Originally published as JCO Early Release 10.1200/JCO.2006.08.8054 on June 11 2007

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Improved Overall Survival in Postmenopausal Women With Early Breast Cancer After Anastrozole Initiated After Treatment With Tamoxifen Compared With Continued Tamoxifen: The ARNO 95 Study

Manfred Kaufmann, Walter Jonat, Jörn Hilfrich, Holger Eidtmann, Günther Gademann, Ivan Zuna, Gunter von Minckwitz

From the J.W. Goethe-University of Frankfurt, Frankfurt am Main; University of Kiel, Kiel; Henriettenstift, Hannover; University of Magdeburg, Magdeburg; and the Institute of Statistics SKM, Wiesbaden, Germany

Address reprint requests to Manfred Kaufmann, MD, Department of Obstetrics and Gynaecology, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany; e-mail: m.kaufmann{at}em.uni-frankfurt.de

	ABSTRACT

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Purpose: In postmenopausal women with estrogen receptor–positive early breast cancer, surgery is usually followed by a 5-year course of tamoxifen. This report presents results of a prospective, open-label, randomized study, designed to evaluate the benefits of switching to anastrozole after 2 years of tamoxifen treatment, compared with continuing on tamoxifen for 5 years.

Patients and Methods: After receiving tamoxifen treatment for 2 years, eligible patients (n = 979) were randomly assigned to switch to anastrozole (1 mg/d) or continue tamoxifen (20 or 30 mg/d) for an additional 3 years. Patients were monitored every 6 months during years 1 to 3 and annually thereafter. The primary efficacy variable was disease-free survival, including local or distant recurrence, new contralateral breast cancer, or death. Secondary variables were overall survival and assessment of safety.

Results: Switching to anastrozole resulted in a significant reduction in the risk of disease recurrence (hazard ratio [HR], 0.66; 95% CI, 0.44 to 1.00; P = .049), and improved overall survival (HR, 0.53; 95% CI, 0.28 to 0.99; P = .045) compared with continuing on tamoxifen. Fewer patients who switched to anastrozole reported serious adverse events (22.7% v 30.8%) compared with those who continued on tamoxifen, mainly due to more patients in the tamoxifen group with endometrial events. The overall safety profile for anastrozole was consistent with previous reports and no new safety issues were identified.

Conclusion: Postmenopausal women who have taken tamoxifen for 2 years as adjuvant therapy are less likely to experience a recurrence of breast cancer and have improved overall survival if they switch to anastrozole compared with continuing to receive tamoxifen.

	INTRODUCTION

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The selective estrogen receptor (ER) modulator tamoxifen has been the mainstay of adjuvant hormone therapy for patients with breast cancer for more than 20 years, with the optimum duration of tamoxifen treatment being regarded generally as 5 years. However, many patients eventually acquire resistance to tamoxifen¹ and long-term tamoxifen therapy is also associated with a variety of adverse effects, including an increased risk of endometrial cancer and thromboembolic events.^2,3 Aromatase inhibitors (AIs) limit estrogen exposure by inhibiting the enzyme (aromatase) that catalyzes the final step of estrogen biosynthesis, thereby reducing the amount of estrogen produced. Five years of the AI anastrozole has been shown to be a more effective and better-tolerated adjuvant endocrine therapy than tamoxifen in postmenopausal women with hormone-responsive early breast cancer, with efficacy and safety data extending beyond 5 years of follow-up.^4,5 Recent studies with anastrozole have demonstrated the efficacy benefits associated with switching to tamoxifen from an AI after 2 to 3 years of tamoxifen therapy.^6-8 Studies with other AIs have also been published.^9-12

Data from the Arimidex-Nolvadex (ARNO) trial 95 have been presented in a combined analysis with the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 8⁸ and in a meta-analysis with the Italian Tamoxifen Arimidex (ITA) trial.¹³ Results of these analyses have demonstrated that postmenopausal women with hormone-sensitive early breast cancer switching from tamoxifen to anastrozole experience significantly fewer disease recurrences than those patients who remain on tamoxifen.

To our knowledge, this is the first report of results from the ARNO 95 study alone, which was designed to evaluate prospectively the benefits of switching to anastrozole from tamoxifen after 2 years compared with continuing tamoxifen therapy, without other adjuvant systemic therapies such as cytostatic drugs.

