Letrozole Compared With Tamoxifen for Elderly Patients With Endocrine-Responsive Early Breast Cancer: The BIG 1-98 Trial
To explore potential differences in efficacy, treatment completion, and adverse events (AEs) in elderly women receiving adjuvant tamoxifen or letrozole for five years in the Breast International Group (BIG) 1-98 trial.
This report includes the 4,922 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial. The median follow-up was 40.4 months. Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was used to examine the patterns of differences in disease-free survival and incidences of AEs according to age. In addition, three categoric age groups were defined: “younger postmenopausal” patients were younger than 65 years (n = 3,127), “older” patients were 65 to 74 years old (n = 1,500), and “elderly” patients were 75 years of age or older (n = 295).
Efficacy results for subpopulations defined by age were similar to the overall trial results: Letrozole significantly improved disease-free survival (DFS), the primary end point, compared with tamoxifen. Elderly patients were less likely to complete trial treatment, but at rates that were similar in the two treatment groups. The incidence of bone fractures, observed more often in the letrozole group, did not differ by age. In elderly patients, letrozole had a significantly higher incidence of any grade 3 to 5 protocol-specified non-fracture AE compared with tamoxifen (P = .002), but differences were not significant for thromboembolic or cardiac AEs.
Adjuvant therapy with tamoxifen for 5 years, which has been the standard of care for women with early-stage, endocrine-responsive breast cancer for many years,1 is now challenged by the advent of third-generation aromatase inhibitors.2 The safety profile of tamoxifen is well-documented, whereas that of third-generation aromatase inhibitors is still evolving. The partial estrogen agonistic activity of tamoxifen and other selective estrogen-receptor modulators (SERMs) increases the risk of endometrial cancer and thromboembolic events, but also provides protection from osteoporosis and possibly cardiac problems.3 Aromatase inhibitors profoundly reduce the already low circulating endogenous levels of estrogens in postmenopausal women by blocking the synthesis of estrogens in non-ovarian tissues including breast tissue,4-6 and have been shown to be similar or superior to tamoxifen as first-line treatment for locally advanced and metastatic breast cancer7-9 without increasing the risks of endometrial cancer and thromboembolic events, but there is a clinical concern about the use of aromatase inhibitors in older women affected by comorbidities such as osteoporosis and cardiovascular disease.
We investigated whether the risks and benefits of letrozole compared to tamoxifen in the Breast International Group (BIG) 1-98 trial10,11 differed in subgroups defined by age, being mindful not to overinterpret subset analyses. The specific goal of the present study was to determine whether the treatment recommendations made for the trial as a whole should be modified for elderly patients.
From March 1998 to May 2003, 8,028 postmenopausal women with hormone receptor-positive breast cancer were randomly assigned in a phase III, double-blind trial to one of the four following treatment regimens: tamoxifen for 5 years, letrozole for 5 years, tamoxifen for 2 years followed by letrozole for 3 years, or letrozole for 2 years followed by tamoxifen for 3 years. The current analysis focuses on the 4,922 patients randomly assigned to the two monotherapy arms. The median follow-up was 40.4 months.
The study was coordinated by the International Breast Cancer Study Group (IBCSG) on behalf of the BIG. The ethics committees and required health authorities of each participating center approved the study protocol, and all patients gave written informed consent. Details of study conduct and results of the primary core analysis of the comparison of letrozole to tamoxifen using data from patients randomly assigned to all four arms,10 and updated results from patients randomly assigned to the two monotherapy arms,11 have been previously reported.
History and physical examination were performed at baseline, semiannually for the first 5 years, and annually thereafter. Total cholesterol (90.8% of the values were non-fasting) was measured at baseline, semiannually for the first 3 years, yearly for the following 2 years, and 1 year after treatment ended.
Specific adverse events (AEs), which were listed on the case-report forms and graded according to the National Cancer Institute Common Toxicity Criteria (version 2) at each study visit during treatment, included myocardial infarction or ischemic event, cerebrovascular accident or transient ischemic attack, angina requiring percutaneous transluminal coronary angioplasty, angina requiring coronary-artery bypass grafting, a thromboembolic event, other cardiovascular events, hypercholesterolemia, bone fracture, vaginal bleeding, nausea, vomiting, hot flashes, and night sweats. Serious AEs were reported in an expedited fashion. All grade 3, 4, and 5 cardiovascular AEs were medically reviewed by senior oncologists (M.R., M.C.-G.) at the IBCSG Coordinating Center. Other cardiovascular morbidities reported at baseline (and specified via a comment field) were also medically reviewed and categorized.
The primary trial end point was disease-free survival (DFS), defined as the time from random assignment to the first of the following events ending DFS: recurrence at local, regional, or distant sites; a new invasive cancer in the contralateral breast; any second, non-breast cancer; or death without a prior cancer event. Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was used to investigate the pattern of difference in 4-year DFS between treatment arms according to patient age at study entry.12,13 A P value for the interaction test of age and treatment arms was provided on the basis of simulations.
