Role of aromatase inhibitors in the treatment of breast cancer

Role of Aromatase

Inhibitors

in the Treatment

of Breast

Toni K. Choueiri, MD, Carlos A. Alemany, MD, Rony M. Abou-Jawde, and G. Thomas Budd, MD Department

Cancer

MD,

of Hematology and Medical Oncology, Taussig Cancer Centel; The Cleveland Clinic Foundation,

Cleveland, Ohio

ABSTRACT

Background: Estrogens play a pivotal role in the development of breast cancer. Endocrine therapy based on estrogen blockade is a well-established treatment in hormone-dependent breast cancer. Tamoxifen citrate has long been considered the “gold standard” due to its relative safety and efficacy Aromatase inhibitors are antiestrogen agents that target specifically the aromatase enzyme, which is the final step in the estrogen production. The first use of aromatase inhibitors in breast cancer was associated with adverse effects such as rash, drowsiness, and adrenal-gland suppression. Newer third-generation agents are emerging as potential alternatives to tamoxifen, associating clinical efficacy with a more favorable safety profile. Objectives: The aim of this article is to review the mechanisms of actions, pharmacology, adverse effects, and clinical applications of the aromatase inhibitors available in the United States. Methods: The terms breast cancer or neoplasia, aromatase, avomatase inhibitors, third-generation, endoctine therapy, and antiestrogens were used to search MEDLINE for English-language studies published between 1966 and April 2004. A parallel search was performed at the corresponding Web site of each of the aromatase inhibitors available in the United States. Identified publications relevant to the article objectives were selected. Results: Anastrozole, letrozole, and exemestane are the 3 commercially available aromatase inhibitors approved by the US Food and Drug Administration for the treatment of hormone receptor-positive breast cancer in postmenopausal women. They have been used in several clinical scenarios, including advanced and early disease and chemoprevention, and in the neoadjuvant setting. There is evidence that aromatase inhibitors are more effective and tolerable than tamoxifen in advanced breast cancer and in the neoadjuvant setting. Based on the results of a large, randomized trial, their use in early disease and in chemoprevention is also promising. Aromatase inhibitors appear safe; however, the long-term safety profile is still unknown, especially concerning bone metabolism. Conclusion: Third-generation aromatase inhibitors are a new treatment modality in estrogen and/or progesteronereceptor positive breast cancer. Although they are replacing the “classic” antiestrogen agents used in metastatic breast cancer, their benefit in early disease and as chemopreventive agents is not completely clear. Ongoing clinical studies should become available within the next few years and will provide additional recommendations for their use in patients with breast cancer. (Clin Ther. 2004;26: 1199-12 14) Copyright 0 2004 Excerpta Medica, Inc. Key words: third-generation aromatase inhibitors, breast cancer, early disease, advanced disease, neoadjuvant, adjuvant, chemoprevention, side effects. Acceptedfor publicationJune 14, 2004. Printed in the USA. Reproduction in whole

Copyright@

2004 Excerpta

MedicaJnc.

or part IS not permitted.

0149-2918/04/$19.00

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CLINICAL THERAPEUTICS@

INTRODUCTION

Most established risk factors for breast cancer act via hormone-related pathways, and increased concentrations of circulating estrogens have been found to be strongly associated with increased risk for breast cancer cell growth in postmenopausal women. 1 Oophorectomy has been used in premenopausal patients to treat breast cancers for >100 years/ Although ovarian estrogen production stops after menopause, estrogen continues to be secreted by peripheral tissues such as muscles and adipose stroma. 3 Another interesting source is in the tumor itself: 70% of breast cancer cells have been found to produce estrogens in vitro. ~ Regardless of the source of estrogen, the need for a potent and safe antiestrogen agent is crucial to counter estrogen effects on breast cancer cell growth. Tamoxifen citrate, a selective estrogen-receptor (ER) antagonist, binds to ERs and inhibits the growth of tumor cells. It has been the standard treatment for node-positive and node-negative cancer for many years, providing a 26% 5-year survival benefit, s Although the benefits from tamoxifen use were prominent, its antagonist effect seemed partial. Moreover, investigators have observed an increased risk for uterine cancers (risk ratio, 2.53), venous thromboembolism, and stroke with tamoxifen. 6 Aromatase inhibitors have a different mechanism of action than tamoxifen. Aromatase inhibitors act to block estrogen synthesis (Figure 1) by inhibiting the

last step of the estrogen biosynthetic pathway, which ensures that the other steroid classes are not affected. First-generation aromatase inhibitors (eg, aminoglutethimide) and second-generation aromatase inhibitors (eg, formestane, fadrozole hydrochloride) have been tested and found to be efficacious. However, their clinical use remains controversial due to significant adverse effects such as rash, drowsiness, and mineralocorticoid suppression. 7,8 Third-generation aromatase inhibitors were developed in the early 1990s, and those approved by the US Food and Drug Administration (FDA) for use in the treatment of breast cancer include anastrozole, letrozole, and exemestane, the structures of which are shown in Figure 2. Their specificity for the enzyme aromatase appears to be complete, with no noticeable effect on the adrenal a x i s . 9 The objective of this article is to review the mechanism of action of each third-generation aromatase inhibitor, with their up-to-date clinical use in the setting of postmenopausal hormone receptor (HR)positive breast cancer. For that purpose, the terms breast cancer or neoplasia, aromatase, aromatase inhibitors, third-generation, endocrine therapy, and antiestrogens were used to search the MEDLINE database for English-language studies published between 1966 and April 2004. The corresponding product information at the Web site of each of the aromatase inhibitors available in the United States was also searched. Identified publications relevant to these objectives were selected.

