This document reflects emerging clinical and scientific advances as of the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed.
ABSTRACT: Aromatase inhibitors appear to be effective as an adjuvant treatment for early-stage and late-stage breast cancer. Their role in chemoprevention of breast cancer in high-risk patients remains to be defined. Side effects of aromatase inhibitors in postmenopausal women are due to estrogen-lowering action at the target tissues and include hot flushes, vaginal dryness, arthralgias, and decreased bone mineral density. In reproductive-aged women, aromatase inhibitors stimulate gonadotropin secretion and increase ovarian follicular activity. The role of aromatase inhibitors in the treatment of endometriosis and in ovulation induction is still being investigated.
The pharmacologic manipulation of hormone levels has been very successful in the treatment of estrogen-dependent disease processes such as breast cancer, endometriosis, and uterine leiomyomas. As part of this approach, aromatase inhibitors have been introduced for the treatment of breast cancer and, more recently, endometriosis. Aromatase inhibitors also have been used as ovulation induction agents.
The aromatase enzyme is a cytochrome P-450 complex encoded by a single gene, and it is widely expressed in tissues, such as brain, breast, placenta, ovary, testes, endometrium, skin, bone, and fat. Within these tissues, aromatase mediates the conversion of andros-tenedione to estrone and testosterone to estradiol in situ. Thus, for tissues that express this enzyme, conversion of circulating androgens from an adrenal or ovarian source will significantly increase the in situ estrogen concentrations and provide these tissues with a proliferative advantage.
Three aromatase inhibitors are currently available in the United States. Exemestane is a steroid-derived aromatase inhibitor that binds irreversibly to aromatase and permanently inactivates the available enzyme. Letrozole and anastrozole are reversible inhibitors of aromatase that compete with androgens for aromatase binding sites. All three aromatase inhibitors appear to have similar clinical efficacy despite these differences in pharmacologic properties.
In postmenopausal women, aromatase inhibitors were first introduced for the treatment of advanced breast cancer. Although these compounds did not increase overall survival, they appeared to be similar or better than megestrol when objective responses were the endpoint (1). The early success of these studies led to clinical trials of aromatase inhibitors in breast cancer patients with resectable, estrogen receptor-positive tumors. The largest of these trials compared anastrozole with tamoxifen, alone or in combination, as adjuvant treatment in women with early breast cancer following surgical resection. The study results demonstrated a small but significantly improved 3-year disease-free survival in postmenopausal women with invasive, operable breast cancer who received anastrazole alone compared with tamoxifen (89.4% versus 87.4%, hazard ratio 0.83 [95% confidence interval, 0.71–0.96]) (2). Subsequent trials have been initiated to examine the effectiveness of aromatase inhibitors in other breast cancer clinical scenarios, including the use of aromatase inhibitors as a sequential therapy following tamoxifen, aromatase inhibitors for the treatment of ductal carcinoma in situ, and aromatase inhibitors for the prevention of breast cancer in high-risk patients (3). Although data from these trials are not complete, it appears that aromatase inhibitors will play a significant role in therapy for estrogen receptor-positive breast cancer.
The short-term and long-term adverse effects of aromatase inhibitors in postmenopausal women are related to lack of estrogen action at aromatase-targeted tissue sites. These side effects include hot flushes, vaginal dryness, arthralgias, decreased bone mineral density, and an increased fracture rate (4). The American Society of Clinical Oncologists recommends that bone mineral density screening be repeated annually in all patients receiving aromatase inhibitor adjuvant therapy, and bisphosphonate therapy should be initiated when T scores are –2.5 or lower (5). To reduce the risk of osteoporosis in high-risk patients, bisphosphonates may be co-administered to patients during long-term treatment with aromatase inhibitors.
In contrast to tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis (6) and endometrial cancer (7), and a reduction in vaginal bleeding. Although the results of early studies suggest that aromatase inhibitors have adverse effects on the cardiovascular system and lipid profiles compared with tamoxifen, these effects are milder or have not been seen when comparing aromatase inhibitors with placebo. This suggests that aromatase inhibitors lack the protective effects found with tamoxifen rather than exhibit true toxicity (8). Increased cardiovascular morbidity or mortality through poor lipid profiles or other mechanisms has not been clearly established in patients treated with aromatase inhibitors compared with tamoxifen or placebo (9). More rigorous study is required in this area because most of the trials were not designed to address cardiac disease.
Aromatase inhibitors also have been used as treatment for premenopausal women with early breast cancer who have chemotherapy-induced amenorrhea. This off-label use should be prescribed with caution because case series have described the resumption of ovarian function following initiation of an aromatase inhibitor regimen (10, 11). Serial monitoring of estradiol and gonadotropin levels to identify women who experience a return of ovarian function may be indicated (10).