Analyses of protocol-specified AEs were limited to the safety population (n = 4,895) which excluded 27 patients who did not receive any trial treatment. The outcomes of interest were: any non-fracture AE, bone fractures, thromboembolic AEs, any cardiac AE, and ischemic cardiac events. The incidence of an AE was compared between treatment arms using two-sided Fisher's exact tests.14 STEPP analyses evaluated the age pattern of AE incidence: in these plots the y-axis shows the incidence (percentage) of the AE for each treatment group. Cox proportional hazards models15 were used to compare time to first AE of a given type between the treatment groups. The models stratified by randomization option (two arm or four arm10) and chemotherapy use, and adjusted for potential risk factors. In addition to treatment effect, age group, and the treatment-by-age group interaction, the Cox models for any non-fracture AE were adjusted for body mass index (BMI; ≥ 30 v < 30 kg/m2), smoking history, presence of hypertension at baseline, presence of diabetes at baseline, and history of medication for hypercholesterolemia. For thromboembolic AEs, cardiac AEs, and ischemic cardiac events, the Cox models were adjusted for the same factors, history of the AE under investigation, and whether the patient had hypercholesterolemia before the AE (time varying). For bone fractures, the Cox models were adjusted for BMI, smoking history, presence of osteoporosis, and prior bone fractures within the last 10 years. Except for bone fractures, analyses were performed on all AEs grade 1 to 5, and were also restricted to AEs grade 3 to 5. Because bone fractures are graded either 2 (fracture not requiring surgery) or 3 (fracture require surgery), bone fracture AEs are not included in the grade 3 to 5 analyses, but are included in the grade 1 to 5 analyses. In the Cox models, to illustrate age-related differences in treatment efficacy and AE profile, three categories for age at study entry were defined: less than 65 years (younger), 65 to 74 years (older), and 75 years or older (elderly).
A competing risk model16 with DFS as a competing event was also used to evaluate the treatment effect on time to first non-fracture grade 3 to 5 AE.
The BIG 1-98 trial included 4,922 postmenopausal patients with hormone-responsive early breast cancer who were randomly assigned to the two continuous therapy groups, 2,463 to letrozole and 2,459 to tamoxifen. The median age at random assignment was 61 years in both treatment groups, ranging from 38 to 90 years. Of the 4,922 patients randomly assigned to the monotherapy arms, 3,127 (63.5%) were younger, 1,500 (30.5%) were older, and 295 (6.0%) were elderly. Figure 1 shows the age distribution in 5-year intervals.
The STEPP analysis in Figure 2 shows 4-year DFS percentages for letrozole and tamoxifen groups in overlapping subpopulations defined by age at study entry. In the overall population, letrozole showed superior efficacy to tamoxifen (P = .006), and this superiority was similar across the age spectrum and not significantly influenced by age (interaction of age and treatment, P = .84).
Elderly patients (≥ 75 years) were less likely to complete trial treatment, but at rates that were similar in the two treatment groups. Of the 4,895 patients who started trial treatment, 1,154 (23.6%) did not complete their planned 5 years of treatment; 22.6% (1,041 of 4,601) among those age younger than 75 and 38.4% (113 of 294) among those 75 and older (P < .0001). In this elderly group, however, the completion rates for the two drugs were similar: 39.7% (58 of 146) did not complete letrozole and 37.2% (55 of 148) tamoxifen (P = .72). The most common reasons for discontinuing treatment early were AEs and progression of disease. Note that at the time of this analysis treatment completion information was still being collected.
Table 1 shows the distribution of risk factors observed according to treatment group and age cohort. There were no statistically significant differences between the two treatment groups for any of the risk factor categories. Figure 3A shows the incidence of any non-fracture grade 3 to 5 AE reported during the treatment period using the STEPP method according to age. A difference between letrozole and tamoxifen appeared to emerge for the oldest subpopulation. Figure 4 shows the Cox model hazard ratio estimates (adjusted for risk factors) comparing letrozole versus tamoxifen for time to first event-specific AE according to age cohort. In the elderly group, we observed more non-fracture AEs in patients receiving letrozole compared with tamoxifen (interaction P = .26 for grade 1 to 5; interaction P = .06 for grade 3 to 5). Competing risk models accounting for disease recurrence (Fig 5) confirmed the results of the Cox models, also showing a significantly earlier occurrence of grade 3 to 5 non-fracture AE in elderly patients receiving letrozole (P = .002).
The incidence of bone fractures was higher among patients treated with letrozole (196 of 2,448 women [8.0%] v 132 of 2,447 women [5.4%] receiving tamoxifen; P < .001). The incidence was generally consistent with regard to age beyond the youngest subpopulations (Fig 3B) and treatment differences adjusted for baseline risk factors favored tamoxifen across age groups (Fig 4; interaction P = .51 for grade 1 to 5). On the basis of Cox model analysis, statistically significant risk factors for bone fractures (grade 1 to 5) during treatment included smoking history (P = .006) and prior bone fracture (P < .0001). We observed fractures in 25 elderly patients (8.5%; 17 letrozole, eight tamoxifen), and the most frequently observed type was wrist (eight patients, six letrozole and two tamoxifen). Femur fractures were reported in five elderly patients (four letrozole and one tamoxifen).
In the total population, thromboembolic events of any grade were less frequently reported in women treated with letrozole (50 of 2,448 women [2.0%] v 94 of 2,447 women [3.8%] receiving tamoxifen; P < .0001). After adjusting for risk factors, the treatment difference in time to first thromboembolic event observed for the two younger age cohorts was less evident in the elderly cohort (Fig 4; interaction P = .54 for grade 1 to 5; interaction P = .29 for grade 3 to 5). On the basis of Cox model analysis, statistically significant risk factors for thromboembolic events during treatment included higher baseline BMI (P = .008 for grade 1 to 5; P = .0005 for grade 3 to 5) and prior thromboembolic events (P < .0001 for grade 1 to 5 and for grade 3 to 5).
