A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women with Primary Breast Cancer
R. Charles Coombes, M.D., Ph.D., Emma Hall, Ph.D., Lorna J. Gibson, M.Phil., Robert Paridaens, M.D., Ph.D., Jacek Jassem, M.D., Ph.D., Thierry Delozier, M.D., Stephen E. Jones, M.D., Isabel Alvarez, M.D., Gianfilippo Bertelli, M.D., Olaf Ortmann, M.D., Ph.D., Alan S. Coates, M.D., Emilio Bajetta, M.D., David Dodwell, M.D., Robert E. Coleman, M.D., Lesley J. Fallowfield, D.Phil., Elizabeth Mickiewicz, M.D., Jorn Andersen, D.M.Sc., Per E. Lønning, M.D., Ph.D., Giorgio Cocconi, M.D., Ph.D., Alan Stewart, M.D., Nick Stuart, D.M., Claire F. Snowdon, M.Sc., Marina Carpentieri, Ph.D., Giorgio Massimini, M.D., Judith M. Bliss, M.Sc., for the Intergroup Exemestane Study
Background Tamoxifen, taken for five years, is the standardadjuvant treatment for postmenopausal women with primary, estrogen-receptor–positivebreast cancer. Despite this treatment, however, some patientshave a relapse.
Methods We conducted a double-blind, randomized trial to testwhether, after two to three years of tamoxifen therapy, switchingto exemestane was more effective than continuing tamoxifen therapyfor the remainder of the five years of treatment. The primaryend point was disease-free survival.
Results Of the 4742 patients enrolled, 2362 were randomly assignedto switch to exemestane, and 2380 to continue to receive tamoxifen.After a median follow-up of 30.6 months, 449 first events (localor metastatic recurrence, contralateral breast cancer, or death)were reported — 183 in the exemestane group and 266 inthe tamoxifen group. The unadjusted hazard ratio in the exemestanegroup as compared with the tamoxifen group was 0.68 (95 percentconfidence interval, 0.56 to 0.82; P<0.001 by the log-ranktest), representing a 32 percent reduction in risk and correspondingto an absolute benefit in terms of disease-free survival of4.7 percent (95 percent confidence interval, 2.6 to 6.8) atthree years after randomization. Overall survival was not significantlydifferent in the two groups, with 93 deaths occurring in theexemestane group and 106 in the tamoxifen group. Severe toxiceffects of exemestane were rare. Contralateral breast canceroccurred in 20 patients in the tamoxifen group and 9 in theexemestane group (P=0.04).
Conclusions Exemestane therapy after two to three years of tamoxifentherapy significantly improved disease-free survival as comparedwith the standard five years of tamoxifen treatment.
Breast cancer is estrogen-dependent in many cases, and reducingthe estrogen levels by means of ovariectomy can cause regressionof established disease,1 especially if the tumor is rich inestrogen receptors.2 The selective estrogen-receptor modulatortamoxifen blocks the action of estrogen by binding to one ofthe activating regions of the estrogen receptor.3,4 When givento women with estrogen-receptor–positive breast cancerfor five years after surgery, tamoxifen reduces the risk ofrecurrence by 47 percent and the risk of death by 26 percent.5The risk–benefit ratio of using tamoxifen for longer thanfive years remains unclear,6,7 and trials addressing this questionare ongoing. International guidelines recommend that patientsshould not receive adjuvant tamoxifen therapy for more thanfive years outside the context of a clinical trial.8
Alternative endocrine therapy is often effective after diseasehas relapsed despite tamoxifen treatment, since at that point,estrogen receptors are still present in most patients.9 Severaltrials have confirmed the superiority of aromatase inhibitorsover progestins in this setting.10,11 Aromatase is an enzymethat catalyzes the conversion of androgens to estrogens. Thereare two classes of third-generation oral aromatase inhibitors:irreversible steroidal inactivators, exemplified by exemestane,12,13and reversible nonsteroidal inhibitors, such as anastrozoleand letrozole.14
Exemestane inhibits aromatization in vivo by about 98 percent.15It is superior to megestrol acetate with respect to time toprogression in advanced breast cancer14 and has antitumor effectsin patients who have no response to third-generation nonsteroidalaromatase inhibitors.16 Preliminary results show that exemestaneis superior to tamoxifen as first-line therapy for metastaticdisease.17 Theoretically, exemestane should not cause endometrialthickening or endometrial cancer, which are occasionally observedafter tamoxifen therapy.18
The Intergroup Exemestane Study (IES) was designed to investigatewhether exemestane, when given to postmenopausal women who remainedfree of recurrence after receiving adjuvant tamoxifen therapyfor two to three years for primary breast cancer, could prolongdisease-free survival, as compared with continued tamoxifentherapy. Here we report the results of the second planned interimanalysis, which we are releasing in accordance with the recommendationof the independent data and safety monitoring committee.
