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The Oncologist, Vol. 8, No. 4, 335–341, August 2003
© 2003 AlphaMed Press

ORIGINAL PAPER
Breast Cancer

Advances in Endocrine Treatments for Postmenopausal Women with Metastatic and Early Breast Cancer

Aman U. Buzdar

The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Correspondence: Aman U. Buzdar, M.D., Department of Breast Medical Oncology, Box 424, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. Telephone: 713-792-2817; Fax: 713-794-4385; e-mail: abuzdar{at}mdanderson.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Metastatic Breast Cancer...
 EBC Adjuvant Therapy
 Discussion
 References
 
After completing this course, the reader will be able to:

  1. Define appropriate candidates for various endocrine therapies.
  2. Discuss the choices of therapies for patients with advanced breast cancer.
  3. Assess the options for adjuvant endocrine therapy for postmenopausal women.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Metastatic Breast Cancer...
 EBC Adjuvant Therapy
 Discussion
 References
 
For the past 25 years, the estrogen antagonist tamoxifen has been the hormonal treatment of choice for postmenopausal patients with hormone-sensitive metastatic and early breast cancer (EBC). However, tamoxifen is associated with certain tolerability and safety concerns. In addition, the hormonal options after progression are limited, and thus, alternative endocrine treatments have been developed. This review provides a synopsis of the newer alternatives in endocrine therapy of breast cancer: the aromatase inhibitors (AIs) and fulvestrant Faslodex®, the estrogen receptor antagonist that downregulates estrogen and progesterone receptors and has no known agonist activity. The third-generation AIs, anastrozole and letrozole, have been shown to be as effective or more effective than megestrol acetate and tamoxifen as second- and first-line therapies for the treatment of postmenopausal patients with metastatic breast cancer, and exemestane has been approved for second-line use. Fulvestrant has been shown to be as effective as anastrozole as second-line therapy for metastatic breast cancer and has been approved in the U.S. for the treatment of postmenopausal women with hormone-receptor-positive metastatic breast cancer following progression on antiestrogen therapy. Anastrozole is the only AI with published clinical trial data and U.S. Food and Drug Administration approval for adjuvant therapy of postmenopausal women with EBC. The ‘Arimidex,’ Tamoxifen, Alone or in Combination (ATAC) trial, a double-blind, multicenter trial with 9,366 patients, compared tamoxifen with anastrozole, alone and in combination, as adjuvant endocrine treatment for postmenopausal patients with operable, invasive, EBC. The first analysis (at a median follow-up of 33.3 months) showed longer disease-free survival and, in general, better tolerability with anastrozole than with tamoxifen. This pattern was maintained at later analyses with a median follow-up of 47 months for efficacy and 37 months for safety and tolerability. Although longer follow-up is warranted, anastrozole appears to be a well-documented choice of endocrine adjuvant therapy for postmenopausal women with hormone-responsive breast cancer.

Key Words. Aromatase inhibitor • Adjuvant • Metastatic breast cancer • Breast cancer • Anastrozole • Fulvestrant


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Metastatic Breast Cancer...
 EBC Adjuvant Therapy
 Discussion
 References
 
Over 100 years ago, Beatson made the link between the endocrine system and breast cancer [1]. Fifty years later, Huggins and colleagues first described surgical adrenalectomy as second-line endocrine therapy [2]. In the early years, there was little understanding of the biological basis underlying the responses, but since then, a large amount of research has described enough of the mechanisms to form a rational foundation of therapy for greater clinical benefit.

Hormone-sensitive breast cancer can be effectively treated with agents that reduce the stimulation of tumor cells by estrogen. For the past 25 years, the estrogen antagonist tamoxifen has been the gold standard for the first-line treatment of hormone-sensitive metastatic breast cancer and as adjuvant therapy for early breast cancer (EBC) in patients with hormone-receptor-positive tumors. Although an effective treatment, there are some limitations to its use due to its partial agonist activity in some tissues; this partial activity results in greater incidences of endometrial cancer [3] and thromboembolic disease [3, 4] and may be involved in the development of resistance to tamoxifen. Alternative treatments are required.

