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Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience
Annals of Oncology 15: 875–884, 2004 DOI: 10.1093/annonc/mdh222
Original article
Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience G. Berclaz1*, S. Li6, K. N. Price6, A. S. Coates7, M. Castiglione-Gertsch3, C.-M. Rudenstam10, S. B. Holmberg11, J. Lindtner12, D. Erien12, J. Collins8, R. Snyder9, B. Thürlimann4, M. F. Fey2, C. Mendiola13, I. Dudley Werner14, E. Simoncini15, D. Crivellari16, R. D. Gelber6 & A. Goldhirsch5,17 On behalf of the International Breast Cancer Study Group 1
Department of Obstetrics and Gynecology; 2Institute of Medical Oncology, Inselspital; 3IBCSG Coordinating Center, Bern; 4Kantonsspital, St Gallen; Oncology Institute of Southern Switzerland, Lugano, Switzerland; 6IBCSG Statistical Center, Dana-Farber Cancer Institute and Frontier Science and Technology Research Foundation, Boston, MA, USA; 7The Cancer Council Australia and University of Sydney, Sydney; 8Department of Surgery, The Royal Melbourne Hospital, Melbourne; 9Department of Oncology, St Vincent’s Hospital, Melbourne, Australia; 10West Swedish Breast Cancer Study Group, Sahlgrenska University Hospital, Göteborg; 11Department of Surgery, SU/Moelndal’s Hospital, Moelndal, Sweden; 12The Institute of Oncology, Ljubljana, Slovenia; 13Madrid Breast Cancer Group, Madrid, Spain; 14Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa; 15Oncologia Medica-Spedali Civili, Brescia; 16Centro di Riferimento Oncologico, Aviano; 17European Institute of Oncology, Milan, Italy 5
Received 8 October 2003; revised 3 February 2004; accepted 4 February 2004
Background: Current information on the prognostic importance of body mass index (BMI) for patients with early breast cancer is based on a variety of equivocal reports. Few have data on BMI in relationship to systemic treatment. Patients and methods: Patients (6792) were randomized to International Breast Cancer Study Group trials from 1978 to 1993, studying chemotherapy and endocrine therapy. BMI was evaluated with eight other factors: menopausal status, nodal status, estrogen receptor status, progesterone receptor status, tumor size, vessel invasion, tumor grade and treatment. BMI was categorized as normal (≤24.9), intermediate (25.0–29.9) or obese (≥30.0). Results: Patients with normal BMI had significantly longer overall survival (OS) and disease-free survival (DFS) than patients with intermediate or obese BMI in pairwise comparisons adjusted for other factors. Subset analyses showed the same effect in pre- and perimenopausal patients and in those receiving chemotherapy alone. When assessed globally and adjusted for other factors, BMI significantly influenced OS (P = 0.03) but not DFS (P = 0.12). Conclusions: BMI is an independent prognostic factor for OS in patients with breast cancer, especially among pre-/perimenopausal patients treated with chemotherapy without endocrine therapy. Key words: body mass index, breast cancer, obesity, prognostic factor, survival
Introduction Previous studies have noted a modest negative association between obesity and survival of breast cancer [1, 2]. However, the methodologies used differed widely [3]. In most of the reports, the effect on prognosis did not persist after adjustment for other factors [4]. Studies reporting the effect of body mass index (BMI) allowing for other prognostic factors such as nodal involvement [5] or menopausal status [6] are also inconsistent, and few studies included patients receiving systemic adjuvant therapy [3]. Given these equivocal results, the importance of BMI as a prognostic factor for breast cancer remained uncertain. To examine the impact of BMI on the prognosis of patients with breast cancer and on outcome with different adjuvant treatments, *Correspondence to: Dr. G. Berclaz, Department of Obstetrics and Gynecology, Inselspital, Effingerstrasse 102, CH-I3010 Bern, Switzerland. Fax: +41-31-632-1652; E-mail: [email protected] © 2004 European Society for Medical Oncology
we analyzed data from 6792 eligible breast cancer patients randomized in trials I–VII of the International (formerly Ludwig) Breast Cancer Study Group (IBCSG).
Patients and methods Patient selection From 1978 to 1993, the IBCSG conducted three generations of trials (I–IV, V and VI–VII) that studied chemotherapy and endocrine therapy. The seven trials accrued 6792 eligible patients who were randomized to receive one of the treatments listed in Table 1. All trials have been reported previously [7–15]. This report includes a cohort of 6370 patients (94%; Table 1) for whom height and weight were recorded in the database. The median follow-up was ∼14 years. BMI [weight (kg)/height (m)2] categories were selected according to the World Health Organization definition: underweight, <18.5 kg/m2; normal range between 18.5 and 24.9 kg/m2; grade 1 overweight between 25 and 29.9 kg/m2; grade 2 overweight between 30.0 and 39.9 kg/m2; and grade 3 overweight
876 Table 1. International Breast Cancer Study Group trials I–VIIa and treatment groups Trial
Patient population
Years of patient accrual
I
Premenopausal
1978–1981
Eligible patients 491
Patients with known BMI 380
Premenopausal
IV
Postmenopausal
CMF ×12b
20
CMFp ×12 1978–1981
327
235
CMFp ×12b
20
Ox + (CMFp ×12)
4+ N+ III
Median years follow-up
b
1–3 N+ II
Treatment group
1978–1981
463
341
Observation
20
Age ≤65 years
(i.c.p. + T) ×12
N+
(CMFp + T) ×12c
Postmenopausal
1978–1981
320
233
c
c
Observation
20
(P + T) ×12c
Age 66–80 years N+ V
Pre-/postmenopausal
1981–1985
1275
1272
N– V
Pre-/perimenopausal
Observation PeCMF
1981–1985
715
715
16
b
PeCMFb
16
PeCMF + (CMFp ×6)
N+
b
CMFp ×6b V
Postmenopausal
1981–1985
514
514
PeCMFb
16
PeCMF + (CMFpT ×6)c
N+
CMFpT ×6c VI
Premenopausal
1986–1993
1475
1472
CMF ×6b CMF ×6 + reint
N+
10 b
CMF ×3b CMF ×3 + reintb VII
Postmenopausal
1986–1993
1212
1208
N+
T alonec T + delayed CMF
10 c
T + (CMF ×3)c T + (CMF ×3) + delayed CMFc Total
6792
6370
BMI, body mass index; C, cyclophosphamide 100 mg/m 2 p.o. days 1–14 of each cycle; i.c.p., prednisone 7.5 mg/day p.o.; M, methotrexate 40 mg/m2 i.v. days 1 and 8 of each cycle; T, tamoxifen 20 mg p.o. once daily given for 1 year in trials III and IV, 6 months in trial V, 5 years in trial VII; F, 5-fluorouracil 600 mg/m2 i.v. days 1 and 8 of each cycle; PeCMF, perioperative CMF; reint, reintroduction of three cycles of CMF; delayed CMF, three cycles of CMF given at months 9, 12 and 15 after randomization; N+, node positive; N–, node negative; p.o., by mouth; i.v., intravenously. a The earliest version of the clinical form for trials I–IV did not ask for height. b Chemotherapy without hormone therapy. c Hormone therapy with or without chemotherapy.
>40.0 kg/m2 [16]. Since the proportions of patients in the underweight group and in the grade 3 overweight group were small (2% in each), we combined the grade 2 overweight group with the grade 3 overweight group and combined the underweight group with the normal weight group, resulting in three BMI categories: normal (≤24.9), intermediate (25.0–29.9) and obese (≥30.0). We examined the relative risk of relapse and death with regard to the BMI categories adjusting for eight factors known to be predictors of disease-free survival (DFS) and overall survival (OS): menopausal status, nodal status, tumor size, vessel invasion, estrogen receptor (ER) status, progesterone receptor status, tumor grade and treatment regimens (Table 2). In this analysis, we did not adjust for age because there was a significant correlation between age and BMI (r = 0.35, P <0.01), indicating an increasing BMI with increasing age.