	PATIENTS AND METHODS

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This was a prospective, randomized, open-label, parallel group, multicenter study to assess differences in efficacy and safety between postmenopausal women with hormone receptor–positive breast cancer who switched from tamoxifen (20 or 30 mg/d taken for 2 years) to anastrozole (1 mg/d taken for up to an additional 3 years), and those who continued to receive tamoxifen (20 or 30 mg/d taken for up to an additional 3 years). The study was performed in accordance with the ethical principles of the Declarations of Helsinki. All patients provided written informed consent before any study procedure.

The primary objective of the study was to compare the disease-free survival (defined as the time from random assignment to the occurrence of local or distant recurrence, new contralateral breast cancer, or death) between patients switched from tamoxifen to anastrozole and those who continued to receive tamoxifen. Secondary objectives were to compare overall survival (defined as the time from random assignment to death from any cause) and safety and tolerability between those who switched from tamoxifen to anastrozole and those who continued to receive tamoxifen.

Patients
Between December 1996 and August 2002, postmenopausal women (age 75 years) with histologically verified, grade 1 to grade 3 invasive breast cancer (pT1-3, node negative, or up to nine tumor-infiltrated lymph nodes [pN0-2] and no distant metastases), who had undergone primary surgery (with or without radiotherapy) and had received 2 years of continuous adjuvant tamoxifen therapy (20 or 30 mg/d) without disease recurrence, were eligible for inclusion in this study. Informed written consent was obtained from all patients enrolled onto the trial.

Study Treatments
Eligible patients were randomly assigned to receive anastrozole (1 mg/d) or to continue with tamoxifen (20 or 30 mg/d) for 3 years in a 1:1 ratio. No other systemic therapy of breast carcinoma was permitted. No patients received chemotherapy because in Germany, patients with hormone-sensitive grade 3 tumors were not considered to be candidates for such treatment at the time of initiation of this study.

Random assignment was performed centrally using a computer-assisted program at the Institute for Medical Biometrics and Medical Informatics, University of Freiburg (Freiburg, Germany) and was stratified by center only. Randomization could be carried out at any time up to 2 years and 6 weeks after primary surgery and completion of radiotherapy (if received). Because patients were assessed for study variables only from the start of randomized treatment, no differentiation was made between those who were randomly assigned during the initial tamoxifen period, and those randomly assigned at the completion of this initial period.

At the time of the initial development of this protocol, tamoxifen 30 mg/d was used consistently in clinical practice in Germany. A protocol amendment in 2001 to reflect a change in clinical guidelines allowed patients to receive tamoxifen 20 mg/d. The protocol amendment permitted selection of either a 20 or 30 mg/d dose at random assignment, but no dose increases were permitted once study treatment had begun.

Study Assessments
Randomly assigned patients underwent a physical examination, and were monitored for disease recurrence and adverse events every 6 months during years 1 to 3 of randomized treatment and annually thereafter. Mammogram, chest x-ray, ultrasound of the liver, and skeletal scintigraphy were performed every 12 months throughout the study and for the 3-year follow-up period.

The primary efficacy variable was disease-free survival, including local or distant recurrence, new contralateral breast cancer, or death. Patients who had not experienced disease recurrence or died were censored at the date of their last assessment. Any patient who died due to breast cancer without any prior recurrence having been recorded was assumed to have suffered a distant recurrence. In such instances, the date of distant recurrence and the date of death were identical. Overall survival was assessed as a secondary efficacy variable. All deaths, serious and nonserious adverse events are reported here.

Statistical Analysis
For this study, a sample size of 1,000 patients (500 per treatment arm) was calculated as being sufficient to provide 80% power at a 5% significance level, to detect an anticipated difference in relapse-free survival of 10% (requiring 220 events and equivalent to a hazard ratio [HR] of 0.68), 7 years after primary surgery between the anastrozole and continued tamoxifen treatment arms.

However, the protocol was amended in 2004 to enable a combined analysis with ABCSG trial 8. This protocol amendment stated that 278 events (in the combined analysis) would have 80% power to detect an HR of 0.71, and allowed for two interim analyses to be performed. As described previously,⁸ the first interim analysis concluded that, for postmenopausal women with hormone-sensitive early breast cancer, switching to anastrozole from tamoxifen was superior to continuing tamoxifen in the adjuvant setting. This report describes the results of the analysis of this trial on its own, after the combined analysis had been completed, using the same data cutoff of September 2004 as the combined analysis.

