|Seifert-Klauss V et al.|
Update on Aromatase Inhibitors
Journal für Reproduktionsmedizin und Endokrinologie - Journal of Reproductive Medicine and Endocrinology 2015; 12 (4): 353-359
Volltext (PDF) Summary
Keywords: aromatase inhibitors, breast cancer, clinical management, endocrine therapy, side effects
Aromatase inhibitors (AI) block the last phase of estrogen production in many types of tissues which express the enzym aromatase, among them muscle, liver, adrenal, brain and fat. The enzyme catalyzes the last step of the biosynthesis of the estrogens, i. e. the aromatisation of testosterone to estradiol and of androstendion to estrone. Aromatase is localized in the membrane of the endoplasmatic reticulum and is also produced in the placenta and the gonads. Mutations in the gene CYP19A1, which codes for aromatase, can lead either to lack or excess of aromatase. Gene polymorphisms also influence the amount of bioavailable estrogen and bone density.
Indications: AI are approved for the treatment of postmenopausal women with hormone receptor positive breast cancer, both in the adjuvant setting as well as after recurrence and in progressive disease. In premenopausal and in perimenopausal women AI cause an increased sensitivity of the ovaries to follicle stimulating hormone (FSH) and can thereby lead to a boosted estrogen answer – this effect is particularly pronounced in early perimenopausal women – so that these situations demand a combination with GnRH-analogue if AI treatment is to be initiated. Alternatively, tamoxifene may be used in premenopausal patients, with or without GnRH analogues. Treatment of premenopausal patients with hormone receptor positive breast cancer with aromatase inhibiting therapy alone constitutes an absolute contraindication. Aromatase inhibitors do not lead to estrogen receptor downregulation or block the receptor such as tamoxifene. An exceptional application is the application in reproductive medicine in women who do not have hormone receptor positive breast cancer: because of the higher sensitivity induced by AI-co-therapy, FSH-doses and -costs for assisted reproduction are reduced, and ovarian hyperstimulation syndrome (OHSS) may be avoided. For premenopausal diseases which are said to be positively affected by estrogen withdrawal, such as endometriosis or fibroids, studies have not shown any significant advantage of AI-therapy so far. Bodybuilders use AI inhibitors to prevent estrogenic side effects of a testosterone therapy through conversion in estrogens and to enhance testosterone levels by blocking its metabolisation. Medical application of AI is discussed for boys with short stature as a more cost-effective alternative to treatment with human growth hormone.
Substances: Currently, the 3 commonly used AI are anastrozol, letrozol (both non- steroidal, displaying competitive binding and reversibleinhibition) and exemestane (steroidal, inactivation of aromatase through covalent binding), show better anticancerous effects compared with tamoxifene.
Effects: AI decrease estradiol serum levels in postmenopausal women from around 30 pmol/l to < 3 pmol/l. Intracellular estrogen-concentrations are reduced, too. Under adjuvant therapy (early breast cancer), this estrogen withdrawal prolongs the time to recurrence, and results in higher rates of disease free survival (absolute reduction of 2.7% after 5 years compared with tamoxifene) while the 100-months-analysis of the ATAC-trial did not find an effect on overall survival (ATAC trialists group). In the metastasized situation, a Cochrane-Review-metaanalysis of 31 trials on AI in a total of 11.403 postmenopausal patients with advanced disease showed statistically significant improved survival under AI of 10% in comparison with the other endocrine therapeutic options tamoxifene (TAM), megestrolacetat (MA) and medroxyprogesterone acetate (MPA) (HR 0.90; 95-%-CI: 0.84–0.97).
Side effects: The most common side effects are hot flushes, joint and bone pain, reduction of bone density, diarrhea and rashes. In women with increased risk for osteoporosis the fracture rate is higher under AI than with the SERM tamoxifene, so that before initiating therapy, a bone density measurement is recommended.
Modes of treatment in breast cancer: Adjuvant therapies with AI include monotherapy over 5 years (in postmenopausal women), combination with GnRHanalogue (in women who are not postmenopausal) and also the switch-concept (2 years of tamoxifene, followed by aromatase inhibitor for 3–5 years or vice versa. High risk situations may warrant „extended use“ with continuation of the therapy after 5 years (up to 10 years). In the metastasized situation, AI are applied in first- as well as in second-line therapy, if there is not a rapid disease progression in vital organs (lung, liver), or as maintenance therapy after chemotherapy. As in the adjuvant setting, in premenopausal women AI must be combined with GnRH analogues. For postmenopausal women with Her2 neu-positive carcinomas, a combination therapy of aromatase inhibitors with trastuzumab or lapatinib has recently been approved. For Her2 neu-negative, hormone receptor positive disease, a combination of exemestane with the m-TOR inhibitor everolimus can be applied after failureof aromatase monotherapy with non-steroidal AI.
Future perspectives:The combination of aromatase inhibitors with the anti-estrogen fulvestrant was not more effective than each substance on its own (SoFEA investigators). Further ongoing trials explore the combination of aromatase inhibitors with neutralising antibodies against IGF-1 or its receptor (e.g. ganitumab), metformin and inhibitors of PI3k and/or Akt. Some of these targeted therapy approaches try to overcome resistance to endocrine therapy, e. g. combinations with mTOR inhibitors are being investigated in clinical trials. Also, the inhibition of PI3k and the new class of CDK4/6 inhibitors represent new promising approaches of combination therapy with aromatase inhibitors.