AROMASIN
InfoSite Home
Role of estrogen and estrogen inhibition in breast cancer
- The role of estrogen in suppression of breast cancer was suggested more than 100 years ago.[1] Subsequently, both endogenous and exogenous estrogen has been implicated in breast cancer pathogenesis.[2] Estrogen binds to its receptor forming a ligand-receptor complex known as estrogen response element (ERE). EREs activate estrogen-response genes and stimulate cell growth and differentiation[3] (Figure 2-1)
- Estrogen is a product of the cholesterol pathway and its synthesis is dependent on the action of the aromatase enzyme and on the androgens, androstenedione and testosterone. Estradiol binds to the estrogen receptor (ER), thus leading to conformational change and formation of EREs, which are localized upstream of estrogen response genes. Activation of these genes results in breast cancer cell proliferation.
- Aromatase is expressed at high levels in the placenta and in ovarian follicles, and is also present at much lower concentrations in adipose tissue, liver, muscle, brain, as well as in normal and tumor breast tissue[4]
- In premenopausal women, the ovaries are the primary source of estrogen[2]
- In postmenopausal women peripheral aromatization of androgens is the primary source of estrogen[2] (Figure 2-2)
- In premenopausal women there are wide fluctuations in serum estrogen concentrations associated with the menstrual cycle[2,4]
- In postmenopausal women, levels of circulating estrogen are low, and its concentrations are constant[2,4]
- Increased breast cancer risk is associated with higher serum estrogen levels and the development of breast cancer in both pre- and postmenopausal women[2,5]
- Elevated cumulative estrogen exposure and increased breast cancer risk are supported by epidemiologic data[2]
- Increased serum estrogen levels are associated with[2]
- Early menarche
- Late first full-term pregnancy
- Late menopause
- Postmenopausal obesity
- Estrogen acts directly through the activation of oncogenes, and indirectly through stimulation of prolactin secretion and growth factor production, to promote breast cancer. Cells exposed to the proliferative effects of estrogen may progress from normal to hyperplastic and then to neoplastic growth[2]
- Local production of estrogen may have an important role in breast cancer initiation and progression. Estrogen concentrations are sevenfold higher in breast adipose tissue than in the plasma for both postmenopausal women who are healthy and those who have breast cancer,[6] and aromatase activity has been reported in 70% of breast tumors[7,8]
- Messenger RNA for aromatase has been found in breast tumor epithelial cells, and aromatase activity has been shown in metastatic breast cells isolated from patients.[8,9] In addition, aromatase activity strongly correlates with an increase in proliferation, as measured by proliferating cell nuclear antigen immunostaining.[9] Collectively, the evidence strongly suggests that tumor-derived estrogen plays a role in promoting the growth of breast cancer[9]
- Aromatase is an enzyme complex responsible for the final step in estrogen synthesis.[5] Aromatase inhibitors bind to the aromatase enzyme, thus preventing the conversion of androgens to estrogens and interfering with downstream activation of ER target genes[3] (Figure 2-1)
- Inhibiting estrogen at the source of its synthesis is a logical target for breast cancer treatment in menopausal women[5]
- AROMASIN is not indicated in premenopausal women. There is a barrier to using aromatase inhibitors as monotherapy in premenopausal women[5]
AROMASIN® (exemestane tablets)
AROMASIN is indicated for adjuvant treatment of postmenopausal women with estrogen receptor-positive early breast cancer who have received 2 to 3 years of tamoxifen and are switched to AROMASIN for completion of a total of 5 consecutive years of adjuvant hormonal therapy.
AROMASIN is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.
Important Safety Information
AROMASIN (exemestane tablets) should not be used in women who are premenopausal, are nursing or pregnant, have a known hypersensitivity to the drug, or are taking estrogen-containing agents.
Dose modification is recommended for patients who are receiving certain medications, including strong CYP 3A4 inducers such as rifampicin and phenytoin.
In patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receiving exemestane than either tamoxifen or placebo.
Reductions in bone mineral density over time are seen with AROMASIN use.
Incidence of adverse events (AEs; %) occurring in ≥10% of patients in any treatment group (AROMASIN vs tamoxifen) in the Intergroup Exemestane Study (IES): hot flushes (21.2 vs 19.9), fatigue (16.1 vs 14.7), arthralgia (14.6 vs 8.6), headache (13.1 vs 10.8), insomnia (12.4 vs 8.9), and increased sweating (11.8 vs 10.4).
In IES, discontinuation rate due to AEs was similar between AROMASIN and tamoxifen (6.3% vs 5.1%). Incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia): AROMASIN 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: AROMASIN 0.4%, tamoxifen 0.3%.
Most common adverse events reported for advanced breast cancer were mild to moderate and included hot flashes (13%), nausea (9%), fatigue (8%), increased sweating (4%), and increased appetite (3%).
References
- Thomson A. Analysis of cases in which öophorectomy was performed for inoperable carcinoma of the breast. BMJ. 1902;2:1538-1541.
- Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344:276-285.
- Johnston SRD, Dowsett M. Aromatase inhibitors for breast cancer: lessons from the laboratory. Nat Rev Cancer. 2003;3:821-831.
- Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003;348:2431-2442.
- Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol. 2001;19:881-894.
- Szymczak J, Milewicz A, Thijssen JHH, et al. Concentration of sex steroids in adipose tissue after menopause. Steroids. 1998;63:319-321.
- Tilson-Mallett N, Santner SJ, Feil PD, Santen RJ. Biological significance of aromatase activity in human breast tumors. J Clin Endocrinol Metab. 1983;57:1125-1128.
- Lu Q, Nakmura J, Savinov A, et al. Expression of aromatase protein and messenger ribonucleic acid in tumor epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancers. Endocrinology. 1996;137:3061-3068.
- Brodie A, Lu Q, Liu Y, Long B. Aromatase inhibitors and their antitumor effects in model systems. Endocr Relat Cancer. 1999;6:205-210.