Pairwise analyses are reported with respect to the two comparisons: intermediate versus normal BMI category and obese versus normal BMI category. We combined the randomized treatment arms into three general treatment groups: observation (no adjuvant therapy), endocrine therapy (tamoxifen for 6 months to 5 years or surgical oophorectomy) with or without chemotherapy, and chemotherapy without endocrine therapy. Chemotherapy dosage was analyzed in patients in trials V, VI and VII, with actual surface area (ASA) and ideal surface area (ISA) recorded (ISA was not collected for trials I–IV). Among the 4755 patients who received chemotherapy and had ISA recorded, 1463 had a dosage based on ISA. Ninety-three per cent of patients were found to have a difference of 0.1–0.3 m2 between ISA and ASA. For patients with obese BMI, there was an average reduction of 12%
877 Table 2. Distribution of BMI according to patient characteristics [all values except P-values are represented as n (%), unless stated otherwise] Factor
Normal
Intermediate
Obese
Total patients
3308 (52)
2038 (32)
1024 (16)
Menopausal status
P-valuea
Total 6370 (100)
<0.01
Pre/peri
2111 (64)
960 (47)
423 (41)
3494 (55)
Post
1197 (36)
1078 (53)
601 (59)
2876 (45)
Negative
695 (21)
386 (19)
191 (19)
Positive
2613 (79)
1652 (81)
833 (81)
Nodal status
0.09
Tumor size
1272 (20) 5098 (80) <0.01
≤2 cm
1533 (46)
847 (42)
363 (35)
2743 (43)
>2 cm
1627 (49)
1131 (56)
636 (62)
3394 (53)
148 ( 5)
60 ( 3)
25 ( 3)
Unknown Vessel invasion
233 ( 4) 0.08
No
1350 (41)
857 (42)
454 (44)
2661 (42)
Yes
1532 (46)
913 (45)
435 (43)
2880 (45)
426 (13)
268 (13)
135 (13)
Unknown ER status
829 (13) 0.07
Negative
958 (29)
561 (28)
279 (27)
1798 (28)
Positive
1836 (56)
1185 (58)
634 (62)
3655 (57)
514 (16)
292 (14)
111 (11)
Unknown PgR status
917 (15) 0.77
Negative
1115 (33)
700 (34)
328 (34)
2143
Positive
1576 (47)
970 (47)
484 (50)
3030
666 (20)
380 (19)
151(16)
Unknown Tumor grade
1197 0.74
1
454 (14)
298 (15)
133 (13)
885 (14)
2
1449 (44)
896 (44)
443 (43)
2788 (44)
3
1154 (35)
715 (35)
375 (37)
2244 (35)
251 ( 8)
129 ( 6)
73 ( 7)
453 ( 7)
336 (10)
211 (10)
102 (10)
649 (10)
841 (25)
761 (37)
417 (41)
2019 (32)
2131 (64)
1066 (52)
505 (49)
Unknown Treatment group Observation Hormone ± chemo Chemo alone Age [median (range)]
<0.01
48 (21–84)
53 (25–80)
55 (26–80)
3702 (58) b
<0.01
BMI, body mass index; ER, estrogen receptor; PgR, progesterone receptor. Does not include unknown, obtained by Fisher’s exact test. b Kruskal–Wallis test. a
between ASA and ISA. In this group, 96% used ISA to calculate dose, while 47% used ISA in the intermediate BMI group, and only 2% in the normal group.
Statistical analysis DFS was defined as the time interval from randomization to relapse, the appearance of a second tumor or death from any cause, whichever occurred first. OS was defined as time from randomization to death from any cause. An additional DFS analysis censored patients (at the time of death) who died of a
non-breast-cancer event. Survival percentages and standard errors were estimated by the Kaplan–Meier method and Greenwood’s formula [17, 18]. In order to determine whether BMI was an independent prognostic factor, we compared two Cox regression models [19]. The first model had all eight factors plus BMI as a full model, and the second had all of the factors except BMI as a reduced model. The effect of BMI on outcome was assessed globally (all three categories) by comparing the two Cox models using log-likelihood tests. Pairwise hazard ratios and confidence intervals (CIs) were then calculated, and the Wald statistic was used for significance tests. P-values ≤0.05
878
Figure 1. Disease-free (A) and overall (B) survival according to body mass index (BMI) group for the 6370 patients from International Breast Cancer Study Group trials I–VII. Pairwise P-values are adjusted for eight prognostic factors.
were considered statistically significant. All tests of statistical significance were two-sided.
Results Table 2 shows the distribution of BMI groups overall and within each level of the eight factors and age, and the respective P-values. Menopausal status, tumor size group, treatment group and age were significantly associated with BMI (P <0.01). When BMI group was assessed as a global univariate prognostic factor, it
significantly influenced both DFS (P <0.01) and OS (P <0.01), with higher BMI associated with shorter DFS and OS compared with lower BMI (Figure 1). After controlling for other factors, BMI as a global independent indicator significantly influenced OS (P = 0.03), but not DFS (P = 0.12). Patients in the obese group tended to die from non-breast-cancer causes (9.5%) more than the normal (6.4%) or intermediate (5.8%) groups (P = 0.02). The additional survival analysis censoring patients who died of a nonbreast-cancer event produced results similar to those for DFS (univariate P <0.01; adjusted P = 0.13). When pairwise BMI categories were compared (obese/normal and intermediate/normal) in univariate analyses, as shown in Table 3, patients in the intermediate BMI category had an 8% higher risk of relapse than patients with normal BMI (P = 0.04) and a 13% higher risk of death (P <0.01). The risk of relapse for patients in the obese BMI category was 17% higher than patients with normal BMI (P <0.01), and the risk of death was 25% higher (P <0.01). After adjusting for the eight other factors, there was no longer a significant difference between normal and intermediate BMI, but there was still a significant difference between normal and obese BMI. Heavier women tended to have shorter DFS and OS with a risk of relapse 10% higher than that for patients in the normal group (P = 0.04), and a risk of death that was 14% higher (P <0.01) (Table 3). Pairwise comparisons (obese versus normal and intermediate versus normal) were used to assess the prognostic significance of BMI within subgroups defined by ER status, menopausal status, nodal status, tumor size and treatment group (Table 3). Within menopausal status subgroups, we found that patients with obese BMI tended to fare significantly worse than normal only within the pre-/perimenopausal group (Table 3; Figure 2A). It should be noted that 90% of the patients in this group received chemotherapy without hormonal therapy (Table 3). No adverse effect of obesity was observed in the postmenopausal group for either pairwise comparison (Figure 2B). In patients with node-positive disease, those in the obese BMI group had a 14% increase in the risk of recurrence and a 21% increase in the risk of death (P <0.01) compared with the normal group. After adjusting for other factors, there remained an OS advantage for the normal BMI group compared with the obese BMI group (Table 3). Although significant differences were observed between the normal and obese BMI groups in univariate analyses of patients with node-negative disease, after adjusting for the other seven factors, the differences were no longer significant. The prognostic impact of BMI group was assessed within the three general treatment categories: observation, endocrine therapy with or without chemotherapy, and chemotherapy alone. Because of the trial designs for different patient groups, these treatment groups were highly correlated with menopausal status and age, with 85% of the patients in the chemotherapy alone group being pre-/perimenopausal, and the median ages within the treatment groups being 57, 60 and 46 years, respectively. Ten per cent (649) of all patients were randomized to an observation arm, 2019 (32%) patients to an endocrine therapy with or without chemotherapy arm, and 3702 (58%) to a chemotherapy alone arm.
