Aromataseinhibitoren: Update 2015

Aromatase inhibitors (AI) block the production of estrogen in many tissues expressing the enzyme aromatase, such as fatty tissue and muscle. The enzyme catalyzes the synthesis of estradiol from testosterone and of estrone from androstendione (a process called aromatization). Indications: AIs are approved for adjuvant or palliative treatment of postmenopausal breast cancer. In premenopausal women AIs lead to higher ovarian sensitivity to FSH, thus resulting in higher serum estrogen levels, and must therefore only be used only in combination with GnRH-analogues. AI treatment alone in premenopausal breast cancer patients is strictly contraindicated. However AIs are used in premenopausal women for ovarian stimulation to reduce dosage and costs of FSH stimulation protocols. There is currently no evidence for higher effectivity of AIs in estrogen dependent diseases such as endometriosis or uterine fibroids. Substances: 3 AIs are currently used in clinical practice and have improved anti-tumor effects compared to tamoxifen: anastrozole, letrozole (non-steroidal AIs, displaying competitive and reversible aromatase inhibition) and exemestane (steroidal AI, inhibits aromatase by covalent bond). Effects: AIs decrease estradiol serum levels as well as intracellular E2 concentration. Adjuvant breast cancer treatment with AIs leads to longer disease free survival (2.7% reduction over 5 years compared to tamoxifen in the ATAC trial), however have shown no effect on overall survival. A Cochrane Review of 31 trials including 11.403 postmenopausal patients with AIs as treatment for metastatic breast cancer found statistically significant improved survival (10% relative improvement, HR 0.90; 95-%-CI: 0.84–0.97) compared to other endocrine treatments tamoxifen, megestrol acetate (MA) and medroxyprogesterone acetate (MPA). Side effects: Frequent side effects are hot flushes, joint and muscle pains, decrease in bone mineral density, diarrhea and exanthema. Due to increased fracture rate in patients at risk for osteoporosis, osteodensitometry -and if applicable osteoporosis treatment- should be initiated before AI treatment starts. Treatment protocols for breast cancer patients: In the adjuvant setting AIs are used up front as 5-year treatment, as switch treatment (2-3 years of tamoxifen followed by 3–5 years of AI or vice versa) or as extended use after 5 years of tamoxifen in patients at higher risk of recurrence. AIs are used as palliative treatment in first- and second-line therapy, as maintenance treatment after chemotherapy or in combination with trastuzumab or lapatinib in Her 2 positive disease. Exemestane can be combined with m-TOR-inhibitor everolimus after failure of non-steroidal AI treatment. Future perspectives: Current promising clinical trials examine combination therapy of AIs with antibodies against IGF-1 or its receptor, metformin and inhibitors of PI3k and Akt, thus trying to overcome endocrine resistance by targeted therapy.