Methods
Study Design
Our study is an international, intergroup, phase 3, randomized,double-blind trial comparing the efficacy and safety of continuedadjuvant tamoxifen therapy with the efficacy and safety of exemestanetherapy in postmenopausal women with primary breast cancer whoremain free of disease after receiving adjuvant tamoxifen therapyfor two to three years. Women were randomly assigned to receiveoral exemestane (25 mg) or tamoxifen (20 mg) daily in orderto complete a total of five years of adjuvant endocrine treatment(Figure 1). Randomization was performed with the use of permutedblocks and was stratified according to center.
The percentage of patients who continue to receive treatment represents the percentage who are not known to have discontinued their randomized treatment and who began initial tamoxifen therapy less than five years before December 31, 2003.
The primary end point was disease-free survival, defined bythe time from randomization to recurrence of breast cancer atany site, diagnosis of a second primary breast cancer, or deathfrom any cause. Secondary end points included overall survival,the incidence of contralateral breast cancer, and long-termtolerability. For consistency and comparability with other reportedtrials,19 we also report breast-cancer–free survival,with censoring of deaths that occurred without a recurrenceof breast cancer or a diagnosis of contralateral breast cancer.Results from substudies assessing the quality of life, uterinethickness, bone metabolism, and bone mineral density will bereported separately.
The study was coordinated by the International CollaborativeCancer Group (ICCG), Imperial College London, and conductedunder the auspices of the Breast International Group (BIG).The trial was governed by a steering committee comprising representativesfrom the ICCG, participating cooperative groups, BIG, and thepharmaceutical-industry sponsor. Data for each cooperative groupwere collected by the group's data center and collated centrallyby the ICCG Data Center. Central review and querying and analysisof data were undertaken by the ICCG Data Center in collaborationwith the Institute of Cancer Research, where the independentstatisticians were based. The sponsor had no access to the trialdata base or interim analyses. The study was overseen by a dataand safety monitoring committee that was independent of theICCG Data Center, the steering committee, and the sponsor.
The institutional review board at each participating institutionapproved the study protocol, and all patients gave written informedconsent. Randomization was performed by the data center foreach cooperative group or through the ICCG Data Center.
Eligibility Criteria
Patients were eligible if they had histologically confirmed,completely resected unilateral invasive breast carcinoma thatwas positive for estrogen receptors (as determined by meansof standard immunostaining procedures) or that was of unknownreceptor status. Patients were postmenopausal (55 years of ageor older with amenorrhea for more than two years, or amenorrheafor more than one year at the time of diagnosis) and had receivedadjuvant tamoxifen therapy for at least two years but not morethan three years and one month. Most patients (95 percent) receivedtamoxifen at a dose of 20 mg daily, but patients who received30 mg daily were eligible (and continued to receive the samedose if they were assigned to the tamoxifen group). Patientswere required to have adequate hematologic, renal, and liverfunction at the time of randomization (defined as a normal bloodcount, a serum creatinine concentration less than 1.5 timesthe upper limit of normal, and a serum alanine aminotransferaseconcentration less than 2.5 times the upper limit of normal).