Androstenedione

Testosterone

~ Aromatase(fat,muscleliver, , brain) Estrone

Aromatase

Aromatase inhibitors ~

Estradiol

°J

® ®,.,

/

Tamoxifen

O®

Breast cancer cell nucleus

Estrogen receptor

Figure I. Mechanism of action of aromatase inhibitors compared with tamoxifen in postmenopausal women.

1200

T. K. Choueiri et al.

Aromatase inhibitors are not used in premenopausal women with functional ovaries or in women with ER and progesterone receptor (PR)negative cancer. One study ~° has shown that aromatase inhibitors do not decrease estrogen levels enough in premenopausal women to affect tumor growth. In addition, the resultant increase in gonadal stimulation after aromatase inhibition can lead to the development of ovarian follicles. ~ A summary comparing anastrozole, letrozole, and exemestane is shown in the table. ANASTROZOLE

Anastrozole,* a potent and selective third-generation nonsteroidal aromatase inhibitor, blocks the conversion of androstenedione to estrone, and testosterone to estradiol. Anastrozole binds reversibly to aromatase and fits into the substrate-binding site, such that azole nitrogens interact with the heme prosthetic g r o u p ) * It is considered a type II, nonsteroidal aromatase inhibitor, a property shared by letrozole. It is available in an oral formulation (1-mg tablets given QD).

*Trademark:Arimidex®(AstraZenecaPharmaceuticalsLP,Wilmington, Delaware).

Pharmacokinetic Properties

Anastrozole is completely absorbed from the gastrointestinal tract after oral administration, and its Tmax is >2 hours. 35,36 The tl/2 for a 1-mg PO dose is -40.6 h o u r s ) r The drug is metabolized in the liver via N-dealkylation, hydroxylation, and glucuronidation. Its inactive metabolite is a triazole) 8 The Css of anastrozole occurs after 7 days of treatment. Approximately 40% of the drug is bound to plasma proteins. > Because the kidney is not a major elimination pathway, dosage adjustment is not necessary, even in patients with severe renal impairment. One pharmacokinetic study 12 of anastrozole in patients with stable hepatic cirrhosis has demonstrated plasma concentrations within the range observed in healthy volunteers. Drug Interactions

Anastrozole inhibits several cytochrome (CY) P450 enzymes, including CYP1A2, CYP2C9, and CYP3A, but it does not cause clinically significant interactions with other CYP-metabolized drugs at physiologically relevant concentrations achieved during therapy with anastrozole. *° Tamoxifen has been shown to lower plasma anastrozole concentrations by -27%. Concurrent use of estrogens may decrease the efficacy of

Anastrozole

Letrozole

."iJ-

N

C

~

C

N

CH2 Figure 2. Structures of anastrozole, letrozole, and exemestane.

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CLINICALTHERAPEUTICS®

anastrozole. .1 Anastrozole does not seem to have any clinically relevant effect on the pharmacokinetic or pharmacodynamic properties of warfarin sodium. .2 Pharmacodynamic Properties

Anastrozole given at a dosage of 1 mg/d PO to postmenopausal women has been shown to inhibit in vivo aromatization by a mean value of 96.7%. It has also been shown to suppress plasma estrone, estradiol, and estrone sulfate by >86.5%, >83.5%, and >93.5%, respectively. .3 The maximal plasma suppression of plasma estrogens occurs after 3 to 4 days of administration) 5 Anastrozole administered at dosages up to 10 mg/d does not seem to have any clinically significant effects on the response of glucocorticoid or mineralocorticoid secretion to adrenocorticotropic hormone stimulation) 6

Clinical St-dies

Tamoxifen has been the standard hormonal treatment for HR-positive breast cancer in both the adjuvant and metastatic settings. It has been found that after disease progression occurs, effective hormonal treatments are limited. Second-line therapies included megestrol acetate (MA) and aminoglutethimide, but their adverse-effect profiles made them less tolerable in an already susceptible population. A d v a n c e d Disease Anastrozole as Second-Line Therapy

Anastrozole was initially investigated as a second-line treatment for metastatic breast cancer. Jonat et al~* compared 2 dosages of anastrozole (1 mg/d and 10 mg/d) with 40 mg/d of MA to treat inoperable advanced breast cancer in 378 patients after progression on

Table. Comparison of the 3 aromatase inhibitors commercially available in the United States.

Characteristic

Anastrozole

Letrozole

Exemestane

Brand name

Arimidex °12*

Femara® 19~-

Aromasin®265

Class

Type II, n onsteroidal I

Elimination halflife, h

40.6

Excretion

Hepatic

Advanced disease (first-line)

Similar objective response compared with tamoxifen Is,14

Type II,nonsteroidal 2.5 48 Renal Better objectiveresponse

Type I, steroidal

Dose per day, mg

Early disease

Better DFS than tamoxifen at 47 mo ~5,~6

25 27 Hepatic/renal Efficacious in Phase II trials 27

than tamoxifen s Better than placebo after 5 y oftamoxifen treatment 21

Better DFS after 2 3 y of tamoxifen than 5-y tamoxifen regimen s

Neoadjuvant

Efficacious in Phase II trials 17

More efficacious than tamoxifen in Phase III trials 22,s

Suggestive Phase II study >

Chemoprevention

Suggestive effect from ATAC trial I s; ongoing IBIS-II trial

Positive benefit in trial by Goss et a121

Ongoing NCIC-CTG trial 3°

Adverse effects

Hot flashes, arthralgias/arthritis, generalized pain, headaches 15

Hot flashes, arthritis, myalgias, arthralgias, bone loss, and dyslipidemias21,24,25