The overall incidence of cardiac events (grade 1 to 5) was similar in the two treatment groups (letrozole 140 of 2,448 women [5.7%] v tamoxifen, 127 of 2,447 [5.2%]; P = .45). After adjusting for risk factors, a significant difference favoring tamoxifen was observed in the older age cohort (65 to 74 years) but not in the elderly cohort (≥ 75 years for both grade 1 to 5 and grade 3 to 5 cardiac AEs; interaction P = .10 for grade 1 to 5; interaction P = .16 for grade 3 to 5; Fig 4). On the basis of Cox model analysis, statistically significant risk factors for cardiac events during treatment included history of hypertension (P = .20 for grade 1 to 5; P = .02 for grade 3 to 5), and prior cardiac events (P < .0001 for grade 1 to 5; P < .0001 for grade 3 to 5).
The overall incidence of ischemic heart events (grade 1 to 5) was similar in the two treatment groups (letrozole, 54 of 2,448 women [2.2%] v tamoxifen, 45 of 2,447 [1.8%]; P = .42). After adjusting for risk factors, a significant difference in time to first grade 3 to 5 ischemic heart event favoring tamoxifen was observed in the older age cohort (65 to 74 years) but not in the younger cohort (< 65 years) or elderly cohort (≥ 75 years; interaction P = .10 for grade 1 to 5; interaction P = .03 for grade 3 to 5; Fig 4). On the basis of Cox model analysis, statistically significant risk factors for ischemic heart events during treatment included history of hypertension (P = .04 for grade 1 to 5; P = .001 for grade 3 to 5), and prior ischemic heart events (P < .0001 for grade 1 to 5; P < .0001 for grade 3 to 5).
AEs resulting in death during treatment, regardless of whether they were considered an effect of treatment, were reported in 46 patients, 26 (1.1%) patients treated with letrozole and 20 (0.8%) patients treated with tamoxifen. Among elderly patients, nine (6.2%) receiving letrozole and two (1.4%) receiving tamoxifen experienced lethal AEs during treatment (all cardiovascular: cardiovascular accident, thromboembolic, and cardiac events).
Breast cancer is common among elderly patients, yet this population is substantially underrepresented in clinical trials, as summarized in the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview.1 Perforce, treatment decisions for such patients are based predominantly on results of trials in younger women, and our trial had only 6% age 75 years or older. We recognize two caveats: that these patients may be healthier than similarly-aged patients not entered onto clinical trials, and that, although this is a relatively large sample by clinical trial enrollment standards, it is still a fairly small subset from which to make definitive recommendations.
The BIG 1-98 trial11 confirmed the superiority of an aromatase inhibitor over tamoxifen for DFS but not overall survival, and it is possible that, in the elderly population, we may never observe an overall survival difference. The present study shows that letrozole is superior to tamoxifen in reducing relapses including distant metastases in all age groups, with no suggestion of heterogeneity evident in the STEPP analyses. With the efficacy benefit clear, we wished to examine the overall experience of treatment and in particular the relative adverse effects of the two treatments according to patient age. Treatment completion rates were lower overall for elderly patients, but were similar with either treatment. It is noteworthy that, in both treatment groups, 37% to 39% of the elderly patients did not complete their assigned treatment, even though the regimen was a single oral administration per day, a consideration in planning future protocols for elderly patients.
Do these data help to decide whether to treat elderly patients with an aromatase inhibitor rather than tamoxifen? No convincing overall patterns of differences were observed in thromboembolic or cardiac event in the elderly group, but in the older (age 64 to 75 years) cohort thromboembolic events appeared more commonly with tamoxifen and cardiac events with letrozole. Competing risk models allowing for disease recurrence showed significantly more grade 3 to 5 non-fracture AEs in elderly patients receiving letrozole (Fig 5). Bone fractures were more frequent with letrozole in all age groups, with no apparent difference in the excess by age.
Older patients had substantially more frequent baseline comorbidities associated with cardiac risk (Table 1), especially hypertension (reported in 24% of younger patients; 42% in older patients; and 56% in elderly patients). In the aging population cardiovascular diseases, mainly heart disease and stroke, are leading causes of morbidity and death.17-22 These diseases are also important in intercurrent non–breast cancer deaths of patients in cancer treatment trials. Tamoxifen decreases levels of total cholesterol and low-density lipoprotein and increases high-density lipoprotein levels,23 both of which are associated with decreased cardiovascular risk. Early adjuvant trials reported that tamoxifen therapy was associated with decreased risks for fatal myocardial infarction and cardiac hospitalizations,24,25 but no overall protective effect was seen in the placebo-controlled Breast Cancer Prevention Trial.26 Similarly, another SERM, raloxifene, was found to confer no protection against coronary events despite favorable changes in lipid levels.27,28 In the present study, the incidence of venous thromboembolic events and cardiac events in elderly patients were similar with tamoxifen and letrozole.
Comorbidities associated with bone health (baseline osteoporosis and prior bone fractures), were more common in elderly patients in this trial, but although the incidence of bone fracture was higher in patients treated with letrozole at all ages, this excess was not markedly different in the elderly patients. Similar effects have been seen in other trials of aromatase inhibitors.29-31 Issues of bone health, especially considering that osteoporosis itself increases with age, need to be taken into consideration when planning adjuvant endocrine treatment for early breast cancer32-34: bone mineral density (BMD) screening is recommended for all women older than 65 years, those 60 to 64 years with risk factors, all patients receiving aromatase inhibitors, and premenopausal women with therapy-associated premature menopause. Hip fracture, although relatively rare in the elderly patients on this study thus far, is attended by substantial early mortality and persisting morbidity in elderly patients35 with difficulty to recover activities of daily living. Unfortunately, BMD is not, by itself, able to distinguish patients that will develop a bone fracture. All risk factors including family history, height, weight, nutrition, and smoking36 need to be evaluated to identify patients at higher risk of bone fracture.