The criteria for exclusion included the presence of a tumorwith known negative estrogen-receptor status; evidence of localrelapse or a distant metastasis since the time of diagnosis;a clinically significant skeletal, cardiac, or endocrine disorder;and the use of hormone-replacement therapy within four weeksbefore randomization. Patients were also excluded if they hadclinical evidence of severe osteoporosis or a history of a previousneoplasm other than carcinoma in situ of the cervix or basal-cellskin carcinoma or if they were taking concomitant anticoagulantagents, a selective estrogen-receptor modulator other than tamoxifen,or any other form of hormonal therapy.
The protocol required adequate treatment of primary disease,including postoperative radiotherapy in patients who had beentreated with breast-preserving surgery. Neoadjuvant chemotherapywas permitted according to a consistent policy within each center.Patients were required to have started chemotherapy within threemonths after diagnosis and to have begun receiving tamoxifenand radiotherapy within three months after the completion ofchemotherapy.
Follow-up Procedures
Symptoms, side effects, findings on clinical examination, andthe level of compliance with treatment were recorded at three-monthintervals during the first year after randomization, every sixmonths during the second and third years, and annually thereafter.Hematologic and biochemical analyses and mammography (if thelocal procedure permitted) were performed annually.
Statistical Analysis
Enrollment of 4400 patients was required in order to detectan absolute difference of 3.6 percent in disease-free survivalthree years after randomization (with 88 percent power and atwo-sided level of significance of 4.3 percent after adjustmentfor interim analyses). The a priori expectation was that theprincipal analysis would be conducted after 716 end-point eventshad occurred. Three interim efficacy analyses were to be conducted,with the use of O'Brien–Fleming stopping boundaries, afterone quarter, one half, and three quarters of the planned totalnumber of events. Emerging trial data and interim analyses werereviewed by the independent data and safety monitoring committee,whose terms of reference dictated that their decisions be guided(but not mandated) by the above stopping rules.
Analyses were performed according to the intention-to-treatprinciple and included all patients who underwent randomization.All data were censored on June 30, 2003, but the snapshot ofdata used for the analysis of efficacy was updated to includeall data received by the ICCG Data Center through December 31,2003. Log-rank tests were used to compare the two groups. Two-sidedP values and 95 percent confidence intervals are reported. Coxproportional-hazards regression was used to adjust for prespecifiedprognostic factors.20 Hazard ratios of less than 1.0 favor exemestane.Kaplan–Meier time-to-event curves are presented. The groupswere compared in terms of the incidence of adverse effects withthe use of chi-square tests. Because of the early release ofthe efficacy results, data on adverse events are provisional;the validation process is ongoing. Here, we emphasize the adverseeffects for which there is a difference between groups witha P value of 0.01 or less.
Results
Study Population
We recruited 4742 women from 37 countries and 20 cooperativegroups between February 1998 and February 2003. Recruitmentcontinued beyond the target enrollment of 4400 in order to completeaccrual to the substudies on the effects on bone and qualityof life. The median follow-up was 30.6 months (interquartilerange, 23.9 to 36.6). The two groups were balanced with regardto base-line characteristics (Table 1). A total of 192 patientswere subsequently found to be ineligible (16 because of previousbreast cancers, 31 because of previous other cancers, 74 becausethey had undergone breast-conserving surgery but had not receivedradiotherapy, 25 because they were of uncertain menopausal status,24 because they had known estrogen-receptor–negative tumors,8 because they had used hormone-replacement therapy within fourweeks before randomization, and 14 for other reasons); thesepatients are included in all analyses on an intention-to-treatbasis.
Table 1. Base-Line Characteristics of the Patients and Tumors and Primary Treatment.
Efficacy
The second interim analysis, which was triggered by the reportingof 358 events, was presented to the data and safety monitoringcommittee on December 2, 2003, and included all data that hadbeen received relating to events and follow-up through June30, 2003. At that meeting, the committee recommended that keyefficacy data be released, because the O'Brien–Flemingstopping boundary (P=0.004) had been exceeded. The steeringcommittee agreed to the release at a meeting on December 3,2003. This report constitutes a refined analysis of that presentedto the data and safety monitoring committee.
