The advantage of letrozole over tamoxifen in the BIG 1-98 trial is consistent in younger postmenopausal women and in those with chemotherapy-induced menopause

Abstract

Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual subclinical ovarian estrogen production), and those with chemotherapy-induced menopause who may experience return of ovarian function. In these situations tamoxifen may be preferable to an aromatase inhibitor. Among 4,922 patients allocated to the monotherapy arms (5 years of letrozole or tamoxifen) in the BIG 1-98 trial we identified two relevant subpopulations: patients with potential residual ovarian function, defined as having natural menopause, treated without adjuvant or neoadjuvant chemotherapy and age ≤55 years (n = 641); and those with chemotherapy-induced menopause (n = 105). Neither of the subpopulations examined showed treatment effects differing from the trial population as a whole (interaction P values are 0.23 and 0.62, respectively). Indeed, both among the 641 patients aged ≤55 years with natural menopause and no chemotherapy (HR 0.77 [0.51, 1.16]) and among the 105 patients with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients.

Introduction

Aromatase inhibitors (AI) are recommended for the adjuvant treatment of postmenopausal endocrine-responsive early breast cancer [1] and are now widely used in this setting globally. Letrozole, a third generation AI, exerts its clinical effect by reversibly inhibiting the aromatase enzyme thereby profoundly reducing estrogen levels in postmenopausal women. This enzyme in the cytochrome P-450 super family and the product of the CYP19 gene occurs in a number of tissues including subcutaneous fat, liver, muscle, brain, normal breast tissue, and mammary adenocarcinoma [2]. The aromatase enzyme is responsible for blocking the final step in the conversion of the adrenal androgen substrate androstenedione to estrogen in the peripheral tissues, the predominant source of estrogen in postmenopausal women. In this setting letrozole reduces estrogen production by more than 90% [3].

However, in women whose ovaries are active, the temporary reduction in estradiol production caused by aromatase inhibition will increase gonadotrophin release and in turn stimulate follicular growth and further estrogen production, thus rendering letrozole and other AIs ineffective in this setting. Case reports suggest that this stimulatory effect on gonadotrophin production may induce ovarian activity and estrogen production in women with chemotherapy-induced amenorrhea or in those close to the menopausal transition [4, 5]. AIs have also been used therapeutically in premenopausal women to stimulate gonadotrophin production and ovulation for treatment of infertility [6, 7].

The results of the BIG 1-98 clinical trial indicate that among postmenopausal women with endocrine-responsive early breast cancer adjuvant letrozole is superior to tamoxifen both in terms of disease-free survival (DFS) and overall survival [8–11]. Patients eligible for BIG 1-98 met criteria for post-menopausal status, but were heterogeneous in that some of the patients had become postmenopausal as a result of chemotherapy and others had experienced a natural menopause at various periods prior to study entry.

We hypothesized that patients with chemotherapy-induced menopause and those with recent natural menopause without chemotherapy might derive reduced benefit from letrozole due to their potential for ovarian estrogen production. The current analysis therefore explores whether patients with chemotherapy-induced menopause and those with potential residual ovarian function, defined as aged less than or equal to 55 years with natural menopause who did not receive chemotherapy, derived lesser benefit from letrozole as compared to tamoxifen than was seen in the trial as a whole.

Methods

Breast International Group (BIG) study 1-98 is a Phase 3, double-blind randomized trial that evaluates the effect of the AI letrozole compared with tamoxifen. From March 1998 to May 2003, 8,010 postmenopausal women with hormone receptor-positive early breast cancer were randomized to one of the four following treatment arms: tamoxifen for 5 years, letrozole for 5 years, tamoxifen for 2 years followed by letrozole for 3 years, and letrozole for 2 years followed by tamoxifen for 3 years. Patients were enrolled in the two-arm randomization option of letrozole or tamoxifen from March 1998 to March 2000 and the four-arm option from April 1999 to May 2003. The current analysis focuses on the 4,922 patients who were randomized to the two monotherapy arms (two- and four-arm randomization options) at 76 months median follow-up [10, 11].