Hot flashes, nausea, diarrhea, fatigue, leukopenia; may be associated with better lipid and bone profiles than with other aromatase inhibitors s,sl ss

DFS = disease@ee survival; ATAC = Arimidex, Tamoxifen Alone or in Combination; IBIS = International Breast Cancer Intervention Study; NCICCTG = National Cancer In~itute of Canada's ClinicalTrials Group. ~Trademark of AstraZeneca Pharmaceuticals LP (Wilmington, Delaware). fTrademark of Novartis PharmaceuticalsCorporation (Ea~ Hanover, New Jersey). STrademarkof Pfizer Inc (NewYork, NewYork).

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tamoxifen treatment. No statistically significant differences were found between the 1-mg and 10-mg doses of anastrozole versus MA in terms of median time to progression (TTP) (132, 156, and 120 days, respectively). Also, there were no significant between-group differences in response rate or time to treatment failure (TTF). However, a significant difference in the toxicity profile was found, with peripheral edema and weight gain more common in the MA group compared with the anastrozole 1-mg group (P = 0.045 and P = 0.022, respectively). Buzdar et al ~5 performed a similar trial in North America, with similar results demonstrating no significant differences in response rate, TTP, TTE and time to death. In this study, quality-of-life assessments were performed, as well as assessment of the severity of bone pain, performance status, and type of analgesics. A difference in physical scores was found in the anastrozole 1-mg group compared with the MA group (P < 0.025). Body weight gain and edema were more common in the MA group (16% and 17%, respectively) versus the anastrozole 1-mg and 10-mg groups (1%-5% and 11%-12%, respectively). Gastrointestinal disturbances were more c o m m o n in the patients randomized to receive anastrozole (38%-43% vs 27% in the MA group). In a double-blind comparison, ~6 anastrozole was compared with fulvestrant, a pure antiestrogen that acts as an ER down-regulator. Four hundred patients were randomized to receive either a daily dose of 1 mg of anastrozole or a monthly IM injection of fulvestrant 250 mg. The primary end point, TTE was similar between the 2 groups (5.4 months vs 3.4 months). The secondary end point, objective response, was similar in the 2 groups (both, 17.5%), but in an unplanned analysis of the patients who responded to either therapy, the median duration of response was 19.0 months in the fulvestrant group versus 10.8 months in the anastrozole cohort (P < 0.01). ~6 A similar European study by Mauriac et al ~r showed objective response rates similar in patients treated with fulvestrant and anastrozole (21.9% vs 19.3%, respectively). The proportion of patients with clinical benefit was also similar between the 2 treatments and between subgroups with and without visceral diseasef r

Anastrozole as First-Line Therapy

The Arimidex Study Group compared anastrozole with tamoxifen as first-line therapy for advanced breast cancer in 2 separate identical trials. 13,1~ In the North American trial, 13 353 women with HRpositive or HR-unknown metastatic breast cancer were randomized to receive 1 mg of anastrozole or 20 mg of tamoxifen QD. In this trial, Nabholtz et al ~3 reported that anastrozole was as effective as tamoxifen in terms of objective response (21% vs 17%, respectively), but showed a clinical benefit (complete response + partial response + stabilization >24 weeks) for anastrozole of 59% versus 46% (2-sided P < 0.010, retrospective analysis) at 24 weeks. Anastrozole showed a significant advantage in terms of TTP (11.1 months vs 5.6 months for tamoxifen; 2-sided P = 0.005). Although both treatments were well tolerated, there were more thromboembolic events in the tamoxifen group (8.2% vs 4.1%), as well as more reports of vaginal bleeding compared with anastrozole (3.8% vs 1.2%). Bonneterre et al ~ conducted a similar trial that involved 668 postmenopausal women, of whom 55% had unknown HR status (compared with 11% in the North American trial~3). The investigators found anastrozole was at least as effective as tamoxifen with regard to objective response (32.9% vs 32.6%, respectively) and TTP (8.2 months vs 8.3 months, respectively). Again, the observation was made for more cases of thromboembolic events as well as vaginal bleeding episodes among the women who received tamoxifen. These 2 studies ~3,1~ were later combined, and a retrospective analysis ~8 of the data showed that for ERpositive and/or PR-positive patients, the median TTP was 10.7 months for the anastrozole group versus 6.4 months for the tamoxifen group (P = 0.02).

