Cover Story: Preventing breast Ca with aromatase inhibitors

December 1, 2003

With new research showing that aromatase inhibitors can dramatically cut the risk of recurring breast cancer, patients will probably have many questions about drugs like anastrozole and letrozole. Two experts review the scientific evidence on these valuable agents.


Cover Story

Preventing breast Ca with aromatase inhibitors

Jump to:Choose article section... A crash course on the history of aromatase inhibitors AIs as a new strategy for treating breast Ca AIs for adjuvant therapy Halted clinical trial and the future of breast Ca treatment Countering bone loss in chemoprevention with AIs Conclusions Key points

By Mohamed F. Mitwally, MD, PhD, and Robert F. Casper, MD

With new research showing that aromatase inhibitors can dramatically cut the risk of recurring breast cancer, patients will probably have many questions about drugs like anastrozole and letrozole. Two experts review the scientific evidence on these valuable agents.


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Aromatase inhibitors recently made front-page news when an international clinical trial was stopped in its tracks. The investigators found powerful evidence to show that letrozole greatly reduces a postmenopausal woman's chance of having breast cancer recur. As a result, this third-generation aromatase inhibitor (AI) is opening up a new treatment option for women who've completed 5 years on tamoxifen, the current gold standard therapy for survivors of early-stage breast cancer.

What's less well-known is that aromatase inhibitors—which block estrogen synthesis—may also offer a promising alternative to a poles-apart procedure—the standard treatment for ovulation induction. (More on that topic next month.)

The drug's diverse applications should come as no surprise, though, given the pivotal role estrogen plays not only in the development of breast cancer, but in the pathogenesis of other reproductive disorders like precocious puberty, endometriosis, fibroids, abnormal uterine bleeding, and premenstrual syndrome. Our goal in this first of a two-part article is to discuss the role of AIs in treating and preventing breast cancer. Part II will focus specifically on ovulation induction in breast cancer survivors.

A crash course on the history of aromatase inhibitors

The enzyme aromatase catalyzes the conversion of androstenedione and testosterone to estrone and estradiol, respectively (Figure 1).1,2 The enzyme is present in ovaries, the brain, adipose tissue, muscle, liver, breast tissue, and in malignant breast tumors. The main sources of circulating estrogens are the ovaries in premenopausal women and adipose tissue in postmenopausal women.3,4



Three decades of AIs. Because aromatase inhibition curbs estrogen production and lowers estrogen levels throughout the body, the enzyme is a logical target in the search for an effective chemotherapeutic agent. Of all the many AIs developed and used in clinical studies over the last 30 years, the most successful—third-generation AIs—are now approved mainly for breast cancer treatment.5,6 AIs have been classified in different ways, including first-, second-, and third-generation; steroidal and nonsteroidal; reversible (ionic binding), and irreversible (suicide inhibitor, covalent binding).7,8

Aminoglutethimide, a first-generation nonsteroidal AI and the first to be used clinically, had a key drawback. It also inhibited other steroidogenic enzymes, including those involved in adrenal steroid production, which meant that patients taking the drug also needed corticosteroid replacement.9 The drug's other adverse effects—lethargy, rashes, nausea, and fever—caused as many as 15% of patients to discontinue it.10,11 Not surprisingly, its lack of specificity and toxic effects fueled the search for more specific AIs. Second- generation AIs included the nonsteroidals rogletimide and fadrozole and the steroidal formestane.

Third-generation AIs. The commercially available third-generation AIs include two nonsteroidal preparations, anastrozole and letrozole, and a steroidal agent, exemestane.12-14 (Another, vorozole, is not commercially available, although it seems to be as effective in inhibiting aromatase as the other preparations.) Anastrozole, (Arimidex) and letrozole, (Femara) are selective AIs, used in North America, Europe, and elsewhere to treat postmenopausal breast cancer. These triazole (antifungal) derivatives are reversible, competitive AIs that are more selective than aminoglutethimide—and 1,000 to 1,500 times more potent. In fact, at doses of 1 to 5 mg/day, they dramatically lower estrogen levels—by 97% to more than 99%, to concentrations below detection by current hormonal assays. Table 1 shows the relative potencies of different AIs.


