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Effect of Once-Weekly Epoetin Beta on Survival in Patients With Metastatic Breast Cancer Receiving Anthracycline- and/or Taxane-Based Chemotherapy: Results of the Breast Cancer—Anemia and the Value of Erythropoietin (BRAVE) Study

Matti Aapro, Robert C. Leonard, Agustí Barnadas, Maurizio Marangolo, Michael Untch, Nikolaos Malamos, José Mayordomo, Dietmar Reichert, José Luiz Pedrini, Lidia Ukarma, Armin Scherhag, Hans-Ulrich Burger

From the Institut Multidisciplinaire d'Oncologie, Clinique de Genolier, Genolier; F. Hoffmann–La Roche Ltd, Basel, Switzerland; Cancer Services and Clinical Haematology, Imperial College, Charing Cross Hospital, London, United Kingdom; Hospital de Sant Pau, Barcelona; Hospital Clinico Universitario de Zaragoza, Zaragoza, Spain; Divisione Oncologia, Ospedale Provinciale Sta Maria delle Croci, Ravenna, Italy; Helios Klinikum, Berlin Buch; Medical Clinic, University Hospital Mannheim, University of Heidelberg, Heidelberg; Staedtische Kliniken Oldenburg, Oldenburg, Germany; Elena Venizelou Hospital, Athens, Greece; and Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil

Corresponding author: Matti Aapro, Institut Multidisciplinaire d'Oncologie, Clinique de Genolier, 1 route du Muids, Genolier, Switzerland 1272; e-mail: maapro{at}genolier.net

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose The Breast Cancer—Anemia and the Value of Erythropoietin (BRAVE) study evaluated whether epoetin beta would improve survival in patients with metastatic breast cancer (MBC).

Patients and Methods BRAVE was an open-label, randomized, multicenter study in patients with MBC treated with anthracycline- and/or taxane-based chemotherapy. Patients (hemoglobin [Hb] < 12.9 g/dL) were randomly assigned (1:1) to epoetin beta 30,000 U subcutaneously once weekly or control for 24 weeks. The primary efficacy variable was overall survival. Secondary efficacy outcomes included progression-free survival, transfusion- and severe anemia–free survival, Hb response, safety, and quality of life (QoL).

Results After 18 months of follow-up, 62 (27%) of 231 patients survived with epoetin beta therapy and 63 (27%) of 232 with control. No difference was detected in overall survival (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522) or progression-free survival (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448). There was a statistically significant benefit on transfusion- and severe anemia–free survival compared with control (HR = 0.59; P = .0097). Median Hb level increased with epoetin beta (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) but did not change with control (11.5 v 11.4 g/dL). Patients receiving epoetin beta experienced more thromboembolic events (TEEs) compared with controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%). Epoetin beta did not significantly improve QoL in this study where patients had a high baseline Hb value.

Conclusion In patients with MBC receiving chemotherapy and initial Hb less than 12.9 g/dL, epoetin beta increased Hb. No difference was detected in overall survival. Because of its superiority design, this study cannot, however, exclude clinically important differences in survival with absolute certainty.

	INTRODUCTION

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Anemia is prevalent in patients with breast cancer (BC).¹ Anthracyclines and taxanes are frequently used for the treatment of metastatic BC (MBC) and are associated with anemia.² Studies have shown that recombinant human erythropoietin (epoetin) therapy increases or maintains hemoglobin (Hb) levels, reduces transfusion need, and improves quality of life (QoL) in patients receiving chemotherapy.^3-6

A systematic review of 60 studies of cancer patients showed that anemia is an adverse prognostic factor for overall and progression-free survival.⁷ Initial studies suggest that treatment of anemia with epoetin in cancer patients may have beneficial effects on survival.^8-13 In contrast, two recent studies suggest that epoetins may increase the risk of tumor progression and impair survival in patients with head and neck or breast cancers.^14-16

The Breast Cancer—Anemia and the Value of Erythropoietin (BRAVE) trial was designed to determine whether epoetin beta 30,000 U once weekly (QW) can influence survival in patients with MBC scheduled to receive anthracycline- and/or taxane-based chemotherapy and to evaluate its efficacy and safety.