879 Table 3. Pairwise comparisons of body mass index for DFS and OS n
DFS
OS
10-year DFS (% ± SE)
Hazards ratioa
95% CI
P-value
10-year OS (% ± SE)
Hazards ratioa
95% CI
P-value
1024
42 ± 2
1.17b
1.07–1.28
<0.01
55 ± 2
1.25b
1.13–1.38
<0.01
Intermediate
2038
44 ± 1
b
0.04
57 ± 1
b
1.13
1.04–1.22
<0.01
Normal
3308
45 ± 1
1024
42 ± 2
1.10c
Intermediate
2038
44 ± 1
c
Normal
3308
45 ± 1
279
41 ± 3
1.13c
0.95–1.35
0.18
Intermediate
561
45 ± 2
c
0.84–1.10
0.58
Normal
958
44 ± 2
634
41 ± 2
1.10c
0.97–1.24
0.13
Intermediate
1185
44 ± 1
c
0.97–1.18
0.17
Normal
1836
45 ± 1
423
41 ± 2
1.16c c
All patients Obese
1.08
1.00–1.16
61 ± 1
All patients Obese
1.04
1.10–1.20 0.97–1.12
0.04
55 ± 2
1.14c
1.03–1.27
<0.01
0.28
57 ± 1
c
1.07
0.98–1.16
0.12
49 ± 3
1.17c
0.97–1.42
0.11
56 ± 2
0.96c
0.83–1.12
0.63
57 ± 2
1.12c
0.97–1.28
0.12
59 ± 2
1.08c
0.97–1.21
0.18
61 ± 1
ER status ER-negative Obese
0.96
56 ± 2
ER-positive Obese
1.07
63 ± 1
Menopausal status Pre/peri Obese
1.02–1.33
0.03
56 ± 3
1.22c
1.05–1.42
0.01
0.28
61 ± 2
c
0.97–1.24
0.09
960
47 ± 2
2111
47 ± 1
601
42 ± 2
1.06c
Intermediate
1078
41 ± 2
c
Normal
1197
43 ± 1
833
37 ± 2
1.10c
0.99–1.21
0.06
Intermediate
1652
39 ± 1
c
0.97–1.14
0.21
Normal
2613
41 ± 1
191
60 ± 4
1.10c
0.88–1.39
0.40
Intermediate
386
61 ± 3
c
0.83–1.20
0.99
Normal
695
60 ± 2
363
50 ± 3
1.14c c
Intermediate Normal
1.06
0.96–1.17
1.11
63 ± 1
Post Obese
1.04
0.94–1.20 0.94–1.16
0.35
55 ± 2
1.10c
0.96–1.26
0.17
0.42
54 ± 2
c
1.06
0.94–1.19
0.35
51 ± 2
1.14c
1.03–1.28
0.02
52 ± 1
1.08c
0.99–1.18
0.10
73 ± 3
1.16c
0.89–1.53
0.28
77 ± 2
1.03c
0.82–1.28
0.83
57 ± 1
Nodal status Positive Obese
1.05
56 ± 1
Negative Obese
1.00
76 ± 2
Tumor size ≤2 cm Obese
847
52 ± 2
1533
54 ± 1
636
36 ± 2
1.09c
Intermediate
1131
38 ± 1
c
Normal
1627
37 ± 1
Intermediate Normal
1.05
0.97–1.34 0.93–1.18
0.10
59 ± 3
1.22c
1.02–1.47
0.03
0.43
62 ± 2
c
1.08
0.94–1.23
0.30
66 ± 1
>2 cm Obese
1.02
0.97–1.22 0.93–1.12
0.15
46 ± 2
1.12c
0.98–1.27
0.09
0.64
47 ± 2
c
0.94–1.16
0.41
47 ± 1
1.05
880 Table 3. (Continued) n
DFS
OS
10-year DFS (% ± SE)
Hazards ratioa
95% CI
P-value
10-year OS (% ± SE)
Hazards ratioa
95% CI
102
53 ± 5
0.90c
0.68–1.20
Intermediate
211
41 ± 3
c
0.85–1.32
Normal
336
45 ± 3
417
42 ± 3
1.04c
0.89–1.21
0.63
Intermediate
761
40 ± 2
c
0.91–1.16
0.66
Normal
841
39 ± 2
505
39 ± 2
1.23c
1.08–1.39
<0.01
Intermediate
1066
46 ± 2
c
0.97–1.18
0.21
Normal
2131
48 ± 1
P-value
0.48
64 ± 5
0.93c
0.68–1.29
0.68
0.61
58 ± 3
1.05c
0.82–1.35
0.68
52 ± 3
1.10c
0.93–1.29
0.27
51 ± 2
1.05c
0.92–1.20
0.49
55 ± 2
1.24c
1.08–1.43
<0.01
61 ± 2
1.10c
0.98–1.23
0.10
Treatment Observation Obese
1.06
61 ± 3
Hormone ± chemotherapy Obese
1.03
52 ± 2
Chemotherapy alone Obese
1.07
64 ± 1
DFS, disease-free survival; OS, overall survival; CI, confidence interval; SE, standard error; ER, estrogen receptor. a Hazards ratio is for severe/normal or intermediate/normal; bunadjusted for other factors; cadjusted for the other seven factors.
Chemotherapy alone was the only treatment group in which BMI was a significant independent prognostic factor (P <0.01), with obese patients tending to have a shorter DFS and OS (Table 3). Only 5% of patients received hormone treatment alone, so this group was not included separately. In this small subset there were no differences in the adjusted or unadjusted outcome according to BMI group. An analysis of site of first failure revealed that patients with intermediate and obese BMI had a significantly (P <0.0001) higher percentage of distant recurrences compared with the normal group (30% normal, 35% intermediate and 36% obese).
Discussion Our results support the hypothesis that BMI is an independent prognostic factor in patients with breast cancer. BMI as a global independent factor does not have a significant impact on DFS, but does have a significant impact on OS, with heavier patients showing worse survival. This finding may be associated with a slightly higher incidence of death before breast cancer recurrence in the obese group (5%) compared with the other two groups (3%). The higher incidence of tumors >2 cm in diameter and the lower percentage of patients exposed to chemotherapy in the obese group are other possible reasons. When the heaviest group is compared with the normal group, BMI has a significant influence on prognosis, even when adjusted for other factors. These findings are in accordance with earlier studies that have shown a poorer OS with increasing weight [1] or BMI [2]. Poorer DFS percentages were also observed in some studies [20]. Other studies did not find an influence of obesity on OS or DFS [21].
One study reported an inverse relationship between low BMI and the risk of breast cancer recurrence [22]. Our study is limited to data already collected, i.e. height and weight. Other assessments such as underwater weighing, skinfold thickness and fat patterning were not available. One of the strongest correlations found between BMI and tumor characteristics was tumor size: 62% of patients with obese BMI had tumors of ≥2 cm diameter compared with 49% of patients with normal BMI. This is in accordance with previous studies [20, 23, 24]. Numerous hypotheses have been put forward to explain these findings. Obese patients tend to have large breasts, which may make palpation of a tumor difficult and therefore delay diagnosis. Alternatively, it has been suggested that obese patients may delay seeking treatment [25]. Other authors [5] consider that the influence of obesity on breast cancer prognosis is unlikely to be an artifact of delayed diagnosis. Our finding that obesity is still a significant predictor of mortality even after adjustment for tumor size supports the conclusions of these latter authors. Another suggested reason for the association between larger tumors and larger BMI is enhancement of tumor growth by endogenous factors. Daling [23] found a higher Ki-67 expression ratio and a higher mitotic count, indicating a possibly more rapid growth rate, in large tumors from patients with higher BMI. However, no correlation could be found in our data between obesity and tumor grading. Like several authors, we found a strong correlation between obesity and lymph node involvement [5]. These observations suggest that obesity may potentiate the metastatic spread of breast tumors. Distant metastases were also found more often in obese patients in bone or visceral sites.
881 in patients <45 years of age at diagnosis. A possible explanation for these results is the promotion of tumor growth by locally increased estrogen levels in the surrounding adipose tissue [28]. Another explanation is that a subset of tumors in young obese patients possesses a higher number of ERs, which might sensitize them to the relative lower estrogen levels observed in obese pre-/perimenopausal patients; this subset of tumors is associated with poorer prognosis [29]. The strong correlation found between high levels of ER and obese BMI supports this hypothesis. Another explanation for this observation is that many pre-/perimenopausal patients will experience permanent chemotherapyinduced amenorrhea. These patients will then be under the influence of the higher estradiol levels of obesity after the induced menopause. They in particular might benefit from an anti-estrogen treatment; however, tamoxifen was not used in 90% of patients in the pre-/perimenopausal group in these trials. The observation that obese patients in the group with endocrine treatment did not have a significantly worse prognosis than lean patients supports this hypothesis. A recent study [30] reported that tamoxifen metabolites were significantly decreased in obese patients and that the same dose of tamoxifen might not be accurate for all women. This ‘underdosage’ might explain the slight difference of prognosis in favor of lean patients in the hormone treatment group. Finally, obesity may have a negative prognostic impact through different signaling pathways, as suggested by its unfavorable influence on ER-negative tumors. In our study, obese patients with aggressive tumors had a higher risk of recurrence and death despite the use of an adjuvant systemic therapy. One of the possible reasons could be that doses calculated on the basis of ideal weight might be inadequate. Lower dose delivery has been linked to inferior outcomes. In contrast, a study with 735 patients using actual body weight to calculate doses of cytotoxic drugs in obese patients [24] also reported a poor prognosis. In conclusion, this retrospective investigation of IBCSG trials I–VII demonstrates that BMI is an independent prognostic factor for OS in patients with breast cancer. We have supporting evidence that obese BMI represents a poor risk feature for outcome, especially in pre-/perimenopausal patients, most of whom received chemotherapy without hormonal therapy. Figure 2. Disease-free survival for the 3494 pre- and perimenopausal patients (A) and the 2876 postmenopausal patients (B) according to body mass index (BMI) group. Pairwise P-values are adjusted for the seven other prognostic factors (i.e. other than menopausal status).