As more than 80% of breast cancer cases occur in women over the age of 50, this review focuses on endocrine treatments for postmenopausal women. For such women, one of the new alternatives to tamoxifen is the use of a third-generation aromatase inhibitor (AI) to suppress the concentration of endogenous estrogens to extremely low levels, thus preventing estrogen stimulation from reaching the tumor. The AIs are indicated for the treatment of breast cancer in women where ovarian function has ceased either due to menopause or due to surgery to remove the ovaries. The first-generation AI aminoglutethimide became available in the late 1970s [5], but despite proven efficacy, its widespread use was limited by its overall toxicity and lack of selectivity for the aromatase enzyme, necessitating concomitant corticosteroid supplementation. Formestane, an effective and more specific aromatase inhibitor, became available in 1993. Due to its specificity, formestane has fewer side effects than aminoglutethimide. However, it does not provide complete, consistent suppression of estrogen synthesis, and there is also extensive first-pass metabolism [6]; formestane is not available in the U.S.

The third-generation specific AIs, which include anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®), and one second-generation AI, fadrozole (Afema®), are now commercially available for the treatment of metastatic breast cancer, although fadrozole can only be obtained in Japan. Exemestane is available only for second-line use after the failure of other hormonal agents; letrozole is available for use in either the first- or second-line setting in locally advanced and metastatic breast cancer; anastrozole is available for use in the adjuvant setting in EBC, as well as in the first- and second-line treatments of locally advanced and metastatic breast cancer.

An alternative endocrine treatment to tamoxifen is fulvestrant (Faslodex®), the estrogen receptor antagonist that downregulates estrogen and progesterone receptors and has no known agonist activity. Fulvestrant has been shown to be as efficacious as anastrozole in patients progressing on tamoxifen [7–9], and it has been approved in the U.S. for the treatment of postmenopausal women with hormone-receptor-positive metastatic breast cancer following progression on antiestrogen therapy.

This review presents recent advances that have been made in endocrine therapy for postmenopausal women with metastatic and EBC and their subsequent impact on treatment strategies.


   METASTATIC BREAST CANCER ENDOCRINE THERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 Metastatic Breast Cancer...
EBC Adjuvant Therapy
 Discussion
 References
 
Second-Line Therapy
As second-line agents in postmenopausal women with metastatic breast cancer, anastrozole and exemestane have been shown to offer significant benefits with respect to survival when compared with the progestin megestrol acetate (MA) [10–12]. Anastrozole has shown superior survival over MA with median times to death of 26.7 versus 22.5 months, respectively (p < 0.025), and the proportions of patients surviving longer than 2 years of 56% versus 46%, respectively, at 31 months follow-up. Similarly, the overall time to death was longer for the anastrozole group than for the MA group (hazard ratio [HR] = 0.78, 97.5% confidence interval [CI] = 0.60–1.0, p < 0.025) [11]. Likewise, treatment with exemestane produced a greater time to progression (TTP) (4.6 months versus 3.9 months) and was associated with a significant survival advantage in comparison with MA (median time to death with exemestane had not yet been reached while with MA it was 28 months), although this study had a shorter overall median follow-up of 48.9 weeks [12].

In a phase III study of second-line therapy with letrozole (0.5 mg and 2.5 mg), the clinically approved dose (2.5 mg daily) had a superior objective response (OR) rate (24% versus 16%), duration of response, time to treatment failure (TTF) (5.1 versus 3.9 months), and tolerability compared with MA [13]. However, in a second phase III study, the 2.5 mg dose of letrozole showed only equivalence to MA with respect to OR [14]. Both studies also reported no significant differences between the letrozole (2.5 mg) and MA groups with respect to TTP and overall survival [13, 14]. Buzdar and colleagues reported that the 0.5 mg dose of letrozole was significantly superior to MA with respect to TTP (p = 0.044) and TTF (p = 0.018) in contrast to the data from both studies that were conducted on the 2.5 mg dose [13, 14].

