ABSTRACT: The aromatase inhibitors are regarded as standard approaches to first- or second-line endocrine therapy in women with hormoneresponsive metastatic breast cancer. Their efficacy and apparent lack of toxicity have led to their evaluation as adjuvant therapy. Although initial results with these agents in early breast cancer are promising, our collective long-term experience documenting tamoxifen’s benefits and our uncertainty about the long-term effects of aromatase inhibitors suggest that it is too early to recommend their routine use in the adjuvant setting. However, anastrozole is also a reasonable therapeutic option in the adjuvant setting, particularly in individuals with a contraindication to tamoxifen such as those with thromboembolic disease or those who develop breast cancer while receiving tamoxifen or raloxifene (Evista) therapy. Anastrozole (Arimidex) was recently approved by the Food and Drug Administration for the adjuvant treatment of postmenopausal women with hormone-receptor–positive early breast cancer. Ongoing trials are assessing the potential role of aromatase inhibitors in the adjuvant, neoadjuvant, and preventive settings.
The modest decline in breast cancer mortality in the United States in the late 1990s (3.4% annually) has been attributed to early detection strategies and effective adjuvant systemic therapy. Despite these promising statistics, the 15-year survival rate for breast cancer is still only about 60%. These data highlight the need for innovative therapies such as the new generation of aromatase inhibitors, including anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara). These drugs specifically target the enzyme aromatase, in contrast to earlier aromatase inhibitors such as aminoglutethimide (Cytadren), which were less selective, less potent, and more toxic.
Currently, the use of tamoxifen for 5 years is regarded as standard treatment for postmenopausal women with early-stage hormone-responsive breast cancer. However, initial data from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial suggest that anastrozole may be at least as effective as tamoxifen for postmenopausal women with estrogen- receptor (ER)-positive tumors.
In this article, we review our current understanding of the role of aromatase inhibitors in the adjuvant treatment of postmenopausal hormone- responsive breast cancer. The review will focus on (1) the function of aromatase inhibitors in breast cancer, (2) clinical trials with aromatase inhibitors in advanced breast cancer, (3) data from trials of aromatase inhibitors in the adjuvant setting including the recently published ATAC trial, (4) results from studies of aromatase inhibitors in the neoadjuvant setting, and (5) current recommendations about adjuvant use of aromatase inhibitors.
Aromatase Inhibitors in Breast Cancer
The enzyme aromatase is part of the cytochrome P450 superfamily. It is required for the peripheral conversion of androstenedione to estro gen, the final step in the estrogen biosynthesis pathway. Aromatase activity is more important in postmenopausal women than in their premenopausal counterparts because most estrogen is produced in the ovaries and regulated by gonadotropins in premenopausal women. In postmenopausal women, conversion of androgen to estrogen in peripheral tissues is the primary source of estrogen.
Aromatase is present in a number of important tissues in females including muscle, fat, skin, neural structures, and breast tissue. Elevated levels of both estrogen and aromatase have been demonstrated in malignant breast tissue, supporting a role for in situ production of estrogen in malignant breast cells. Extensive preclinical and clinical data show that estrogen increases the growth and proliferation of breast cancer cells, and estrogen deprivation leads to tumor regression.
Mechanisms of Action
Aromatase inhibitors use two distinct mechanisms to block the action of aromatase and thereby reduce estrogen production. Type I inhibitors such as exemestane and formestane (Lentaron) are androgen-like compounds that bind irreversibly to the substrate-complex, causing permanent inactivation of the enzyme.[8,9] This could potentially lead to prolonged estrogen deprivation even after the drug is cleared. These drugs are also known as aromatase inactivators. Type II inhibitors such as aminoglutethimide, letrozole, and anastrozole are nonsteroidal compounds that reversibly bind to the heme-iron component of the aromatase enzyme, thereby inhibiting the conversion of androgen to estrogen in an indirect fashion.
Aminoglutethimide, the first clinically available aromatase inhibitor, was introduced in the late 1970s for the second-line treatment of postmenopausal women with advanced breast cancer. The widespread use of this inhibitor was limited by its toxicity and lack of selectivity for the aromatase enzyme, leading to suppression of other steroidal synthetic pathways such as those for glucocorticoids and mineralocorticoids.