In obese postmenopausal women, aromatization of androstenedione in the adipose tissue is the major source of estrogen production and this may result in enhanced tumor growth. Furthermore, obese and postmenopausal patients show decreased levels of sex hormone-binding globulin, thus increasing free estradiol available to target tissues. In premenopausal women, the opposite situation is found, with total estradiol decreasing as BMI increases [26]. In our study, poorer prognosis with elevated BMI was found only within the pre-/perimenopausal patients. Two studies [23, 27] found a relationship between increasing BMI and lower survival
Acknowledgements We thank the patients, physicians, nurses and data managers who participated in the IBCSG trials. Furthermore, we acknowledge the initial support provided by the Ludwig Institute for Cancer Research and the Cancer League of Ticino, and the continuing support for central coordination, data management and statistics provided by the Swedish Cancer Society, the Cancer Council Australia, the Australian New Zealand Breast Cancer Trials Group, the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, the Swiss Cancer League and the United States National Cancer Institute (CA-75362). We also acknowledge support for the Cape Town participants and the St Gallen participants from the Cancer Association of South Africa and the Foundation for Clinical Cancer
882 Research of Eastern Switzerland, respectively. The IBCSG trials I–VII participants and authors are listed in Appendix A.
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883 Appendix A. International Breast Cancer Study Group G trials I–VII: participants and authors Scientific Committee
A. Goldhirsch, A. S. Coates (Co-chairs)
Foundation Council
J. Collins (President), B. Thürlimann (Vice-president), H.-J. Senn (Treasurer), S. B. Holmberg, J. Lindtner, A. Veronesi, H. Cortés-Funes
Coordinating Center (Bern, Switzerland)
M. Castiglione (CEO), M. L. Nasi, A. Hiltbrunner, G. Egli, C. Jenatsch, A. Saurer
Statistical Center, Harvard School of Public Health and Dana-Farber Cancer Institute (Boston, MA)
R. Gelber (Group Statistician), K. Price, H. Peterson, M. Zelen, S. Gelber, A. O’Neill
Data Management Center, Frontier Science and Technical Research Foundation (Amherst, NY)
M. Isley, R. Hinkle, L. Blacher
Pathology Office, Institute of Cancer Research, Royal Cancer Hospital (Sutton, UK)
B. Davis, R. Bettelheim, W. Hartmann, A. M. Neville
Centro di Riferimento Oncologico (Aviano, Italy)
D. Crivellari, S. Monfardini, E. Galligioni, A. Veronesi, A. Buonadonna, S. Massarut, C. Rossi, E. Candiani, A. Carbone, R. Volpe, M. Roncadin, M. Arcicasa, G. F. Santini, F. Villalta, F. Coran, S. Morassut
Spedali Civili e Fondazione Beretta (Brescia, Italy)
G. Marini, E. Simoncini, P. Marpicati, A. Barni, P. Grigolato, L. Morassi, U. Sartori, D.DiLorenzo, A. Albertini, G. Marinone, M. Zorzi, M. Braga, L. Lucini
Groote Schuur Hospital and University of Cape Town (Republic of South Africa)
D. M. Dent, A. Gudgeon, E. Murray, I. D. Werner, P. Steynor, A. Hacking, J. Terblanche, A. Tiltman, E. Dowdle, R. Sealy, P. Palmer, P. Helman, E. McEvoy, J. Toop
University of Essen, West German Tumor Center (Essen, Germany)
C. G. Schmidt, K. Höffken, F. Schüning, L. D. Lender, H. Ludwig, R. Callies
University of Düsseldorf (Germany)
A. E. Schindler, P. Faber, H. G. Schnürch, H. Bender, H. Bojar
West Swedish Breast Cancer Study Group (Göteborg, Sweden)
C.-M. Rudenstam, A. Wallgren, S. Ottosson-Lönn, R. Hultborn, G. Colldahl-Jäderström, E. Cahlin, J. Mattsson , S. Jansson, L. Ivarsson, O. Ruusvik, L. G. Niklasson, S. Dahlin, G. Karlsson, B. Lindberg, A. Sundbäck, S. Bergegårdh, H. Salander, C. Andersson, M. Heideman, Y. Hessman, O. Nelzén, G. Claes, T. Ramhult, J. H. Svensson, P. Liedberg, J. Säve-Söderbergh, S. Nilsson, J. Fornander, Ch. Johnsen, L. Mattson, C. G. Backstrom, G. Bergegardh, G. Ekelond, G. Wallin, O. Thoren, L. Lundell, U. Ljungqvist, L.-O. Hafström, S. B. Holmberg, S. Persson
General Hospital (Gorizia, Italy)
S. Foladore, G. Pamich, C. B. Marino, A. Murgia, V. Milan
The Institute of Oncology (Ljubljana, Slovenia)
J. Lindtner, D. Erzen, E. Majdic, B. Stabuc, R. Golouh, J. Lamovec, J. Jancar, I. Vrhovec, M. Kramberger, J. Novak, M. Naglas, M. Sencar, J. Cervek, S. Sebek, O. Cerar, T. Cufer
The Royal Free Hospital (London, UK)
S. Parbhoo, E. Boessen, B. Stoll, F. Sennanayake, K. Griffiths
Madrid Breast Cancer Group (Madrid, Spain)
H. Cortés-Funes, D. Mendiola, C. Gravalos, Colomer, M. Mendez, F. Cruz Vigo, P. Miranda, A. Sierra, F. Martinez-Tello, A. Garzon, S. Alonso, A. Ferrero, C. Vargas, M. L. Larroder, F. Calero, A. Suarez, F. Pastrana, S. Chruchaga, C. Guzman, B Rodriguez, F. Cruz Caro, M. L. Marcos, M. A. Figueras, R. Huertas
Australian New Zealand Breast Cancer Trials Group (ANZ BCTG) Operations Office, University of Newcastle
J. F. Forbes, A. Wilson, D. Lindsay
Statistical Center, NHMRC CTC, University of Sydney (Sydney Australia)
R. J. Simes, E. Beller, C. Stone, V. Gebski
The Cancer Council Victoria (formerly Anti-Cancer Council of Victoria; Melbourne, Australia)
J. Collins, P. Gregory, P. Kitchen, S. Hart, S. Neil, M. Henderson, I. Russell, T. Gale, R. Snyder, R. McLennan, M. Schwarz, W. I. Burns, M. Green, R. Drummond, A. Rodger, J. McKendrick, R. Bennett, J. Funder, L. Harrison, V. Humenuik, P. Jeal, R. Reed, L. Sisely, R. Millar, J. Griffiths, J. Zalcberg, P. Briggs, A. Zimet, P. Brodie, P. Ellims
Flinders Medical Centre (Bedford Park, South Australia)
S. Birrell, M. Eaton, C. Hoffmann, B. Koczwara, C. Karapetis, T. Malden, W. McLeay, R. Seshadri
Newcastle Mater Misericordiae Hospital Waratah (Newcastle, Australia) and Gold Coast Hospital (Queensland, Australia)
J. F. Forbes, J. Stewart, D. Jackson, R. Gourlay, J. Bishop, S. Cox, S. Ackland, A. Bonaventura, C. Hamilton, J. Denham, P. O’Brien, M. Back, S. Brae, A. Price, Muragasu, H. Foster, D. Clarke, R. Sillar, I. MacDonald, R. Hitchins
Royal Adelaide Hospital (Adelaide, Australia)
I. N. Olver, A. Robertson, P. G. Gill, M. L. Carter, P. Malycha, E. Yeoh, G. Ward, A. S. Y. Leong, J. Lommax-Smith, D. Horsfall, R. D’Angelo, E. Abdi
Royal Perth Hospital (Perth, Australia)
E. Bayliss
Sir Charles Gairdner Hospital (Nedlands, Western Australia)
M. Byrne, G. van Hazel, J. Dewar, M. Buck, D. Ingram, G. Sterrett, P. M. Reynolds, H. J. Sheiner, K. B. Shilkin, R. Hahnel, S. Levitt, D. Kermode, H. Hahnel
University of Sydney, Dubbo Base Hospital and Royal Prince Alfred Hospital (Sydney, Australia)