All efficacy analyses were performed using the full analysis set, which included all patients who completed their initial tamoxifen treatment and had been randomly assigned to anastrozole or continued tamoxifen. The safety analysis population included all randomly assigned patients who received at least one dose of study medication after random assignment.

Statistical analyses were performed using the Statistical Analysis System version 8.01 (SAS Institute, Cary, NC). The proportion of patients without a recurrence of their disease and the proportion of patients alive at year 3 was summarized in the intent-to-treat (ITT) population using the Kaplan-Meier method. The effect of treatment on disease-free survival and overall survival was analyzed using a Cox proportional hazards model and data are presented as estimated HRs (anastrozole:tamoxifen) with two-sided 95% CIs and P values, before and after adjustment for potential prognostic factors such as age, tumor size, and lymph node status.

Treatment groups were compared for proportions of serious adverse events and treatment-related serious adverse events using odds ratios (OR) with 95% CI and the Mantel-Haenszel test. No adjustments for multiple comparisons were made.

	RESULTS

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Patients
Of a total of 1,040 patients were enrolled onto the study, 979 were eligible to receive randomized study therapy (ITT population); 61 of 1,040 enrolled patients did not complete the initial tamoxifen period and were therefore excluded from the ITT population and not randomly assigned to study treatment. Four hundred eighty-nine patients were randomly assigned to switch to anastrozole and 490 were randomly assigned to continue on tamoxifen (Fig 1).

View larger version (29K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Trial profile. All patients had estrogen receptor (ER) –negative and/or progesterone receptor (PR) –positive disease. Positive receptor status was defined by either dextran-coated charcoal analysis (ER–or PR–positive > 20 fmol/mg tissue protein), or immunohistochemical or enzyme-immunological determination.

The treatment groups were broadly similar for all demographic and baseline breast cancer characteristics assessed (Table 1).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier probability of (A) disease-free survival and (B) overall survival (intent-to-treat population). For (A), locoregional recurrence, distant recurrence, contralateral new breast primary or death. HR, hazard ratio.

There was a numerical advantage in favor of anastrozole for the incidence of any recurrence event (local or distant recurrence, contralateral breast cancer; Table 2). The incidence of contralateral breast cancer was low, with seven events (1.4%) in patients switched to anastrozole and five events (1.0%) in patients who continued with tamoxifen.

After adjustment for potential prognostic factors (age, tumor size and grade, lymph node status, and type of primary surgery), switching to adjuvant anastrozole from adjuvant tamoxifen still resulted in a statistically significant improvement in disease-free survival (HR, 0.61; 95% CI, 0.40 to 0.93; P = .023) and overall survival (HR, 0.48; 95% CI, 0.25 to 0.91; P = .026) compared with continuing on tamoxifen.

Safety
The overall safety profile for anastrozole was consistent with the known safety profile established in postmenopausal women with hormone receptor–positive early breast cancer^4,6-8; no new safety issues were identified. All of the patients in this study tolerated 2 years of treatment with tamoxifen.

Fewer patients died after switching to anastrozole treatment (n = 15; 3.4%) compared with those patients who continued on tamoxifen (n = 27; 6.0%; Table 3). This was the case both for deaths after recurrence and for those in the absence of recurrence. There were no serious adverse events with an outcome of death.

A similar number of patients reported vascular events in each treatment group, although there were differences in distribution of events between trial arms. More patients in the group continuing on tamoxifen reported deep venous thromboembolic events, while a greater incidence of ischemic cardiovascular events was reported in patients switched to anastrozole than in those who continued on tamoxifen; the difference between these groups being predominantly due to four patients who switched to anastrozole reporting an incident of angina pectoris, an event not reported by any patient continuing on tamoxifen. There was one myocardial infarction reported in the study, for a patient continuing on tamoxifen treatment.

More patients in the anastrozole group experienced musculoskeletal events, although the number of patients reporting fractures was similar for each treatment arm.

A similar number of patients reported new primary cancers at a variety of sites in the two treatment groups (Table 3).