	PATIENTS AND METHODS

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Study Population
Female patients (age 18 years) with histologically or cytologically diagnosed assessable MBC, scheduled to start anthracycline- and/or taxane-based chemotherapy, were enrolled. Patients had to have Hb level less than 12.9 g/dL at screening, life expectancy more than 6 months, WHO performance status of 0 to 2, and no erythropoietic therapy within 2 months before study start, and provide signed consent.

Major exclusion criteria included patients unsuitable for treatment with anthracycline- and/or taxane-based chemotherapy or scheduled for high-dose chemotherapy with autologous bone marrow or peripheral-blood stem-cell transplantation; presence or history of brain metastases; concomitant radiometabolic therapy; platelet count less than 50 or more than 450 x 10⁹/L; poorly controlled hypertension (sitting systolic blood pressure 170 mmHg and diastolic blood pressure 100 mmHg); functional iron deficiency (transferrin saturation < 20%) that could not be treated with iron supplementation before baseline; anemia caused by bleeding, folic acid deficiency, vitamin B₁₂ deficiency, hemolysis, or history of congenital hemoglobinopathy; acute infection; and pregnancy or lactation.

Study Design
This was an open-label, randomized, multicenter, two-arm study of patients with MBC treated with chemotherapy (anthracycline- and/or taxane-based) conducted at 82 centers in Asia, Central/South America, and Europe. A superiority design was chosen to test the hypothesis that epoetin beta treatment would improve survival. The design and conduct of the study complied with good clinical practice in accordance with the Declaration of Helsinki and local requirements. The study was approved by the appropriate independent ethics committees. All investigators agreed to the protocol and its efficacy analyses. On the basis of the protocol, a predefined statistical analysis plan was agreed between the sponsor, F. Hoffmann–La Roche (Basel, Switzerland), and the steering committee before database closure. The sponsor conducted all statistical analyses. All data were interpreted in close collaboration with the sponsor and the steering committee, who had access to all data. The study was open label to avoid unnecessary risk and potential compromise of ethical integrity associated with injection of placebo.

Patients were recruited between November 2002 and June 2004. After a 2-week screening period, eligible patients were centrally randomized (1:1) to receive epoetin beta (NeoRecormon, F. Hoffmann–La Roche Ltd, Basel, Switzerland) subcutaneously 30,000 U QW, or control (transfusions allowed as clinically indicated in both arms) over 24 weeks (Fig 1). Random assignment using a block design was stratified by chemotherapy type, hormonal status, and country. Clinical visits were scheduled every 3 to 4 weeks for laboratory assessments.

View larger version (29K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Patient disposition. ITT, intention to treat. (*) One patient randomly assigned to the control arm received no scheduled chemotherapy during the study and was excluded from the safety population.

Epoetin beta treatment and chemotherapy started on the same day. Iron therapy (oral or intravenous) was administered to patients in either study arm at any point during treatment if transferrin saturation was less than 20%.

Clinical assessments at screening, baseline, and each visit included during the 24-week treatment period were vital signs, physical examination, medical history, blood pressure, iron parameters and hematology parameters (Hb and hematocrit), ECG, and C-reactive protein levels. After 24 weeks of treatment, follow-up visits were scheduled every 3 months until the last patient enrolled was followed for a total of 24 months (6 months of treatment and 18 months of follow-up).

Efficacy Assessments
The primary efficacy outcome was a comparison of overall survival between treatment groups.

Secondary efficacy variables included progression-free survival, transfusion- and severe anemia–free survival, and QoL. Progression-free survival was assessed every 6 to 8 weeks during the 24-week treatment period and every 3 months thereafter. Tumor measurements (assessed by Response Evaluation Criteria in Solid Tumors [RECIST]) were assessed every 6 to 8 weeks during the 24-week treatment period, and at subsequent intervals based on clinical judgment by the treating physician.

