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Originally published as JCO Early Release 10.1200/JCO.2007.11.9453 on August 6 2007 © 2007 American Society of Clinical Oncology. Prognostic and Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors in a Randomized Trial Comparing Letrozole and Tamoxifen Adjuvant Therapy for Postmenopausal Early Breast Cancer: BIG 1-98
From the Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Milan, Italy; International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA; Department of Pathological Anatomy, University of Bari, Bari, Italy; Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy; Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy; Department of Pathology, Nordsjaellands Hospital, Hilleroed, Denmark; Service d'Anatomie et de Cytologie Pathologiques, Centre Hospitalier-site-Belfort-Montbéliard, Montbéliard, France; Department of Gyn Oncol and Multidisciplinary Breast Centre, UZ-KULeuven, Leuven, Belgium; Department of Pathology, National Institute of Oncology, Budapest, Hungary; Australian New Zealand Breast Cancer Trials Group, University of Newcastle and Anatomical Pathology, Hunter Area Pathology Service, John Hunter Hospital, New Lambton Heights, NSW, Australia; Kantonsspital, St Gallen, Swiss Group for Clinical Cancer Research, Bern, Switzerland; Senology Center of Eastern Switzerland, Kantonsspital, St Gallen, Switzerland, Swiss Group for Clinical Cancer Research; IBCSG Statistical Center, Dana-Farber Cancer Institute, Frontier Science and Technology Research Foundation, Harvard School of Public Health, Boston, MA; IBCSG Coordinating Center, Bern, Switzerland; IBCSG Statistical Center and Frontier Science and Technology Research Foundation, Boston, MA; European Institute of Oncology, Milan, Italy; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Division of Cancer Sciences and Molecular Pathology, Western Infirmary, University of Glasgow, UK; International Breast Cancer Study Group, Bern, Switzerland and University of Sydney, Australia Address reprint requests to Giuseppe Viale, MD, FRCPath, Divisione di Anatomia Patologica e Medicina di Laboratorio, Istituto Europeo di Oncologia, Via Ripamonti, 435, 20141 Milano, Italy; e-mail: giuseppe.viale{at}ieo.it
Purpose To evaluate locally versus centrally assessed estrogen (ER) and progesterone (PgR) receptor status and the impact of PgR on letrozole adjuvant therapy compared with tamoxifen in postmenopausal women with early breast cancer. Patients and Methods Breast International Group (BIG) 1-98 randomly assigned 8,010 patients to four arms comparing letrozole and tamoxifen with sequences of each agent. The Central Pathology Office received material for 6,549 patients (82%), of which 79% were assessable (6,291 patients). Prognostic and predictive value of both local and central hormone receptor expression on disease-free survival (DFS) were evaluated among 3,650 assessable patients assigned to the monotherapy arms. Prognostic value and the treatment effect were estimated for centrally assessed ER and PgR expression levels using the Subpopulation Treatment Effect Pattern Plot.
Results Central review confirmed 97% of tumors as hormone receptor–positive (ER and/or PgR Conclusion Central review changed the assessment of receptor status in a substantial proportion of patients, and should be performed whenever possible in similar trials. PgR expression did not affect the relative efficacy of letrozole over tamoxifen.
Several large adjuvant trials have examined the use of aromatase inhibitors in postmenopausal women with early breast cancer either in place of or following tamoxifen. The Arimidex Tamoxifen Alone or in Combination (ATAC) trial studied initial anastrozole1 while the Breast International Group (BIG) 1-98 trial used letrozole.2 Switching to exemestane following 2 to 3 years of tamoxifen was studied in the Intergroup Exemestane Study (IES),3 and switching to anastrozole, in a joint analysis of the Austrian (ABCSG Trial 8) and German (ARNO95) trials,4 and in Boccardo et al.5 Extended adjuvant therapy with letrozole after 5 years of tamoxifen was reported from the MA.17 trial.6 Each of these trials has been updated,7-12 and each has shown a superiority of the aromatase inhibitor over 5 years of tamoxifen treatment, or a placebo (MA.17). Estrogen receptor (ER) and progesterone receptor (PgR) content in the primary tumor of patients with early-stage invasive breast cancer are powerful predictors of response to adjuvant endocrine therapies.13 It is recommended that endocrine receptors be measured on all primary breast cancer specimens,14 and endocrine responsiveness is the primary basis for selection of adjuvant systemic therapy.15 In a hypothesis-generating analysis of the influence of receptor levels as measured at participating institutions in the ATAC study, Dowsett et al16 found that the superiority of anastrozole over tamoxifen was more marked in patients with tumors expressing ER but not PgR, and suggested that this finding should be evaluated in similar trials. No such effect has been reported from the IES9 or BIG 1-982,8 trials and no significant difference was seen in the ABCSG/ARNO studies4 based on institutional assessment of PgR status. Central review of tumors for ER and PgR on a subset of 30% of the ATAC patients is in progress.17 The present study reports the results of central pathological review of ER and PgR status in BIG 1-98, and particularly examines the impact of PgR expression on the relative efficacy of letrozole and tamoxifen.
The design and conduct of the study have been described previously.2 BIG 1-98 is a randomized, phase III, four-arm double-blind trial comparing monotherapy with letrozole or with tamoxifen for 5 years, or sequential administration of tamoxifen for 2 years followed by letrozole for 3 years, or the reverse sequence. Eligible postmenopausal women had early breast cancer assessed as ER- and/or PgR positive. Between March 1998 and March 2000, patients were randomly assigned to one of the monotherapy arms, and from April 1999 to May 2003, to all four arms. The ethics committees and required health authorities of each participating center approved the study protocol, and all patients gave written informed consent. The primary efficacy analysis among 8,010 patients2 was updated as specified by protocol, and reported among the 4,922 patients who were randomly assigned to the monotherapy arms only.8 Analyses of patient outcomes are therefore limited to the patients who were randomly assigned to the monotherapy arms.
Local Pathology Assessment
Central Pathology Review
Assessment of ER and PgR and Quality Assurance
Statistical Methods The primary trial end point was disease-free survival (DFS), which was defined as the time from random assignment to the earliest time of invasive recurrence; a new invasive breast cancer in the contralateral breast; any second (nonbreast) malignancy; or death from any cause.2 The distribution of DFS and 3- and 4-year DFS were estimated using the Kaplan-Meier method.20 Cox proportional hazards regression21 (stratified for randomization option, ie, two or four treatment arms, and chemotherapy use) was used to estimate hazard ratios (HRs) and 95% CIs, and assess interactions of the treatment effect according to subgroups defined by ER and PgR status. The nonparametric STEPP (Subpopulation Treatment Effect Pattern Plot) methodology22 was used to investigate trends in treatment effect differences across the continuum of PgR expression.