A total of 449 first events were reported: 183 in the exemestanegroup and 266 in the tamoxifen group (Table 2). The unadjustedhazard ratio in the exemestane group as compared with the tamoxifengroup was 0.68 (95 percent confidence interval, 0.56 to 0.82;P=0.00005 by the log-rank test), which corresponds to an absolutebenefit of 4.7 percent (95 percent confidence interval, 2.6to 6.8) at three years (Figure 2). Disease-free survival threeyears after randomization was 91.5 percent (95 percent confidenceinterval, 90.0 to 92.7) in the exemestane group and 86.8 percent(95 percent confidence interval, 85.1 to 88.3) in the tamoxifengroup. In a subsidiary analysis of breast-cancer–freesurvival in which deaths of patients who did not have a recurrenceor contralateral breast cancer were censored, the hazard ratiowas 0.63 (95 percent confidence interval, 0.51 to 0.77; P=0.00001;144 events in the exemestane group vs. 227 in the tamoxifengroup). Survival free of distant disease was also better inthe exemestane group (hazard ratio, 0.66; 95 percent confidenceinterval, 0.52 to 0.83; P=0.0004). A total of 199 patients havedied (93 in the exemestane group and 106 in the tamoxifen group).There is no statistically significant difference in overallsurvival at this stage (hazard ratio, 0.88; 95 percent confidenceinterval, 0.67 to 1.16; P=0.37) (Figure 2). The causes of deathare listed in Table 2. Exemestane significantly reduced therisk of contralateral breast cancer (hazard ratio, 0.44; 95percent confidence interval, 0.20 to 0.98; P=0.04).
Figure 2. Kaplan–Meier Estimates of Disease-free Survival (Panel A) and Overall Survival (Panel B).
The hazard ratios are for the exemestane group as compared with the tamoxifen group. P values were determined by the log-rank test. An additional six patients in the exemestane group and four patients in the tamoxifen group had a recurrence or a second primary cancer in the contralateral breast or died more than four years after randomization (Panel A); an additional four patients in the exemestane group and two patients in the tamoxifen group died more than four years after randomization (Panel B).
Adjusting for the prespecified prognostic factors did not affectthe hazard ratios (Table 3), and there was no evidence of heterogeneityamong subgroups defined according to estrogen-receptor status,combined estrogen-receptor and progesterone-receptor status,number of positive nodes, receipt or type of previous chemotherapy,or use at any time of hormone-replacement therapy (Figure 3).
Figure 3. Subgroup Analysis of Disease-free Survival.
The hazard ratio given for all patients was adjusted for estrogen-receptor status, nodal status, receipt or nonreceipt of chemotherapy, and use or nonuse of hormone-replacement therapy (P=0.00004). The size of the rectangles is proportional to the size of the subgroups.
Adverse Effects and Safety
Exemestane was associated with a higher incidence of arthralgiaand diarrhea than tamoxifen, but gynecologic symptoms, vaginalbleeding, and muscle cramps were more common with tamoxifen(Table 4). Thromboembolic events were recorded more frequentlyin the tamoxifen group than in the exemestane group (55 patients[2.4 percent] vs. 30 patients [1.3 percent], P=0.007). Therewas also a suggestion of an increased incidence of osteoporosisand visual disturbances associated with exemestane. Fractureswere reported more frequently in the exemestane group than inthe tamoxifen group, although the difference was not statisticallysignificant (72 patients [3.1 percent] vs. 53 patients [2.3percent], P=0.08). More patients in the tamoxifen group thanin the exemestane group had a second primary non-breast cancerthat occurred before a distant relapse (53 patients [2.2 percent]vs. 27 patients [1.1 percent]; hazard ratio, 0.51; 95 percentconfidence interval, 0.32 to 0.80; P=0.003) (Table 2). Specifically,cancer of the endometrium, lung cancer, and melanoma developedin fewer patients in the exemestane group than in the tamoxifengroup, although these individual differences were not statisticallysignificant.