	DISCUSSION

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The data presented herein demonstrate that postmenopausal women receiving adjuvant tamoxifen therapy for the treatment of hormone receptor–positive early breast cancer benefit from switching to adjuvant anastrozole after 2 years of treatment, rather than continuing with tamoxifen. This benefit was seen in terms of a lower risk of disease recurrence, an improvement in overall survival, and a lower incidence of serious adverse events. Notably, this is the first time an individual trial using an AI has demonstrated an improvement in overall survival in a well-defined ITT patient population. The Intergroup Exemestane Study (IES), at 58 months' median follow-up (N = 4,724), also showed significant improvements in disease-free survival, time to contralateral breast cancer, and time to distant recurrence among those women who switched to an AI, in this case exemestane, compared with those who remained on tamoxifen. However, only a trend toward a significant benefit (HR, 0.85; 95% CI, 0.71 to 1.02; P = .08) was observed for a switching strategy in the ITT population.¹⁰ When a nonprospectively planned subset analysis excluding 122 ER-negative patients was performed, overall survival in the ER positive/unknown population just reached significance (HR, 0.83; 95% CI, 0.69 to 1.00; P = .05).¹⁰ Overall, the IES data lend further weight to the argument that postmenopausal women with hormone receptor–positive early breast cancer will benefit from switching to an AI after 2 to 3 years of initial adjuvant tamoxifen therapy.

Although patient numbers observed beyond 5 years are limited, the Kaplan-Meier disease-free survival curves derived from the ARNO 95 data suggest that the apparent absolute difference in treatment effect between the anastrozole and tamoxifen treatment groups at the end of the study period was maintained throughout the follow-up period to date, indicating that the conclusions of this study are unlikely to be changed with further follow-up. The safety profiles for anastrozole and tamoxifen were consistent with those previously reported in postmenopausal women with hormone receptor–positive early breast cancer.^4,6-8 However, it is notable that there was an identical number of bone fractures in both treatment groups; this may have been caused by the osteoprotective effect of the tamoxifen treatment for 2 years before anastrozole therapy.

The AIs are gaining acceptance when used as an alternative adjuvant treatment to tamoxifen and recent studies have indicated clinically relevant benefits over tamoxifen in the primary adjuvant setting.^4,12 The results of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial have shown that adjuvant anastrozole significantly prolongs disease-free survival and time to recurrence, reduces the risk of metastasis and contralateral breast cancer, and has improved tolerability compared with tamoxifen therapy over 5 years.^4,5 Data for letrozole from the Breast International Group 1-98 trial, at 26 months of median follow-up, supported results seen in the ATAC trial.¹²

Studies with the AIs anastrozole and exemestane also support a benefit for switching to an alternative agent after 2 to 3 years' tamoxifen therapy.^6-11 These studies have focused on switching after an initial 2 to 3 years of tamoxifen therapy, as this was considered to offer the maximum benefit for tamoxifen in terms of efficacy while minimizing the long-term health implications.^6,8,9 The ITA study was the first of the anastrozole switching studies to report⁶ and recently, 5-year data have also been presented.⁷ In the ITA study, patients were randomly assigned to receive anastrozole 1 mg/d after 2 to 3 years of tamoxifen therapy for a total duration of 5 years of adjuvant treatment. In common with the women who took part in our study, participants who were switched to anastrozole in the ITA trial after their initial tamoxifen therapy experienced significantly longer disease-free and local recurrence-free survival than those women who continued with tamoxifen.^6,7 The initial results of ABCSG 8 have been published as a prospectively planned combined analysis with the data from this trial⁸; the studies were designed with near identical inclusion criteria and outcome measures. The combined analysis included data from more than 3,200 postmenopausal women with hormone receptor–positive early breast cancer, and indicated a 40% decrease in the risk of any breast cancer-related event among women switched to anastrozole after 2 to 3 years of tamoxifen therapy.⁸

Based on currently available data, AIs not only have proven efficacy and tolerability advantages as initial adjuvant treatment compared with tamoxifen, but also as adjuvant treatment after 2 to 3 years of tamoxifen.