Role of Coordinating Group, Trial Steering Committee, and Funding Source
Comparison of Patients With and Without Material for Central Review There were no substantial differences in the distributions of tumor size or grade, or nodal status among patients with and without assessable material, except that the assessable cohort included fewer patients with unknown disease factors and fewer locally assessed ER-negative tumors. Patients with assessable material were more often treated with less-than-mastectomy and radiation therapy, and fewer had prior chemotherapy. Comparisons were consistent whether looking at the population of all randomly assigned patients, or the monotherapy patients only. The assessable cohort was markedly different from the nonassessable cohort with regard to the duration of follow-up, DFS, and relative treatment effects. Among the 4,922 patients who were assigned to monotherapy, an 18% reduction in risk of an event (HR = 0.82; 95% CI, 0.71 to 0.95; P = .007) was observed for patients assigned letrozole as compared with tamoxifen at a median follow-up time of 51 months,8 with estimated 86% 4-year DFS. The assessable cohort of 3,650 patients had shorter follow-up time as compared with the 1,272 not assessable (48 v 71 months), had better outcome than those not assessable (87% v 84%, 4-year DFS), and the treatment effect was more pronounced, with a hazard ratio favoring letrozole (HR = 0.74; 95% CI, 0.62 to 0.88) compared with nonassessable patients (HR = 1.04; 95% CI, 0.81 to 1.34; Fig 1). Centers that began recruitment earlier tended not to submit material, thus shortening the median follow-up.
Local Hormone Receptor Assessment Of entered patients, 98% had ER-positive tumors as determined locally, and 93% had steroid hormone receptors assessed locally using immunohistochemistry. Seven of 25 participating countries used extraction assays for at least 10% of tumors. ER-positivity rate was associated with assay type and was lower among tumors assayed with extraction versus IHC assays (95.6% v 98% ER positive). A substantial number of patients (14%) had tumors without a local assessment of PgR. Five countries assessed PgR in fewer than 80% of patients. Among those assessed locally, 76% were PgR positive. PgR-positivity rate was associated with assay type, and (opposite of ER) was higher among tumors assayed with extraction versus IHC assays (86% v 75% PgR positive).
Central Hormone Receptor Review
Comparison of Local Assessment and Central Review Of 105 patients classified locally as ER negative, central review found 73 to have at least 10% staining and a further eight to have staining of 1% to 9%. Conversely, of the 6,100 patients classified locally as ER positive, central review found ER to be absent in 66 (1.1%) and low in 54 (0.9%; Table 2). For PgR, the discordance was more marked: of 1,223 assessed locally as PgR negative, central review reclassified 544 (44.5%) as having PgR of at least 10% and 308 (25.2%) with 1% to 9% staining. Of the 4,014 assessed locally as PgR positive, central review found 183 (4.6%) with absent PgR and a further 247 (6.2%) with 1% to 9% staining (Table 3). Local assessment classified 7,999 of 8,010 entered patients (99.9%) as hormone receptor–positive (ie, ER positive and/or PgR positive). Central review of 6,291 tumors classified 6,101 (97.0%) as positive at a 10% cutoff and 6,161 (97.9%) as positive at a 1% cutoff (Table 4). Concordance varied by country, with nine countries having a concordance of  80%. Countries and cooperative groups that provided a lower proportion of material for central review tended also to have lower concordance.
Predictive and Prognostic Value of Hormone Receptor Status To investigate the predictive and prognostic value of hormone receptor status, analyses were limited to the 3,650 patients (74%) with assessable material of the 4,922 patients assigned to monotherapy with letrozole or tamoxifen for whom results with updated follow-up were recently reported.8
Comparing Local and Central Status
The relative influence of central and local PgR status (regardless of ER status) on prognosis is less clear (Fig 2B). The 247 patients whose tumors were classified locally as PgR positive and reclassified as PgR negative by central review had an estimated 86% 3-year DFS, lower than patients whose tumors were classified locally and centrally as PgR negative (90% 3-year DFS) and to patients whose tumors were reclassified centrally as PgR positive (91% 3-year DFS). Patients whose tumors were not evaluated locally and classified centrally as PgR negative did poorly (73% 3-year DFS). Combining the two receptors to define an overall assessment of hormone receptor status (either ER positive and/or PgR positive v both negative), the 94 patients whose tumors were classified locally as hormone receptor–positive and reclassified as hormone receptor–negative by central review had poor outcome on average, with estimated 65% 3-year DFS, as compared with 91% 3-year DFS among patients whose tumors were classified locally and centrally as hormone receptor–positive (Fig 2C). Conclusions were similar if using the central classification with a 1% cutoff (data not shown).
Centrally Assessed ER Expression
Centrally Assessed PgR Expression Because of the clearly poor outcome of patients with tumors not expressing ER and the few patients classified as expressing PgR but not ER, analyses to investigate the predictive value of PgR were limited to the 3,533 patients who were confirmed to have ER-expressing tumors by central review, of whom 3,508 patients had assessable PgR expression. PgR expression was associated with DFS (P < .0001; Fig 3B). There was benefit, in terms of DFS, of letrozole over tamoxifen regardless of PgR expression level: for patients whose tumors were PgR-absent, HR = 0.84 (95% CI, 0.54 to 1.31); for PgR-expressing tumors, HR = 0.70 (95% CI, 0.57 to 0.85). There was no statistical evidence of heterogeneity in the treatment effect according to level of PgR expression (P = .47 for interaction; Fig 1), illustrated in the STEPP analysis of DFS by treatment, which shows consistent separation between treatment groups across the continuum of PgR expression levels (Fig 4).