Disease Adjuvant Setting Early

Tamoxifen has long been the standard hormonal adjuvant therapy for early breast cancer. An overview of the randomized trials involving - 3 0 , 0 0 0 patients 5 showed a significant reduction of relapses and deaths at 5 years in women who received 20 mg of tamoxifen compared with those receiving placebo (P < 0.001). In 1996, the Arimidex, Tamoxifen Alone or in Combination (ATAC) Trialists' Group, comprising investigators from 21 countries, conducted one of the

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largest clinical trials in breast cancer to date, 15 comparing a daily dose of 1 mg of anastrozole with that of 20 mg of tamoxifen for 5 years. A third arm of the trial combined the use of both medications. A total of 9366 patients were randomized between the 3 groups. Eighty-four percent of the patients were known to have HR-positive cancer. After a mean follow-up of 33 months, disease-free survival (DFS) was higher in the anastrozole group (89.4% vs 87.4%; P = 0.013). In the combined-drug group, results for DFS were not significantly different from those in the tamoxifen-monotherapy group (87.2% vs 87.4%). The improvement in DFS with anastrozole was seen in the subgroup of HR-positive patients, but not in the HR-negative patients. In terms of tolerability, the anastrozole monotherapy was better tolerated than tamoxifen with regard to endometrial cancer (P = 0.02), vaginal bleeding and discharge (both, P < 0.001), cerebrovascular events (P < 0.001), and hot flashes (P < 0.001). The tamoxifen group had few musculoskeletal disorders (eg, arthralgias, myalgias) and fractures (both, P < 0.001) compared with anastrozole. A second formal report of the ATAC Trialists' Group 16 found a continued benefit in the anastrozolemonotherapy group with regard to DFS (86.9% vs 84.5%) after a median follow-up of 47 months. The combination arm of tamoxifen + anastrozole was discontinued after the first report showed no benefit compared with tamoxifen. All the previously reported adverse effects of vaginal dryness/bleeding, thromboembolic events, cerebrovascular events, and hot flashes continued to be significantly more common in the tamoxifen arm (P < 0.001). Musculoskeletal disorders and fractures continued to be more prevalent in the anastrozole group (30.3% and 7.1%, respectively) compared with those patients receiving tamoxifen (24.7% and 5.7%, respectively; both, P < 0.001). Because of the long-term safety record of tamoxifen and the relatively short follow-up of this study, tamoxifen is still regarded as the standard adjuvant hormonal treatment. .9 As a result of the ATAC trial, anastrozole was approved by the FDA for adjuvant use in the United States. The choice of adjuvant therapy is now individualized, based on a riskbenefit analysis, because it is unclear whether longterm anastrozole treatment impacts bone density significantly. 1204

Neoadjuvant Setting Neoadjuvant therapy using active chemotherapy agents is reserved for patients with large primary tumors, involvement of the thoracic wall, skin infiltration, and/or extensive lymph node involvement. Mastectomy is sometimes not an option for elderly (age >65) individuals on the basis of poor performance status, comorbid conditions, and/or patient refusal. 5° Tamoxifen has been used as neoadjuvant therapy and has been associated with high rates of tumor regression, but only for short periods of time (-3 months), lr A small, single-center, randomized, Phase II trial by Dixon et a151 evaluated anastrozole to determine its efficacy as neoadjuvant therapy in postmenopausal women with newly diagnosed, ER-rich, locally advanced or large (>3 cm) breast cancers. Twentyfour patients were randomized to receive either 1 mg or 10 mg of anastrozole QD for 12 weeks. The median reductions in tumor volumes as measured by ultrasound for those patients were 80.5% and 69.6% for anastrozole (1 mg and 10 mg, respectively) after 12 weeks of treatment (P < 0.05). Of the 17 patients who would have required a mastectomy at the initiation of treatment, 15 (88.2%) were suitable for breastconservation surgery after anastrozole treatment. These results suggest that anastrozole is an effective neoadjuvant therapy in postmenopausal women with ER-rich, large, operable breast cancer. Additional studies with large numbers of patients are needed to confirm these findings. Anastrozole in the Prevention of Breast Cancer

Tamoxifen is the only hormonal therapy approved by the FDA for the prevention of breast cancer in women at high risk, based on the National Surgical Adjuvant Breast and Bowel Project (NSABP) Pl trial. 6 Based on another NSABP study, 18 the standard of care for patients with HR-positive ductal carcinoma in situ is adjuvant tamoxifen for 5 years after adjuvant postoperative radiotherapy. Interest in studying anastrozole as a chemopreventive agent was fueled after the ATAC trial showed that the incidence of contralateral breast cancer was numerically lower but statistically nonsignificant in the group receiving anastrozole (25 vs 40 cases in the tamoxifen group). When the HR receptor-positive

T. K. Choueiri et al.

cases were analyzed alone, 20 patients in the anastrozole group had contralateral breast cancer versus 35 in the tamoxifen group (P = 0.04). 51 This prompted the International Breast Cancer Intervention Study (IBIS) to start a double-blind, randomized, controlled trial (IBIS-II) to test whether 1 mg/d of anastrozole given for 5 years to women with high-risk breast cancer would prevent more new breast cancers compared with 20 mg/d of tamoxifen. A substudy will also include patients with ductal carcinoma in situ. Anastrozole for Advanced Breast Cancer in Premenopausal W o m e n There is promising evidence that anastrozole in combination with a gonadotropin-releasing hormone agonist is effective in premenopausal patients with advanced breast cancer who had failed a gonadotropin-releasing hormone agonist-tamoxifen combination regimen. 52 Forward et a152 reported that 12 of 16 patients (75%) achieved objective response or durable stable disease at 6 months, with a median duration of remission of 17+ months (range, 6-47 months). These patients received monthly goserelin acetate (3.6 mg) injections in combination with daily anastrozole (1 mg). Anastrozole use continues to be reserved for clinical trials in premenopausal patients. Adverse Effects The most common adverse effects of anastrozole treatment are hot flashes (up to 35% of patients), weakness, arthralgias/arthritis, generalized pain, and headaches. 12 Anastrozole can increase mean serum total cholesterol by 0.5 mmol/L, although it is unclear whether, and perhaps unlikely that, this would result in clinical effects. 12 Anastrozole is more likely than tamoxifen to cause musculoskeletal disorders and fractures, based on data from the ATAC trial. 15,16 However, less vaginal bleeding and discharge, fewer cerebrovascular events, and fewer hot flashes were noted with anastrozole compared with tamoxifen (P < 0.001). 15 LETROZOLE Letrozole,* like anastrozole and exemestane, is a thirdgeneration aromatase inhibitor that produces near*Trademark: Femara ® (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey).