The trial protocol did not dictate whether or not to give chemotherapy (adjuvant or neoadjuvant). The protocol allowed adjuvant and/or neoadjuvant chemotherapy, given prior to study entry or concurrently with the assigned endocrine therapy. In most cases chemotherapy was completed prior to study entry. Patients were evaluated for menopausal status at study entry. To be eligible patients had to be postmenopausal, age 45 years or older, and to fit into one of the following categories: any age with bilateral oophorectomy; radiation ovarian ablation with ≥3 months amenorrhea; hysterectomized patients either over 55 years or if <55 years with postmenopausal follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol levels; for patients who did not receive HRT within 3 months of randomization, amenorrhea duration of >12 months for patients under 50 years or >6 months for those 50 years and over; for patients who received HRT within 3 months of randomization, HRT must have ceased for at least 1 month and if under 55 years must have had postmenopausal FSH, LH and estradiol levels. Patients who were not postmenopausal at the start of chemotherapy and completed ≥6 cycles cyclophosphamide, methotrexate and 5-fluorouracil (CMF) or ≥4 cycles doxorubicin and cyclophosphamide (AC) and age ≥45 and FSH, LH, and estradiol in postmenopausal range prior to randomization were eligible and defined as having had chemotherapy-induced menopause.

Two subpopulations of patients were analyzed: those with chemotherapy-induced menopause and those with potential residual ovarian function, defined as young (age ≤55 years) patients who had natural menopause without any chemotherapy. In the absence of data on date of last menses, the latter subpopulation was considered the most likely to have residual subclinical ovarian function.

The primary trial end point was DFS, defined as the time from randomization to the first of the following events: recurrence at local, regional, or distant sites; a new invasive cancer in the contralateral breast; any second (non-breast) malignancy; or death without a prior cancer event. Follow-up was censored at last disease assessment, or among patients randomized to receive 5 years of tamoxifen but who chose to crossover to letrozole (subsequent to the presentation of initial efficacy results favoring letrozole in 2005) was censored at the time of crossover [10]. Baseline characteristics were compared using two-sided Fisher’s exact tests and two sample t tests. Treatment groups were compared via a stratified log-rank test of DFS, with randomization option (two-arm or four-arm) as a stratification factor, and Kaplan–Meier plots were generated. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) stratified by randomization option; multivariable models were adjusted for age at randomization, local therapy received, tumor size, tumor grade, ER/PgR status (locally assessed), HER2 status (centrally assessed), nodal status, and presence of peritumoral vascular invasion. The interactions of treatment by subpopulation were tested by Cox proportional hazards models including treatment groups, an indicator of the subpopulation, and the interaction term.

For all patients who had natural menopause without chemotherapy, Subpopulation Treatment Effect Pattern Plot (STEPP) analysis [12] was used to investigate the pattern of difference in 5-year DFS between treatment arms according to patient age at randomization. Based on simulations, a P value for the interaction test of age and treatment was calculated.

Results

The BIG 1-98 trial included 4,922 postmenopausal patients with hormone-responsive early breast cancer who were randomized to the two monotherapy groups, 2,463 to letrozole and 2,459 to tamoxifen. Of them, 3,633 (73.8%) were classified as having natural menopause, treated without chemotherapy; 1,118 (22.7%) were classified as natural menopause treated with chemotherapy; and 105 (1.3%) were classified as chemotherapy-induced menopause (Table 1). Of the patients with natural menopause treated without chemotherapy, 641 were age ≤55 years at randomization.

Table 1.