This study involves the central review of thousands of pathological specimens from patients entered in the BIG 1-98 trial across 25 countries. Yet, the cohort studied, based on assessable material from 74% of randomized patients, was not entirely typical of the trial population as a whole. Patients whose material was unavailable for review were enrolled in centers which began recruiting patients early, had poorer outcome overall, and showed less or no benefit from the use of letrozole instead of tamoxifen. Countries and cooperative groups that provided a lower proportion of specimens for central review tended also to have lower concordance of local and central assessment. We thus question whether the nonassessable material would also show low concordance with central assessment. The inclusion of patients whose tumors were not hormone receptor–positive would result in poorer overall outcome and a diluted treatment effect. Nevertheless, the value of central review is clear. Approximately 1% of tumors assessed locally as ER positive were reclassified centrally as ER negative, and, though fewer in number, approximately 1% of tumors classified as ER negative locally were reassessed as ER positive following central review. Reclassification of receptor status occurred in both directions, and the central review was validated by its superior prognostic discrimination. Also, a substantial number of patients assessed locally as PgR negative were reassessed centrally as PgR positive, and a smaller number changed in the reverse direction. False-positive results by local testing constitute an interesting issue that has not been widely studied, but obviously led to the use of an ineffective therapy for patients misclassified. These findings highlight the need for accurate and standardized assessment of any biologic parameter used to select antitumor treatments. Several previous studies have underscored the need for internal and external quality control in the immunohistochemical analysis of protein expression.23 The authors highlighted the lack of any assessment of observer errors in the interpretation of results in most studies dealing with protein immunohistochemical expression in clinical trials. Discordant results between local and central laboratories have been recently analyzed with specific reference to another antigen (HER-2) in the setting of adjuvant therapy in breast cancer.24 This study reported concordance between local and central assessment in only 81.6% of the patients when the same US Food and Drug Administration–approved test kit was employed, and only 75% when different immunohistochemical procedures were used locally. The authors strongly suggest quality assurance programs to be widely adopted. Our data provide additional support for the use of a cutoff of 1% staining cells for both ER and PgR as indicating a better prognosis and at least some degree of endocrine responsiveness. This is in accord with our previous experience (Viale et al, submitted for publication) and similar to Collins et al26 and Harvey et al,27 who recommended an Allred total score18 of 3 or above (which may equate to 1% weak staining).
Our study shows that the endocrine treatment effect on DFS of postmenopausal patients with breast cancer is primarily influenced by ER status. The role of PgR could be determined only in patients with ER-expressing tumors, since few with tumors not expressing ER entered the trial. Of these, a better outcome was seen among patients with PgR-positive ( Using real-time polymerase chain reaction assessment of ER and PgR status, Baehner et al28 found that the level of PgR was prognostic in untreated patients but not predictive of tamoxifen benefit, a finding parallel with our observation that PgR expression level did not predict the additional value of letrozole on ER-expressing tumors. Our data do not confirm the hypothesis that aromatase inhibitors may offer a particular advantage over tamoxifen in patients whose tumors express ER but not PgR raised by Dowsett et al16 based on local laboratory PgR assessment in the ATAC trial. Our results conform more closely with the findings of no effect of PgR on relative efficacy of aromatase inhibitor and tamoxifen in the IES9 and the lack of significant difference seen in the ARNO/ABCSG trials.4
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: Aron Goldhirsch, Novartis (C) Stock Ownership: Beat Thürlimann, Novartis Honoraria: Aron Goldhirsch, Novartis Research Funding: Patrick Neven, Novartis; Aron Goldhirsch, Novartis Expert Testimony: None Other Remuneration: None
Conception and design: Giuseppe Viale, Richard D. Gelber, Monica Castiglione-Gertsch, Aron Goldhirsch, Alan S. Coates Administrative support: Giuseppe Viale, Richard D. Gelber, Monica Castiglione-Gertsch, Karen N. Price, Barry A. Gusterson Provision of study materials or patients: Giuseppe Viale, Mauro G. Mastropasqua, Patrizia Dell'Orto, Birgitte Bruun Rasmussen, Johnny Raffoul, Patrick Neven, Zsolt Orosz, Stephen Braye, Christian Öhlschlegel, Beat Thürlimann, Aron Goldhirsch Collection and assembly of data: Giuseppe Viale, Meredith M. Regan, Mauro G. Mastropasqua, Patrizia Dell'Orto, Karen N. Price Data analysis and interpretation: Giuseppe Viale, Meredith M. Regan, Eugenio Maiorano, Mauro G. Mastropasqua, Alan S. Coates Manuscript writing: Giuseppe Viale, Meredith M. Regan, Eugenio Maiorano, Mauro G. Mastropasqua, Karen N. Price, Alan S. Coates Final approval of manuscript: Giuseppe Viale, Meredith M. Regan, Eugenio Maiorano, Mauro G. Mastropasqua, Patrizia Dell'Orto, Birgitte Bruun Rasmussen, Johnny Raffoul, Patrick Neven, Zsolt Orosz, Stephen Braye, Christian Öhlschlegel, Beat Thürlimann, Richard D. Gelber, Monica Castiglione-Gertsch, Karen N. Price, Aron Goldhirsch, Barry A. Gusterson, Alan S. Coates
BREAST INTERNATIONAL GROUP (BIG) 1-98 Collaborative Group Participants Steering Committee. B. Thürlimann (Chair), L. Blacher, M. Castiglione, A. S. Coates, T. Cufer, J. F. Forbes, R. D. Gelber, A. Goldhirsch, A. Hiltbrunner, S. B. Holmberg, A. Keshaviah, R. Maibach, A. Martoni, L. Mauriac, H. T. Mouridsen, K. N. Price, M. Rabaglio, A. Santoro, I. E. Smith, C. Straehle, G. Viale. Novartis: H. A. Chaudri-Ross, A. Covelli, D. B. Evans, W. Hackl, E. Raman, M.G. Porro. IBCSG Scientific Committee. A. Goldhirsch, A. S. Coates (Co-Chairs), L. Blacher, M. Castiglione, J. F. Forbes, R. D. Gelber, B. A. Gusterson, A. Hiltbrunner, C. Hürny, E. Murray, K. N. Price, M. Rabaglio, R. Studer, G. Viale, A. Wallgren. IBCSG Foundation Council. B. Thürlimann (President), M. Castiglione, A. S. Coates, J. P. Collins, H. Cortés Funes, R. D. Gelber, A. Goldhirsch, M. Green, A. Hiltbrunner, S. B. Holmberg, D. K. Hossfeld, I. Láng, J. Lindtner, M Destoppani, C.-M. Rudenstam, R. Stahel, H.-J. Senn, A. Veronesi. Coordinating Center (Berne, Switzerland): M. Castiglione (CEO), A. Hiltbrunner (Director), M. Rabaglio, G. Egli, B. Cliffe, S. Ribeli-Hofmann, F. Munarini, R. Kammler, R. Studer, B. Ruepp, R. Maibach, N. Munarini. Statistical Center (Dana-Farber Cancer Institute, Boston, MA, USA): R. D. Gelber (Group Statistician), K. N. Price (Director of Scientific Administration), A. Keshaviah (Trial Statistician), H. Litman, H. Huang, L. J. Somos, B. Timmers, L. Nickerson. Data Management Center (Frontier Science & Technology Research Foundation, Amherst, NY, USA): L. Blacher (Director of Data Management), T. Heckman Scolese (Coordinating Data Manager), M. Belisle, M. Caporale, J. Celano, L. Dalfonso, L. Dooley, S. Fischer, K. Galloway, J. Gould, R. Hinkle, M. Holody, G. Jones, R. Krall, S. Lippert, J. Meshulam, L. Mundy, A. Pavlov-Shapiro, K. Scott, M. Scott, S. Shepard, J. Swick, L. Uhteg, D. Weinbaum, C. Westby, T. Zielinski. Central Pathology Review Office (European Institute of Oncology, Division of Pathology, Milano, Italy): G. Viale, P. Dell'Orto, M. Mastropasqua, B. Del Curto; (University of Glasgow, Glasgow, UK): B. A. Gusterson, E. Mallon;. Data and Safety Monitoring Committee. J.E. Garber, S.W. Lagakos, I. Lindgren, W. Gradishar. Study Support (Novartis Corp. Basel, Switzerland): E. Waldie, I. van Hoomissen, M. De Smet, W. Schmidt, A. Bolton, W. Hackl.