complete estrogen suppression and has a negligible effect on mineralocorticoid or glucocorticoid synthesis, in contrast to the earlier first- and second-generation aromatase inhibitors. 53 Because of its nonsteroidal nature, it is considered a type II aromatase inhibitor, a property shared by anastrozole but not exemestane. It binds reversibly to the heme group of the CYP450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis of >98% in all tissues. 5~ It is available in an oral formulation (2.5-mg tablets given QD with or without food). Pharmacokinetic Properties Letrozole is rapidly absorbed in the gastrointestinal tract without being affected by food. Its tl/2 is - 4 8 hours, and it reaches a Css in 2 to 6 weeks at a dosage of 2.5 mg/d. 55 The C is maintained over time and continuous accumulation of letrozole does not occur. 18 Letrozole is weakly bound to protein, mainly albumin, and has a large Vd (mean, 1.87 [0.47] L/kg). The major pathway of letrozole clearance is through renal excretion of the pharmacologically inactive carbinol metabolite. 9 No dose adjustments are needed in patients with renal or hepatic insufficiency, although such patients should be carefully monitored for adverse effects. 56 Drug Interactions Studies have shown a low potential for drug-drug interactions with letrozole. Of particular interest are cimetidine hydrochloride and warfarin, both known to interact with many drugs. Coadministration of letrozole with these drugs does not result in significant clinical interactions. 18 On the other hand, a 40% reduction in the letrozole AUC is seen when tamoxifen is administered concomitantly. The clinical pharmacologic meaning of this interaction remains unknown and may be irrelevant because combined therapy with these drugs is investigational. 57 Pharmacodynamic Properties One initial study 6° in vitro and in vivo showed that letrozole is several hundredfold more potent than aminoglutethimide (a first-generation aromatase inhibitor) and can be 10- to 30-fold more potent than anastrozole in inhibiting rat mammary tumors. Doses of 0.5 mg or higher were shown to suppress estradiol and estrone below the limit of detection in the assays.

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Plasma concentrations of cortisol, aldosterone, thyroid hormones, and androgens were not affected by letrozole treatment. 58 Geisler et al 5~ found letrozole to be a more potent suppressor of total-body aromatization and plasma estrogen levels compared with anastrozole in 12 postmenopausal women with metastatic breast cancer. Clinical Studies Advanced Disease Letrozole as Second-Line Therapy

Letrozole has been shown to have efficacy similar to that of MA in 2 large, randomized studies. 59,6° Dombernowsky et a159 randomized 551 patients with locally advanced, locoregionally recurrent or metastatic breast cancer, previously treated with antiestrogens, to receive letrozole 2.5 mg, letrozole 0.5 mg, or MA 160 mg once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables with up to 33 months of follow-up evaluation and for survival up to 45 months. The group of patients who received letrozole 2.5 mg/d had a significantly higher overall objective response (24%) compared with the patients who received MA (16%; P = 0.04) or letrozole 0.5 mg (13%; P = 0.004). Duration of objective response (P = 0.04) and TTF (P = 0.02) were significant for letrozole 2.5 mg compared with MA. Letrozole was associated with less weight gain and edema than MA, with 11% of patients discontinuing treatment compared with only 3% with letrozole. In a 5-year, multinational, multicenter, doubleblind, randomized stud> Buzdar et al 6° enrolled 602 patients and compared 2 dosages of letrozole (0.5 mg and 2.5 mg QD) and MA (40 mg QID) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. In contrast to the trial by Dombernowsky et al, 59 no statistically significant differences in overall objective response or TTP were found between the 3 treatment groups.

Letrozole as First-Line Therapy In a multicenter, double-blind study, Mouridsen et al2° randomized >900 women with locally advanced or metastatic disease to receive either 2.5 mg of letrozole or 20 mg of tamoxifen QD, with a median follow-up of 18 months. Objective response rate was higher for 1206

letrozole (30% vs 20%; P < 0.001), as was the rate of clinical benefit (49% vs 38%; P = 0.001). No difference in overall survival between the 2 groups was demonstrated. The 2 arms of the study had similar baseline characteristics, including disease stage, sites, and HR status. The data are clear: letrozole is more effective than tamoxifen as first-line treatment in advanced breast cancer. On the basis of this important study, letrozole gained an indication for use as first-line therapy in advanced breast cancer. Early Disease