Comparative potencies of different AIs

Aromatase inhibitorDoseAverage percentage of total body aromatase inhibition
Aminoglutethimide in conjunction with hydrocortisone1,000 mg plus 40 mg of hydrocortisone (daily)90.6%
Anastrozole1 mg/day97.3%
Exemestane25 mg/day97.9%
Fadrozole2 mg/day82.4%
Formestane250 mg (every 2 weeks, IM)84.8%
Letrozole2.5 mg/day>99.1%
Vorozole1 mg/day93.0%


Third-generation AIs are completely absorbed after oral administration, with an average terminal half-life of roughly 45 hours; they're cleared from systemic circulation mainly by the liver. GI disturbances account for most of the adverse events, although side effects seldom limit therapy. Other adverse effects include asthenia, hot flashes, headache, and leg pain.11-14 Table 2 lists their advantages, based mainly on literature from postmenopausal women with breast cancer.


Advantages of third-generation aromatase inhibitors

No accumulation of the medications or their metabolites


AIs as a new strategy for treating breast Ca

We've known for more than a century that depriving certain breast cancer cells of estrogen can play a key role in controlling the disease. The news that oophorectomy causes advanced breast cancer to regress made that clear.15 Holding estrogen production in check with AIs is a new and exciting strategy in the endocrine treatment of breast cancer. And that strategy doesn't stop with breast cancer: AIs are also being considered for chemoprevention of other estrogen-dependent cancers like endometrial cancer. Accumulating data on the success of AIs in managing breast cancer make these drugs promising alternatives to tamoxifen, the current gold standard of care, for estrogen-receptor-positive breast cancers, which make up the majority of breast cancers.16-19

Comparing SERMS to AIs. Selective estrogen receptor modulators (SERMS) like tamoxifen differ from AIs in their mechanism of action. SERMS inhibit the growth of breast tumors by competitive antagonism of estrogen at its receptor site; but their actions are complex, because they also have partial estrogen-agonist effects—which can be both good and bad. Their agonist effects may help prevent bone demineralization in postmenopausal women.20,21 But this same mechanism may also increase the risks of uterine cancer and thromboembolism.22-24

In contrast, AIs markedly suppress plasma estrogen levels in postmenopausal women by inhibiting or inactivating aromatase; but they don't have estrogen receptor agonist or antagonist activity.

Using AIs to manage breast Ca. Recently, researchers reviewed the role of AIs in breast cancer, a topic that has been investigated most extensively in postmenopausal women with breast cancer.25 In premenopausal women, AIs increase gonadotropin secretion because of the reduced estrogen-negative feedback on the hypothalamus and pituitary.26 For that reason, AIs have been tried in combination with a gonadotropin-releasing-hormone agonist to suppress ovarian function.27 Obviously, AIs alone are contraindicated in premenopausal women with breast cancer who have normal ovarian function. Moreover, their use is usually contraindicated in women with estrogen-receptor(ER)-negative and progesterone-receptor-negative cancer, given that such tumors don't respond to other forms of endocrine therapy.

Advanced breast cancer. Several recent double-blind studies involving patients whose tumors were hormone-receptor-positive (or of unknown receptor status), found that third-generation AIs were superior to tamoxifen as first-line treatment for advanced disease.28-30 In contrast, third-generation AIs showed little additional benefit as second-line therapy for advanced breast cancer.31 However, AIs caused very few serious side effects and caused less unwanted weight gain when compared to megestrol acetate. Currently, the benefits of AIs in first-line therapy have diminished the clinical relevance of these findings.

Neoadjuvant therapy. Using tamoxifen as an alternative to surgery has been very successful in producing short-term tumor regression; but it has not been very helpful in long-term local control. That fact has prompted clinicians to view endocrine therapy before surgery—rather than instead of it—as a more attractive option.32 Initiating endocrine therapy before surgery would permit a surgeon to downstage primary cancers to avoid mastectomy and to measure the tumor's in vivo responsiveness to endocrine therapy.33,34 Preoperative administration of third-generation AIs (anastrozole, letrozole, and exemestane) has yielded rates of tumor regression higher than those previously reported for tamoxifen.35,36

AIs for adjuvant therapy

As noted earlier, tamoxifen, given for approximately 5 years after surgery to patients with early, ER-positive breast cancer, is the current standard of care worldwide. This approach reduces the risk of recurrence by 47% and lowers the risk of death by about 26%.37

Unfortunately, tamoxifen is only partially effective in this scenario and continuing this drug beyond 5 years hasn't provided any additional benefit.37 Furthermore, the drug increases the risk of uterine cancer and thromboembolism, and also causes hot flashes and vaginal discharge.38 That said, it's important to stress that the number of lives saved from breast cancer overall far outweighs the small absolute risk for endometrial cancer and thromboembolism. However, despite the benefits tamoxifen offers, there is room for improvement.