Menopause categories among all 4922 patients randomized to monotherapy

	Letrozole (n = 2463)		Tamoxifen (n = 2459)		Total (n = 4922)
	N	%	N	%	N	%
Natural menopause treated without CT	1826	74.1	1807	73.5	3633	73.8
Age ≤55 years at randomization	320	13.0	321	13.1	641	13.0
Age >55 years at randomization	1506	61.1	1486	60.4	2992	60.8
Natural menopause treated with CT	558	22.7	560	22.8	1118	22.7
CT-induced menopause	51	2.1	54	2.2	105	2.1
Othersa	28	1.1	38	1.5	66	1.3

CT chemotherapy

^aIncludes those patients who were determined not postmenopausal at randomization by medical reviewer and those whose HRT stopped <4 weeks prior to start of trial treatment

Chemotherapy-induced menopause

Of the 105 patients with chemotherapy-induced menopause, one was considered to have regained ovarian function and unblinding was requested. Thirteen of the patients reported vaginal bleeding (6 letrozole and 7 tamoxifen). However, data on return of menses was not routinely collected, and ovarian function was not monitored biochemically. Overall, the treatment groups were well-balanced with no statistically significant differences for any of the baseline characteristics (Table 2). The mean age at randomization was 49 years in both treatment groups, ranging from 45 to 59 years. Seventeen (31.5%) of 54 patients randomized to the tamoxifen only arm crossed over to letrozole after at least 3 years of tamoxifen treatment. As would be expected among patients treated with chemotherapy, tumor characteristics were of higher risk than the overall population—with a statistically significant higher proportion of node positivity, grade 3 or >2 cm tumors.

Table 2.

Baseline patient and disease characteristics

	CT-induced menopause				Young (≤55 years) natural menopause not treated with prior CT
	Letrozole (n = 51)		Tamoxifen (n = 54)		Letrozole (n = 320)		Tamoxifen (n = 321)
	Mean	SD	Mean	SD	Mean	SD	Mean	SD
Age at randomization (years):	48.8	2.9	49.0	3.0	52.7	2.2	52.5	2.5
	N	%	N	%	N	%	N	%
Tumor size
≤2 cm	27	52.9	26	48.1	237	74.1	230	71.7
>2 cm	22	43.1	26	48.1	80	25.0	88	27.4
Unknown	2	3.9	2	3.7	3	0.9	3	0.9
Tumor grade
Grade 1	6	11.8	10	18.5	94	29.4	112	34.9
Grade 2	25	49.0	23	42.6	154	48.1	146	45.5
Grade 3	16	31.4	18	33.3	19	5.9	22	6.9
Unknown	4	7.8	3	5.6	53	16.6	41	12.8
Nodal status
Negative (including Nx)	16	31.4	19	35.2	233	72.8	212	66.0
Positive	35	68.6	35	64.8	83	25.9	107	33.3
Unknown	0	0	0	0	4	1.3	2	0.6
ER/PgR status (locally assessed)
Pos/pos	40	78.4	39	72.2	194	60.6	169	52.6
Pos/neg or Neg/pos	9	17.6	13	24.1	72	22.5	85	26.5
Neg/neg	0	0	0	0	0	0	1	0.3
ER or PgR unknown	2	3.9	2	3.7	54	16.9	66	20.6
HER2 status (centrally assessed)
Negative	27	52.9	34	63.0	236	73.8	239	74.5
Positive	4	7.8	3	5.6	22	6.9	18	5.6
Unknown	20	39.2	17	31.5	62	19.4	64	19.9
Peritumoral vascular invasion
No	25	49.0	38	70.4	247	77.2	252	78.5
Yes	21	41.2	13	24.1	42	13.1	37	11.5
Unable to assess	5	9.8	3	5.6	31	9.7	32	10.0
Local therapy received
Breast-conserving surgery with RT	26	51.0	28	51.9	195	60.9	175	54.5
Breast-conserving surgery without RT	0	0	1	1.9	8	2.5	8	2.5
Mastectomy with RT	17	33.3	15	27.8	39	12.2	60	18.7
Mastectomy without RT	8	15.7	10	18.5	78	24.4	78	24.3
Total	51	100.0	54	100.0	320	100.0	321	100.0

CT chemotherapy, ER estrogen receptor, PgR progesterone receptor, RT radiotherapy, HER2 human epidermal growth factor receptor 2

Kaplan–Meier plots of DFS in this subpopulation for letrozole and tamoxifen are shown in Fig. 1. The magnitude of the trend favoring letrozole (HR 0.51 [0.19, 1.39], univariate Cox model) was slightly stronger relative to the entire monotherapy population [10] (HR = 0.84 [0.74, 0.95], Fig. 2). The interaction of treatment effects and whether the patient had chemotherapy-induced menopause was not statistically significant (P = 0.23). A multivariate Cox model of DFS allowing for other prognostic factors favored patients who received letrozole (HR 0.21, [0.05, 0.94]) in this subpopulation.