M. H. N. Tattersall, A. Coates, F. Niesche, R. West, S. Renwick, J. Donovan, P. Duval, R. J. Simes, A. Ng, D. Glenn, R. A. North, J. Beith, R. G. O’Connor, M. Rice, G. Stevens, J. Grassby, S. Pendlebury, C. McLeod, M. Boyer, A. Sullivan, J. Hobbs, R. Fox, D. Hedley, D. Raghavan, D. Green, T. Foo, T. J. Nash, J. Grygiel
884 Appendix A. (Continued) Auckland Breast Cancer Study Group (Auckland, New Zealand)
R. G. Kay, I. M. Holdaway, V. J. Harvey, C. S. Benjamin, P. Thompson, A. Bierre, M. Miller, B. Hochstein, A. Lethaby, J. Webber, M. F. Jagusch, L. Neave, B. M. Mason, B. Evans, J. F. Carter, J. C. Gillman, D. Mack, D. Benson-Cooper, J. Probert, H. Wood, J. Anderson, L. Yee, G. C. Hitchcock
Wellington Hospital (Wellington, New Zealand)
J. S. Simpson, E. C. Watson, C. T. Collins, A. J. Gray, J. W. Logan, J. J. Landreth, W. Brander, P. Cairney, L. Holloway, I. M. Holdaway, C. Unsworth
SAKK (Swiss Group for Clinical Cancer Research) Inselspital; Bern) M. F. Fey, S. Aebi, E. Dreher, H. Schneider, K. Buser, J. Ludin, G. Beck, A. Haenel, J. M. Lüthi, H. J. Altermatt, M. Nandedkar, R. Joss, U. Herrmann, G. Berclaz, M. Castiglione-Gertsch Kantonsspital (St Gallen, Switzerland)
H. J. Senn, W. F. Jungi, B. Thürlimann, Ch. Oehlschlegel, G. Ries, M. Töpfer, U. Lorenz, O. Schiltknecht, B. Späti, W. W. Rittman, R. Amgwerd, M. Stanisic, U. Schmid, Th. Hardmeier, U. Lütolf, E. Hochuli, U. Haller, A. Ehrsam
Ospedale San Giovanni (Bellinzona, Switzerland)
F. Cavalli, O. Pagani, H. Neuenschwander, C. Sessa, G. Martinelli, M. Ghielmini, E. Zucca, J. Bernier, E. S. Pedrinis, T. Rusca, G. Losa, P. Luscieti, E. Passega, W. Müller, L. Bronz, P. Rey, M. Galfetti, W. Sanzeni, S. Martinoli, T. Gyr, L. Leidi, G. Pastorelli, M. Varini, M. Ginier, S. Longhi, A. Goldhirsch
Kantonsspital (Basel, Switzerland)
R. Herrmann, J. F. Harder, S. Bartens, U. Eppenberger, J. Torhorst, J. P. Obrecht, F. Harder, H. Stamm, U. Laffer, A. C. Almendral, C. F. Rochlitz, S. Baumann
Hôpital des Cadolles (Neuchâtel, Switzerland)
D. Piguet, P. Siegenthaler, V. Barrelet, R. P. Baumann
Kantonsspital (Zürich, Switzerland)
B. Pestalozzi, C. Sauter, V. Engeler, U. Haller, U. Metzger, P. Huguenin, R. Caduff, G. Martz
Centre Hôpitalier Universitaire (Lausanne, Switzerland)
L. Perey, S. Leyvraz, P. Anani, F. Gomez, D. Wellman, G. Chapuis, P. De Grandi, P. Reymond, M. Gillet, J. F. Delaloye
Hôpital Cantonal (Geneva, Switzerland)
P. Alberto, H. Bonnefoi, P. Schäfer, F. Krauer, M. Forni, M. Aapro, R. Egeli, R. Megevand, E. Jacot-des-Combes, A. Schindler, B. Borisch, S. Diebold, F. Misset
Kantonsspital Graubünden (Chur, Switzerland)
F. Egli, P. Forrer, A. Willi, R. Steiner, J. Allemann, T. Rüedi, A. Leutenegger, U. Dalla Torre
Swiss Cancer League (Bern, Switzerland)
U. Metzger, W. Weber, G. Noseda
Original article
Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience G. Berclaz1*, S. Li6, K. N. Price6, A. S. Coates7, M. Castiglione-Gertsch3, C.-M. Rudenstam10, S. B. Holmberg11, J. Lindtner12, D. Erien12, J. Collins8, R. Snyder9, B. Thürlimann4, M. F. Fey2, C. Mendiola13, I. Dudley Werner14, E. Simoncini15, D. Crivellari16, R. D. Gelber6 & A. Goldhirsch5,17 On behalf of the International Breast Cancer Study Group 1
Department of Obstetrics and Gynecology; 2Institute of Medical Oncology, Inselspital; 3IBCSG Coordinating Center, Bern; 4Kantonsspital, St Gallen; Oncology Institute of Southern Switzerland, Lugano, Switzerland; 6IBCSG Statistical Center, Dana-Farber Cancer Institute and Frontier Science and Technology Research Foundation, Boston, MA, USA; 7The Cancer Council Australia and University of Sydney, Sydney; 8Department of Surgery, The Royal Melbourne Hospital, Melbourne; 9Department of Oncology, St Vincent’s Hospital, Melbourne, Australia; 10West Swedish Breast Cancer Study Group, Sahlgrenska University Hospital, Göteborg; 11Department of Surgery, SU/Moelndal’s Hospital, Moelndal, Sweden; 12The Institute of Oncology, Ljubljana, Slovenia; 13Madrid Breast Cancer Group, Madrid, Spain; 14Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa; 15Oncologia Medica-Spedali Civili, Brescia; 16Centro di Riferimento Oncologico, Aviano; 17European Institute of Oncology, Milan, Italy 5
Received 8 October 2003; revised 3 February 2004; accepted 4 February 2004
Background: Current information on the prognostic importance of body mass index (BMI) for patients with early breast cancer is based on a variety of equivocal reports. Few have data on BMI in relationship to systemic treatment. Patients and methods: Patients (6792) were randomized to International Breast Cancer Study Group trials from 1978 to 1993, studying chemotherapy and endocrine therapy. BMI was evaluated with eight other factors: menopausal status, nodal status, estrogen receptor status, progesterone receptor status, tumor size, vessel invasion, tumor grade and treatment. BMI was categorized as normal (≤24.9), intermediate (25.0–29.9) or obese (≥30.0). Results: Patients with normal BMI had significantly longer overall survival (OS) and disease-free survival (DFS) than patients with intermediate or obese BMI in pairwise comparisons adjusted for other factors. Subset analyses showed the same effect in pre- and perimenopausal patients and in those receiving chemotherapy alone. When assessed globally and adjusted for other factors, BMI significantly influenced OS (P = 0.03) but not DFS (P = 0.12). Conclusions: BMI is an independent prognostic factor for OS in patients with breast cancer, especially among pre-/perimenopausal patients treated with chemotherapy without endocrine therapy. Key words: body mass index, breast cancer, obesity, prognostic factor, survival
Introduction Previous studies have noted a modest negative association between obesity and survival of breast cancer [1, 2]. However, the methodologies used differed widely [3]. In most of the reports, the effect on prognosis did not persist after adjustment for other factors [4]. Studies reporting the effect of body mass index (BMI) allowing for other prognostic factors such as nodal involvement [5] or menopausal status [6] are also inconsistent, and few studies included patients receiving systemic adjuvant therapy [3]. Given these equivocal results, the importance of BMI as a prognostic factor for breast cancer remained uncertain. To examine the impact of BMI on the prognosis of patients with breast cancer and on outcome with different adjuvant treatments, *Correspondence to: Dr. G. Berclaz, Department of Obstetrics and Gynecology, Inselspital, Effingerstrasse 102, CH-I3010 Bern, Switzerland. Fax: +41-31-632-1652; E-mail: [email protected] © 2004 European Society for Medical Oncology
we analyzed data from 6792 eligible breast cancer patients randomized in trials I–VII of the International (formerly Ludwig) Breast Cancer Study Group (IBCSG).