The first trial of an AI for adjuvant therapy began more than 20 years ago using aminoglutethimide. Although the drug reduced the risk of tumor recurrence or death early on, this benefit disappeared with longer follow-up.39,40 More recently, sequential administration of aminoglutethimide after tamoxifen therapy, as compared with tamoxifen alone, was associated with a trend toward improved survival.41

At least 10 studies of adjuvant therapy with third-generation AIs that were started within the last decade are still ongoing. Some of these trials directly compared AIs to tamoxifen while others combined AIs with tamoxifen simultaneously or as sequential therapy. The first and largest of these was the Arimidex and Tamoxifen Alone or in Combination (ATAC) trial. The first analysis of ATAC, conducted at a median follow-up of 33 months, showed a small but statistically significant reduction in the rate of breast cancer recurrence with anastrozole as compared to tamoxifen. Interestingly enough, the combination of anastrozole and tamoxifen in the ATAC trial has not been found superior to tamoxifen alone.42

These findings are promising but preliminary. However, in patients with a history of thromboembolism, or those who tolerate tamoxifen poorly, adjuvant therapy with anastrozole seems to be a useful alternative. For that reason, anastrozole was recently granted fast-track approval in the United States and elsewhere for adjuvant treatment of early hormone-receptor-positive breast cancer in postmenopausal women, particularly if tamoxifen is contraindicated. One caveat, though: the American Society of Clinical Oncology evidence-based technology assessment advises women who've already begun tamoxifen therapy not to switch treatments in midstream.12

Halted clinical trial and the future of breast Ca treatment

The results of an international clinical trial recently reported by Goss and colleagues will have a considerable impact on the future of early breast cancer treatment.43 The trial, led by the National Cancer Institute of Canada Clinical Trials Group, included 5,187 women with receptor-positive breast cancer who had completed a 5-year course of tamoxifen and who were then randomized to receive treatment with letrozole—or placebo—for a further 5 years. In the first interim analysis, after a median follow-up of 2.4 years, the independent data and safety monitoring committee recommended terminating the trial and promptly communicating to participants the AI's far-better-than-expected survival results.

Indeed, the study found higher estimated 4-year disease-free survival rates with letrozole (93%) compared to placebo (87%) (P<0.0001). Put another way, letrozole reduced the risk of local or metastatic recurrence or a new contralateral breast cancer by 43% (95% CI, 0.43–0.75; P=0.00008.) Patients in the letrozole arm had more hot flushes, arthritis, arthralgia and myalgia than the placebo group (P<0.05), while vaginal bleeding was more common in the placebo group (P=0.01).

But how do these findings apply in clinical practice? In an editorial accompanying the research report, Bryant and Wolmark tackled that issue, concluding that in light of the short follow-up and the study's premature termination, we need to obtain more data on the adverse effects of AIs.44 That's really the only way to derive an appropriate risk-benefit analysis that would allow treatment decisions. They also voiced concerns that the study's early cessation may have underestimated the adverse effects of long-term AI use, including osteoporosis and cardiovascular events. Unfortunately, because of our limited experience with letrozole, there are inadequate data on its long-term effects for early-stage breast cancer on both survival and adverse events.

Countering bone loss in chemoprevention with AIs

Chemoprevention with AIs might be especially suitable for women with risk factors for breast cancer. Two chemoprevention trials have already shown that tamoxifen reduces the incidence of breast cancer, and previous trials of adjuvant tamoxifen have likewise shown an almost 50% reduction in developing cancer in the contralateral breast.24,45,46 Some researchers call for first developing strategies to avoid the anticipated loss of bone density that AIs induce, before trying these drugs for chemoprevention.25 They propose an alternative approach of using a smaller dose of AI in order to lower the levels of circulating estrogens but not obliterate them.

We suggest another alternative: adding a low dose of estrogen (with or without progestin) to AI treatment, similar to hormonal add-back therapy with GnRH agonists.47 The AI will likely lower local estrogen concentrations in the breast to levels that protect against developing breast cancer, while the low-dose add-back HRT will prevent hot flushes and loss of bone mineral density. This strategy, therefore, could allow long-term use of AIs for prevention of breast cancer.


In short, third-generation AIs represent a new approach to endocrine therapy for postmenopausal women with ER-positive breast cancer. For advanced disease, letrozole is clearly better than tamoxifen, while anastrozole is at least as good. In early breast cancer, adjuvant therapy with anastrozole already appears to be superior to tamoxifen in reducing the risk of relapse, and letrozole appears to be more effective than tamoxifen as preoperative therapy. It's possible that third-generation AIs have a future role in chemoprevention, but the long-term effects of profound estrogen suppression in postmenopausal women are unknown. As their role evolves, therefore, careful monitoring for bone demineralization and other potential problems—like the effect on lipids and brain cognitive functions—is essential.