Fig. 1.

Kaplan–Meier estimates of disease-free survival (DFS) according to treatment group for the 105 patients with chemotherapy-induced menopause at the time of entry into the BIG 1-98 trial

Fig. 2.

Univariate Cox model estimates of hazard ratios for disease-free survival (DFS; letrozole vs. tamoxifen) among all monotherapy patients [10], patients with chemotherapy-induced menopause, and patients with age ≤55 years old at randomization with natural menopause who received no chemotherapy. The box size is proportional to the inverse of the standard error of the hazard ratio estimates. The horizontal line gives the 95% confidence interval

Potential residual ovarian function (young patients who had natural menopause and no chemotherapy)

Among the patients who experienced natural menopause, 641 were age ≤55 and did not receive any chemotherapy. In this subpopulation, the treatment groups were balanced with no statistically significant differences for most of the baseline characteristics examined, except for nodal status: more patients treated with letrozole were node negative (72.8%) compared to the patients treated with tamoxifen (66.0%) (P = 0.05; Table 2). Of the 321 patients in this subpopulation who were randomized to tamoxifen, 83 (25.9%) crossed over to letrozole after at least 3 years of tamoxifen treatment. This subpopulation of younger patients who had natural menopause and did not receive chemotherapy had a lower risk profile than the overall BIG 1-98 population with statistically significantly less node positivity and fewer grade 3 and >2 cm tumors.

Kaplan–Meier plots of DFS for letrozole and tamoxifen are given in Fig. 3. As for chemotherapy-induced menopause patients, young natural menopause patients also appeared to derive greater benefit from letrozole than tamoxifen (HR 0.77 [0.51, 1.16], univariate Cox model), and the magnitude of the trend favoring letrozole was comparable to that in the entire monotherapy population (HR = 0.84, Fig. 2). The interaction of treatment effects and whether the patient was in this subgroup was not statistically significant (P = 0.62). A multivariate Cox model of DFS again favored patients who received letrozole (HR 0.79, [0.51, 1.22]) in this subpopulation.

Fig. 3.

Kaplan–Meier estimates of disease-free survival (DFS) according to treatment group for the 641 patients with potential residual ovarian function the BIG 1-98 trial, defined as ≤55 years old at randomization with natural menopause who received no chemotherapy

For all 3,633 patients who had natural menopause without chemotherapy, the STEPP analysis in Fig. 4 compares 5-year DFS percents for letrozole and tamoxifen arms in overlapping subpopulations defined by age at randomization. The analysis shows no evidence of heterogeneity in the treatment comparison across age (P = 0.67 for interaction).

Fig. 4.

Subpopulation Treatment Effect Pattern Plots (STEPP) of 5-year disease-free survival (DFS) percents for letrozole vs. tamoxifen for overlapping subpopulations defined according to age at randomization for all 3633 patients with natural menopause who received no chemotherapy. The x-axis is the median age for overlapping subpopulations, each including approximately 300 patients. The P values, based on simulations, test for the interaction of age and treatment group

Discussion

The analysis of two subgroups of BIG 1-98 presented here does not support the concern which motivated its conduct: that the benefit of letrozole over tamoxifen might be reduced or reversed following chemotherapy-induced menopause or in the early years following natural menopause without chemotherapy. Indeed in both the chemotherapy-induced menopause subpopulation (HR = 0.51) and in the young natural menopause group (HR = 0.77) the trend favoring letrozole over tamoxifen was numerically stronger than in the entire monotherapy population (HR = 0.84).