Hb levels were assessed at each clinic visit during treatment. An analysis of Hb response (increase in Hb 2 g/dL from baseline with no blood transfusion in the 6 weeks before the last available Hb measurement) was performed following the 24-week treatment period.

Safety Assessments
Safety was assessed through recording of adverse events, laboratory parameters, and vital signs. Adverse events and serious adverse events were recorded continuously throughout the 24-week treatment phase and graded using National Cancer Institute Common Toxicity Criteria (CTCAE V3). During the 18-month follow-up period, only serious adverse events considered by the investigator as treatment related were recorded. Laboratory tests were determined at screening, baseline, and every 3 to 4 weeks until therapy stopped. An independent data and safety monitoring board reviewed data at regular intervals.

Statistical Analysis
A sample size of approximately 460 patients (230 patients per treatment arm, including a 10% drop-out rate) was calculated to detect an improved survival hazard rate of 29% with a power of 80% (hazard ratio [HR] for epoetin beta v control = 0.71), at a two-sided significance level of 5%, using the log-rank test in patients receiving epoetin beta compared with control. Sample size was based on a 24-month recruitment period and 18 months follow-up for the last patient recruited; that is, follow-up was between 18 and 42 months for all patients and at least 277 fatal events. Efficacy variables were analyzed for the intention-to-treat population.

The effects of epoetin beta on overall survival, progression-free survival, transfusion- and severe anemia–free survival, and thromboembolic events (TEEs) were evaluated with Kaplan-Meier estimates, log-rank test, and Cox regression models.

Differences in the Hb response between the two treatment arms were tested with a two-sided ² test with Schouten correction. Changes in QoL Functional Assessment of Cancer Therapy Anemia subscale (FACT-An) scores from baseline were also analyzed by analysis of covariance including baseline QoL as a further covariate.

The safety population included all randomly assigned patients who received at least one dose of chemotherapy or epoetin beta. All safety analyses were based on the safety population.

	RESULTS

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Patient Characteristics and Disposition
Overall, 463 patients were enrolled (Fig 1). One assigned to the control arm received no scheduled chemotherapy during the study, and was excluded from the safety population. In total, 340 (73%) completed the study treatment period and 123 (27%) withdrew (epoetin beta, n = 69; control, n = 54; Fig 1).

Demographic and clinical characteristics showed no major differences between the two study arms (Table 1). Concomitant iron supplementation was slightly higher in the epoetin beta group (85%) compared with the control group (80%).

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Change in median (interquartile range) hemoglobin (Hb) levels in patients with metastatic breast cancer in the epoetin beta arm (n = 230) and the control arm (n = 230; intention-to-treat population). Hb values at baseline (BL) were not reported for two patients in the control group and one patient in the epoetin beta group.

During the study, 41.1% of patients in the epoetin beta group received a dose of 30,000 U QW. In total, 27.3% of patients had epoetin beta dose reduced or stopped and 44.6% had their dose doubled to 60,000 U QW.

Survival and Disease Progression
After a total follow-up of between 24 and 43 months, 169 patients (73%) had died in the epoetin beta and control groups (total number of deaths: 338). The most common reason for death was progression of MBC. For the primary end point, there was no difference in overall survival between the two groups (HR = 1.07; 95% CI, 0.87 to 1.33; P = .522; Fig 3A). At study end, 220 (95%) had evidence of progressive disease in the epoetin beta group and 222 (96%) in the control group. There was no difference in progression-free survival between the two groups (HR = 1.07; 95% CI, 0.89 to 1.30; P = .448; Fig 3B). In addition, 191 patients (83%) remained transfusion- and severe anemia–free in the epoetin beta group and 168 (72%) in the control group. There was a highly significant benefit on transfusion- and severe anemia–free survival in the epoetin beta group compared with the control group (HR = 0.59; 95% CI, 0.40 to 0.88; P .01; Fig 3C).

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier estimate of (A) overall survival, (B) progression-free survival (each at 18-month follow-up), and (C) transfusion- and severe anemia–free survival at 18-month follow-up (at end of treatment phase).

QoL
Over the 24-week treatment period, there were no statistically significant differences between the two treatment groups for any of the FACT-An subscale scores (all P > .6).