Drs. Casper and Mitwally hold a patent on aromatase inhibitors for ovulation induction, licensed to Ares-Serono.

In Part II next month, we'll look at the emerging role of aromatase inhibitors as an alternative to clomiphene citrate and gonadotropins for stimulating fertility in breast cancer survivors.


1. Cole PA, Robinson CH. Mechanism and inhibition of cytochrome P-450 aromatase. J Med Chem. 1990; 33:2933-2942.

2. Akhtar M, Njar VC, Wright JN. Mechanistic studies on aromatase and related C-C bond cleaving P-450 enzymes. J Steroid Biochem Mol Biol. 1993;44:375-387.

3. Santen RJ, Manni A, Harvey H, et al. Endocrine treatment of breast cancer in women. Endocr Rev. 1990;11:221-265.

4. Lonning PE. Aromatase inhibition for breast cancer treatment. Acta Oncol. 1996;35:38-43.

5. Buzdar A, Howell A. Advances in aromatase inhibition: clinical efficacy and tolerability in the treatment of breast cancer. Clin Cancer Res. 2001;7:2620-2635.

6. Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol. 2001;19:881-894.

7. Brueggemeier RW. Aromatase inhibitors: mechanisms of steroidal inhibitors. Breast Cancer Res Treat. 1994;30: 31-42.

8. Vanden Bossche HV, Moereels H, Koymans LM. Aromatase inhibitors: mechanisms for non-steroidal inhibitors. Breast Cancer Res Treat. 1994;30:43-55.

9. Santen RJ, Lipton A, Kendall J. Successful medical adrenalectomy with aminoglutethimide. Role of altered drug metabolism. JAMA. 1974;230:1661-1665.

10. Lipton A, Santen RJ. Proceedings: Medical adrenalectomy using aminoglutethimide and dexamethasone in advanced breast cancer. Cancer. 1974;33:503-512.

11. Newsome HH, Brown PW, Terz JJ, et al. Medical and surgical adrenalectomy in patients with advanced breast carcinoma. Cancer. 1977;39:542-546.

12. Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor–positive breast cancer: status report 2002. J Clin Oncol. 2002;20:3317-3327.

13. Marty M, Gershanovich M, Campos B, et al. Letrozole, a new potent, selective aromatase inhibitor (AI) superior to aminoglutethimide (AG) in postmenopausal women with advanced breast cancer (ABC) previously treated with anti-estrogens. Proceedings of the American Society of Clinical Oncology. 1997;16:156a. Abstract 544.

14. Dowsett M. Biological background to aromatase inhibition. The Breast. 1996 5:196-201.

15. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma. Suggestions for a new method of treatment with illustrative cases. Lancet. 1896;2:104-107.

16. Muss HB, Case LD, Atkins JN, et al. Tamoxifen versus high-dose oral medroxyprogesterone acetate as initial endocrine therapy for patients with metastatic breast cancer: a Piedmont Oncology Association study. J Clin Oncol. 1994;12:1630-1638.

17. Kellokumpu-Lehtinen P, Huovinen R, Johansson R. Hormonal treatment of advanced breast cancer. A randomized trial of tamoxifen versus nandrolone decanoate. Cancer. 1987;60:2376-2381.

18. Gale KE, Andersen JW, Tormey DC, et al. Hormonal treatment for metastatic breast cancer. An Eastern Cooperative Oncology Group Phase III trial comparing aminoglutethimide to tamoxifen. Cancer. 1994;73:354-361.

19. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;351:1451-1467.

20. Powles TJ, Hickish T, Kanis JA, et al. Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol. 1996;14:78-84.

21. Love RR, Barden HS, Mazess RB, et al. Effect of tamoxifen on lumbar spine bone mineral density in postmenopausal women after 5 years. Arch Intern Med. 1994;154:2585-2588.

22. Fung MF, Reid A, Faught W, et al. Prospective longitudinal study of ultrasound screening for endometrial abnormalities in women with breast cancer receiving tamoxifen. Gynecol Oncol. 2003;91:154-159.

23. Tamoxifen and endometrial cancer. ACOG Committee Opinion. No. 232. Washington, D.C.: American College of Obstetricians and Gynecologists, 2000.

24. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388.

25. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003;348:2431-2442.