The results presented herein show that patients switched to anastrozole after an initial period of tamoxifen therapy experience significant improvements in terms of disease-free and overall survival. Our results provide additional evidence that 5 years of tamoxifen is no longer the optimum adjuvant therapy for postmenopausal women with hormone receptor–positive early breast cancer, and will be of considerable relevance to the large number of women currently receiving long-term endocrine therapy with tamoxifen.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Manfred Kaufmann, AstraZeneca, Pfizer; Walter Jonat, AstraZeneca, Novartis; Jörn Hilfrich, AstraZeneca, Pfizer; Holger Eidtmann, AstraZeneca, Pfizer; Gunter von Minckwitz, AstraZeneca, Novartis Stock: N/A Honoraria: Manfred Kaufmann, AstraZeneca, Pfizer, Novartis; Walter Jonat, AstraZeneca, Novartis; Jörn Hilfrich, AstraZeneca, Pfizer; Holger Eidtmann, AstraZeneca, Pfizer; Gunter von Minckwitz, AstraZeneca, Novartis Research Funds: Manfred Kaufmann, AstraZeneca; Walter Jonat, AstraZeneca; Jörn Hilfrich, AstraZeneca; Holger Eidtmann, AstraZeneca; Gunter von Minckwitz, AstraZeneca, Novartis Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Manfred Kaufmann, Walter Jonat, Jörn Hilfrich, Holger Eidtmann, Günther Gademann, Ivan Zuna, Gunter von Minckwitz

Financial support: Manfred Kaufmann, Walter Jonat, Jörn Hilfrich, Holger Eidtmann, Günther Gademann, Gunter von Minckwitz

Administrative support: Manfred Kaufmann, Walter Jonat, Jörn Hilfrich, Holger Eidtmann, Günther Gademann, Gunter von Minckwitz

Provision of study materials or patients: Manfred Kaufmann, Walter Jonat, Jörn Hilfrich, Holger Eidtmann, Günther Gademann, Gunter von Minckwitz

Collection and assembly of data: Manfred Kaufmann, Walter Jonat, Jörn Hilfrich, Holger Eidtmann, Günther Gademann, Ivan Zuna, Gunter von Minckwitz

Data analysis and interpretation: Manfred Kaufmann, Walter Jonat, Jörn Hilfrich, Holger Eidtmann, Günther Gademann, Ivan Zuna, Gunter von Minckwitz

Manuscript writing: Manfred Kaufmann, Walter Jonat, Ivan Zuna

Final approval of manuscript: Manfred Kaufmann, Walter Jonat, Jörn Hilfrich, Holger Eidtmann, Günther Gademann, Ivan Zuna, Gunter von Minckwitz

	Appendix

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ARNO 95 Trial Steering Committee
M Kaufmann (J.W. Goethe-University of Frankfurt, Frankfurt am Main); W Jonat (University of Kiel, Kiel); J Hilfrich (Henriettenstift, Hannover); I Zuna (Institute of Statistics SKM, Wiesbaden, Germany).