BIG Australia: The Cancer Council Victoria, Melbourne, VIC: F. Abell, R. Basser, R. Bell, B. Brady, D. Blakey, P. Briggs, I. Burns, P. Campbell, M. Chao, J. Chirgwin, B. Chua, K. Clarke, J. Collins, R. De Boer, J. C. Din, R. Doig, A. Dowling, R. Drummond, N. Efe, S. T. Fan, M. Francis, P. Francis, V. Ganju, P. Gibbs, G. Goss, M. Green, P. Gregory, J. Griffiths, I. Haines, M. Henderson, R. Holmes, P. James, J. Kiffler, M. Lehman, M. Leyden, L. Lim, G. Lindeman, R. Lynch, B. Mann, J. McKendrick, S. McLachlan, R. McLennan, G. Mitchell, S. Mitra, C. Murphy, I. Parker, K. Phillips, I. Porter, G. Richardson, J. Scarlet, S. Sewak, J. Shapiro, R. Snyder, R. Stanley, C. Steer, D. Stoney, A. Strickland, G. Toner, C. Underhill, K. White, M. White, A. Wirth, S. Wong; W P Holman Clinic, Launceston General Hospital, Launceston, Tasmania: D. Byram, I. Byard; Liverpool Hospital, Sydney, NSW: S. Della-Fiorentina, A. Goldrick, E. Hovey, E. Moylan, E. Segelov; Mount Hospital, Perth, WA: A. Chan, M. Buck, D. Hastrich, D. Ingram, G. Van Hazel, P. Willsher; Nepean Cancer Care Centre, Sydney, NSW: N. Wilcken, C. Crombie; Newcastle Mater Hospital, Newcastle, NSW: J. F. Forbes, F. Abell, S. Ackland, A. Bonaventura, S. Cox, J. Denham, R. Gourlay, D. Jackson, R. Sillar, J. Stewart; Prince of Wales Hospital, Sydney, NSW: C. Lewis, B. Brigham, D. Goldstein, M. Friedlander; Princess Alexandra Hospital, Woollongabba, QLD: E. Walpole, D. Thompson; Royal Adelaide Hospital, Adelaide, SA: P. G. Gill, M. Bochner, J. Coventry, J. Kollias, P. Malycha, I. Olver; Royal Brisbane and Women's Hospital, Brisbane, QLD: M. Colosimo, R. Cheuk, L. Kenny, N. McCarthy, D. Wyld; Royal Hobart Hospital, Hobart, Tasmania: R. Young, R. Harrup, R. Kimber, R. Lowenthal; Royal Perth Hospital, Perth, WA: J. Trotter, E. Bayliss, A. Chan, D. Ransom; Sir Charles Gairdner Hospital, Perth, WA: M. Byrne, M. Buck, J. Dewar, A. Nowak, A. Powell, G. Van Hazel; Toowoomba Hospital, Toowoomba, QLD: E. A. Abdi, R. Brodribb, Z. Volobueva; Westmead Hospital, Sydney, NSW: P. Harnett, V. Ahern, H. Gurney, N. Wilcken. New Zealand: Auckland Hospital, Auckland: V. J. Harvey, B. Evans, W. Jones, M. McCrystal, D. Porter, P. Thompson, M. Vaughan; Christchurch Hospital, Christchurch: D. Gibbs, C. Atkinson, R. Burcombe, B. Fitzharris, B. Hickey, M. Jeffery, B. Robinson; Dunedin Hospital, Dunedin: B. McLaren, S. Costello, J. North, D. Perez; Waikato Hospital, Hamilton: I. D. Campbell, L. Gilbert, R. Gannaway, M. Jameson, I. Kennedy, J. Long, G. Round, L. Spellman, D. Whittle, D. Woolerton. Brazil: Hospital de Clinicas de Porto Alegre, Porto Alegre: C. Menke, J. Biazús, R. Cericatto, J. Cavalheiro, N. Xavier, A. Bittelbrunn, E. Rabin. Chile: Chilean Cooperative Group for Oncologic Research, GOCCHI. J. Gutiérrez (Chairman), R. Arriagada (Scientific Adviser), L. Bronfman (Principal Investigator), M. Zuñiga (Data Manager); Clinica Las Condes, Santiago: J. Gutiérrez, J. C. Acevedo, S. Torres, A. León, E. Salazar; Hospital DIPRECA, Las Condes, Santiago: L. Soto Diaz, R. Duval, N. Oddeshede, M. C. Venti; Hospital San Juan de Dios, Santiago: K. Peña, L. Puente, V. Maidana; IRAM/Instituto de Radiomedicina, Vitacura, Santiago: R. Baeza, R. Arriagada, P. Olfos, J. Solé, E. Vinés, C. Mariani. Hungary: National Institute of Oncology, Budapest. I. Láng, E. Hitre, E. Szabó, Z. Horváth, E. Ganofszky, E. Juhos. Italy: Centro di Riferimento Oncologico, Aviano. A. Veronesi, D. Crivellari, M. D. Magri, A. Buonadonna, F. Coran, E. Borsatti, E. Candiani, S. Massarut, M. Roncadin, M. Arcicasa, A. Carbone, T. Perin, A. Gloghini; Ospedali Riuniti di Bergamo, Bergamo: C. Tondini, R. Labianca, P. Poletti, A. Bettini; Ospedale degli Infermi, Biella: M. Clerico, M. Vincenti, A. Malossi, E. Seles, E. Perfetti, B. Sartorello; Spedali Civili, Brescia: E. Simoncini, G. Marini, P. Marpicati, R. Farfaglia, A. M. Bianchi, P. Grigolato, L. Lucini, P. Frata, A. Huscher, E. Micheletti, C. Fogazzi; U. O. Medicina Oncologica, Ospedale Capri, Ospedale Mirandola: F. Artioli, K. Cagossi, L. Scaltriti, E. Bandieri, L. Botticelli, G. Giovanardi; Ospedale di Cattolica "Cervesi," Cattolica: A. Ravaioli, E. Pasquini, B. Rudnas; Ospedale Civile, Gorizia: L. Foghin; Ospedale "A. Manzoni" Lecco, Lecco: M. Visini, L. Zavallone, G. Ucci; Istituto Europeo di Oncologia, Milano: M. Colleoni, G. Viale, P. Veronesi, G. Peruzzotti, L. Corsetto, R. Ghisini, G. Renne, A. Luini, L. Orlando, R. Torrisi, A. Rocca, T. De Pas, E. Munzone, V. Galimberti, S. Zurrida, M. Intra, F. Nolé, R. Orecchia, G. Martinelli, F. de Braud, A. Goldhirsch; Ospedale Infermi, Rimini: A. Ravaioli, L. Gianni. Peru: Instituto de Enfermedades Neoplásicas, Lima. H. Gome. Slovenia: Institute of Oncology, Ljubljana. T. Cufer, B. Pajk, J. Cervek. South Africa: Groote Schuur Hospital and University of Cape Town, Cape Town: I. D. Werner, E. Murray, D. Govender, S. Dalvie, T. Erasmus, B. Robertson, B. Read, E. Nel, J. Toop, N. Nedeva, E. Panieri; Sandton Oncology