Patients and methods Patient selection From 1978 to 1993, the IBCSG conducted three generations of trials (I–IV, V and VI–VII) that studied chemotherapy and endocrine therapy. The seven trials accrued 6792 eligible patients who were randomized to receive one of the treatments listed in Table 1. All trials have been reported previously [7–15]. This report includes a cohort of 6370 patients (94%; Table 1) for whom height and weight were recorded in the database. The median follow-up was ∼14 years. BMI [weight (kg)/height (m)2] categories were selected according to the World Health Organization definition: underweight, <18.5 kg/m2; normal range between 18.5 and 24.9 kg/m2; grade 1 overweight between 25 and 29.9 kg/m2; grade 2 overweight between 30.0 and 39.9 kg/m2; and grade 3 overweight
876 Table 1. International Breast Cancer Study Group trials I–VIIa and treatment groups Trial
Patient population
Years of patient accrual
I
Premenopausal
1978–1981
Eligible patients 491
Patients with known BMI 380
Premenopausal
IV
Postmenopausal
CMF ×12b
20
CMFp ×12 1978–1981
327
235
CMFp ×12b
20
Ox + (CMFp ×12)
4+ N+ III
Median years follow-up
b
1–3 N+ II
Treatment group
1978–1981
463
341
Observation
20
Age ≤65 years
(i.c.p. + T) ×12
N+
(CMFp + T) ×12c
Postmenopausal
1978–1981
320
233
c
c
Observation
20
(P + T) ×12c
Age 66–80 years N+ V
Pre-/postmenopausal
1981–1985
1275
1272
N– V
Pre-/perimenopausal
Observation PeCMF
1981–1985
715
715
16
b
PeCMFb
16
PeCMF + (CMFp ×6)
N+
b
CMFp ×6b V
Postmenopausal
1981–1985
514
514
PeCMFb
16
PeCMF + (CMFpT ×6)c
N+
CMFpT ×6c VI
Premenopausal
1986–1993
1475
1472
CMF ×6b CMF ×6 + reint
N+
10 b
CMF ×3b CMF ×3 + reintb VII
Postmenopausal
1986–1993
1212
1208
N+
T alonec T + delayed CMF
10 c
T + (CMF ×3)c T + (CMF ×3) + delayed CMFc Total
6792
6370
BMI, body mass index; C, cyclophosphamide 100 mg/m 2 p.o. days 1–14 of each cycle; i.c.p., prednisone 7.5 mg/day p.o.; M, methotrexate 40 mg/m2 i.v. days 1 and 8 of each cycle; T, tamoxifen 20 mg p.o. once daily given for 1 year in trials III and IV, 6 months in trial V, 5 years in trial VII; F, 5-fluorouracil 600 mg/m2 i.v. days 1 and 8 of each cycle; PeCMF, perioperative CMF; reint, reintroduction of three cycles of CMF; delayed CMF, three cycles of CMF given at months 9, 12 and 15 after randomization; N+, node positive; N–, node negative; p.o., by mouth; i.v., intravenously. a The earliest version of the clinical form for trials I–IV did not ask for height. b Chemotherapy without hormone therapy. c Hormone therapy with or without chemotherapy.
>40.0 kg/m2 [16]. Since the proportions of patients in the underweight group and in the grade 3 overweight group were small (2% in each), we combined the grade 2 overweight group with the grade 3 overweight group and combined the underweight group with the normal weight group, resulting in three BMI categories: normal (≤24.9), intermediate (25.0–29.9) and obese (≥30.0). We examined the relative risk of relapse and death with regard to the BMI categories adjusting for eight factors known to be predictors of disease-free survival (DFS) and overall survival (OS): menopausal status, nodal status, tumor size, vessel invasion, estrogen receptor (ER) status, progesterone receptor status, tumor grade and treatment regimens (Table 2). In this analysis, we did not adjust for age because there was a significant correlation between age and BMI (r = 0.35, P <0.01), indicating an increasing BMI with increasing age.
Pairwise analyses are reported with respect to the two comparisons: intermediate versus normal BMI category and obese versus normal BMI category. We combined the randomized treatment arms into three general treatment groups: observation (no adjuvant therapy), endocrine therapy (tamoxifen for 6 months to 5 years or surgical oophorectomy) with or without chemotherapy, and chemotherapy without endocrine therapy. Chemotherapy dosage was analyzed in patients in trials V, VI and VII, with actual surface area (ASA) and ideal surface area (ISA) recorded (ISA was not collected for trials I–IV). Among the 4755 patients who received chemotherapy and had ISA recorded, 1463 had a dosage based on ISA. Ninety-three per cent of patients were found to have a difference of 0.1–0.3 m2 between ISA and ASA. For patients with obese BMI, there was an average reduction of 12%
877 Table 2. Distribution of BMI according to patient characteristics [all values except P-values are represented as n (%), unless stated otherwise] Factor
Normal
Intermediate
Obese
Total patients
3308 (52)
2038 (32)
1024 (16)
Menopausal status
P-valuea
Total 6370 (100)
<0.01
Pre/peri
2111 (64)
960 (47)
423 (41)
3494 (55)
Post
1197 (36)
1078 (53)
601 (59)
2876 (45)
Negative
695 (21)
386 (19)
191 (19)
Positive
2613 (79)
1652 (81)
833 (81)
Nodal status
0.09
Tumor size
1272 (20) 5098 (80) <0.01
≤2 cm
1533 (46)
847 (42)
363 (35)
2743 (43)
>2 cm
1627 (49)
1131 (56)
636 (62)
3394 (53)
148 ( 5)
60 ( 3)
25 ( 3)
Unknown Vessel invasion
233 ( 4) 0.08
No
1350 (41)
857 (42)
454 (44)
2661 (42)
Yes
1532 (46)
913 (45)
435 (43)
2880 (45)
426 (13)
268 (13)
135 (13)
Unknown ER status
829 (13) 0.07
Negative
958 (29)
561 (28)
279 (27)
1798 (28)
Positive
1836 (56)
1185 (58)
634 (62)
3655 (57)
514 (16)
292 (14)
111 (11)
Unknown PgR status
917 (15) 0.77
Negative
1115 (33)
700 (34)
328 (34)
2143
Positive
1576 (47)
970 (47)
484 (50)
3030
666 (20)
380 (19)
151(16)
Unknown Tumor grade
1197 0.74
1
454 (14)
298 (15)
133 (13)
885 (14)
2
1449 (44)
896 (44)
443 (43)
2788 (44)
3
1154 (35)
715 (35)
375 (37)
2244 (35)
251 ( 8)
129 ( 6)
73 ( 7)
453 ( 7)
336 (10)
211 (10)
102 (10)
649 (10)
841 (25)
761 (37)
417 (41)
2019 (32)
2131 (64)
1066 (52)
505 (49)
Unknown Treatment group Observation Hormone ± chemo Chemo alone Age [median (range)]
<0.01
48 (21–84)
53 (25–80)
55 (26–80)
3702 (58) b
<0.01
BMI, body mass index; ER, estrogen receptor; PgR, progesterone receptor. Does not include unknown, obtained by Fisher’s exact test. b Kruskal–Wallis test. a
between ASA and ISA. In this group, 96% used ISA to calculate dose, while 47% used ISA in the intermediate BMI group, and only 2% in the normal group.
Statistical analysis DFS was defined as the time interval from randomization to relapse, the appearance of a second tumor or death from any cause, whichever occurred first. OS was defined as time from randomization to death from any cause. An additional DFS analysis censored patients (at the time of death) who died of a
non-breast-cancer event. Survival percentages and standard errors were estimated by the Kaplan–Meier method and Greenwood’s formula [17, 18]. In order to determine whether BMI was an independent prognostic factor, we compared two Cox regression models [19]. The first model had all eight factors plus BMI as a full model, and the second had all of the factors except BMI as a reduced model. The effect of BMI on outcome was assessed globally (all three categories) by comparing the two Cox models using log-likelihood tests. Pairwise hazard ratios and confidence intervals (CIs) were then calculated, and the Wald statistic was used for significance tests. P-values ≤0.05
878
Figure 1. Disease-free (A) and overall (B) survival according to body mass index (BMI) group for the 6370 patients from International Breast Cancer Study Group trials I–VII. Pairwise P-values are adjusted for eight prognostic factors.
were considered statistically significant. All tests of statistical significance were two-sided.