The optimum duration of treatment with aromatase inhibitors in the adjuvant setting remains an open question, and it may be that the trade-off between efficacy and AEs would favor a shorter period than is regarded as optimal among younger patients. Severe toxicities in our study typically appeared after 2 years of treatment (in 73% of patients treated with letrozole and 60% of patients treated with tamoxifen; data not shown). The IBCSG recently reported a long-term (20 years) survival advantage with only 1 year of treatment with tamoxifen in patients older than 65 years.37 Another unresolved question is whether the sequence of tamoxifen followed by an aromatase inhibitor or the reverse may improve the AE profile, especially relating to bone and cardiac events in elderly patients. This question may be clarified when results are available from the sequential therapy arms of the BIG 1-98 study.
In summary, in our experience, letrozole is an effective adjuvant treatment, superior to tamoxifen for controlling breast cancer regardless of age. For elderly patients, the trade-off of severe or worse AEs and disease control, illustrated in Figure 5, can help put differences between the two agents in perspective. In elderly patients, a patient-profile–based approach should be considered to reduce the risk of serious AEs. When hormonal therapy is proposed to a new patient, all risk factors for cardiovascular disease and for osteoporosis should be evaluated.38 Thus, in the presence of comorbidities such as osteoporosis with preexisting bone fractures or cardiac diseases tamoxifen may be preferred, whereas, on the contrary, an increased risk for or a prior history of thromboembolic disease might favor the choice of letrozole. In general, however, this analysis suggests that age per se should not unduly affect the choice of adjuvant endocrine therapy.
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: Aron Goldhirsch, International Breast Cancer Study Group (U) Consultant or Advisory Role: Henning Mouridsen, Novartis (C); Louis Mauriac, Novartis (C); John F. Forbes, Novartis (C), AstraZeneca (C); Lucia Del Mastro, Novartis (C) Stock Ownership: Beat Thürlimann, Novartis Honoraria: Beat Thürlimann, Novartis, Pfizer, AstraZeneca; Henning Mouridsen, Novartis, Pfizer; Louis Mauriac, Novartis; John F. Forbes, Novartis, Eli Lilly & Co; Lucia Del Mastro, Novartis; Ian E. Smith, Novartis; Aron Goldhirsch, Novartis Research Funding: Louis Mauriac, Novartis; Robert J. Paridaens, Novartis; Richard D. Gelber, Novartis; Jacquie H. Chirgwin, Novartis; Aron Goldhirsch, Novartis Expert Testimony: None Other Remuneration: Alan S. Coates, Novartis; Aron Goldhirsch, Novartis
Conception and design: Diana Crivellari
Administrative support: Alan S. Coates, Karen N. Price, Henning Mouridsen, Louis Mauriac, John F. Forbes, Monica Castiglione-Gertsch, Aron Goldhirsch
Provision of study materials or patients: Diana Crivellari, Beat Thürlimann, Henning Mouridsen, Louis Mauriac, John F. Forbes, Robert J. Paridaens, Marco Colleoni, István Láng, Lucia Del Mastro, Laurence Gladieff, Ian E. Smith, Jacquie H. Chirgwin, Aron Goldhirsch
Collection and assembly of data: Karen N. Price, Monica Castiglione-Gertsch, Richard D. Gelber, Manuela Rabaglio
Data analysis and interpretation: Diana Crivellari, Zhuoxin Sun, Alan S. Coates, Karen N. Price, Richard D. Gelber
Manuscript writing: Diana Crivellari, Zhuoxin Sun, Alan S. Coates, Karen N. Price, Henning Mouridsen, Richard D. Gelber
Final approval of manuscript: Diana Crivellari, Zhuoxin Sun, Alan S. Coates, Karen N. Price, Beat Thürlimann, Henning Mouridsen, Louis Mauriac, John F. Forbes, Robert J. Paridaens, Monica Castiglione-Gertsch, Richard D. Gelber, Marco Colleoni, István Láng, Lucia Del Mastro, Laurence Gladieff, Manuela Rabaglio, Ian E. Smith, Jacquie H. Chirgwin, Aron Goldhirsch
B. Thürlimann (chair), S. Aebi, L. Blacher, M. Castiglione, A.S. Coates, T. Cufer, J.F. Forbes, R.D. Gelber, A. Giobbie-Hurder A. Goldhirsch, A. Hiltbrunner, S.B. Holmberg, R. Maibach, A. Martoni, L. Mauriac, G. McGrogan, H.T. Mouridsen, R. Paridaens, K.N. Price, M. Rabaglio, B.B. Rasmussen, M.M. Regan, A. Santoro, I.E. Smith, A. Wardley, C. Strahle, and G. Viale.
H.A. Chaudri-Ross, D. Emanuel, D.B. Evans, C. Sguotti, and U. Trostmann.
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, and A. Wallgren.
B. Thürlimann (president), M. Castiglione, A.S. Coates, J.P. Collins, R.D. Gelber, A. Goldhirsch, M. Green, A. Hiltbrunner, S.B. Holmberg, D.K. Hossfeld, P. Karlsson, I. Láng, M. de Stoppani, C.-M. Rudenstam, R. Stahel, and A. Veronesi.