Safety and Tolerability
Epoetin beta was generally well tolerated during the treatment period. The percentage of patients reporting adverse events was similar between the two treatment groups (Table 2). Adverse events considered by the investigator to be related to epoetin beta treatment were reported in 34 patients (15%). These included nausea (four patients; 2%), headache (four patients; 2%), and pyrexia (three patients; 1%). Serious adverse events occurred in 42% of patients receiving epoetin beta compared with 31% receiving control. There was no difference in the proportion of grade 3 or 4 adverse events between the two groups (48% in both arms). Drug-related serious adverse events were reported in only five patients (2%) in the epoetin beta group (Table 2). Overall, adverse events leading to withdrawal occurred in 43 patients (19%) receiving epoetin beta compared with 29 (13%) receiving control treatment.

	DISCUSSION

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In this study, no difference was detected for the primary end point, overall survival between patients receiving epoetin beta and those receiving standard care. However, because the trial was not designed as a noninferiority study, caution should be exercised in terms of excluding clinically important differences in survival on the basis of this study. There was no difference in progression-free survival between the two groups (HR = 1.07; 95% CI, 0.89 to 1.30; P = .448; Fig 3B). Subcutaneous epoetin beta QW was associated with a highly significant increase in Hb of 1.5 g/dL in patients with MBC receiving anthracycline- and/or taxane-based chemotherapy and a baseline Hb of less than 12.9 g/dL. In contrast, there was a highly significant difference in transfusion- and severe anemia–free survival in favor of patients receiving epoetin beta compared with those receiving standard care (HR = 0.59; 95% CI, 0.40 to 0.88; P = .01; Fig 3C).

Importantly, the design and results of this study should be interpreted in the context of current licensed indications and guidelines for epoetin use. BRAVE was designed in the year 2000, and inclusion criteria specified patients with Hb less than 12.9 g/dL. The recent European Organisation for Research and Treatment of Cancer guidelines for the use of erythropoietic proteins in anemic patients with cancer recommend QW administration for symptomatic patients with Hb 9 to 11 g/dL and a target Hb level of 12 to 13 g/dL.¹⁷ In comparison, the US (American Society of Hematology/American Society of Clinical Oncology and National Comprehensive Cancer Network) guidelines recommend erythropoietic therapy for patients with Hb less than 10 g/dL and advocate a target Hb level of approximately 12 g/dL.^18,19

The neutral effect of epoetin beta on survival in this study is in contrast to earlier studies.^10-11 In patients with cancer receiving non–platinum-based chemotherapy, a trend (P = .13) toward improved survival was observed in patients treated with epoetin alfa compared with those receiving placebo.¹⁰ A trend toward improved progression-free survival was also observed with darbepoetin alfa in patients with lung cancer receiving chemotherapy. The median duration of progression-free survival was 22 weeks in the darbepoetin alfa group and 20 weeks in the placebo group.¹¹

In another study with MBC patients who received chemotherapy (the Breast Cancer Erythropoietin Survival Trial [BEST]; N = 939, double-blind design), significantly higher mortality was observed in patients receiving epoetin alfa 40,000 U QW compared with those receiving placebo (HR = 1.37; P = .01).¹⁵ On the basis of this increase in mortality, and a respective recommendation from the independent data monitoring committee, the study was terminated prematurely.^14-15

In the BEST study, the difference in mortality favoring patients receiving placebo seemed limited to the initial 16 weeks of observation. Within the first 4 months of therapy, there were 41 early deaths (8.7%) in the epoetin alfa group and 16 (3.4%) in the placebo group. The primary cause of death attributed by the investigators was disease progression (6% epoetin alfa v 2.8% placebo). Although no final explanation was provided for observed differences in mortality, the authors speculated that flaws in the study design and conduct, baseline imbalances in risk factors, and the difference in fatal TEEs between the two study groups (epoetin alfa [1.3%; n = 6] v placebo [0.4%; n = 2]) may have contributed. Importantly, results of the BEST study were not confirmed by the findings of the present study.