Centre, Johannesburg: D. Vorobiof, M. Chasen, G. McMichael, C. Mohammed. Local funding provided by the Cancer Association of South Africa Sweden: West Swedish Breast Cancer Study Group. S. B. Holmberg; Sahlgrenska U Hospital, Moelndal: S. B. Holmberg, J. Mattsson; Boras Hospital, Boras; Karlstads Hospital, Karlstads: H. Sellström; Kungalvs Hospital, Kungalvs: B. Lindberg. Switzerland: Swiss Group for Clinical Cancer Research (SAKK). A. Goldhirsch (up to January 2004), R. Herrmann (from June 2004): Kantonsspital Aarau, Zentrum f. Onkologie, Aarau: A. Schönenberger, W. Mingrone, Ch. Honegger, E. Bärtschi, M. Neter, M. Rederer, G. Schär; University Hospital Basel, Basel: C. Rochlitz, R. Herrmann, D. Oertli, E. Wight, H. Moch; Institute of Oncology of Southern Switzerland: Ospedale San Giovanni, Bellinzona: J. Bernier, L. Bronz, F. Cavalli, E. Gallerani, A. Richetti, A. Franzetti; Ospedale Regionale di Lugano (Civico & Italiano), Lugano: M. Conti-Beltraminelli, M. Ghielmini, T. Gyr, S. Mauri, P. C. Saletti; Ospedale Regionale Beata Vergine, Mendrisio: A. Goldhirsch, O. Pagani, R. Graffeo, M. Locatelli, S. Longhi, P.C. Rey, M. Ruggeri; Ospedale Regionale La Carità, Locarno: E. Zucca, D. Wyss; Istituto Cantonale di Patologia, Locarno: L. Mazzucchelli, E. Pedrinis, T. Rusca; Inselspital, Berne: S. Aebi, M. F. Fey, M. Castiglione, M. Rabaglio; Kantonsspital Olten, Olten: S. Aebi, M. F. Fey, M. Zuber, G. Beck; Bürgerspital, Solothurn: S. Aebi, M. F. Fey, R. Schönenberger; Spital Thun-Simmental AG Thun: J.M. Lüthi, D. Rauch; Hôpital Cantonal Universitaire HCUG, Geneva: H. Bonnefoi; Rätisches Kantons- und Regionalspital, Chur: F. Egli, R. Steiner, P. Fehr; Centre Pluridisciplinaire d'Oncologie, Lausanne: L. Perey, P. de Grandi, W. Jeanneret, S. Leyvraz, J.-F. Delaloye; Kantonsspital St. Gallen, St. Gallen: B. Thürlimann, D. Köberle, F. Weisser, S., Mattmann, A. Müller, T. Cerny, B. Späti, M. Höfliger, G. Fürstenberger, B. Bolliger, C. Öhlschlegel, U. Lorenz, M. Bamert, J. Kehl-Blank, E. Vogel; Kantonales Spital Herisau, Herisau: B. Thürlimann, D. Hess, I. Senn, D. Köberle, A. Ehrsam, C. Nauer, C. Öhlschlegel, J. Kehl-Blank, E. Vogel; Stadtspital Triemli, Zürich: L. Widmer, M. Häfner; Universitätsspital Zürich, Zürich: B. C. Pestalozzi, M. Fehr, R. Caduff, Z. Varga, R. Trüb, D. Fink. Swiss Private MDs. Private Praxis, Zürich: B. A. Bättig; Sonnenhof-Klinik Engeried, Berne: K. Buser; Frauenklinik Limmattalspital, Schlieren: N. Bürki; Private Praxis, Birsfelden: A. Dieterle; Private Praxis, Biel: L. Hasler; Private Praxis, Baar: M. Mannhart-Harms; Brust-Zentrum, Zürich: C. Rageth; Private Praxis, Berne: J. Richner; Private Praxis, Bellinzona: V. Spataro; Private Praxis, Winterthur: M. Umbricht. United Kingdom: King's College Hospital/Breast Unit, London. P. Ellis, S. Harris, N. Akbar, H. McVicars, C. Lees, R. Raman, G. Crane. Danish Group (DBCG) H. T. Mouridsen; Rigshospitalet, Copenhagen: H. T. Mouridsen; Vejle Hospital, Vejle: E. Jakobsen; Odense University Hospital, Odense: S. Cold; KAS Herlev/Herlev University Hospital, Herlev: C. Kamby; Aalborg Sygehus Syd, Aalborg: M. Ewertz; Hilleroed Hospital, Hilleroed: P.M. Vestlev; Aarhus University Hospital, Aarhus: J. Andersen; Roskilde County Hospital, Roskilde: P. Grundtvig; Esbjerg Central Hospital, Esbjerg: E. Sandberg; Naestved Central Hospital, Naestved: P. Philip; Soenderborg Sygehus, Soenderborg: E. L. Madsen; Herning Central Hospital, Herning: K. A. Moeller; Viborg Sygehus, Viborg: V. Haahr; Landspitali University Hospital, Reykjavik, Iceland: J. Johansson. French Group (FNCLCC) Institut Bergonié, Bordeaux. L. Mauriac, M. Debled, P. Campo; Centre Hospitalier de la Côte Basque, Bayonne D. Larregain-Fournier, S. Remy, Centre Jean Perrin, Clermont-Ferrand: H. Auvray; Centre Georges François Leclerc, Dijon: C. De Gislain, F. Delille, M.-C. Porteret; Centre Oscar Lambret, Lille: V. Servent, M. Chapoutier; CHRU, Limoges: N. Tubiana-Mathieu, S. Lavau-Denes, P. Bosc; Centre Léon Bérard, Lyon: J. P. Guastalla, Th. Bachelot, C. Arbault; Centre Hospitalier Meaux, Meaux: G. Netter-Pinon; C.H.G. André Boulloche, Montbéliard: V. Perrin, A. Monnier, Y. Hammoud; Centre Paul Lamarque, Montpellier: G. Romieu, L. Culine, V. Pinosa; Clinique Francheville, Périgueux: L. Cany, C. Maguire; Hôpital de la Milétrie, Poitiers: A. Daban, M. Le Saux, C. Grandon; Centre Eugène Marquis, Rennes: P. Kerbrat, C. Catheline; Centre Henri Becquerel, Rouen: C. Veyret, E. Jugieau, V. Talon; Centre René Gauducheau, Saint-Herblain: A. Le Mevel, S. Maury; Centre Claudius Régaud, Toulouse: L. Gladieff, N. Lignon. North Yorkshire Group D. Dodwell; Harrogate District Hospital, Harrogate, North Yorkshire: D. Dodwell; Huddersfield Royal Infirmary, Huddersfield: J. Joffe; Castlehill Hospital, Hull: P. Drew; Airedale General Hospital, Keighley,W. Yorkshire: A. Nejim; Leeds General Infirmary, Leeds: D. Dodwell, K. Horgan; St. James's University Hospital, Leeds: M. Lansdown, T. Perren; Weston Park Hospital, Sheffield: R. E. Coleman. Independent Centers/Groups Argentina: Centro Oncológico Confidence, Buenos Aires. D. Campos; Hospital Allemán, Buenos Aires: F. Cóppola; Hospital Británico, Buenos Aires: J. Martinez; Hospital Evita, Buenos Aires: M. Freue; Hospital Posadas, Buenos Aires: C. Wainstein; Hospital Zubizarreta, Buenos Aires: A. Zori Comba; Instituto Dr. Estevez, Buenos Aires: E. Cazap; Instituto Oncológico Dr. Angel H. Roffo, Buenos Aires: E. Mickiewicz; Sanatorio Municipal Julio A. Mendez, Buenos Aires: L. Balbiani; Centro Privado de Ginecología, Córdoba: A. Osuna; Hospital Privado de Córdoba, Córdoba: E. Palazzo; Instituto Modelo de Ginecología y Obstetricia, Córdoba: M. de Romedis; Fundación Mainetti-Centro Oncológico de Excelencia, La Pllata: S. Cagnolati; Hospital Privado de la Comunidad, Mar del Plata: C. A. Delfino, G. Caccia; Escuela de Medicina Nuclear (COIR), Mendoza: R. L. de Angelis; Centro Oncológico de Rosario, Rosario: L. Fein, R. Sala; Hospital Provincial de Rosario, Rosario: C. Nassurdi, A. Colombo Berra; Clínica Especializada ISIS, Santa Fe: R. Viroglio, C. Blajman; Hospital Regional de Concepción, Tucumán: H. Requejo; Instituto de Maternidad y Ginecología Nuestra Señoras de las Mercedes, Tucumán: L. Silberman. Australia: Flinders Medical Centre, Adelaide, SA: S. Birrell, M. Eaton, C. Hoffman; Queen Elizabeth Hospital, Adelaide, SA: V. Humeniuk; The Canberra Hospital, Canberra, ACT; P. Craft, R. Stuart-Harris, D. Yip; The Geelong Hospital, Geelong, VIC: R. Bell, F. Abell, M. Francis, J. Kiffer, R. Lynch, R. McLennan, K. White; Royal Melbourne Hospital, Melbourne, VIC: M. Green, R. Basser, J. Collins, R. De Boer, J. C. Din, N. Efe, S. T. Fan, G. Lindeman, S. Wong; Western General Hospital, Melbourne, VIC: M. Green, R. Basser, J. Collins, R. De Boer, J. C. Din, N. Efe, S. T. Fan, G. Lindeman, S. Wong; Newcastle Mater Hospital, Newcastle, NSW: J. Stewart, F. Abell, S. Ackland, A. Bonaventura; Royal Perth Hospital, Perth, WA: J. Trotter, E. Bayliss, A. Chan, D. Ransom, A. Redfern; St. George Hospital, Sydney, NSW: P. de Souza, M. Links; St. Vincent's Hospital, Sydney, NSW: D. Dalley, J. Grygiel, R. Ward; Murray Valley Private Hospital, Wodonga, VIC: C. Underhill, K. Clarke, C. Steer; Princess Alexandra Hospital, Woolloongabba, QLD: E. Walpole, D. Thompson. Belgium: Institut Jules Bordet, Bruxelles. J. M. Nogaret; University Hospitals Leuven, Leuven: M.R. Christiaens, P. Neven, R. Paridaens, A. Smeets, I. Vergote, C. Weltens, H. Wildiers; Les Cliniques Saint-Joseph ASBL, Liège: C. Focan; Clinique du Parc Léopold, Bruxelles: L. Marcelis; C. H. Etterbeek - Ixelles, Bruxelles: J. P. Kains; Service d'Oncologie Clinique Notre-Dame, Charleroi: J.-L. Canon; C. H. U. André Vèsale, Montigny-Le Tilleul: D. Brohèe. Canada: Cambridge Memorial Hospital, Cambridge: J. Gowing; CHUM- Campus Notre-Dame, Montreal. L. Yelle; Hôpital Maisonneuve-Rosemont, Montreal: P. Dubé. Chile: Fundacion Lopez Perez, Santiago. C. Vogel; Hospital Carlos Van Buren, Valparaiso: M. León Prieto. Czech Republic: Institute of Oncology, Brno. K. Petrakova, M. Palacova, R. Demlova; Dept. of Clinical and Radiation Oncology, Ceske Budejovice: H. Siffnerova, J. Fischer, I. Bustova; Centre of Breast Diseases, Prague: H. Kankova, M. Pintova; Institute of Radiation Oncology, Prague: P. Vitek; University Hospital, Prague: J. Abrahamova, D. Kordikova; University Hospital Prague: L. Petruzelka, E. Sedlackova, H. Honova. Germany. Onkologische Gemeinschaftspraxis, Augsburg: B. Heinrich; Zentralklinikum/Frauenklinik, Augsburg: A. Wischnik; Universitätsklinikum Essen, Essen: C. Oberhoff, A. E. Schindler; Universitäts-Frauenklinik d. JLU Giessen, Giessen: K. Münstedt; Onkologische Gemeinschaftspraxis, Göttingen: D. Meyer; Martin-Luther-Universität Halle-Wittenberg, Halle: R. Grosse, H. Kölbl; Universitätskliniken des Saarlandes, Homburg: W. Schmidt, D. Mink; Universitäts-Frauenklinik und Poliklinik Universitätskrankenhaus Eppendorf, Hamburg: F. Jänicke; Kliniken d. Med. Hochschule, Frauenklinik, Hannover: H. J. Lück; Krankenanstalt Mutterhaus der Borromäerinnen, Trier: W. Dornoff; Gynäkologische Abteilung des St. Josefshospital, Wiesbaden: G. Hoffmann; Gynäkologische Abteilung d. Marienhospitals, Universität Witten-Herdecke, Witten: J. Hackmann, W. Bader. Hungary: SZOTE Onkoterápiás Klinika, Szeged. Z. Kahan; BM Központi Kórház, Budapest: G. Pajkos, K. Kristo; SOTE Radiológiai és Onkoterápiás Klinika, Budapest: M. Dank; Uzsoki Utcai Kórház, Budapest: T. Nagykalnai, L. Landherr; Almási Balogh Pál Kórház, Ózd: E. Kner; Területi Kórház Onkologia, Szentes: M. Kispál; Szent Borbála Kórház, Megyei Onkológiai Gondozó, Tatabánya: Á. Dani. Italy: Policlinico S. Orsola-Malpighi, Bologna. A. Martoni, C. Zamagni, S. Giaquinta, E. Piana; Ospedale S. Croce, Fano: R. Mattioli, L. Imperatori; Istituto Clinica Humanitas, Milan/Rozzano: A. Santoro, C. Carnaghi, L. Rimassa; Azienda Ospedaliera San Filippo Neri, Rome: G. Gasparini, G. Sciarretta, A. Morabito; Az. Ospedaliera