A. Hiltbrunner (director), M. Rabaglio, G. Egli, B. Cliffe, S. Ribeli-Hofmann, R. Kammler, R. Studer, B. Ruepp, R. Maibach, and N. Munarini.
R.D. Gelber (group statistician), K.N. Price (director of scientific administration), A. Giobbe-Hurder (trial statistician), M. Regan, H. Huang, and L. Nickerson.
L. Blacher (director of data management), T. 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, and T. Zielinski.
B.A. Gusterson, E. Mallon; (European Institute of Oncology, Division of Pathology, Milan, Italy): G. Viale, P. Dell'Orto, M. Mastropasqua, and B. Del Curto.
U. Trostmann, E. Waldie, I. van Hoomissen, M. De Smet, W. Schmidt, A. Bolton, and W. Hackl.
Board Chair, R.D. Snyder; Group Coordinator, J.F. Forbes; Chair, Scientific Advisory Committee, A.S. Coates; ANZ BCTG Operations Office (Newcastle, Australia)—D. Lindsay (head data management), D. Preece (senior study coordinator), J. Cowell, D. Talbot, and A. Whipp.
The Cancer Council Victoria, Melbourne, Victoria (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, and S. Wong; W.P. Holman Clinic, Launceston General Hospital, Launceston, Tasmania—D. Byram and I. Byard; Liverpool Hospital, Sydney, New South Wales (NSW)—S. Della-Fiorentina, A. Goldrick, E. Hovey, E. Moylan, and E. Segelov; Mount Hospital, Perth, Western Australia (WA)—A. Chan, M. Buck, D. Hastrich, D. Ingram, G. Van Hazel, and P. Willsher; Nepean Cancer Care Centre, Sydney, NSW—N. Wilcken and C. Crombie; Calvary Mater Newcastle, Newcastle, NSW—J.F. Forbes, F. Abell, S. Ackland, A. Bonaventura, S. Cox, J. Denham, R. Gourlay, D. Jackson, R. Sillar, and J. Stewart; Prince of Wales Hospital, Sydney, NSW—C. Lewis, B. Brigham, D. Goldstein, and M. Friedlander; Princess Alexandra Hospital, Woollongabba, Queensland (QLD)—E. Walpole and D. Thompson; Royal Adelaide Hospital, Adelaide, South Australia (SA)—P.G. Gill, M. Bochner, J. Coventry, J. Kollias, P. Malycha, and I. Olver; Royal Brisbane and Women's Hospital, Brisbane, QLD—M. Colosimo, R. Cheuk, L. Kenny, N. McCarthy, and D. Wyld; Royal Hobart Hospital, Hobart, Tasmania—R. Young, R. Harrup, R. Kimber, and R. Lowenthal; Royal Perth Hospital, Perth, WA—J. Trotter, E. Bayliss, A. Chan, and D. Ransom; Sir Charles Gairdner Hospital, Perth, WA—M. Byrne, M. Buck, J. Dewar, A. Nowak, A. Powell, and G. Van Hazel; Toowoomba Hospital, Toowoomba, QLD—E.A. Abdi, R. Brodribb, and Z. Volobueva; Westmead Hospital, Sydney, NSW—P. Harnett, V. Ahern, H. Gurney, and N. Wilcken.
Auckland Hospital, Auckland—V.J. Harvey, B. Evans, W. Jones, M. McCrystal, D. Porter, P. Thompson, and M. Vaughan; Christchurch Hospital, Christchurch—D. Gibbs, C. Atkinson, R. Burcombe, B. Fitzharris, B. Hickey, M. Jeffery, and B. Robinson; Dunedin Hospital, Dunedin—B. McLaren, S. Costello, J. North, and D. Perez; Waikato Hospital, Hamilton—I.D. Campbell, L. Gilbert, R. Gannaway, M. Jameson, I. Kennedy, J. Long, G. Round, L. Spellman, D. Whittle, and D. Woolerton.
Hospital de Clinicas de Porto Alegre, Porto Alegre—C. Menke, J. Biazús, R. Cericatto, J. Cavalheiro, N. Xavier, A. Bittelbrunn, and E. Rabin.
Chilean Cooperative Group for Oncologic Research—J. Gutiérrez (chairman), R. Arriagada (scientific adviser), L. Bronfman (principal investigator), and M. Zuñiga (data manager); Clinica Las Condes, Santiago—J. Gutiérrez, J.C. Acevedo, S. Torres, A. León, and E. Salazar; Hospital DIPRECA, Las Condes, Santiago—L. Soto Diaz, R. Duval, N. Oddeshede, and M.C. Venti; Hospital San Juan de Dios, Santiago—K. Peña, L. Puente, and V. Maidana; IRAM/Instituto de Radiomedicina, Vitacura, Santiago—R. Baeza, R. Arriagada, P. Olfos, J. Solé, E. Vinés, and C. Mariani.
National Institute of Oncology, Budapest—I. Láng, E. Hitre, E. Szabó, Z. Horváth, E. Ganofszky, and E. Juhos.