BRAVE was conducted to ensure complete data collection for disease progression and survival status with follow-up for 18 months after the last patient's final treatment visit. There were no significant differences in survival or disease progression at 4 (P = .46), 12 (P = .61), or 18 (P = .52) months at the end of the follow-up phase (Figs 3A and 3B). Moreover, there was no difference in the number of fatal TEEs between the two study groups (four patients in each group).

The neutral findings on survival and disease progression of this open-label study in patients with MBC accord with data from a study in patients with lymphoproliferative malignancies²⁰ and with meta-analyses showing no negative impact of epoetins on survival and disease progression in patients with cancer.^12,21-24 The 95% CI of 0.87 to 1.33 for the HR makes treatment effects outside this CI unlikely.

In contrast to previous studies,^3-5 the present study did not show a significant improvement in QoL. The inclusion criteria of the BRAVE study allowed patients with baseline Hb levels less than 12.9 g/dL to be randomly assigned, whereas maximum improvements in QoL are usually achieved only when Hb levels are titrated up to 11 to 13 g/dL.²⁵ Incremental benefits in QoL have not been described in cancer patients with Hb values more than 13 g/dL. The subgroup of only 154 patients with Hb less than 11 g/dL at baseline was insufficiently powered to demonstrate significant QoL benefit. Similarly, the BEST study was also not designed or powered to show significant QoL benefit (inclusion Hb < 13 g/dL), evidenced by the lack of a significant difference between epoetin alfa and placebo for all six QoL analyses.¹⁵

In summary, in this study enrolling patients with MBC receiving anthracycline- and/or taxane-based chemotherapy and an inclusion Hb of less than 12.9 g/dL, epoetin beta 30,000 U QW was effective in raising Hb and was well tolerated. No difference in the primary end point of overall survival was detected. Because of its superiority design, this study cannot, however, exclude clinically important differences in survival with absolute certainty. Moreover, recent changes in licensed indications and guidelines for epoetin use in patients with cancer receiving chemotherapy made after the study start means the treatment of most patients in the study did not follow current recommendations. Accordingly, general extrapolation of these findings to patients treated within currently licensed indications for epoetins in Europe or the United States is not possible.

	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: Lidia Ukarma, Roche; Armin Scherhag, Roche; Hans-Ulrich Burger, Roche Leadership: N/A Consultant: Matti Aapro, Roche, Amgen; Robert C. Leonard, Roche; Agustí Barnadas, Roche, Pfizer; Michael Untch, Roche Stock: N/A Honoraria: Matti Aapro, Roche, Amgen, Sanofi-Aventis; Robert C. Leonard, Roche; Agustí Barnadas, Roche, Pfizer, Novartis; Hans-Ulrich Burger, Roche Research Funds: Matti Aapro, Roche; Agustí Barnadas, Lilly; Maurizio Marangolo, Eli-Lilly; José Luiz Pedrini, Roche, Novartis Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Matti Aapro, Robert C. Leonard, Agustí Barnadas, Maurizio Marangolo, Michael Untch, Dietmar Reichert, Lidia Ukarma, Armin Scherhag, Hans-Ulrich Burger

Provision of study materials or patients: Matti Aapro, Agustí Barnadas, Michael Untch, José Mayordomo, Dietmar Reichert, José Luiz Pedrini, Lidia Ukarma

Collection and assembly of data: José Mayordomo, Lidia Ukarma, Armin Scherhag

Data analysis and interpretation: Matti Aapro, Robert C. Leonard, Agustí Barnadas, Maurizio Marangolo, Michael Untch, Dietmar Reichert, Lidia Ukarma, Armin Scherhag, Hans-Ulrich Burger

Manuscript writing: Matti Aapro, Robert C. Leonard, Agustí Barnadas, Michael Untch, Dietmar Reichert, Lidia Ukarma, Armin Scherhag, Hans-Ulrich Burger

Final approval of manuscript: Matti Aapro, Robert C. Leonard, Agustí Barnadas, Maurizio Marangolo, Michael Untch, Nikolaos Malamos, José Mayordomo, Dietmar Reichert, Lidia Ukarma, Armin Scherhag, Hans-Ulrich Burger