The patients in the chemotherapy-induced menopause subpopulation were selected to receive adjuvant chemotherapy and thus were, as would be expected, a higher risk population than the overall trial population. Higher risk patients in BIG 1-98 have been shown to benefit more from letrozole compared to tamoxifen than the lower risk patients [13]. It is therefore reassuring to note that this higher risk group did not lose benefit from letrozole by potential return of ovarian function.

Limitations of this analysis include the lack of specific collection of information on date of last menstrual period and the absence of definitive collection of incidence of return of ovarian function or of ovarian function monitoring. However, these results support the use of letrozole in patients meeting the menopausal status requirements for entry into BIG 1-98, including those experiencing chemotherapy-induced menopause and those with natural menopause who were ≤55 years at randomization.

Recovery of ovarian function following chemotherapy-induced menopause has been reported in between 9 and 43% [14–20] mainly among patients in their forties. Analysis of amenorrhea and return of menses in the IBCSG study VI population (in which patients received between 3 and 9 cycles of CMF) [20] indicated an incidence of amenorrhea of 18% in patients under 40, with a recovery rate of 43%, and an amenorrhea incidence of 74% and recovery rate of 9% in those 40 years and over, indicating a clear effect of age. Swain et al. [21] also reported results from 708 patients receiving 4 cycles of AC and 4 cycles of docetaxel in NSABP B30 indicating that for those who experienced chemotherapy-induced menopause (83%), recovery of menses by 24 months occurred in 45.3% aged under 40, 10.9% aged between 40 and 50 and in 3.2% of patients aged over 50.

Recovery of ovarian function can be delayed. The study of Abusief et al. [14], which included 431 patients treated with doxorubicin and cyclophosphamide with or without paclitaxel demonstrated a chemotherapy-induced menopause rate of 72%, with recovery of ovarian function between 6 and 12 months following completion of chemotherapy in 14% and after more than 12 months in a further 3%. In the study of 145 patients by Minisini et al. [18] the median time to recovery was 8 months with an overall recovery rate of 35.3%.

CMF appears to be the most gonadotoxic regimen and it appears likely that the amount of cyclophosphamide received is the main determining factor for chemotherapy-induced menopause. In a recent further report of the NSABP B-30 results [22], amenorrhea at 12 months was higher for cyclophosphamide containing regimens—69.8% for doxorubicin (D) and cyclophosphamide (C) followed by docetaxel (T), 57.7% for combination TAC and 37.9% for AT. Taxanes probably do not add to the rate of amenorrhea; in fact in the Minisini study [18], patients receiving taxane had a statistically significant increase in chance of recovery of ovarian function.

Notwithstanding the limitations of data collection, patients in BIG 1-98 may have a lower rate of recovery of ovarian function than reported in these studies, presumably due in part to their older age (median 49; range 45–59), than that in most of the studies cited. An additional factor may be the strict definition for postmenopausal status which included biochemical testing for those with chemotherapy-induced menopause and for patients with potential residual ovarian function under 55 years [8]. The chemotherapy received was perhaps also a factor. 27.6% of the 105 chemotherapy-induced menopause patients received CMF, 62.9% received anthracycline plus cyclophosphamide regimens and 9.5% patients received CMF in combination with anthracycline.

Taking into consideration the observed recovery of ovarian function following chemotherapy-induced menopause and the possible stimulatory effect on ovarian function of AIs, caution has been advised with the use of AIs in patient populations where recovery is more likely [4, 16, 23, 24], and guidelines have been suggested for monitoring ovarian function in patients starting AIs [25]. Clemons [24] suggests that biochemical monitoring is so unreliable that no patient with questionable ovarian function should receive an AI without some form of ovarian suppression for fear of missing optimal adjuvant benefit. However, the results presented here would suggest that this may be less of a concern clinically among patients meeting BIG 1-98 menopausal criteria. These results might not be generalizable to other patient groups in clinical practice. For example, this analysis of BIG 1-98 does not provide guidance for younger patients (under 45) with chemotherapy-induced menopause, as none were included in the population. Continued caution in AI use in these patients is required. For individual women, especially younger women with chemotherapy-induced menopause and selected patients close to the menopause transition, monitoring probably remains appropriate with serial blood tests for the first 12–24 months. Further research in this population also would seem warranted.