GABG (ARNO 95) Investigators
A K Bergmann (Universitaetsklinikum Tuebingen); F von Bismarck (Klinikum Rechts der Isar, Muenchen); K Brunnert (Klinik fuer Senologie und Plastische Chirurgie Osnabrueck); M Butterwegge (Marienhospital Osnabrueck); O Camara (Universitaetsklinik Jena); M Carstensen (Albertinen Krankenhaus Hamburg); K Christl (Krankenhaus Eggenfelden); M H R Eichbaum (Universitaetsklinikum Heidelberg); J Feltz-Suessenbach (Klinikum Schaumburg, Stadthagen); R Fricker (Stadtkrankenhaus Hanau); M Friedrich (Universitaetsklinik Schleswig Holstein, Campus Luebeck); L Funk (St. Vincentius Krankenhaeuser Karlsruhe); E Goepel (Gynaekologische Gemeinschaftspraxis Hamburg); S Graeber (Universitaet Halle); C A Hanusch (Frauenklinik vom Roten Kreuz Muenchen); L Heilmann (Stadtkrankenhaus Ruesselsheim); VJ Heilmann (Universitaetsklinik Ulm); T Hitschold (Stadtkrankenhaus Worms); A Hoenig (Universitaetsklinik Wuerzburg); M Holbeck (Martin Luther Krankenhaus Schleswig); G Hopf (Elisabeth Krankenhaus Kassel); T Horvath (Kreisklinik Albstadt); H Jank (DRK Kliniken Westend Berlin); M Johnscher (Bonifatius Hospital Lingen); G Kaltenecker (Staedtisches Klinikum Karlsruhe); C Karg (Kreiskrankenhaus Waiblingen); T Liersch (Universitaetsklinik Goettingen); E Lindenlauf (Jung Stilling Krankenhaus Siegen); B Lisboa (Universitaetsklinikum Eppendorf Hamburg); S Loibl (Universitaetsklinik Frankfurt); K Luermann (Klinikum Hoyerswerda); I Maier (Klinikum Rosenheim); B Mueller (Klinikum der Stadt Mannheim); C Mundhenke (Universitaetsklinik Schleswig Holstein, Campus Kiel); A Neff (Clemenshospital Muenster); T Reimer (Universitaetsklinik Rostock); K Rensing (Universitaetsklinik Muenster); I Schrader (Henriettenstiftung Hannover); D Schulze (St Vincenz Krankenhaus Paderborn); I Schulz-Im-Busch (St. Josephs Hospital Cloppenburg); K W Schweppe (Ammerland Klinik Westerstede); G Sergius (St Joseph Krankenhaus Berlin); H K Sommer (Kreiskrankenhaus Neustadt); K Stahl (Prosper Hospital Recklinghausen); S Stein (Staedtische Krankenanstalten Idar-Oberstein); J Steller (Helios Research Center Titisee-Neustadt); E Stickeler (Universitaetsklinik Freiburg); R Stiglmayr (Siloah Krankenhaus Pforzheim); W Wiest (St Vincenz und St Elisabeth Hospital Mainz); K J Winzer (Universitaetsklinikum Charité Berlin); H Wolf (Kreiskrankenhaus Leonberg); K Wollschlaeger (Universitaetsfrauenklinik Magdeburg); and B Zieren-Ernhardt (Universitaetsklinik Charité Berlin, Germany).

	ACKNOWLEDGMENTS

 
We thank all our patients, who had the spirit to fight their disease and to help others to find better treatment options. We thank all doctors, nurses, and investigators contributing to this trial. We thank Mark Walker, PhD, from Complete Medical Communications, who provided medical writing support.

	NOTES

 
published online ahead of print at www.jco.org on June 11, 2007.

Supported by grants from AstraZeneca, Germany.

Presented in part in abstract format at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006.

This trial is registered with ClinicalTrials.gov, No. NCT00287534.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Osborne CK, Fuqua SA: Mechanisms of tamoxifen resistance. Breast Cancer Res Treat 32:49-55, 1994[CrossRef][Medline]

2. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline]

3. Fisher B, Costantino JP, Redmond CK, et al: Endometrial cancer in tamoxifen-treated breast cancer patients: Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86:527-537, 1994[Abstract/Free Full Text]

4. ATAC Trialists' Group: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60-62, 2005[CrossRef][Medline]

5. The ATAC Trialists' Group: Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: Long-term safety analysis of the ATAC trial. Lancet Oncol 7:633-643, 2006[CrossRef][Medline]

6. Boccardo F, Rubagotti A, Puntoni M, et al: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: Preliminary results of the Italian Tamoxifen Anastrozole trial. J Clin Oncol 23:5138-5147, 2005[Abstract/Free Full Text]

7. Boccardo F, Rubagotti A, Puntoni M, et al: Switching to anastrozole (ANA) vs continued tamoxifen (TAM) treatment of early breast cancer (EBC): Updated results of the Italian tamoxifen anastrozole (ITA) trial. J Clin Oncol 23:10s, 2005 (abstr 526)

8. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2005[CrossRef][Medline]

9. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004[Abstract/Free Full Text]

10. Coombes RC, Paridaens R, Jassem J, et al: First mature analysis of the Intergroup Exemestane Study. J Clin Oncol 24:9s, 2006 (abstr LBA527)[CrossRef]

11. Coombes RC, Hall E, Snowdon CF, et al: The Intergroup Exemestane Study: A randomized trial in postmenopausal patients with early breast cancer who remain disease-free after two to three years of tamoxifen - updated survival analysis. Breast Cancer Res Treat 88:S7, 2004 (suppl 1; abstr 3)

12. The Breast International Group (BIG) 1-98 Collaborative Group: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005[Abstract/Free Full Text]

13. Jonat W, Gnant M, Boccardo F, et al: Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: A meta-analysis. Lancet Oncol 7:991-996, 2006[CrossRef][Medline]

Submitted August 18, 2006; accepted January 29, 2007.

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