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The following committee members and investigators participated in the BRAVE study. Steering Committee: M. Aapro (Genolier, Switzerland), R.C. Leonard (London, United Kingdom), A. Barnadas (Barcelona, Spain), M. Marangolo (Ravenna, Italy), M. Untch (Berlin Buch, Germany); Data and Safety Monitoring Board: J. Jassem (Gdask, Poland), T.J. Littlewood (Oxford, United Kingdom), D. Messinger (Mannheim, Germany), R. Pirker (Vienna, Austria); Investigators: Austria—A. Lang (Feldkirch), H. Samonigg (Graz), J. Schüller (Wien), C. Wiltschke (Wien); Belgium—L. Dirix (Wilrijk), R. Paridaens (Leuven), J. Van Erps (Aalst), A. Vindevoghel (Namur); Brazil—C. Beato (Jau), B. Ferrari (Belo Horizonte), J.L. Pedrini (Porto Alegre); Denmark—P.M. Vestlev (Herlev), M. Andersson (Koebenhavn), A.B. Jensen (Aarhus); France—B. Audhuy (Colmar), D. Coeffic (Grenoble), J.M. Grunenwald (Mulhouse), M. Rotarski (Bayonne), H. Simon (Brest), V. Trillet-Lenoir (Pierre Benite), N. Tubiana-Mathieu (Limoges); Germany— M. Clemens (Trier), N. Marschner (Freiburg), P. Middeke (Duisburg), U. Nitz (Duesseldorf), D. Reichert (Oldenburg), C. Thomssen (Halle); Greece—K. Dimitriadis (Thessaloniki), N.A. Malamos (Athens), I. Stergiou (Thessaloniki), I. Varthalitis (Chania); Hungary— I. Lang (Budapest), T. Pinter (Gyor), L. Thurzo (Szeged); Italy—S. Barni (Treviglio), O. Bertetto (Torino), C. Boni (Reggio Emilia), M. Clerico (Biella), A. Contu (Sassari), N. Gebbia (Palermo), C. Iacono (Ragusa), R. Labianca (Bergamo), L. Manzione (Potenza), M. Marangolo (Ravenna), F. Puglisi (Udine), A. Rosa Bian (Thiene), A. Santoro (Milan); Mexico—L. Barriguete (Chihuahua), M.G. Cervantes Sanchez (Mexico City), J. Tokunaga (Tijuana); Netherlands—H.P. Sleeboom (Den Haag); Poland—E. Filipczyk-Cisarz (Wroclaw), A. Jagiello-Gruszfeld (Olsztyn), M. Mazurkiewicz (Lublin), P. Tomczak (Poznan); Spain—A. Barnadas (Barcelona), R. Colomer (Girona), E. Esteban Gonzalez (Oviedo), C. Falo (Barcelona), V. Guillem Porta (Valencia), J. Mayordomo (Zaragoza); Switzerland—M. Aapro (Genolier), H. Bonnefoi (Geneve); Taiwan—H.-T. Chang (Kaohsiung), T.-W. Chang (Tainan), H.-C. Wang (Taipei); Thailand—W. Arpornwirat (Bangkok), S. Laohavinij (Bangkok), V. Srimuninnimit (Bangkok); United Kingdom—P.J. Barrett-Lee (Cardiff), A.N. Branson (Newcastle-Upon-Tyne), M. Brunt (Stoke-on-Trent), S. Chan (Nottingham), N. Davidson (Chelmsford), A. Hong (Exeter), R. Leonard (London), J. Levay (Ipswich), J. McAleer (Belfast), D. Miles (London), K. O'Byrne (Leicester), T. Perren (Leeds), R. Stein (London), and G. Wilson (Manchester).

	NOTES

 
Supported by F. Hoffmann–La Roche Ltd, Basel, Switzerland.

Presented as a poster at the 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX.

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

	REFERENCES

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Submitted March 7, 2007; accepted October 24, 2007.

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