Adjuvant Setting A recent placebo-controlled trial by Goss et a121 investigated whether postmenopausal women with HR-positive tumors would still benefit from letrozole after the completion of 5 years of adjuvant treatment with tamoxifen. The study, known as MA.17, was led by the National Cancer Institute of Canada and involved 5187 women. At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast (75 in the letrozole group and 132 in the placebo group), with an estimated 4-year DFS of 93% and 87%, respectively, in the 2 groups (P < 0.001). A similar number of patients died in both groups (31 [41.3%] and 42 [31.8%] patients in the letrozole and placebo groups, respectively). After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial and prompt communication of the results to the participants. The optimal duration of the treatment and the question of long-term toxicities were left undefined, creating serious limitations. The lack of overall survival benefit in this study may have been due to the short period of follow-up. Ongoing adjuvant trials are currently pending. Neoadjuvant Setting An aromatase inhibitor instead of or prior to surgery is an attractive alternative in elderly patients with breast cancer, especially because tamoxifen has been associated with high rates of tumor regression, but only for - 3 months. 61 In 2001, a randomized, controlled study by Eiermann et a122 compared letrozole with tamoxifen in the neoadjuvant setting. A total of 337 postmenopausal women with ER- or PR-positive primary untreated

T. K. Choueiri et al.

breast cancer were randomly assigned to receive treatment with either letrozole 2.5 mg or tamoxifen 20 mg, QD for 4 months. Overall objective response rate (clinical palpation) was significantly higher in the letrozole group than in the tamoxifen group (55% vs 36%, respectively; P < 0.001). Secondary end points--ultrasound response, 35% versus 25% (P = 0.042); mammographic response, 34% versus 16% (P < 0.001); and rate of breast-conservation surgery, 45% versus 35% (P = 0.022)--were higher with letrozole treatment than with tamoxifen, respectively. A similar study conducted by Ellis et a123 in 324 patients showed that of patients who were ER- and/or PR-positive and received letrozole, 60% responded and 48% underwent successful breast-conservation surgery. The response to tamoxifen was 41% (P = 0.004), and fewer patients underwent breast conservation in that group (36%; P = 0.036). Differences in response rates between letrozole and tamoxifen were most marked for tumors that were positive for ErbB-1 and/or ErbB-2 and ER (88% vs 21%; P < 0.001). 23 Ongoing studies comparing letrozole and other aromatase inhibitors before surgery are pending. If the data reveal encouraging results, clinicians may see letrozole used as an alternative to surgery in highsurgical-risk older patients with large tumors. Chemoprevention The recent study by Goss et a121 showed a reduction of 46% of new primary tumors in the contralateral breast, comparable to reductions among women in the NSABP B-24 tamoxifen prevention trial. 18 This result suggests by extrapolation that letrozole might reduce the incidence of early breast cancer. The risks and benefits must always be weighed in this setting, especially with the acceleration of bone loss by aromatase inhibitors in general. The use of letrozole in the preventive setting is currently investigational. Adverse Effects The safety profile of letrozole is similar to those of other aromatase inhibitors and is due to complete estrogen suppression. In one study, 2. letrozole did not affect serum lipid profile, but it had an unfavorable effect on lipid profile in a European study. 62 In the MA.17 study, 21 the rates of cardiovascular events and hypercholesterolemia were similar between the letrozole and

placebo groups after 2.4 years. On the other hand, tamoxifen treatment has been shown to lower serum total cholesterol, low-density lipoprotein cholesterol, and lipoprotein(a). 25 As for bone loss, letrozole has been shown to induce bone resorption, with a 25% increase in the levels of the bone resorption marker C-telopeptide cross-links. 2~ In the study by Goss et al, 21 the rates of new-onset osteoporosis and fractures were similar between the letrozole and placebo groups (3.6% vs 2.9%, respectively). However, one should always keep in mind that the study was terminated after 2.4 years and that the long-term deleterious effects of letrozole on bone metabolism remain largely unknown. Calcium and vitamin D intake in addition to bone density monitoring should be considered with long-term letrozole treatment. Other adverse effects of letrozole treatment that reached statistical significance with the MA. 17 study included hot flashes, arthritis, myalgias, and arthralgias. 21 Vaginal bleeding, on the other hand, was statistically less frequent in the letrozole treatment than in the placebo group (P = 0.01), but it is still unclear whether this result implies that letrozole reduces the risk for endometrial cancer. EXEMESTANE Exemestane* is the latest third-generation aromatase inhibitor to be approved by the FDA for the hormonal treatment of breast cancer. It is a unique steroidal, irreversible aromatase inhibitor, producing 98% aromatase suppression. 63 Exemestane is structurally related to the natural estrogen precursor androstenedione, and this similarity may have implications for both its therapeutic efficacy as well as its adverse effects. 63 It is available in an oral formulation (25-mg tablets given QD with food). Pharmacokinetic Properties Orally administered exemestane has been shown to be rapidly absorbed, with a Tma x of - 2 hours. A highfat breakfast appeared to increase exemestane levels by 40%, but this has little clinical significance. 26 At a dosage of 25 mg/d, it achieves a Css within 7 days. It has a mean tl/2 of 27 hours and is distributed extensively to tissue, where it binds tightly to aromatase *Trademark: Aromasin® (Pfizer Inc, New York, New York).

