Aromatase inhibition 2013: clinical state of the art and questions that remain to be solved

Abstract

Following their successful implementation for the treatment of metastatic breast cancer, the 'third-generation' aromatase inhibitors (anastrozole, letrozole, and exemestane) have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancers. These drugs are characterized by potent aromatase inhibition, causing >98% inhibition of estrogen synthesis in vivo. A recent meta-analysis found no difference in anti-tumor efficacy between these three compounds. As of today, aromatase inhibitor monotherapy and sequential treatment using tamoxifen followed by an aromatase inhibitor for a total of 5 years are considered equipotent treatment options. However, current trials are addressing the potential benefit of extending treatment duration beyond 5 years. Regarding side effects, aromatase inhibitors are not found associated with enhanced risk of cardiovascular disease, and enhanced bone loss is prevented by adding bisphosphonates in concert for those at danger of developing osteoporosis. However, arthralgia and carpal tunnel syndrome preclude drug administration among a few patients. While recent findings have questioned the use of aromatase inhibitors among overweight and, in particular, obese patients, this problem seems to focus on premenopausal patients treated with an aromatase inhibitor and an LH-RH analog in concert, questioning the efficacy of LH-RH analogs rather than aromatase inhibitors among overweight patients. Finally, recent findings revealing a benefit from adding the mTOR inhibitor everolimus to endocrine treatment indicate targeted therapy against defined growth factor pathways to be a way forward, by reversing acquired resistance to endocrine therapy.

Keywords: adjuvant therapy; aromatase inhibitors; breast cancer; endocrine therapy; resistance.

Figure 1

Local vs total body aromatization as a source for estrogen. There is an extensive exchange of estrone (E₁) and estradiol (E₂) between the plasma and the breast and breast cancer tissue due to total body aromatization, which overrules the local aromatization in the breast. Local administration of an aromatase inhibitor is therefore not a rational strategy. A, androstenedione; E₂-ER, estradiol bound to estrogen receptor; E₁S, estrone sulfate.

Figure 2

Signaling mechanisms important for endocrine resistance and which are currently targeted in clinical trials, combined with aromatase inhibitors. (1) IGF1 or IGF1R neutralizing antibodies (AMG-479 in study NCT00626106 a.o.). (2) HER-2 blocking therapy (trastuzumab emtansine in study NCT01745965 a.o.). (3) Inhibitors of PI3K, Akt, and/or mTOR pathway (everolimus in study NCT01698918 a.o.). (4) Src inhibitors (dasatinib in study NCT00696072 a.o.). (5) AMPK activator (metformin in study NCT01654185 a.o.). (6) Inhibitors of Ras-Raf-MEK-MAPK pathway (MEK inhibitor AZD6244, combined with fulvestrant after progression on aromatase inhibitor in NCT01160718). (7) Gamma secretase inhibitor (RO4929097 in study NCT01208441 a.o.). (8) HDAC inhibitors (vorinostat in study NCT01153672 a.o.). (9) CDK4/6 inhibitor (PD0332991 in study NCT01740427 a.o.).