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, and A. Gloghini; Ospedali Riuniti di Bergamo, Bergamo—C. Tondini, R. Labianca, P. Poletti, and A. Bettini; Ospedale degli Infermi, Biella—M. Clerico, M. Vincenti, A. Malossi, E. Seles, E. Perfetti, and 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, and C. Fogazzi; U.O. Medicina Oncologica, Ospedale Carpi, Ospedale Mirandola—F. Artioli, K. Cagossi, L. Scaltriti, E. Bandieri, L. Botticelli, and G. Giovanardi; Ospedale di Cattolica “Cervesi,” Cattolica—A. Ravaioli, E. Pasquini, and B. Rudnas; Ospedale Civile, Gorizia—L. Foghin; Ospedale “A. Manzoni” Lecco, Lecco—M. Visini, L. Zavallone, and G. Ucci; Istituto Europeo di Oncologia, Milan—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, and A. Goldhirsch; Ospedale Infermi, Rimini—A. Ravaioli and L. Gianni.
Instituto de Enfermedades Neoplásicas, Lima—H. Gome.
Institute of Oncology, Ljubljana—T. Cufer, B. Pajk, and J. Cervek.
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, and E. Panieri; Sandton Oncology Centre, Johannesburg—D. Vorobiof, M. Chasen, G. McMichael, and C. Mohammed. Local funding provided by the Cancer Association of South Africa.
West Swedish Breast Cancer Study Group—S.B. Holmberg; Sahlgrenska U Hospital, Moelndal—S.B. Holmberg and J. Mattsson; Boras Hospital, Boras; Karlstads Hospital, Karlstads—H. Sellström; Kungalvs Hospital, Kungalvs—B. Lindberg.
Swiss Group for Clinical Cancer Research (SAKK)—A. Goldhirsch (up to January 2004) and R. Herrmann (from June 2004)—Kantonsspital Aarau, Zentrum f. Onkologie, Aarau—A. Schönenberger, W. Mingrone, C. Honegger, E. Bärtschi, M. Neter, M. Rederer, and G. Schär; University Hospital Basel, Basel—C. Rochlitz, R. Herrmann, D. Oertli, E. Wight, and H. Moch; Institute of Oncology of Southern Switzerland—Ospedale San Giovanni, Bellinzona—J. Bernier, L. Bronz, F. Cavalli, E. Gallerani, A. Richetti, and A. Franzetti; Ospedale Regionale di Lugano (Civico & Italiano), Lugano—M. Conti-Beltraminelli, M. Ghielmini, T. Gyr, S. Mauri, and P.C. Saletti; Ospedale Regionale Beata Vergine, Mendrisio—A. Goldhirsch, O. Pagani, R. Graffeo, M. Locatelli, S. Longhi, P.C. Rey, and M. Ruggeri; Ospedale Regionale La Carità, Locarno—E. Zucca and D. Wyss; Istituto Cantonale di Patologia, Locarno—L. Mazzucchelli, E. Pedrinis, and T. Rusca; Inselspital, Berne—S. Aebi, M.F. Fey, and M. Rabaglio; Kantonsspital Olten, Olten—S. Aebi, M.F. Fey, M. Zuber, and G. Beck; Bürgerspital, Solothurn—S. Aebi, M.F. Fey, and R. Schönenberger; Spital Thun-Simmental AG Thun—J.M. Lüthi and 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, and 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, and E. Vogel; Kantonales Spital Herisau, Herisau—B. Thürlimann, D. Hess, I. Senn, D. Köberle, A. Ehrsam, C. Nauer, C. Öhlschlegel, J. Kehl-Blank, and E. Vogel; Stadtspital Triemli, Zürich—L. Widmer and M. Häfner; Universitätsspital Zürich, Zürich—B.C. Pestalozzi, M. Fehr, R. Caduff, Z. Varga, R. Trüb, and D. Fink.
Private Practice, Zürich—B.A. Bättig; Sonnenhof-Klinik Engeried, Berne—K. Buser; Frauenklinik Limmattalspital, Schlieren—N. Bürki; Private Practice, Birsfelden—A. Dieterle; Private Practice, Biel—L. Hasler; Private Practice, Baar—M. Mannhart-Harms; Brust-Zentrum, Zürich—C. Rageth; Private Practice, Berne—J. Richner; Private Practice, Bellinzona—V. Spataro; Private Practice, Winterthur—M. Umbricht.
King's College Hospital/Breast Unit, London—P. Ellis, S. Harris, N. Akbar, H. McVicars, C. Lees, R. Raman, and G. Crane.
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.
Institut Bergonié, Bordeaux—L. Mauriac, M. Debled, and P. Campo; Centre Hospitalier de la Côte Basque, Bayonne—D. Larregain-Fournier and S. Remy, Centre Jean Perrin, Clermont-Ferrand—H. Auvray; Centre Georges François Leclerc, Dijon—C. De Gislain, F. Delille, and M.-C. Porteret; Centre Oscar Lambret, Lille—V. Servent, and M. Chapoutier; CHRU, Limoges—N. Tubiana-Mathieu, S. Lavau-Denes, and P. Bosc; Centre Léon Bérard, Lyon—J.P. Guastalla, Th. Bachelot, and C. Arbault; Centre Hospitalier Meaux, Meaux—G. Netter-Pinon; C.H.G. André Boulloche, Montbéliard—V. Perrin, A. Monnier, and Y. Hammoud; Centre Paul Lamarque, Montpellier—G. Romieu, L. Culine, and V. Pinosa; Clinique Francheville, Périgueux—L. Cany and C. Maguire; Hôpital de la Milétrie, Poitiers—A. Daban, M. Le Saux, and C. Grandon; Centre Eugène Marquis, Rennes—P. Kerbrat and C. Catheline; Centre Henri Becquerel, Rouen—C. Veyret, E. Jugieau, and V. Talon; Centre René Gauducheau, Saint-Herblain—A. Le Mevel and S. Maury; Centre Claudius Régaud, Toulouse—L. Gladieff and N. Lignon.