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and other plasma proteins. 6. After repeated dosing, the mean oral clearance in women with advanced breast cancer has been shown to be 45% less than the oral clearance in healthy postmenopausal women; however, this does not seem to be clinically significant. 6. Exemestane also has been shown to be equally metabolized by the kidneys and the liver, with no dose adjustments necessary in patients with renal or hepatic failure. 65

Drug Interactions In a clinical study, 66 ketoconazole showed no significant influence on the pharmacokinetic properties of exemestane. Although no other formal drug-drug interaction studies have been conducted, significant effects on exemestane clearance by CYP isozyme inhibitors appear unlikely. 26 However, exemestane is strongly bound to plasma proteins and might, in theory, interfere and displace highly protein-bound drugs such as warfarin. Pharmacodynamic Properties Exemestane 25 mg/d has been shown to reduce whole-body aromatization (as measured by radiolabeled androstenedione injection) by 98% in postmenopausal women with breast cancer, a percentage comparable to those of anastrozole and letrozole. 6r Exemestane has not been found to affect cortisol or aldosterone secretion at baseline or in response to adrenocorticotropic hormone at any dose. 31 Clinical Studies Advanced Disease Exemestane as Second-Line Therapy

A substantial number of Phase II studies of exemestane have shown efficacy in patients with advanced breast cancer who progressed on hormonal therapies, including tamoxifen and nonsteroidal aromatase inhibitors. 32,65,68 In a multicenter, Phase III, doubleblind study, 769 postmenopausal patients with advanced breast cancer that progressed during treatment with tamoxifen were randomized to receive exemestane 25 mg QD or MA 40 mg QID for 108 weeks or until progression. Median survival time was significantly longer in the exemestane group (P = 0.039). 33 This study and 1 other 68 have raised the possibility that exemestane may be advantageous compared with nonsteroidal aromatase inhibitors. It is unclear 1208

whether this additive beneficial clinical outcome over reversible "family members," such as anastrozole and letrozole, 69,7° occurs through estrogen suppression only or is additionally mediated through the androgen receptor. Longer-term experience with exemestane will elucidate this issue. Exemestane as First-LineTherapy A Phase II study 27 has reported the efficacy and safety of exemestane 25 mg QD as initial therapy. Patients were randomized to receive exemestane 25 mg/d or tamoxifen 20 mg/d in this open-label study. Patients were evaluated at least every 6 months. Blinded, independently reviewed response rates for exemestane and tamoxifen were 41% and 17%, respectively. Fifty-seven percent of exemestane-treated patients and 42% of tamoxifen-treated patients experienced clinical benefit, defined as complete or partial response, or disease stabilization lasting at least 6 months. This study has been extended to a Phase III study, but the results are not yet known. Early Disease Adjuvant Setting In a recent randomized trial, Coombes et a128 tested whether, after 2 to 3 years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen treatment for the remainder of a 5-year regimen. The primary end point was DFS. Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane and 2380 to continue receiving tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported (183 in the exemestane group and 266 in the tamoxifen group). The P values were < 0.001, corresponding to a 32% risk reduction and an absolute benefit in terms of DFS of 4.7% at 3 years after randomization. Overall survival was not significantly different between the 2 groups, with 93 deaths occurring in the exemestane group (3.9%) and 106 in the tamoxifen group (4.5%). Grade 4 (severe) toxic effects of exemestane were rare (<0.05%). Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (0.8% vs 0.4%, respectively; P = 0.04). The North American Breast Cancer Intergroup is currently comparing anastrozole with exemestane,

1-. K. Choueiri et al.

with a second randomization to celecoxib or placebo, in study MA.27. This study is being performed in the postsurgical adjuvant setting in postmenopausal patients with ER- or PR-positive breast cancer.

Neoadjuvant Setting Miller and Dixon 29 studied 12 postmenopausal women with untreated large or locally advanced, ERrich tumors. The effect of exemestane 25 mg/d for 3 months on aromatization peripherally and in breast cancer and surrounding normal tissue was determined. Changes in tumor volume were based on clinical examination, ultrasound, and mammography. Exemestane treatment was associated with a median reduction in tumor volume of 85.5% for clinical examination, 82.5% for ultrasound, and 84.0% for mammography. Eight of 10 patients who would have required mastectomy before treatment were able to undergo breast-conserving surgery after treatment. Clinical benefits were accompanied by a marked reduction in cellular proliferation and PR expression. These data show promise in the use of exemestane as neoadjuvant therapy for breast cancer in postmenopausal women. However, this study included a small sample size and did not compare exemestane with another antiestrogen, as did the study by Eiermann et a122 of letrozole. Chemoprevention

Elevated prostaglandin E 2 levels from cyclooxygenase-2 induction by preinvasive and invasive breast lesions increase a number of tumor-promoting pathways, including aromatase. Additive or synergistic effects between celecoxib, a cyclooxygenase-2 inhibitor, and exemestane have been demonstrated 71 and have led to the National Cancer Institute of Canada> Clinical Trials Group MAP.3 trial, which will randomize women at elevated risk to receive placebo or exemestane with or without celecoxib. 7~ The results of this chemoprevention study are awaited with interest. Adverse Effects

The adverse effects of exemestane have been evaluated in multiple studies in patients with advanced breast cancer. Although exposure to the drug has been short (mostly <6 months), exemestane was associated with low-grade hot flashes, nausea, diarrhea,