Letrozole (0.5 mg and 2.5 mg) was better than the prototype AI aminoglutethimide with respect to TTP (p = 0.008), TTF (p = 0.003), and overall survival (28 versus 20 months) (p = 0.002) in a phase III randomized trial [15]. There was a trend toward an improved response rate with the use of letrozole (20% versus 12%), although this did not reach statistical significance (p = 0.06).

In a combined analysis of two phase III studies [7] in postmenopausal women with metastatic breast cancer progressing on their prior endocrine therapy, fulvestrant (250 mg i.m. once monthly) was at least as effective as anastrozole (1 mg) in TTP. The median TTP for fulvestrant and anastrozole was 5.5 and 4.1 months, respectively (HR = 0.95, 95.14% CI = 0.82–1.10, p = 0.48). Both OR and clinical benefit (CB) were similar in the two groups. The OR rates for fulvestrant and anastrozole were 19.2% and 16.5%, respectively (odds ratio = 1.21; 95% CI = 0.84–1.74, p = 0.31) and CB rates for fulvestrant and anastrozole were 43.5% and 40.9%, respectively.

First-Line Therapy
The place of tamoxifen as the gold standard for the first-line treatment of postmenopausal women with metastatic breast cancer is now challenged by the newer-generation AIs. Anastrozole was the first endocrine agent to show significant benefit over tamoxifen in a phase III first-line trial [16]. The median TTP in the anastrozole arm was significantly longer than in the tamoxifen arm (11.1 months versus 5.6 months, p = 0.005). The tamoxifen:anastrozole HR was 1.44 (lower one-sided 95% confidence limit = 1.16) [16]. Analysis of receptor-positive disease in two randomized trials showed a benefit of anastrozole over tamoxifen with respect to TTP (10.7 versus 6.4 months, p = 0.022) [17].

Data from a phase III randomized study with letrozole also showed that TTP was significantly longer in the letrozole arm than in the tamoxifen arm, 41 versus 26 weeks. The letrozole:tamoxifen HR was 0.70 (95% CI = 0.60–0.82, p = 0.0001) [18].

In contrast to anastrozole and letrozole, no published phase III data exist comparing exemestane with tamoxifen as first-line therapy in metastatic breast cancer. The most recent update of a small open-label phase II study of exemestane versus tamoxifen shows a benefit in terms of OR rate for exemestane (45% versus 14%), although there are no statistics available to date [19].

As first-line therapy in the overall population, there was no significant difference in TTP between the fulvestrant (250 mg i.m. injection once monthly) and tamoxifen (20 mg daily) groups (median = 6.8 versus 8.3 months; HR = 1.18, 95% CI = 0.98–1.44, p = 0.088). There also were no significant differences between the fulvestrant (250 mg i.m. injection once monthly) and tamoxifen (20 mg daily) groups in patients with estrogen-receptor-positive and/or progesterone-receptor-positive tumors in TTP (median TTP for fulvestrant and tamoxifen was 8.2 and 8.3 months, respectively; HR = 1.10, 95% CI = 0.89–1.36, p = 0.388) or in CB (fulvestrant versus tamoxifen = 57.1% versus 62.7%, p = 0.218) or OR (fulvestrant versus tamoxifen = 33.2% versus 31.1%, p = 0.637) rates. In the first-line setting, the most appropriate patient population requires further definition [20].

Based on their excellent activity as first- and second-line therapies in the metastatic disease setting, the third-generation AIs are now being evaluated in the adjuvant setting, with results now available for anastrozole.