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.
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.
Flinders Medical Centre, Adelaide, SA—S. Birrell, M. Eaton, and C. Hoffman; Queen Elizabeth Hospital, Adelaide, SA—V. Humeniuk; The Canberra Hospital, Canberra, ACT; P. Craft, R. Stuart-Harris, and D. Yip; The Geelong Hospital, Geelong, VIC—R. Bell, F. Abell, M. Francis, J. Kiffer, R. Lynch, R. McLennan, and 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, and 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, and S. Wong; Newcastle Mater Hospital, Newcastle, NSW—J. Stewart, F. Abell, S. Ackland, and A. Bonaventura; Royal Perth Hospital, Perth, WA—J. Trotter, E. Bayliss, A. Chan, D. Ransom, and A. Redfern; St. George Hospital, Sydney, NSW—P. de Souza and M. Links; St. Vincent's Hospital, Sydney, NSW—D. Dalley, J. Grygiel, and R. Ward; Murray Valley Private Hospital, Wodonga, VIC—C. Underhill, K. Clarke, and C. Steer; Princess Alexandra Hospital, Woolloongabba, QLD—E. Walpole and D. Thompson.
Institut Jules Bordet, Bruxelles—J.M. Nogaret; University Hospitals Leuven, Leuven—M.R. Christiaens, P. Neven, R. Paridaens, A. Smeets, I. Vergote, C. Weltens, and 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.
Cambridge Memorial Hospital, Cambridge—J. Gowing; CHUM- Campus Notre-Dame, Montreal—L. Yelle; Hôpital Maisonneuve-Rosemont, Montreal—P. Dubé.
Fundacion Lopez Perez, Santiago—C. Vogel; Hospital Carlos Van Buren, Valparaiso—M. León Prieto.
Institute of Oncology, Brno—K. Petrakova, M. Palacova, and R. Demlova; Dept. of Clinical and Radiation Oncology, Ceske Budejovice—H. Siffnerova, J. Fischer, and I. Bustova; Centre of Breast Diseases, Prague—H. Kankova, and M. Pintova; Institute of Radiation Oncology, Prague—P. Vitek; University Hospital, Prague—J. Abrahamova, and D. Kordikova; University Hospital Prague—L. Petruzelka, E. Sedlackova, and H. Honova.
Onkologische Gemeinschaftspraxis, Augsburg—B. Heinrich; Zentralklinikum/Frauenklinik, Augsburg—A. Wischnik; Universitätsklinikum Essen, Essen—C. Oberhoff and A.E. Schindler; Universitäts-Frauenklinik d. JLU Giessen, Giessen—K. Münstedt; Onkologische Gemeinschaftspraxis, Göttingen—D. Meyer; Martin-Luther-Universität Halle-Wittenberg, Halle—R. Grosse and H. Kölbl; Universitätskliniken des Saarlandes, Homburg—W. Schmidt and 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 and W. Bader.
SZOTE Onkoterápiás Klinika, Szeged—Z. Kahan; BM Központi Kórház, Budapest—G. Pajkos and K. Kristo; SOTE Radiológiai és Onkoterápiás Klinika, Budapest—M. Dank; Uzsoki Utcai Kórház, Budapest—T. Nagykalnai and L. Landherr; Almási Balogh Pál Kórház, Ózd—E. Kner; Területi Kórház Onkologia, Szentes—M. Kispál; Szent Borbála Kórház, Megyei Onkológiai Gondozó, Tatabánya—Á. Dani.
Policlinico S. Orsola-Malpighi, Bologna—A. Martoni, C. Zamagni, S. Giaquinta, and E. Piana; Ospedale S. Croce, Fano—R. Mattioli and L. Imperatori; Istituto Clinica Humanitas, Milan/Rozzano—A. Santoro, C. Carnaghi, and L. Rimassa; Azienda Ospedaliera San Filippo Neri, Rome—G. Gasparini, G. Sciarretta, and A. Morabito; Az. Ospedaliera Treviglio-Caravaggio, Treviglio—S. Barni, M. Cazzaniga, and M. Cabiddu; Policlinico Universitario (PUDG), Udine—F. Puglisi; Ospedale di Torrette, Ancona—R. Cellerino, S. Antognoli, and F. Freddari; Universitiy of Cagliari, Policlinico Universitario, Cagliari—G. Mantovani, E. Massa, and G. Astara; Ospedale Civile Feltre, Feltre—R. Segati; Istituto Nazionali Ricerca Cancro, Genova—R. Rosso, L. Del Mastro, M. Venturini, and C. Bighin; Istituto Nazionale dei Tumori, Milan—E. Bajetta, N. Zilembo, D. Paleari, and G. Procopio; Azienda Ospedaliera di Parma, Parma—S. Salvagni, M.A. Perrone, and V. Franciosi; Azienda Ospedaliera “S. Salvatore,” Pesaro—G. Catalano and S. Luzi Fedeli; Azienda Ospedaliera “Ospedale di Circolo e Fondazione Macchi” Varese—G. Pinotti, G. Giardina and I. Vallini; Universitiy of Cagliari, Policlinico Universitario, Cagliari—B. Massidda, M.T. Ionta, and M.C. Deidda; Ospedale Maggiore, Lodi—G. Nalli and G. Sita; Policlinico Universitario, Palermo—I. Carreca, S. Cucciarré, and D. Burgio; Ospedale Civile dello Spirito Santo, Pescara—M. Lombardo, G. Pandoli, and P. Di Stefano; Azienda Ospedaliera Santa Maria Nuova, Reggio Emilia—C. Boni, G. Bisagni, M.C. Banzi, and P. Linarello; Azienda Ospedaliera Desenzano del Garda, Manerbio—G. Colosini, A. Spasiano, and A. Caldonazzo; Ospedale Civile ASL 20, Tortona—M.G. Pacquola.