Randomly assigned treatment was stopped early in 667 patients(365 in the exemestane group and 302 in the tamoxifen group;14.1 percent of the total study population) for reasons otherthan relapse or death, after a median total duration of treatmentof 36.1 months (from the initiation of tamoxifen therapy). Atotal of 138 patients in the exemestane group and 121 in thetamoxifen group discontinued therapy because of adverse events,and another 164 patients in the exemestane group and 116 inthe tamoxifen group refused to continue therapy. An additional63 patients in the exemestane group and 65 in the tamoxifengroup have discontinued their randomly assigned treatment forother reasons, including protocol violations, or have been lostto follow-up. On the basis of the time since randomization,9 percent of patients are likely to be still receiving treatment.
Discussion
We found that switching patients to adjuvant treatment withexemestane after two to three years of tamoxifen therapy wasassociated with a statistically and clinically significant improvementin disease-free survival, which included a reduction in theincidence of metastatic disease. This strategy also reducedthe risks of contralateral breast cancer, endometrial cancer,and intriguingly, other primary cancers. At the time of thisreport, the observed number of deaths over the relatively shortfollow-up period precludes the detection of a statisticallysignificant difference in overall survival.
The data and safety monitoring committee recommended the earlyrelease of results on the basis of a planned interim analysis.More than 90 percent of the patients will have completed theirrandomly assigned treatment by the time this report is published;thus, the trial should still be able to achieve its long-termassessment of survival benefit. There are several theoreticalreasons to suggest a benefit of sequential endocrine therapyinvolving switching from tamoxifen to an aromatase inhibitorafter two to three years. First, many patients with breast cancerhave a relapse and die of metastatic disease within five yearsafter the initial diagnosis. Second, in both patients with primarycancer and those with metastatic disease, resistance occursas early as 12 to 18 months after the initiation of tamoxifentherapy. In some patients with resistant disease, tamoxifenmay act as an agonist, potentially stimulating the divisionof breast-cancer cells. Third, serious side effects of tamoxifen,including thromboembolism and uterine carcinoma, can occur afterprolonged use. Fourth, since tamoxifen can decrease bone resorption,21we reasoned that pretreatment with tamoxifen might lessen theeffect of any osteopenia caused by exemestane.
When we designed this study, there was considerable uncertaintyregarding the optimal duration of adjuvant tamoxifen therapyin patients with primary breast cancer. The 1990 overview bythe Early Breast Cancer Trialists' Collaborative Group had suggestedthat there was a likely benefit of continuing tamoxifen therapyfor five years.22 Randomized trials directly comparing two yearsof tamoxifen therapy with five years of tamoxifen therapy23,24confirmed that there was a relative risk reduction of 18 to19 percent with the longer-term therapy. Thus, although fiveyears of tamoxifen treatment was the identified standard, switchingtreatment after only two to three years was postulated to offerpatients the bulk of the benefit of tamoxifen while minimizingthe risk of long-term side effects.
Despite the promising results of the Anastrozole, TamoxifenAlone or in Combination Trialists' Group (ATAC) study, whichshowed that anastrozole was superior to tamoxifen,25 five yearsof tamoxifen therapy remains the widely recommended standardfor adjuvant treatment,8 although the Food and Drug Administrationrecently approved anastrozole monotherapy as an alternative.A study by Goss et al.19 found that after five years of tamoxifentherapy, patients who received letrozole had a higher rate ofdisease-free survival than those who received placebo. Our large,multicenter study challenges the concept of five years of monotherapywith endocrine agents after the surgical treatment of primarybreast cancer. Two smaller studies conducted by Italian researchershave used sequential aminoglutethimide after tamoxifen therapyin 308 patients26 and anastrozole after tamoxifen therapy in426 patients.27 Although they were underpowered, both trialssuggested that the sequence may be better than tamoxifen alone,supporting the results we present here.
