic diagnosis with bone density testing (especially in women > 60 years).

Skin lesions are rather rare: cutaneous vasculitis, leukocytoclastic vasculitis, erythema nodosum, non-specific erythema, subacute cutaneous lupus erythematosus (Shoda H et al. 2005; Woodford RG et al. 2019). Occasionally, radiation recall dermatitis has also been described (Kim YJ et al. 2020). Depending on the skin condition, topical corticosteroids are recommended as therapy. Gfls. an alternative aromatase inhibitor is recommended.

Compared to the estrogen receptor antagonists less thromboembolic events and endometrial carcinomas occur.

In principle, these drugs are contraindicated in women before menopause (pregnancy, lactation).

Anastrozole must not be used in women with severe liver or kidney dysfunction.

Anastrozole (Arimidex®, generic products)

Letrozole (Femara®, generic products)

Exemestan (Aromasin®, generic products)

The risk of thromboembolic events and endometrial carcinoma is lower during therapy with aromatase inhibitors than under therapy with selective estrogen receptor modulators such as tamoxifen.

The aromatase inhibitors are misused in bodybuilding and as doping agents. They inhibit the conversion of anabolic steroids into oestrogens and are intended to prevent the development of gynaecomastia.

1. Coates AS et al (2014) Tailoring therapies-improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer Robert Koch-Institute Ann Oncol 26: 1533-1546
2. Cuzick J et al (2010) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 11: 1135-1141
3. Digklia A , Tzika et al (2014) Cutaneous leukocytoclastic vasculitis associated with letrozole. J Oncol Pharm Pract 20:146-148.
4. Goss PE (1999) Risks versus benefits in the clinical application of aromatase inhibitors. Endocr Relat Cancer 6: 325-32
5. Goss PE et al (2013) Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole. Ann Oncol 24: 355-361
6. Metzger Filho O et al (2015) Relative effectiveness of letrozole compared with tamoxifen for patients with lobular carcinoma in the BIG 1-98 Trial. J Clin Oncol 33: 2772-2779
7. Pagani O et al (2014) Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 371: 107-118
8. Piccart M et al (2014) Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2 Ann Oncol 25: 2357-2362
9. Santen RJ et al (1999) Use of aromatase inhibitors in breast carcinoma. Endocr Relat Cancer 6: 75-92
10. Sulkes A (2005) The emerging role of the new aromatase inhibitors in the treatment of breast cancer. Isr Med Assoc J 7: 257-261
11. Robert Koch Institute (2015) Cancer in Germany 2011/2012. 10th Edition.
12. Woodford RG et al (2019) Leukocytoclastic vasculitis associated with use of aromatase inhibitors. Internal Med J 49:1162-1167.