Recent review of outcomes for participants in the MA. 17 trial of extended adjuvant letrozole [26], who became postmenopausal following 5 years of adjuvant tamoxifen, has shown a very substantial benefit for extended adjuvant letrozole.

This finding and the results from the current analysis of BIG 1-98 indicate that women with recent cessation of ovarian function are candidates for treatment with AIs in most cases, and may potentially gain more than patients who are older and have a more established menopause. In conclusion, our results support the contention that among patients over 45 years who are either naturally postmenopausal or have become postmenopausal following chemotherapy, letrozole is likely to be effective. The incidence of recovery of ovarian function in this patient population is very low, though this possibility must always be considered to ensure appropriate endocrine adjuvant treatment for each individual patient.

Appendix

BIG 1-98 Collaborative Group Participants

Steering Committee: B. Thürlimann (Chair), S. Aebi, L. Blacher, H. Bonnefoi, A. S. Coates, T. Cufer, B. Ejlertsen, J. F. Forbes, R. D. Gelber, A. Giobbie-Hurder, A. Goldhirsch, A. Hiltbrunner, S. B. Holmberg, R. Maibach, A. Martoni, L. Mauriac, G. MacGrogan, H. T. Mouridsen, R. Paridaens, D. Phuong, K. N. Price, M. Rabaglio, B. B. Rasmussen, M. M. Regan, A. Santoro, I. E. Smith, A. Wardley, G. Viale. Novartis: H. A. Chaudri-Ross, S. Segal.

IBCSG Foundation Council (members from 1998 to 2010): S. Aebi, A. S. Coates, M. Colleoni, J. P. Collins, H. Cortés Funes, R. D. Gelber, A. Goldhirsch, M. Green, A. Hiltbrunner, S. B. Holmberg, P. Karlsson, I Kössler, I. Láng, J. Lindtner, F Paganetti, M. de Stoppani, C.-M. Rudenstam, H.-J. Senn, R. Stahel, B. Thürlimann, A. Veronesi.

Coordinating Center (Berne, Switzerland): M. Castiglione (Chief Executive Officer 1998–2007), A. Hiltbrunner (Director), M. Rabaglio, G. Egli, H. Hawle, 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 (Director), M. M. Regan (Group Statistician), K. N. Price (Director of Scientific Administration), A. Giobbie-Hurder (Trial Statistician), A. Keshaviah, H. Litman, Z. Sun, 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 (University of Glasgow, Glasgow, UK): B. A. Gusterson, E. Mallon; (European Institute of Oncology, Division of Pathology, Milano, Italy): G. Viale, P. Dell’Orto, M. Mastropasqua, B. Del Curto.

Study Support (Novartis Corp. Basel, Switzerland): E. Waldie, I. van Hoomissen, M. De Smet, U. Trostmann, W. Schmidt, A. Bolton, W. Hackl.

Breast International Group (BIG)

International Breast Cancer Study Group (IBCSG)

Australian New Zealand Breast Cancer Trials Group (ANZ BCTG): R. D. Snyder, J. Chirgwin, J. F. Forbes, A. S. Coates, F. Boyle, D. Lindsay, D. Preece, J. Cowell, D. Talbot, A. Whipp.

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; Calvary Mater Newcastle, 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 (June 2004 to June 2010), B. Thürlimann (from July 2010): 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, T. Ruhstaller, 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 Pare Léopold, Bruxelles: L. Marcelis; C. H. Etterbeek—Ixelles, Bruxelles: J. P. Kains; Service d’Oncologic Clinique Notre-Dame, Charleroi: J.-L. Canon; C. H. U. AndréVèsale, 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; Terúleti Kórház Onkologia, Szentes: M. Kispál; Szent Borbála Kórház, Megyei Onkolégiai 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.