In 1993, 4-hydroxyandrostenedione, or formestane, became available as an intramuscular injection. It was more specific and associated with fewer systemic side effects but had to be given frequently and in large doses because of its extensive firstpass metabolism. In the mid- 1990s, a new generation of aromatase inhibitors including letrozole, anastrozole, and exemestane became available in the United States, and fadrozole was released abroad. These new drugs are administered orally and have long half-lives, enabling once-daily dosing.
All three aromatase inhibitors have been shown to almost completely suppress aromatase activity (97%-99%) in postmenopausal women, leading to a significant decrease in estrogen production within 7 days. Maximal estradiol suppression occurs 50% earlier in women taking anastrozole and letrozole compared to exemestane. Aminoglutethimide also suppresses aromatase activity in postmenopausal women by up to 85% but does not reduce estrogen levels to the same degree.[8,12-15] Of note, aromatase inhibitors have been shown to suppress estrogen alone in premenopausal women who are already receiving gonadotropin-releasing hormone agonists.[3,16,17]
The new aromatase inhibitors are also more selective and potent, resulting in decreased toxicity compared with aminoglutethimide, although type I steroidal inhibitors like exemestane can cause dose-related androgenic side effects. Neither anastrozole nor exemestane affects cortisol and aldosterone levels, but both can suppress sex hormone-binding globulin levels. Letrozole can decrease cortisol and increase both aldosterone and sex hormone-binding globulin levels. Whether any of these biochemical and pharmacologic differences translate into significant clinical differences remains to be seen.[3,8]
There are also differences in how the aromatase inhibitors interact with tamoxifen. The simultaneous use of aminoglutethimide and tamoxifen leads to a 70% decrease in tamoxifen concentrations. On the other hand, the combination of tamoxifen and letrozole results in a 40% reduction in plasma concentrations of letrozole.[ 20-21] Anastrozole does not seem to interact with tamoxifen when given in combination.[22,23] These results are important in the consideration of combined endocrine therapy.
1. Ries L, Kosary C, Hankey B (eds): SEER
Cancer Statistics Review, 1973-1996, National
Cancer Institute NIH Pub No. 99-2789. Bethesda,
Md, National Cancer Institute, 1996.
2. American Cancer Society: Breast Cancer
Facts and Figures 2001-2002. Atlanta, American
Cancer Society, 2002.
3. Goss PE, Strasser K: Aromatase inhibitors
in the treatment and prevention of breast
cancer. J Clin Oncol 19:881-894, 2001.
4. Osborne CK: Tamoxifen in the treatment
of breast cancer. N Engl J Med 339:1609-1618,
5. The ATAC Trialists Group: 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 359:2131-2139, 2002.
6. Clemons M, Goss P: Estrogen and the risk
of breast cancer. N Engl J Med 344:276-285,
7. Gruber CJ, Tschugguel W, Schneeberger
C, et al: Production and actions of estrogens.
N Engl J Med 346:340-352, 2002.
8. Boeddinghaus IM, Dowsett M: Comparative
clinical pharmacology and pharmacokinetic
interactions of aromatase inhibitors.
J Steroid Biochem Mol Biol 79:85-91,
9. Lonning PE, Geisler J, Johannessen DC,
et al: Pharmacokinetics and metabolism of
formestane in breast cancer patients. J Steroid
Biochem Mol Biol 77:39-47, 2001.
10. 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 73:354-361,
11. Buzdar A, Howell A: Advances in aromatase
inhibition: Clinical efficacy and tolerability
in the treatment of breast cancer. Clin
Cancer Res 7:2620-2635, 2001.
12. Howell A, Downey S, Anderson E: New
endocrine therapies for breast cancer. Eur J
Cancer 32A:576-588, 1996.
13. Dowsett M, Jones A, Johnston SR, et al:
In vivo measurement of aromatase inhibition
by letrozole (CGS 20267) in postmenopausal
patients with breast cancer. Clin Cancer Res
14. Geisler J, King N, Anker G, et al: In vivo
inhibition of aromatization by exemestane, a
novel irreversible aromatase inhibitor, in postmenopausal
breast cancer patients. Clin Cancer
Res 4:2089-2093, 1998.
15. MacNeill FA, Jones AL, Jacobs S, et al:
The influence of aminoglutethimide and its analogue
rogletimide on peripheral aromatisation
in breast cancer. Br J Cancer 66:692-697, 1992.