   EBC ADJUVANT THERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 Metastatic Breast Cancer...
 EBC Adjuvant Therapy
Discussion
 References
 
The ‘Arimidex,’ Tamoxifen, Alone or in Combination (ATAC) trial is a randomized, double-blind, multicenter study in postmenopausal women (n = 9,366) with invasive operable breast cancer—the largest single cancer treatment trial published to date. After completing primary therapy, eligible patients received anastrozole alone (1 mg), tamoxifen alone (20 mg), or a combination of the two. The primary objectives were to evaluate disease-free survival (DFS) and safety/tolerability. Secondary end points were time to recurrence (TTR, defined in a similar way to DFS but censoring patients who had died from non-breast-cancer-related deaths prior to recurrence) and incidence of new contralateral primary breast tumors [21].

The efficacy data at the first and updated analysis are summarized in Table 1Go [21–23]. The first analysis of the ATAC trial became available in December 2001. These results showed anastrozole to have a longer DFS and longer TTR with a better tolerability profile than tamoxifen [20]. The first analysis was planned when there were 1,056 events, including recurrences or deaths from any cause, and the actual first analysis was carried out when 1,079 events were recorded, at a median follow-up of 33.3 months. Anastrozole was superior to tamoxifen for the primary and secondary efficacy end points. It is of interest that the combination was not significantly different from tamoxifen alone for any efficacy or safety end points. Disease-free survival was significantly longer in the anastrozole group than in the tamoxifen group and the combination group (Table 1Go and Fig. 1Go) [21]. Since the combination showed no benefit over tamoxifen alone, the combination arm of the trial was discontinued after this analysis.


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  		Table 1. ATAC trial efficacy and tolerability results at the first and updated analyses [21–23]
 


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  		Figure 1. Probability of first event in the intention-to-treat population of the ATAC trial (reproduced by kind permission of The Lancet). Abbreviations: A = anastrozole; T = tamoxifen; C = combination; CI = confidence interval.

 
In the hormone-receptor-positive group, DFS was also significantly longer for the anastrozole group than for the tamoxifen or combination groups (Table 1Go). Anastrozole was superior to tamoxifen in TTR in the overall group and in the hormone-receptor-positive subgroup (Table 1Go and Fig. 2Go) [21]. There were significantly fewer contralateral breast cancers as a first event in the anastrozole (0.5%, 14/3,125) versus the tamoxifen (1.1%, 33/3,116) groups (Table 1Go and Fig. 3Go) [21], which meant a 58% reduction in the risk of developing contralateral breast cancer for those women in the anastrozole group compared with those in the tamoxifen group.



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  		Figure 2. Probability of recurrence in the hormone receptor-positive population of the ATAC trial (reproduced by kind permission of The Lancet). Abbreviations: A = anastrozole; T = tamoxifen; C = combination; CI = confidence interval.

 


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  		Figure 3. Incidence of new (contralateral) breast primaries in the intention-to-treat population in the first analysis of the ATAC trial. Abbreviations: DCIS = ductal carcinoma in situ; OR = odds ratio; CI = confidence interval.

 
The efficacy reanalysis at a median follow-up of 47 months [22] confirmed the continued DFS and TTR benefits in the anastrozole-treated group, and these benefits were accentuated in the known receptor-positive population (Table 1Go). A lower occurrence of contralateral breast cancer continued to be seen with anastrozole, which was significant in the hormone-receptor-positive group (Table 1Go) [22].

In terms of tolerability, at the first analysis, anastrozole was superior to tamoxifen for hot flashes, vaginal discharge, vaginal bleeding (all p < 0.0001), ischemic cerebrovascular events (p = 0.0006), thromboembolic events (p = 0.0006) (including deep-vein thrombosis, p = 0.02), and endometrial cancer (p = 0.02). Tamoxifen was superior to anastrozole for musculoskeletal disorders and fractures (p < 0.0001 for both) [21]. Adverse event rates were similar between the combination and tamoxifen arms at the first analysis.