The improvement in disease-free survival achieved by switchingfrom tamoxifen to exemestane is consistent with the hypothesisthat breast cancer frequently becomes resistant to tamoxifenwithin five years after treatment is initiated. The molecularmechanisms underlying such resistance are unclear. Laboratorystudies indicate that a reduction in the antagonist propertiesof tamoxifen caused by the up-regulation of tyrosine kinasereceptors (in particular, HER2 and epidermal growth-factor receptors),downstream protein kinases (such as mitogen-activated proteinkinase28 and protein kinase B, or Akt29), or both may resultin a significant increase in the agonist activity of tamoxifen,as well as increased sensitivity to estradiol. These effectscould explain the benefit that has been observed to result fromlowering the estradiol level through the sequential use of anaromatase inhibitor.9
Results in the subgroup with estrogen-receptor–positivebreast cancer were very similar to those among all patients.According to an unplanned subgroup analysis, exemestane seemedto be equally effective in both progesterone-receptor–positiveand progesterone-receptor–negative subgroups, as wellas in node-positive and node-negative subgroups, contrary tothe report suggesting that patients with estrogen-receptor–positiveand progesterone-receptor–negative carcinomas may preferentiallybenefit from anastrozole therapy.30
The reduction in the incidence of contralateral breast cancerin the exemestane group as compared with the tamoxifen group(hazard ratio, 0.44; 95 percent confidence interval, 0.20 to0.98; P=0.04) suggests that preventive strategies involvingthe prolonged use of tamoxifen monotherapy31,32 may not be optimal.The nonsignificant decrease in the rate of endometrial canceris consistent with expectations, since tamoxifen therapy isa well-recognized risk factor for endometrial cancer.33,34 Thedecreased incidence of other second primary (non-breast) cancersis more difficult to explain. Reports of associations betweentamoxifen therapy and cancer at other sites have been inconclusive,34and such associations were not substantiated by the Early BreastCancer Trialists' Collaborative Group study.5 Thus, it is notclear whether the observed differences in the incidence of newprimary cancers represent increases in risks due to tamoxifentreatment, a previously unreported protective effect of an aromataseinactivator, or chance findings.
The rate of discontinuation of treatment was slightly higherin the exemestane group than in the tamoxifen group, perhapsreflecting differences in the side-effect profiles of the twotreatments that may have been particularly evident to patientsswitching from one treatment to another. The analysis of adverseevents indicated that there was a lower incidence of thromboembolicevents among women who switched to exemestane. There was a slightbut nonsignificant increase in the rate of osteoporosis andreported fractures in the exemestane group as compared withthe tamoxifen group. Recent studies have shown that all third-generationaromatase inhibitors or inactivators increase bone resorption.35,36The substudy of the IES on bone mineral density aims to determinethe degree of bone mineral loss in patients who have been treatedwith tamoxifen and then switched to exemestane. The increasein the rate of arthralgia in the exemestane group is similarto that seen with other aromatase inhibitors,37 and diarrheahas been reported previously in patients receiving exemestane.16Cholesterol levels, which were reduced by tamoxifen treatment,38were found to be unaltered in another study of exemestane39but were not systematically measured in the present study; wehave not observed a significantly increased incidence of myocardialinfarction (1.0 percent in the exemestane group vs. 0.4 percentin the tamoxifen group).
Several issues still need to be clarified, including the correctsequence of therapy, which we believe to be an important factorin the success of this study and that reported by Goss et al.,19as well as the effect of aromatase inhibition on bone metabolism.The answers to these questions will have to await the resultsof ongoing and new studies. Our results add to the evidencethat the sequential use of aromatase inactivators and tamoxifenprovides additional options for improving adjuvant endocrinetherapy for postmenopausal women with hormone-responsive primarybreast cancer. Our results indicate that five years of tamoxifenmonotherapy after surgery may be suboptimal for postmenopausalpatients with estrogen-receptor–positive breast cancerand suggest that clinicians should consider switching patientsto exemestane between two and three years after the start oftamoxifen therapy.
Supported by Pfizer. The coordinating units at Imperial CollegeLondon and the Institute of Cancer Research also receive fundingsupport from Cancer Research U.K.