26. Sinha S, Kaseta J, Santner SJ, et al. Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat. Breast Cancer Res Treat. 1998;48:45-51.

27. Stein RC, Dowsett M, Hedley A, et al. The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer. Br J Cancer. 1990;62:679-683.

28. Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001;19:2596-2606.

29. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000;18:3758-3767.

30. Bonneterre J, Thurlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000;18:3748-3757.

31. Hamilton A, Piccart M. The third-generation non-steroidal aromatase inhibitors: a review of their clinical benefits in the second-line hormonal treatment of advanced breast cancer. Ann Oncol. 1999;10:377-384.

32. Cheung KL, Howell A, Robertson JF. Preoperative endocrine therapy for breast cancer. Endocr Relat Cancer. 2000;7:131-141.

33. Smith IE, Lipton L. Preoperative/neoadjuvant medical therapy for early breast cancer. Lancet Oncol. 2001; 2:561-570.

34. Forrest AP, Levack PA, Chetty U, et al. A human tumour model. Lancet. 1986;2:840-842.

35. Dixon JM, Neoadjuvant endocrine therapy. In: Miller WR, Santen RJ, eds. Aromatase Inhibition and Breast Cancer. New York: Marcel Dekker, 2001:103-116.

36. Miller WR, Dixon JM. Endocrine and clinical endpoints of exemestane as neoadjuvant therapy. Cancer Control. 2002;9:9-15.

37. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen for lymph-node negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93:684-690.

38. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;351:1451-1467.

39. Coombes RC, Powles TJ, Easton D, et al. Adjuvant aminoglutethimide therapy for postmenopausal patients with primary breast cancer. Cancer Res. 1987;47: 2494-2497.

40. Jones AL, Powles TJ, Law M, et al. Adjuvant aminoglutethimide for postmenopausal patients with primary breast cancer: analysis at 8 years. J Clin Oncol. 1992;10:1547-1552.

41. Boccardo F, Rubagotti A, Amoroso D, et al. Sequential tamoxifen and aminoglutethimide versus tamoxifen alone in the adjuvant treatment of postmenopausal breast cancer patients: results of an Italian cooperative study. J Clin Oncol. 2001;19:4209-4215.

42. Baum M, Budzar AV, Cuzick J, 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;359:2131-2139.

43. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J. Med. 2003;349:1793-1802.

44. Bryant J, Wolmark N. Letrozole after tamoxifen for breast cancer—What is the price of success? N Engl J Med. 2003;349:1855-1857.

45. Cuzick J, Forbes J, Edwards R, et al. First results from the International Breast Cancer Intervention Study (IBIS-I.: a randomised prevention trial. Lancet. 2002;360:817-824.

46. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen for breast cancer patients with negative lymph nodes and estrogen receptor positive tumors. J Natl Cancer Inst. 1996;88:1529-1542

47. Mitwally MF, Gotlieb L, Casper RF. Prevention of bone loss and hypoestrogenic symptoms by estrogen and interrupted progestogen add-back in long-term GnRH-agonist down-regulated patients with endometriosis and premenstrual syndrome. Menopause. 2002;9:236-241.

Dr. Mitwally is Clinical Fellow, Reproductive Sciences Division, Department of Obstetrics and Gynecology, University of Toronto, and The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada, and Resident, Department of Gynecology and Obstetrics, University at Buffalo, School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, N. Y.; Dr. Casper is Professor, Reproductive Sciences Division, Department of Obstetrics and Gynecology, University of Toronto, and The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.

Key points

  • By blocking production of estrogen, third-generation aromatase inhibitors (AIs) represent a new endocrinologic approach to breast cancer. The AI letrozole greatly reduced breast cancer recurrence in women with early ER-positive disease who'd taken 5 years of tamoxifen. Moreover, AIs are even challenging tamoxifen, the current gold standard.

  • For advanced disease, letrozole is convincingly better than tamoxifen, while the AI anastrozole is at least as good.

  • Anastrozole has received fast-track approval in the US and elsewhere for adjuvant treatment of early hormone-receptor-positive breast cancer in postmenopausal women, particularly if tamoxifen is contraindicated. Letrozole appears to be more effective than tamoxifen as preoperative therapy.

  • Any future role in chemoprevention for third-generation AIs hinges on the as-yet-unknown long-term effects of profound estrogen suppression in postmenopausal women.


Robert Casper, Mohamed Mitwally. Cover Story: Preventing breast Ca with aromatase inhibitors. Contemporary Ob/Gyn Dec. 1, 2003;48:68-80.