Treviglio-Caravaggio, Treviglio: S. Barni, M. Cazzaniga, M. Cabiddu; Policlinico Universitario (PUDG), Udine: F. Puglisi; Ospedale di Torrette, Ancona: R. Cellerino, S. Antognoli, F. Freddari; Universitiy of Cagliari, Policlinico Universitario, Cagliari: G. Mantovani, E. Massa, G. Astara; Ospedale Civile Feltre, Feltre: R. Segati; Istituto Nazionali Ricerca Cancro, Genova: R. Rosso, L. Del Mastro, M. Venturini, C. Bighin; Istituto Nazionale dei Tumori, Milano: E. Bajetta, N. Zilembo, D. Paleari, G. Procopio; Azienda Ospedaliera di Parma, Parma: S. Salvagni, M. A. Perrone, V. Franciosi; Azienda Ospedaliera "S. Salvatore," Pesaro: G. Catalano, S. Luzi Fedeli; Azienda Ospedaliera "Ospedale di Circolo e Fondazione Macchi" Varese: G. Pinotti, G. Giardina, I. Vallini; Universitiy of Cagliari, Policlinico Universitario, Cagliari: B. Massidda, M. T. Ionta, M. C. Deidda; Ospedale Maggiore, Lodi: G. Nalli, G. Sita; Policlinico Universitario, Palermo: I. Carreca, S. Cucciarré, D. Burgio; Ospedale Civile dello Spirito Santo, Pescara: M. Lombardo, G. Pandoli, P. Di Stefano; Azienda Ospedaliera Santa Maria Nuova, Reggio Emilia: C. Boni, G. Bisagni, M. C. Banzi, P. Linarello; Azienda Ospedaliera Desenzano del Garda, Manerbio: G. Colosini, A. Spasiano, A. Caldonazzo; Ospedale Civile ASL 20, Tortona: M. G. Pacquola. Netherlands: Ziekenhuis Leyenburg, Den Haag. H. P. Sleeboom; Catharina Ziekenhuis, Eindhoven: H. J. T. Rutten; St. Anna Ziekenhuis, Geldrop: E. J. T. Luiten; Tweesteden Ziekenhuis, Tilburg: H. Th. J. Roerdink; Maxima Medisch Centrum, Veldhoven: R. H. M. Roumen. New Zealand: Dunedin Hospital, Dunedin: B. McLaren, S. Costello, J. North, D. Perez, K., Bayston, M. Pfieffer; Waikato Hospital, Hamilton: I. Kennedy, I. D. Campbell, L. Gilbert, R. Gannaway, M. Jameson, J. Long, G. Round, L. Spellman, D. Whittle, D. Woolerton. Poland: Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk: J. Jassem, M. Welnicka-Jaskiewicz, E. Senkus-Konefka, K. Matuszewska; Rydygier's Memorial Hospital, Krakow-Nova Huta: P. Koralewski, J. Pernal; Klinika Nowotworów Piersi i, Chirurgii Rekonstrukcyjnej-Warszawa, Warszawa: T. Pienkowski, E. Brewczynska, B. Bauer-Kosinska, R. Sienkiewicz-Kozlowska, A. Jagiello-Gruszfeld, K. Sudol.; Centrum Onkologii w Bydgoszczy, Oddzial Onkologii Klinicznej, Bydgoszcz: J. Tujakowski, B. Zurawski; Collegium Medicum Jagiellonian University, Krakow: J. Pawlega, E. Jablonska, A. Zygulska; Oddzial Kliniczny Onkologiczny, Centralnego Szpitala Klinicznego Wojskowej, Akademii Medycznej-Warszawa, Warszawa: M. Górnasiowa; Dolnoslaskie Centrum Onkologii, Wroclaw: E. Filypczyk-Cisarz, K. Pajak. Portugal: Hospital de S. João, Porto. M. Damasceno; Instituto Português de Oncologia de Coimbra, Coimbra: J. Q. Albano; Hospital de Santa Maria, Lisboa: B. da Costa, L. Costa; Instituto Português de Oncologia de Lisboa, Lisboa: A. Henriques, H. Amaral; Hospital Geral de Santo António, Porto: F. Marques. Russia: Cancer Research Centre, Moscow. D. V. Komov, S. B. Polikarpova; Moscow Municipal Hospital No. 62, Moscow: A. N. Makhson, N. V. Zabaznyi; Moscow Research Institute of Diagnostics and Surgery, Moscow: E. K. Vozny, N. Y. Dobrovolskaya, S. Bolshakova, O. V. Yurgina; N. M. Emmanuel Institute of Biochemical Physics, Moscow: D. B. Korman, I. A. Maslova; N.N. Petrov Research Institute of Oncology, St. Petersburg: V. Semiglazov, V. Ivanov; Saint-Petersburg City Oncological Dispensary, St. Petersburg: G. Manikhas, G. Dolmatov. South Africa: Mamma Clinic, Tygerberg Hospital, Cape Town. J. Apffelstaedt; Southern Cross Hospital, Cape Town: D. Eedes; Pretoria Academic Hospital, Pretoria: C. Slabber; Pretoria East Hospital, Pretoria: M. A. Coccia-Portugal; Eastern Cape Oncology Centre, Port Elizabeth: K. Maart. Spain: Hospital Ruber Internacional, Madrid. J. E. Alés Martinez, P. Aramburo, R. Sánchez; Hospital Son Dureta, Palma del Mallorca: J. Rifa, J. Martin; Centro Oncológico Integral de Madrid (CONIM), Madrid: R. Pérez-Carrión, J. L. González Larriba, A. Cubillo; Hospital Universitario San Carlos, Madrid: M. M. Jiménez, A. Casado; Hospital Central de Asturias, Oviedo: J. Fra, J. M. Vieitez, E. Esteban, A. J. Lacave. Switzerland: Universitätsfrauenklinik, Basel. E. Wight, S. Bartens, R. Decio, U. Güth; Klinik am Park, Zürich: U. Breitenstein. Turkey: Ankara University Ibni Sina Hospital, Ankara: F. Icli, D. Dincol; Hacettepe University Oncology Institute, Ankara: E. Baltali, Y. Ozisik; Istanbul University Oncology Institute, Istanbul: E. Topuz, M. Basaran, A. Aydiner; Ege University Medical School, Izmir: E. Ozdedeli; 9 Eylul University Medical School, Izmir: O. Harmancioglu, A. U. Yilmaz. United Kingdom: The Royal Marsden Hospital, London, Royal Marsden NHS Trust, Surrey. I. E. Smith; University of Dundee, Dundee: A. M. Thompson; Christie Hospital NHS Trust, South Manchester University Hospital Trust, Manchester: A. Wardley; Royal Bournemouth Hospital, Bournemouth: T. Hickish; North Middlesex Hospital, London: F. Neave. Uruguay: Hospital de Clinicas Dr. Manuel Quintela, Montevideo, Uruguay: G. Sabini.