Results Table 2 shows the distribution of BMI groups overall and within each level of the eight factors and age, and the respective P-values. Menopausal status, tumor size group, treatment group and age were significantly associated with BMI (P <0.01). When BMI group was assessed as a global univariate prognostic factor, it
significantly influenced both DFS (P <0.01) and OS (P <0.01), with higher BMI associated with shorter DFS and OS compared with lower BMI (Figure 1). After controlling for other factors, BMI as a global independent indicator significantly influenced OS (P = 0.03), but not DFS (P = 0.12). Patients in the obese group tended to die from non-breast-cancer causes (9.5%) more than the normal (6.4%) or intermediate (5.8%) groups (P = 0.02). The additional survival analysis censoring patients who died of a nonbreast-cancer event produced results similar to those for DFS (univariate P <0.01; adjusted P = 0.13). When pairwise BMI categories were compared (obese/normal and intermediate/normal) in univariate analyses, as shown in Table 3, patients in the intermediate BMI category had an 8% higher risk of relapse than patients with normal BMI (P = 0.04) and a 13% higher risk of death (P <0.01). The risk of relapse for patients in the obese BMI category was 17% higher than patients with normal BMI (P <0.01), and the risk of death was 25% higher (P <0.01). After adjusting for the eight other factors, there was no longer a significant difference between normal and intermediate BMI, but there was still a significant difference between normal and obese BMI. Heavier women tended to have shorter DFS and OS with a risk of relapse 10% higher than that for patients in the normal group (P = 0.04), and a risk of death that was 14% higher (P <0.01) (Table 3). Pairwise comparisons (obese versus normal and intermediate versus normal) were used to assess the prognostic significance of BMI within subgroups defined by ER status, menopausal status, nodal status, tumor size and treatment group (Table 3). Within menopausal status subgroups, we found that patients with obese BMI tended to fare significantly worse than normal only within the pre-/perimenopausal group (Table 3; Figure 2A). It should be noted that 90% of the patients in this group received chemotherapy without hormonal therapy (Table 3). No adverse effect of obesity was observed in the postmenopausal group for either pairwise comparison (Figure 2B). In patients with node-positive disease, those in the obese BMI group had a 14% increase in the risk of recurrence and a 21% increase in the risk of death (P <0.01) compared with the normal group. After adjusting for other factors, there remained an OS advantage for the normal BMI group compared with the obese BMI group (Table 3). Although significant differences were observed between the normal and obese BMI groups in univariate analyses of patients with node-negative disease, after adjusting for the other seven factors, the differences were no longer significant. The prognostic impact of BMI group was assessed within the three general treatment categories: observation, endocrine therapy with or without chemotherapy, and chemotherapy alone. Because of the trial designs for different patient groups, these treatment groups were highly correlated with menopausal status and age, with 85% of the patients in the chemotherapy alone group being pre-/perimenopausal, and the median ages within the treatment groups being 57, 60 and 46 years, respectively. Ten per cent (649) of all patients were randomized to an observation arm, 2019 (32%) patients to an endocrine therapy with or without chemotherapy arm, and 3702 (58%) to a chemotherapy alone arm.
879 Table 3. Pairwise comparisons of body mass index for DFS and OS n
DFS
OS
10-year DFS (% ± SE)
Hazards ratioa
95% CI
P-value
10-year OS (% ± SE)
Hazards ratioa
95% CI
P-value
1024
42 ± 2
1.17b
1.07–1.28
<0.01
55 ± 2
1.25b
1.13–1.38
<0.01
Intermediate
2038
44 ± 1
b
0.04
57 ± 1
b
1.13
1.04–1.22
<0.01
Normal
3308
45 ± 1
1024
42 ± 2
1.10c
Intermediate
2038
44 ± 1
c
Normal
3308
45 ± 1
279
41 ± 3
1.13c
0.95–1.35
0.18
Intermediate
561
45 ± 2
c
0.84–1.10
0.58
Normal
958
44 ± 2
634
41 ± 2
1.10c
0.97–1.24
0.13
Intermediate
1185
44 ± 1
c
0.97–1.18
0.17
Normal
1836
45 ± 1
423
41 ± 2
1.16c c
All patients Obese
1.08
1.00–1.16
61 ± 1
All patients Obese
1.04
1.10–1.20 0.97–1.12
0.04
55 ± 2
1.14c
1.03–1.27
<0.01
0.28
57 ± 1
c
1.07
0.98–1.16
0.12
49 ± 3
1.17c
0.97–1.42
0.11
56 ± 2
0.96c
0.83–1.12
0.63
57 ± 2
1.12c
0.97–1.28
0.12
59 ± 2
1.08c
0.97–1.21
0.18
61 ± 1
ER status ER-negative Obese
0.96
56 ± 2
ER-positive Obese
1.07
63 ± 1
Menopausal status Pre/peri Obese
1.02–1.33
0.03
56 ± 3
1.22c
1.05–1.42
0.01
0.28
61 ± 2
c
0.97–1.24
0.09
960
47 ± 2
2111
47 ± 1
601
42 ± 2
1.06c
Intermediate
1078
41 ± 2
c
Normal
1197
43 ± 1
833
37 ± 2
1.10c
0.99–1.21
0.06
Intermediate
1652
39 ± 1
c
0.97–1.14
0.21
Normal
2613
41 ± 1
191
60 ± 4
1.10c
0.88–1.39
0.40
Intermediate
386
61 ± 3
c
0.83–1.20
0.99
Normal
695
60 ± 2
363
50 ± 3
1.14c c
Intermediate Normal
1.06
0.96–1.17
1.11
63 ± 1
Post Obese
1.04
0.94–1.20 0.94–1.16
0.35
55 ± 2
1.10c
0.96–1.26
0.17
0.42
54 ± 2
c
1.06
0.94–1.19
0.35
51 ± 2
1.14c
1.03–1.28
0.02
52 ± 1
1.08c
0.99–1.18
0.10
73 ± 3
1.16c
0.89–1.53
0.28
77 ± 2
1.03c
0.82–1.28
0.83
57 ± 1
Nodal status Positive Obese
1.05
56 ± 1
Negative Obese
1.00
76 ± 2
Tumor size ≤2 cm Obese
847
52 ± 2
1533
54 ± 1
636
36 ± 2
1.09c
Intermediate
1131
38 ± 1
c
Normal
1627
37 ± 1
Intermediate Normal
1.05
0.97–1.34 0.93–1.18
0.10
59 ± 3
1.22c
1.02–1.47
0.03
0.43
62 ± 2
c
1.08
0.94–1.23
0.30
66 ± 1
>2 cm Obese
1.02
0.97–1.22 0.93–1.12
0.15
46 ± 2
1.12c
0.98–1.27
0.09
0.64
47 ± 2
c
0.94–1.16
0.41
47 ± 1
1.05
880 Table 3. (Continued) n
DFS
OS
10-year DFS (% ± SE)
Hazards ratioa
95% CI
P-value
10-year OS (% ± SE)
Hazards ratioa
95% CI
102
53 ± 5
0.90c
0.68–1.20
Intermediate
211
41 ± 3
c
0.85–1.32
Normal
336
45 ± 3
417
42 ± 3
1.04c
0.89–1.21
0.63
Intermediate
761
40 ± 2
c
0.91–1.16
0.66
Normal
841
39 ± 2
505
39 ± 2
1.23c
1.08–1.39
<0.01
Intermediate
1066
46 ± 2
c
0.97–1.18
0.21
Normal
2131
48 ± 1
P-value
0.48
64 ± 5
0.93c
0.68–1.29
0.68
0.61
58 ± 3
1.05c
0.82–1.35
0.68
52 ± 3
1.10c
0.93–1.29
0.27
51 ± 2
1.05c
0.92–1.20
0.49
55 ± 2
1.24c
1.08–1.43
<0.01
61 ± 2
1.10c
0.98–1.23
0.10
Treatment Observation Obese
1.06
61 ± 3
Hormone ± chemotherapy Obese
1.03
52 ± 2
Chemotherapy alone Obese
1.07
64 ± 1
DFS, disease-free survival; OS, overall survival; CI, confidence interval; SE, standard error; ER, estrogen receptor. a Hazards ratio is for severe/normal or intermediate/normal; bunadjusted for other factors; cadjusted for the other seven factors.
Chemotherapy alone was the only treatment group in which BMI was a significant independent prognostic factor (P <0.01), with obese patients tending to have a shorter DFS and OS (Table 3). Only 5% of patients received hormone treatment alone, so this group was not included separately. In this small subset there were no differences in the adjusted or unadjusted outcome according to BMI group. An analysis of site of first failure revealed that patients with intermediate and obese BMI had a significantly (P <0.0001) higher percentage of distant recurrences compared with the normal group (30% normal, 35% intermediate and 36% obese).
Discussion Our results support the hypothesis that BMI is an independent prognostic factor in patients with breast cancer. BMI as a global independent factor does not have a significant impact on DFS, but does have a significant impact on OS, with heavier patients showing worse survival. This finding may be associated with a slightly higher incidence of death before breast cancer recurrence in the obese group (5%) compared with the other two groups (3%). The higher incidence of tumors >2 cm in diameter and the lower percentage of patients exposed to chemotherapy in the obese group are other possible reasons. When the heaviest group is compared with the normal group, BMI has a significant influence on prognosis, even when adjusted for other factors. These findings are in accordance with earlier studies that have shown a poorer OS with increasing weight [1] or BMI [2]. Poorer DFS percentages were also observed in some studies [20]. Other studies did not find an influence of obesity on OS or DFS [21].