and fatigue. 3°-32'64'65 Kaufmann et a133 showed that laboratory abnormalities (mostly grade 1 or 2) occurred more frequently in exemestane-treated patients than in MA-treated patients and included mild leukopenia or lymphopenia and increases in alanine aminotransferase and/or alkaline phosphatase levels. In the largest exemestane trial to date, Coombes et a128 showed that exemestane was associated with a higher incidence of arthralgias (P = 0.01) and diarrhea (P < 0.001) than tamoxifen, but with less vaginal bleeding (P = 0.05) and muscle cramps (P < 0.001). There was a higher incidence of osteoporosis (P = 0.05) and visual disturbances (P = 0.04) with exemestane. 28 Another relevant point about exemestane's safety that may be different than other aromatase inhibitors concerns its effect on bone metabolism. This effect has been shown in a short-term (3-month) study r2 in healthy postmenopausal volunteers, in which exemestane and letrozole were given at the standard dosages of 25 mg/d and 2.5 mg/d, respectively. There was a sharp increase in bone turnover in those given letrozole but not in the exemestane group. In the study by Coombes et al, 28 the exemestane arm, compared with the tamoxifen arm, had numerically higher but statistically nonsignificant incidences of fracture and osteoporosis. These results indicate that exemestane might have deleterious effects on bone metabolism, but to a lesser degree than letrozole. Head-tohead comparisons of bone metabolism between aromatase inhibitors are lacking. The MAP.3 study, evaluating exemestane with or without celecoxib as a preventive therapy for breast cancer in women at high risk will include substudies addressing the effects of exemestane treatment on bone and lipid metabolism, rl WHICH THIRD-GENERATION AROHATASE I N H I B I T O R T O CHOOSE?

Although letrozole has been shown to result in a significantly higher degree of inhibition of aromatase than anastrozole in a crossover, pharmacodynamic trial, 5. it is completely unclear whether this difference has any implications in routine clinical practice. The trial by Mouridsen et al 2° showed that TTP and objective response reached statistical significance favoring letrozole. Conversely, TTP but not objective response was found to be statistically significant with 1209

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anastrozole compared with tamoxifen in advanced disease. 13,1<~s Recently, Rose et al r3 randomized 713 patients with advanced breast cancer that had progressed during antiestrogen therapy to receive either anastrozole or letrozole. There was no significant difference in TTP, overall survival, or safety profile between the treatment arms. However, the overall response rate was higher with letrozole than with anastrozole (19.1% vs 12.3%; P = 0.013), including in predefined subgroups (unknown receptor status, soft-tissue and viscera-dominant site of disease). The authors concluded that advanced breast cancer might be more responsive to letrozole as second-line therapy. Another comparative study r~ concerning aromatase inhibitors addressed cost-utility. The analysis was conducted to determine whether the approved third-generation aromatase inhibitors were economically attractive alternatives to tamoxifen from the perspective of the publicly funded Canadian health care system. When the costs and benefits were combined, the data generated an incremental cost per quality-adjusted progression-free year of Cans 12,500 and CanS19,600 for letrozole and anastrozole, respectively, relative to tamoxifen. Thus, letrozole could be preferentially considered when efficacy and cost-effectiveness are considered together based on this trial, r~ A similar single-blinded study r5 in the United Kingdom involving 72 patients, using a validated quality-of-life questionnaire, found letrozole to be superior to anastrozole with respect to both quality of life and toxicity in metastatic breast cancer. To date, no US studies have compared cost-utility or quality of life between letrozole and anastrozole. There also are no comparative analyses between exemestane and other aromatase inhibitors, although occasional further responses have been reported in patients with relapses after therapy with anastrozole or letrozole. 32 Overall, current evidence suggests that there are unlikely to be major clinical differences between the 3 agents. Additional data similar to those found in the study by Rose et al r3 are awaited with interest. Even if quality of life and cost-effectiveness are taken into consideration, it is still too early to advocate letrozole over anastrozole on the basis of a few small studies, r
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CONCLUSION

In this review of 3 FDA-approved aromatase inhibitors--anastrozole, letrozole, and exemestane-in the treatment of advanced breast cancer, anastrozole was shown to have efficacy similar to that of tamoxifen, and letrozole was shown to be potentially more effective than tamoxifen. The role of aromatase inhibitors in early disease has not been completely elucidated, but the ATAC trial suggests that they are effective despite the lack of long-term follow-up. Because of the long-term safety data on tamoxifen, the American Society of Clinical Oncology issued an evidence-based update in 2003, affirming tamoxifen as the gold standard adjuvant hormonal treatment in postmenopausal breast cancer. The results of the IBIS-II trial using anastrozole as a chemopreventive agent for women with a high risk for breast cancer, as well as the MAP.3 trial comparing exemestane with and without celecoxib versus placebo, are awaited with interest. Serious adverse effects such as venous thromboembolism, stroke, and endometrial cancers are less likely with the aromatase inhibitors than with tamoxifen. Of the 3 agents, exemestane is the most recently FDA approved and may be distinct because its steroidal structure potentially protects bone and lipid metabolism from estrogen ablation. Ongoing clinical studies will provide more insight into the safety profiles of the aromatase inhibitors, and it is hoped that clinicians will be able to select the optimal treatment that will provide most benefit to their patients. REFERENCES

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the 12-week treatment with exemestane or letrozole. Breast Cancer Res Treat. 2002;76:$76. Abstract. 73. Rose C, Vtoraya O, Pluzanska A, et al. An open randomised trial of second-line endocrine therapy in advanced breast cancer. Comparison of the aromatase inhibitors letrozole and anastrozole. Eur d Cancer. 2003;39:2318-2327. 74. Dranitsaris G, Verma S, Trudeau M. Cost utility analysis of first-line hormonal therapy in advanced breast cancer: Comparison of two aromatase inhibitors to tamoxifen. Am d Clin Oncol. 2003;26:289-296. 75. Thomas R. Examining quality of life issues in relation to endocrine therapy for breast cancer. Amd Clin Oncol. 2003 ;26:540-544.

Address correspondence to: Toni K. Choueiri, MD, D e p a r t m e n t of H e m a t o l o g y and Medical Oncology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, O H 44195. E-mail: [email protected]

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