16. 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
17. Wouters W, De Coster R, Tuman RW, et
al: Aromatase inhibition by R 76713: Experimental
and clinical pharmacology. J Steroid
Biochem 34:427-430, 1989.
18. di Salle E, Ornati G, Giudici D: Exemestane
(FCE24304); a new steroidal aromatase
inhibitor. J Steroid Biochem Mol Biol 43:143,
19. Lien EA, Anker G, Lonning PE, et al:
Decreased serum concentrations of tamoxifen
and its metabolites induced by aminoglutethimide.
Cancer Res 50:5851-5857, 1990.
20. Dowsett M, Pfister CU, Johnston SR, et
al: Pharmacokinetic interaction between letrozole
and tamoxifen in postmenopausal patients with advanced breast cancer. The Breast 6:245,
Mentioned in This Article
Brand names are listed in parentheses only
if a drug is not available generically and is
marketed as no more than two trademarked or
registered products. More familiar alternative
generic designations may also be included
References continued on following page.
21. Ingle JN, Suman VJ, Jordan VC, et al:
Combinational hormonal therapy involving aromatase
inhibitors in the management of women
with breast cancer. Endocr Relat Cancer
22. Dowsett M, Tobias JS, Howell A, et al:
The effect of anastrozole on the pharmacokinetics
of tamoxifen in post-menopausal women
with early breast cancer. Br J Cancer
23. The ATAC Trialists Group: Pharmacokinetics
of anastrozole and tamoxifen alone,
and in combination, during adjuvant endocrine
therapy for early breast cancer in postmenopausal
women: A sub-protocol of the “Arimidex
and tamoxifen alone or in combination”
(ATAC) trial. Br J Cancer 85:317-324, 2001.
24. Kaufmann M, Bajetta E, Dirix LY, et al:
Exemestane is superior to megestrol acetate
after tamoxifen failure in postmenopausal women
with advanced breast cancer: Results of a
phase III randomized double-blind trial. The
Exemestane Study Group. J Clin Oncol
25. Jonat W, Howell A, Blomqvist C, et al:
A randomised trial comparing two doses of the
new selective aromatase inhibitor anastrozole
(Arimidex) with megestrol acetate in postmenopausal
patients with advanced breast cancer.
Eur J Cancer 32A:404-412, 1996.
26. Dombernowsky P, Smith I, Falkson G,
et al: Letrozole, a new oral aromatase inhibitor
for advanced breast cancer: Double-blind randomized
trial showing a dose effect and improved
efficacy and tolerability compared with
megestrol acetate. J Clin Oncol 16:453-461,
27. Buzdar AU, Jones SE, Vogel CL, et al: A
phase III trial comparing anastrozole (1 and 10
milligrams), a potent and selective aromatase
inhibitor, with megestrol acetate in postmenopausal
women with advanced breast carcinoma.
Arimidex Study Group. Cancer 79:730-739,
28. Buzdar AU, Jonat W, Howell A, 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 83:1142-1152, 1998.
29. Buzdar A, Douma J, Davidson N, et al:
Phase III, multicenter, double-blind, randomized
study of letrozole, an aromatase inhibitor,
for advanced breast cancer versus megestrol
acetate. J Clin Oncol 19:3357-3366, 2001.
30. Gershanovich M, Chaudri HA, Campos
D, et al: Letrozole, a new oral aromatase inhibitor:
Randomised trial comparing 2.5 mg daily,
0.5 mg daily and aminoglutethimide in postmenopausal
women with advanced breast cancer.
Letrozole International Trial Group (AR/
BC3). Ann Oncol 9:639-645, 1998.
31. Nabholtz JM, Buzdar A, Pollak M, et al:
Anastrozole is superior to tamoxifen as firstline
therapy for advanced breast cancer in postmenopausal
women: Results of a North
American multicenter randomized trial. Arimidex
Study Group. J Clin Oncol 18:3758-3767,
32. 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
33. Bonneterre J, Thurlimann B, Robertson
JF, et al: Anastrozole versus tamoxifen as firstline
therapy for advanced breast cancer in 668
postmenopausal women: Results of the Tamoxifen
or Arimidex Randomized Group Efficacy
and Tolerability study. J Clin Oncol 18:3748-
34. Geisler J, Haynes B, Anker G, et al:
Influence of letrozole and anastrozole on total
body aromatization and plasma estrogen levels
in postmenopausal breast cancer patients evaluated
in a randomized, cross-over study. J Clin
Oncol 20:751-757, 2002.