The analysis of the updated safety data was performed after an additional 7 months of follow-up from the first safety analysis [23], with a median 37 months’ follow-up at this analysis. The results were similar to those seen at the first analysis (Table 2Go). Anastrozole was associated with significantly fewer withdrawals from treatment than tamoxifen (anastrozole versus tamoxifen, 21.9% versus 26.0%, p = 0.0002), including significantly fewer withdrawals due to drug-related adverse events (anastrozole versus tamoxifen, 5.1% versus 7.2%, p < 0.0001) [23].


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  		Table 2. Predefined adverse events at the updated analysis of the ATAC trial for which there were significant differences between anastrozole and tamoxifen at the first analysis
 
Following the first results from the ATAC trial [21], the American Society of Clinical Oncology (ASCO) Health Services Research Committee conducted a technology assessment of adjuvant therapy for hormone-sensitive early operable breast cancer [24]. Considering that anastrozole is the only AI with data available for the adjuvant setting (although not yet with 5+ years of exposure) and considering the well-known side-effect profile of tamoxifen, the panel suggested that a 5-year course of tamoxifen should remain the standard adjuvant hormonal therapy, pending updated data from the ATAC trial and other trials of third-generation AIs in the adjuvant setting [24]. Regarding tolerability, anastrozole showed that short-term side effects were comparable with, or fewer than, those seen with tamoxifen, with the exception of musculoskeletal disorders and fractures. The panel further suggested that it would be reasonable for a patient to be treated with anastrozole if there was a history of cardiovascular disease or thromboembolic events or if the patient developed complications or intolerable side effects attributable to tamoxifen. Additionally, the panel recommended that "physicians discuss the available information with patients, and, in making a decision, acknowledge that treatment approaches can change over time. Individual health care providers and their patients will need to come to their own conclusions, with careful consideration of all the available data" [24].


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Metastatic Breast Cancer...
 EBC Adjuvant Therapy
 Discussion
References
 
The results of the major clinical trials discussed have influenced the sequence in which hormonal therapies are used to treat metastatic breast cancer (Fig. 4Go), with anastrozole being the first AI to be approved for first-line use in the treatment of postmenopausal patients with locally advanced or metastatic breast cancer. Letrozole has also been approved as first-line therapy for the treatment of postmenopausal patients with metastatic breast cancer, and fulvestrant is approved for second-line treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer following progression on antiestrogen therapy.



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  		Figure 4. Major clinical trials with anastrozole, letrozole, exemestane, and fulvestrant influencing the sequence of treatment used in early and advanced breast cancer.

 
Anastrozole is currently the only agent, apart from tamoxifen, that has been shown to be an effective adjuvant hormonal therapy for postmenopausal women with EBC. The U.S. Food and Drug Administration approved anastrozole in September 2002 for the adjuvant treatment of EBC in postmenopausal women with hormone-receptor-positive disease; data from phase III clinical trials for adjuvant use of other AIs are unlikely to be available for 2–3 years. Since anastrozole has been shown to be more effective than tamoxifen as adjuvant therapy [21], it may become the preferred choice for early-stage breast cancer. Sequencing data for anastrozole and tamoxifen [25] have shown that tamoxifen is effective after progression on anastrozole; tamoxifen is, therefore, likely to be effective in patients whose cancer has recurred after adjuvant anastrozole. Although longer follow-up is needed to assess the full benefit of anastrozole in the adjuvant setting in terms of its efficacy and safety, anastrozole currently provides a choice of adjuvant endocrine therapy for postmenopausal women with hormone-responsive tumors.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Metastatic Breast Cancer...
 EBC Adjuvant Therapy
 Discussion
 References
 