In premenopausal women, aromatase inhibitors reduce hypothalamic–pituitary estrogen feedback that leads to increased gonadotropin-releasing hormone (GnRH) secretion, concomitant elevations in luteinizing hormone and follicle-stimulating hormone, and increased ovarian follicular development. The gonado-tropin-stimulating action of letrozole has been used off-label in the treatment of patients with ovulatory dysfunction, such as polycystic ovary syndrome, and for increasing the number of ovarian follicles recruited for ovulation in women who are already ovulatory (12, 13). In a meta-analysis of four published trials, including 662 women with polycystic ovary syndrome, pregnancy rates were similar between women treated with clomiphene and women treated with letrozole (relative risk, 1.02; 95% confidence interval, 0.83–1.26) (14). Some have raised concerns about this off-label use because letrozole may disrupt the normal aromatase activity in tissues during early fetal development and can be potentially teratogenic if administered inadvertently during early pregnancy. However, a large study of 911 newborns conceived using letrozole for ovulation induction showed no difference in rates of congenital malformations (15). In addition, the half-life of letrozole (approximately 30–60 hours) is shorter than that of clomiphene citrate (5–7 days) and, thus, should be effectively cleared from the body by the time of embryo implantation, likely preventing a teratogenic effect when used in ovulation induction (14). Possible advantages of letrozole over clomiphene citrate include reduced multiple pregnancies, lower estradiol levels, and an absence of antiestrogenic adverse effects on the endometrium. However, there is no evidence that letrozole is more effective than clomiphene for ovulation induction. Letrozole may have a role in the treatment of clomiphene-resistant patients (16).
The recent demonstration that aromatase is expressed at higher levels in endometriosis implants than in normal endometrium has led to pilot studies using anastrozole co-administered with progestins in patients with endometriosis resistant to conventional medical and surgical therapies (17). These small studies suggest that aromatase inhibitors could reduce endometriosis-associated pelvic pain, whereas the progestin could effectively suppress gonadotropins and reduce ovarian activity. Results of subsequent trials have shown similar efficacy for relief of pelvic pain when aromatase inhibitors were combined with combination oral contraceptives (18), or when aromatase inhibitors were given concomitantly with a GnRH agonist (19). There are no randomized controlled trials comparing aromatase inhibitors with traditional medical treatment for endometriosis. Side effect profiles of aromatase inhibitor regimens (including a progestin or oral contraceptive as add-back therapy) are favorable compared with regimens containing GnRH agonists or danazol. These aromatase inhibitor regimens with add-back progestin or oral contraceptives do not appear to be associated with significant bone loss after 6 months of treatment and may be suitable for long-term use (20). Randomized controlled trials are needed to establish the efficacy and side effects of these regimens.
Aromatase inhibitors appear to be effective as an adjuvant treatment for early-stage and late-stage breast cancer. Their role in chemoprevention of breast cancer in high-risk patients remains to be defined. Side effects of aromatase inhibitors in postmenopausal women are due to estrogen-lowering action at the target tissues and include hot flushes, vaginal dryness, arthralgias, and decreased bone mineral density. Although there are no long-term data with regard to side effects and complications associated with the use of aromatase inhibitors in breast cancer patients, the overall safety profile of aromatase inhibitors is good, with less endometrial and thromboembolic toxicity than tamoxifen. In reproductive-aged women, aromatase inhibitors stimulate gonadotropin secretion and increase ovarian follicular activity. The role of aromatase inhibitors in the treatment of endometriosis and in ovulation induction is still being investigated.
- Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group. Cancer 1998;83:1142–52.
- Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359: 2131–9.
- Bickenbach KA, Jaskowiak N. Aromatase inhibitors: an overview for surgeons. J Am Coll Surg 2006;203:376–89.
- Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365:60–2.
- Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003;21: 4042–57.
- Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350:1081–92.
- Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 2005;366:455–62.
- Conte P, Frassoldati A. Aromatase inhibitors in the adjuvant treatment of postmenopausal women with early breast cancer: Putting safety issues into perspective. Breast J 2007; 13:28–35.
- Gandhi S, Verma S. Aromatase inhibitors and cardiac toxicity: getting to the heart of the matter. Breast Cancer Res Treat 2007;106:1–9.
- Smith IE, Dowsett M, Yap YS, Walsh G, Lonning PE, Santen RJ, et al. Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines. J Clin Oncol 2006;24:2444–7.
- Burstein HJ, Mayer E, Patridge AH, O'Kane H, Litsas G, Come SE, et al. Inadvertent use of aromatase inhibitors in patients with breast cancer with residual ovarian function: cases and lessons. Clin Breast Cancer 2006;7:158–61.
- Fisher SA, Reid RL, Van Vugt DA, Casper RF. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril 2002;78:280–5.
- Bedaiwy MA, Forman R, Mousa NA, Al Inany HG, Casper RF. Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation. Hum Reprod 2006; 21:2838–44.
- Casper RF. Letrozole versus clomiphene citrate: which is better for ovulation induction? Fertil Steril 2007 June 21. DOI: 10.1016/j.fertnstert.2007.03.094.
- Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761–5.
- Badawy A, Abdel Aal I, Abulatta M. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial. Fertil Steril 2007 Jun 18. DOI: 10.1016/j.fertnstert.2007.02.062.
- Ailawadi RK, Jobanputra S, Kataria M, Gurates B, Bulun SE. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study. Fertil Steril 2004;81:290–6.
- Amsterdam LL, Gentry W, Jobanputra S, Wolf M, Rubin SD, Bulun SE. Anastrazole and oral contraceptives: a novel treatment for endometriosis. Fertil Steril 2005;84:300–4.
- Soysal S, Soysal ME, Ozer S, Gul N, Gezgin T. The effects of post-surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis: a prospective randomized trial. Hum Reprod 2004;19:160–7.
- Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis? Fertil Steril 2006;85: 1307–18.