35. Rose C, Vtoraya O, Pluzanska A, et al:
Letrozole (Femara) vs anastrozole (Arimidex):
Second-line treatment in postmenopausal women
with advanced breast cancer (abstract 131).
Proc Am Soc Clin Oncol 21:34a, 2002.
36. Lonning PE, Bajetta E, Murray R, et al:
Activity of exemestane in metastatic breast cancer
after failure of nonsteroidal aromatase
inhibitors: A phase II trial. J Clin Oncol
37. Jones AL, Powles TJ, Law M, et al:
Adjuvant aminoglutethimide for postmenopausal
patients with primary breast cancer:
Analysis at 8 years. J Clin Oncol 10:1547-
38. 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 19:4209-4215, 2001.
39. Osborne CK, Hobbs K, Clark GM: Effect
of estrogens and antiestrogens on growth
of human breast cancer cells in athymic nude
mice. Cancer Res 45:584-590, 1985.
40. Early Breast Cancer Trialists’ Collaborative
Group: Tamoxifen for early breast cancer:
An overview of the randomised trials.
Lancet 351:1451-1467, 1998.
41. Fisher B, Costantino J, Redmond C, et
al: A randomized clinical trial evaluating tamoxifen
in the treatment of patients with nodenegative
breast cancer who have
estrogen-receptor-positive tumors. N Engl J
Med 320:479-484, 1989.
42. Miller WR, Telford J, Love C, et al:
Effects of letrozole as primary medical therapy
on in situ estrogen synthesis and endogenous
levels within the breast. The Breast 7:276, 1998.
43. Geisler J, Bernsten L, Ottestad L, et al:
Comparison of the effects of neoadjuvant
“Arimidex” (anastrozole) on plasma and intratumor
tissue estrogen levels in postmenopausal
breast cancer patients. The Breast 8:241, 1999.
44. Dixon JM, Love CD, Renshaw L, et al:
Lessons from the use of aromatase inhibitors in
the neoadjuvant setting. Endocr Relat Cancer
45. Dixon JM, Renshaw L, Bellamy C, et al:
The effects of neoadjuvant anastrozole (Arimidex)
on tumor volume in postmenopausal wom-en with breast cancer: A randomized, doubleblind,
single-center study. Clin Cancer Res
46. Dixon MJ, Renshaw C, Bellamy DA, et
al: “Arimidex” as neoadjuvant therapy causes
large reductions in tumor volume in postmenopausal
women with large operable breast cancers
(abstract 345). Proc Am Soc Clin Oncol
47. Miller WR, Dixon JM: Endocrine and
clinical endpoints of exemestane as neoadjuvant
therapy. Cancer Control 9:9-15, 2002.
48. Dixon JM, Love CDB, Tucker C, et al:
Letrozole as primary medical therapy for locally
advanced and large operable breast cancer.
Eur J Cancer 34:S13, 1998.
49. Ellis MJ, Coop A, Singh B, et al: Letrozole
is more effective neoadjuvant endocrine
therapy than tamoxifen for ErbB-1- and/or
ErbB-2-positive, estrogen receptor-positive primary
breast cancer: Evidence from a phase III
randomized trial. J Clin Oncol 19:3808-3816,
50. The National Institutes of Health Consensus
Development Conference: Adjuvant
Therapy for Breast Cancer. Bethesda, Md, Nov
1-3, 2000. J Natl Cancer Inst Monogr, pp 1-
51. Goldhirsch A, Glick JH, Gelber RD, et
al: Meeting highlights: International Consensus
Panel on the Treatment of Primary Breast
Cancer. Seventh International Conference on
Adjuvant Therapy of Primary Breast Cancer. J
Clin Oncol 19:3817-3827, 2001.
52. 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 20:1-15,
53. Harper-Wynne C, Ross G, Sacks N, et
al: Effects of the aromatase inhibitor letrozole
on normal breast epithelial cell proliferation
and metabolic indices in postmenopausal women:
A pilot study for breast cancer prevention.
Cancer Epidemiol Biomarkers Prev 11:614-
54. Dowsett M: Theoretical considerations
for the ideal aromatase inhibitor. Breast Cancer
Res Treat 49(suppl 1):S39-S44, 1998.