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.T.J. Roerdink; Maxima Medisch Centrum, Veldhoven—R.H.M. Roumen.
Dunedin Hospital, Dunedin—B. McLaren, S. Costello, J. North, D. Perez, K. Bayston, and M. Pfieffer; Waikato Hospital, Hamilton—I. Kennedy, I.D. Campbell, L. Gilbert, R. Gannaway, M. Jameson, J. Long, G. Round, L. Spellman, D. Whittle, and D. Woolerton.
Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk—J. Jassem, M. Welnicka-Jaskiewicz, E. Senkus-Konefka, and K. Matuszewska; Rydygier's Memorial Hospital, Krakow-Nova Huta—P. Koralewski and J. Pernal; Klinika Nowotworów Piersi i, Chirurgii Rekonstrukcyjnej-Warszawa, Warszawa—T. Pienkowski, E. Brewczynska, B. Bauer-Kosinska, R. Sienkiewicz-Kozlowska, A. Jagiello-Gruszfeld, and K. Sudol.; Centrum Onkologii w Bydgoszczy, Oddzial Onkologii Klinicznej, Bydgoszcz—J. Tujakowski and B. Zurawski; Collegium Medicum Jagiellonian University, Krakow—J. Pawlega, E. Jablonska, and A. Zygulska; Oddzial Kliniczny Onkologiczny, Centralnego Szpitala Klinicznego Wojskowej, Akademii Medycznej-Warszawa, Warszawa—M. Górnasiowa; Dolnoslaskie Centrum Onkologii, Wroclaw—E. Filypczyk-Cisarz and K. Pajak.
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 v H. Amaral; Hospital Geral de Santo António, Porto—F. Marques.
Cancer Research Centre, Moscow—D.V. Komov and S.B. Polikarpova; Moscow Municipal Hospital No. 62, Moscow—A.N. Makhson and N.V. Zabaznyi; Moscow Research Institute of Diagnostics and Surgery, Moscow—E.K. Vozny, N.Y. Dobrovolskaya, S. Bolshakova, and O.V. Yurgina; N.M. Emmanuel Institute of Biochemical Physics, Moscow—D.B. Korman and I.A. Maslova; N.N. Petrov Research Institute of Oncology, St. Petersburg—V. Semiglazov and V. Ivanov; Saint-Petersburg City Oncological Dispensary, St. Petersburg—G. Manikhas and G. Dolmatov.
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.
Hospital Ruber Internacional, Madrid—J.E. Alés Martinez, P. Aramburo, and R. Sánchez; Hospital Son Dureta, Palma del Mallorca—J. Rifa and J. Martin; Centro Oncológico Integral de Madrid (CONIM), Madrid—R. Pérez-Carrión, J.L. González Larriba, and A. Cubillo; Hospital Universitario San Carlos, Madrid—M.M. Jiménez and A. Casado; Hospital Central de Asturias, Oviedo—J. Fra, J.M. Vieitez, E. Esteban, and A.J. Lacave.
Universitätsfrauenklinik, Basel—E. Wight, S. Bartens, R. Decio, and U. Güth; Klinik am Park, Zürich—U. Breitenstein.
Ankara University Ibni Sina Hospital, Ankara—F. Icli and D. Dincol; Hacettepe University Oncology Institute, Ankara—E. Baltali and Y. Ozisik; Istanbul University Oncology Institute, Istanbul—E. Topuz, M. Basaran, and A. Aydiner; Ege University Medical School, Izmir—E. Ozdedeli; 9 Eylul University Medical School, Izmir—O. Harmancioglu and A.U. Yilmaz.
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.
Hospital de Clinicas Dr. Manuel Quintela, Montevideo—G. Sabini.
|Condition||Age Cohort (years)|
|≤ 64||65-74||≥ 75|
|No. of patients||1,545||1,566||757||733||146||148|
|Body mass index, kg/m2|
|History of smoking, %||39.2||38.8||28.5||31.2||17.1||19.6|
|Disease history, %|
|Diabetes (requiring treatment other than diet)||3.5||3.7||7.3||8.6||10.3||10.8|
|Cerebrovascular accident or transient ischemic attack||1.4||1.1||2.4||2.0||4.8||4.1|
|Any cardiac events||6.5||5.9||12.5||14.3||23.3||19.6|
|Ischemic cardiac events||3.2||2.7||8.2||9.0||12.3||12.2|
|History of receiving medication for hypercholesterolemia, %||6.9||5.8||12.7||10.4||13.0||8.8|
|History of receiving bisphosphonates, %||0.1||0.3||0.5||0.1||0.7||0|
|Received prior chemotherapy, %||30.4||30.5||17.2||16.1||4.1||9.5|
published online ahead of print at www.jco.org on March 10, 2008.
Sponsored by Novartis, the Swedish Cancer Society, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research (SAKK), National Cancer Institute Grant No. CA-75362, Cancer Research Switzerland/Oncosuisse, and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK).
Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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