In addition to grant support to all authors from Pfizer, Prof.Coombes reports having received lecture fees from Pfizer, AstraZeneca,and Aventis; Prof. Paridaens consulting or lecture fees fromAmgen, Pfizer, Lilly, and Novartis; Dr. Jassem lecture feesfrom Novartis; Dr. Jones consulting or lecture fees from AstraZenecaand Pfizer; Dr Alvarez lecture fees from Schering-Plough; Dr.Bertelli lecture fees from Novartis and Pfizer; Dr. Ortmannconsulting fees from Pharmacia and AstraZeneca and lecture feesfrom Pfizer and Organon; Dr. Bajetta lecture fees from Pfizer;Dr. Dodwell consulting fees from Pfizer; Prof. Coleman consultingor lecture fees from Pfizer, Novartis, and AstraZeneca and grantsupport from AstraZeneca; Prof. Fallowfield lecture fees fromAstraZeneca, Johnson and Johnson, and Roche; Dr. Andersen consultingfees from Pfizer; Prof. Lønning consulting and lecturefees from Pfizer; and Dr. Stewart consulting and lecture feesfrom AstraZeneca; Dr. Stewart also holds equity in AstraZeneca.Dr. Stuart reports having received consulting fees from AstraZeneca.Drs. Carpentieri and Massimini are employees of Pfizer and holdequity in the company.
We are indebted to the women who participated in the study;to the Breast International Group for their support; to thestudy steering committee; to the independent data monitoringcommittee; and to the doctors, nurses, monitors, and data managersfrom the Argentine Breast Cancer Group, the Australian–NewZealand Breast Cancer Trials Group, the Central and EasternEuropean Oncology Group, the Danish Breast Cancer Group, theEuropean Organization for Research and Treatment of Cancer,the Grupo Español de Investigacíon del Cancerde Mama, the Gruppo Oncologico Nord Ovest, the Gruppo OncologicoItaliano di Ricerca Clinica, the International Breast CancerStudy Group, the International Collaborative Cancer Group, theIsraeli Clinical Oncology Group, the Italian Trials in MedicalOncology, the North West England Group, the Norwegian BreastCancer Group, the Yorkshire Breast Group, the Federation Nationaledes Centres de Lutte contre le Cancer, the German ExemestaneAdjuvant Group, the Wales Cancer Trials Network, U.S. Oncology,and the Swedish Breast Cancer Group. Additional acknowledgmentscan be found in Supplementary Appendix 1 (available with thefull text of this article at www.nejm.org).
Source Information
From the Department of Cancer Medicine, Imperial College and Charing Cross Hospital, London (R.C.C., L.J.G., C.F.S.); Institute of Cancer Research, Sutton (E.H., J.M.B.); South West Wales Cancer Institute, Swansea (G.B.); Cookridge Hospital, Leeds (D.D.); Cancer Research Centre, Weston Park Hospital, Sheffield (R.E.C.); Psychosocial Oncology Group, University of Sussex, Brighton (L.J.F.); Christie Hospital, Manchester (A.S.); and Ysbyty Gwynedd, Bangor, Gwynedd (N.S.) — all in the United Kingdom; Universitair Ziekenhuis, Leuven, Belgium (R.P.); Medical University of Gdansk, Gdansk, Poland (J.J.); Centre François Baclesse, Caen, France (T.D.); U.S. Oncology Research, Houston (S.E.J.); Hospital Donostia, San Sebastián, Spain (I.A.); University of Regensburg, Regensburg, Germany (O.O.); University of Sydney, Sydney, Australia (A.S.C.); Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy (E.B.); Instituto Angel Roffo, Buenos Aires, Argentina (E.M.); Århus University Hospital, Århus, Denmark (J.A.); Haukeland Hospital, University of Bergen, Bergen, Norway (P.E.L.); University Hospital, Parma, Italy (G.C.); and Pharmacia Italia, Pfizer Group, Nerviano, Italy (M.C., G.M.).
Address reprint requests to Dr. Coombes at the Department of Cancer Medicine, Imperial College London, 6th Fl., Cyclotron Bldg., Hammersmith Hospital, Du Cane Rd., London W12 0NN, United Kingdom.
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A correction has been published: N Engl J Med 2004;351(23):2461.
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