The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer

Abstract

Summary The third‐generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole have largely replaced tamoxifen as the preferred treatment for hormone receptor – positive breast cancer in postmenopausal women. Approximately 185,000 new cases of invasive breast cancer are diagnosed yearly, and at least half of these women are both postmenopausal and eligible for adjuvant therapy with AIs. In addition, AIs are currently being tested as primary prevention therapy in large randomised trials involving tens of thousands of women at increased risk for breast cancer. Given the volume of use, internists will increasingly see postmenopausal women who are taking or considering treatment with AIs. Physicians need to be able to: (i) briefly discuss the pros and cons of using a selective estrogen receptor modulator such as tamoxifen or raloxifene vs. an AI for risk reduction and (ii) recognise and manage AI‐associated adverse events. The primary purpose of this review is to help internists with these two tasks.

Potential Role ofUGT1A4Promoter SNPs in Anastrozole Pharmacogenomics

“…The current third-generation AIs (anastrozole, exemestane, and letrozole) are highly specific to the aromatase enzyme and have fewer adverse effects than do previous generations of AIs (Fabian, 2007). Anastrozole binds reversibly to the aromatase enzyme and inhibits the conversion of androgens to estrogens in peripheral tissues outside the central nervous system and a few central nervous system sites in various regions in the brain (Simpson, 2003).…”

Antiproliferation Activity of a Small Molecule Repressor of Liver Receptor Homolog 1

“…The aromatase cytochrome P450 (CYP19) regulates much of postmenopause estrogen synthesis, and higher amounts of estrogen in the blood are linked to an increased risk of breast cancer (Fabian, 2007;Key et al, 2011). Simpson and coworkers first reported high expression of LRH-1 in preadipocytes, and they associated LRH-1 expression with transcriptional activation of CYP19 (Clyne et al, 2002).…”

Use of anastrozole in the chemoprevention and treatment of breast cancer: A literature review

“…Furthermore, it is also indicated for early cancer treatment, tumor chemoprevention and postmenopausal women using TAM, especially if the drug is used during a prolonged period of time and has been indicated in the disease's recurrence, i.e., as another therapeutic endocrine option. 9,10 Prolonged use of anastrozole has no effects on the concentrations of steroid hormones cortisol, aldosterone, androstenedione and 16-hydroxyprogesterone, confirming that it is highly selective for the inhibition of aromatase without interfering in other pathways of adrenal stereoidogenesis. The lack of alterations in luteinizing hormone and folllicle-stimulating hormone demonstrates that anastrozole has no estrogenic, progestational or androgenic activity, and it does not affect the synthesis of gonadotropins.…”

“…7,8 Aromatase inhibitors (AIs) have recently been approved as a first-line endocrine therapy for postmenopausal women with hormone-sensitive and metastatic breast cancer. 9,10 There are three generations of AIs and the last, represented by exemestane, letrozol and anastro- Source: adapted from Freedman et al 6 FIGURE 2 Molecular structure of the androgen substrates of aromatase and the corresponding estrogen products. Anastrozole and all third-generation compounds have become endocrine drugs of choice for postmenopausal breast cancer patients, as they are associated with a stronger activity and better general tolerability compared with tamoxifen (TAM), a first-generation selective estrogen receptor modulator (SERM) 13 that has been associated with potentially fatal adverse effects such as an increased incidence of endometrial cancer, thromboembolism and cerebrovascular event.…”