We thank the many pathologists who submitted tumor blocks and slides, Rosita Kammler, and Stefania Andrighetto. We thank the patients, physicians, nurses, and data managers who participated in this clinical trial; Novartis; and the IBCSG (funded by the Swedish Cancer Society, The Cancer Council Australia, ANZ-BCTG, FSTRF, the Swiss Group for Clinical Cancer Research [SAKK], US National Cancer Institute [CA-75362], and the Foundation for Clinical Cancer Research of Eastern Switzerland [OSKK]).
published online ahead of print at www.jco.org on August 6, 2007. Presented in part at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Baum M, Budzar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002[CrossRef][Medline] 2. 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 3. 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 4. 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] 5. 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 6. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003 7. Boccardo F, Rubagotti A, Aldrighetti D, et al: Switching to an aromatase inhibitor provides mortality benefit in early breast carcinoma: Pooled analysis of 2 consecutive trials. Cancer, Feb 12 [epub ahead of print], 2007 8. Coates AS, Keshaviah A, Thurlimann B, et al: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: Update of study BIG 1-98. J Clin Oncol 25:486-492, 2007 9. Coombes RC, Kilburn LS, Snowdon CF, et al: Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): A randomised controlled trial. Lancet 369:559-570, 2007[CrossRef][Medline] 10. Goss PE, Ingle JN, Martino S, et al: randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262-1271, 2005 11. Howell A, Cuzick J, Baum M, et al: 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] 12. 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] 13. Bardou VJ, Arpino G, Elledge RM, et al: Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 21:1973-1979, 2003 14. Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer: Adopted on May 17, 1996 by the American Society of Clinical Oncology. J Clin Oncol 14:2843-2877, 1996 15. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 16:1569-1583, 2005 16. Dowsett M, Cuzick J, Wale C, et al: retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status: An hypothesis-generating study. J Clin Oncol 23:7512-7517, 2005 17. Dowsett M, Allred DC, on behalf of the TransATAC Investigators: Relationship between quantitative ER and PgR expression and HER2 status with recurrence in the ATAC trial. Breast Cancer Res Treat 100:S21, 2006 (abstr 48, suppl 1) 18. Allred DC, Harvey JM, Berardo M, et al: Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155-168, 1998[Medline] 19. Regan MM, Viale G, Mastropasqua MG, et al: Re-evaluating adjuvant breast cancer trials: Assessing hormone receptor status by immunohistochemical versus extraction assays. J Natl Cancer Inst 98:1571-1581, 2006 20. Kaplan EL, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457-481, 1958[CrossRef] 21. Cox DR: Regression models and life tables (with discussion). J Royal Stat Soc B 34:187-220, 1972 22. Bonetti M, Gelber RD: A graphical method to assess treatment-covariate interactions using the Cox model on subsets of the data. Stat Med 19:2595-2609, 2000[CrossRef][Medline] 23. Kirkegaard T, Edwards J, Tovey S, et al: Observer variation in immunohistochemical analysis of protein expression, time for a change? Histopathology 48:787-794, 2006[CrossRef][Medline] 24. Perez EA, Suman VJ, Davidson NE, et al: HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J Clin Oncol 24:3032-3038, 2006 25. Reference deleted by author. 26. Collins LC, Botero ML, Schnitt SJ: Bimodal frequency distribution of estrogen receptor immunohistochemical staining results in breast cancer: An analysis of 825 cases. Am J Clin Pathol 123:16-20, 2005[CrossRef][Medline] 27. Harvey JM, Clark GM, Osborne CK, et al: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474-1481, 1999 28. Baehner FL, Habel LA, Quesenberry CP, et al: Quantitative RT-PCR analysis of ER and PR by Oncotype DXTM indicates distinct and different associations with prognosis and prediction of tamoxifen benefit. Breast Cancer Res Treat 100:S20, 2006 Submitted April 2, 2007; accepted June 15, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10%). Of 105 tumors locally ER-negative, 73 were found to have more than 10% positive cells, and eight had 1% to 9%. Of 6,100 tumors locally ER positive, 66 were found to have no staining, and 54 had only 1% to 9%. Discordance was more marked for PgR than ER. Patients with tumors reclassified centrally as ER-negative, or as hormone receptor–negative, had poor DFS. Centrally assessed ER and PgR showed prognostic value. Among patients with centrally assessed ER-expressing tumors, letrozole showed better DFS than tamoxifen, irrespective of PgR expression level. 