  1. Beatson JT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet ii 1896:104–107:162–165.[CrossRef]
  2. Huggins C, Bergenstal DM. Inhibition of human mammary and prostatic cancer by adrenalectomy. Cancer Res 1952;12:134–141.
  3. Fisher B, Dignam J, Bryant J et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996;88:1529–1542.[Abstract/Free Full Text]
  4. Jaiyesimi IA, Buzdar AU, Decker DA et al. Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol 1995;13:513–529.[Abstract/Free Full Text]
  5. Wells SA Jr, Santen RJ, Lipton A et al. Medical adrenalectomy with aminoglutethimide: clinical studies in postmenopausal patients with metastatic breast carcinoma. Ann Surg 1978;187:475–484.[Medline]
  6. Goss PE, Powles TJ, Dowsett M et al. Treatment of advanced postmenopausal breast cancer with the aromatase inhibitor, 4-hydroxyandrostenedione: phase II report. Cancer Res 1986;46:4823–4826.[Abstract/Free Full Text]
  7. Howell A, Osborne CK, Robertson JFR et al. ICI 182,780 (FaslodexTM) versus anastrozole (ArimidexTM) for the treatment of advanced breast cancer in postmenopausal women: prospective combined analysis of two multicenter trials. Eur J Cancer 2001;37(suppl 6):S151.
  8. Howell A, Robertson JF, Quaresma Albano J et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 2002;20:3396–3403.[Abstract/Free Full Text]
  9. Osborne CK, Pippen J, Jones SE et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 2002;20:3386–3395.[Abstract/Free Full Text]
  10. Buzdar A, Jonat W, Howell A et al. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group. J Clin Oncol 1996;14:2000–2011.[Abstract/Free Full Text]
  11. 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 1998;83:1142–1152.[CrossRef][Medline]
  12. 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 2000;18:1399–1411.[Abstract/Free Full Text]
  13. 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 1998;16:453–461.[Abstract]
  14. Buzdar A, Douma J, Davidson N et al. A phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 2001;19:3357–3366.[Abstract/Free Full Text]
  15. 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. Ann Oncol 1998;9:639–645.[Abstract/Free Full Text]
  16. 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;18:3758–3776.[Abstract/Free Full Text]
  17. Bonneterre J, Buzdar A, Nabholtz JM et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Results of two randomized trials designed for combined analysis. Cancer 2001;92:2247–2258.[CrossRef][Medline]
  18. 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.[Abstract/Free Full Text]
  19. Dirix L, Piccart MJ, Lohrisch C et al. Efficacy of and tolerance to exemestane (E) versus tamoxifen (T) in first-line hormone therapy (HT) of postmenopausal metastatic breast cancer (MBC) patients (pts): a European Organisation for the Research and Treatment of Cancer (EORTC Breast Group) phase II trial with Pharmacia and Upjohn. Proc Am Soc Clin Oncol 2001;20:29a.
  20. Robertson JFR, Howell A, Abram P et al. Fulvestrant versus tamoxifen for the first-line treatment of advanced breast cancer (ABC) in postmenopausal women. Ann Oncol 2002;13:46.
  21. 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 2002;359:2131–2139.[CrossRef][Medline]
  22. Buzdar AU. The ATAC (‘Arimidex’, Tamoxifen, Alone or in Combination) trial in postmenopausal women with early breast cancer: updated efficacy results based on a median follow-up of 47 months. ATAC Trialists’ Group. Breast Cancer Res Treat 2003;77:295.[CrossRef]
  23. Sainsbury R. Beneficial side-effect profile of anastrozole compared with tamoxifen confirmed by additional 7 months of exposure data: a safety update from the ’Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial. ATAC Trialists’ Group. Breast Cancer Res Treat 2002;76(suppl 1):S156.
  24. 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.[Abstract/Free Full Text]
  25. Thürlimann B, Hess D, Koeberle D et al. Anastrozole (‘Arimidex’) versus tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer: results of the double-blind crossover SAKK trial 21/95—a sub-study of Anastrozole Trial 0027. Breast Cancer Res Treat 2002;76(suppl 1):S73.
  26. Bonneterre J, Thürlimann 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.[Abstract/Free Full Text]
Received February 21, 2003; accepted for publication May 13, 2003.




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