One study reported an inverse relationship between low BMI and the risk of breast cancer recurrence [22]. Our study is limited to data already collected, i.e. height and weight. Other assessments such as underwater weighing, skinfold thickness and fat patterning were not available. One of the strongest correlations found between BMI and tumor characteristics was tumor size: 62% of patients with obese BMI had tumors of ≥2 cm diameter compared with 49% of patients with normal BMI. This is in accordance with previous studies [20, 23, 24]. Numerous hypotheses have been put forward to explain these findings. Obese patients tend to have large breasts, which may make palpation of a tumor difficult and therefore delay diagnosis. Alternatively, it has been suggested that obese patients may delay seeking treatment [25]. Other authors [5] consider that the influence of obesity on breast cancer prognosis is unlikely to be an artifact of delayed diagnosis. Our finding that obesity is still a significant predictor of mortality even after adjustment for tumor size supports the conclusions of these latter authors. Another suggested reason for the association between larger tumors and larger BMI is enhancement of tumor growth by endogenous factors. Daling [23] found a higher Ki-67 expression ratio and a higher mitotic count, indicating a possibly more rapid growth rate, in large tumors from patients with higher BMI. However, no correlation could be found in our data between obesity and tumor grading. Like several authors, we found a strong correlation between obesity and lymph node involvement [5]. These observations suggest that obesity may potentiate the metastatic spread of breast tumors. Distant metastases were also found more often in obese patients in bone or visceral sites.
881 in patients <45 years of age at diagnosis. A possible explanation for these results is the promotion of tumor growth by locally increased estrogen levels in the surrounding adipose tissue [28]. Another explanation is that a subset of tumors in young obese patients possesses a higher number of ERs, which might sensitize them to the relative lower estrogen levels observed in obese pre-/perimenopausal patients; this subset of tumors is associated with poorer prognosis [29]. The strong correlation found between high levels of ER and obese BMI supports this hypothesis. Another explanation for this observation is that many pre-/perimenopausal patients will experience permanent chemotherapyinduced amenorrhea. These patients will then be under the influence of the higher estradiol levels of obesity after the induced menopause. They in particular might benefit from an anti-estrogen treatment; however, tamoxifen was not used in 90% of patients in the pre-/perimenopausal group in these trials. The observation that obese patients in the group with endocrine treatment did not have a significantly worse prognosis than lean patients supports this hypothesis. A recent study [30] reported that tamoxifen metabolites were significantly decreased in obese patients and that the same dose of tamoxifen might not be accurate for all women. This ‘underdosage’ might explain the slight difference of prognosis in favor of lean patients in the hormone treatment group. Finally, obesity may have a negative prognostic impact through different signaling pathways, as suggested by its unfavorable influence on ER-negative tumors. In our study, obese patients with aggressive tumors had a higher risk of recurrence and death despite the use of an adjuvant systemic therapy. One of the possible reasons could be that doses calculated on the basis of ideal weight might be inadequate. Lower dose delivery has been linked to inferior outcomes. In contrast, a study with 735 patients using actual body weight to calculate doses of cytotoxic drugs in obese patients [24] also reported a poor prognosis. In conclusion, this retrospective investigation of IBCSG trials I–VII demonstrates that BMI is an independent prognostic factor for OS in patients with breast cancer. We have supporting evidence that obese BMI represents a poor risk feature for outcome, especially in pre-/perimenopausal patients, most of whom received chemotherapy without hormonal therapy. Figure 2. Disease-free survival for the 3494 pre- and perimenopausal patients (A) and the 2876 postmenopausal patients (B) according to body mass index (BMI) group. Pairwise P-values are adjusted for the seven other prognostic factors (i.e. other than menopausal status).
In obese postmenopausal women, aromatization of androstenedione in the adipose tissue is the major source of estrogen production and this may result in enhanced tumor growth. Furthermore, obese and postmenopausal patients show decreased levels of sex hormone-binding globulin, thus increasing free estradiol available to target tissues. In premenopausal women, the opposite situation is found, with total estradiol decreasing as BMI increases [26]. In our study, poorer prognosis with elevated BMI was found only within the pre-/perimenopausal patients. Two studies [23, 27] found a relationship between increasing BMI and lower survival
Acknowledgements We thank the patients, physicians, nurses and data managers who participated in the IBCSG trials. Furthermore, we acknowledge the initial support provided by the Ludwig Institute for Cancer Research and the Cancer League of Ticino, and the continuing support for central coordination, data management and statistics provided by the Swedish Cancer Society, the Cancer Council Australia, the Australian New Zealand Breast Cancer Trials Group, the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, the Swiss Cancer League and the United States National Cancer Institute (CA-75362). We also acknowledge support for the Cape Town participants and the St Gallen participants from the Cancer Association of South Africa and the Foundation for Clinical Cancer
882 Research of Eastern Switzerland, respectively. The IBCSG trials I–VII participants and authors are listed in Appendix A.
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883 Appendix A. International Breast Cancer Study Group G trials I–VII: participants and authors Scientific Committee
A. Goldhirsch, A. S. Coates (Co-chairs)
Foundation Council
J. Collins (President), B. Thürlimann (Vice-president), H.-J. Senn (Treasurer), S. B. Holmberg, J. Lindtner, A. Veronesi, H. Cortés-Funes
Coordinating Center (Bern, Switzerland)
M. Castiglione (CEO), M. L. Nasi, A. Hiltbrunner, G. Egli, C. Jenatsch, A. Saurer
Statistical Center, Harvard School of Public Health and Dana-Farber Cancer Institute (Boston, MA)
R. Gelber (Group Statistician), K. Price, H. Peterson, M. Zelen, S. Gelber, A. O’Neill
Data Management Center, Frontier Science and Technical Research Foundation (Amherst, NY)
M. Isley, R. Hinkle, L. Blacher
Pathology Office, Institute of Cancer Research, Royal Cancer Hospital (Sutton, UK)
B. Davis, R. Bettelheim, W. Hartmann, A. M. Neville
Centro di Riferimento Oncologico (Aviano, Italy)
D. Crivellari, S. Monfardini, E. Galligioni, A. Veronesi, A. Buonadonna, S. Massarut, C. Rossi, E. Candiani, A. Carbone, R. Volpe, M. Roncadin, M. Arcicasa, G. F. Santini, F. Villalta, F. Coran, S. Morassut
Spedali Civili e Fondazione Beretta (Brescia, Italy)
G. Marini, E. Simoncini, P. Marpicati, A. Barni, P. Grigolato, L. Morassi, U. Sartori, D.DiLorenzo, A. Albertini, G. Marinone, M. Zorzi, M. Braga, L. Lucini
Groote Schuur Hospital and University of Cape Town (Republic of South Africa)
D. M. Dent, A. Gudgeon, E. Murray, I. D. Werner, P. Steynor, A. Hacking, J. Terblanche, A. Tiltman, E. Dowdle, R. Sealy, P. Palmer, P. Helman, E. McEvoy, J. Toop
University of Essen, West German Tumor Center (Essen, Germany)
C. G. Schmidt, K. Höffken, F. Schüning, L. D. Lender, H. Ludwig, R. Callies
University of Düsseldorf (Germany)
A. E. Schindler, P. Faber, H. G. Schnürch, H. Bender, H. Bojar
West Swedish Breast Cancer Study Group (Göteborg, Sweden)
C.-M. Rudenstam, A. Wallgren, S. Ottosson-Lönn, R. Hultborn, G. Colldahl-Jäderström, E. Cahlin, J. Mattsson , S. Jansson, L. Ivarsson, O. Ruusvik, L. G. Niklasson, S. Dahlin, G. Karlsson, B. Lindberg, A. Sundbäck, S. Bergegårdh, H. Salander, C. Andersson, M. Heideman, Y. Hessman, O. Nelzén, G. Claes, T. Ramhult, J. H. Svensson, P. Liedberg, J. Säve-Söderbergh, S. Nilsson, J. Fornander, Ch. Johnsen, L. Mattson, C. G. Backstrom, G. Bergegardh, G. Ekelond, G. Wallin, O. Thoren, L. Lundell, U. Ljungqvist, L.-O. Hafström, S. B. Holmberg, S. Persson
General Hospital (Gorizia, Italy)
S. Foladore, G. Pamich, C. B. Marino, A. Murgia, V. Milan
The Institute of Oncology (Ljubljana, Slovenia)
J. Lindtner, D. Erzen, E. Majdic, B. Stabuc, R. Golouh, J. Lamovec, J. Jancar, I. Vrhovec, M. Kramberger, J. Novak, M. Naglas, M. Sencar, J. Cervek, S. Sebek, O. Cerar, T. Cufer
The Royal Free Hospital (London, UK)
S. Parbhoo, E. Boessen, B. Stoll, F. Sennanayake, K. Griffiths
Madrid Breast Cancer Group (Madrid, Spain)
H. Cortés-Funes, D. Mendiola, C. Gravalos, Colomer, M. Mendez, F. Cruz Vigo, P. Miranda, A. Sierra, F. Martinez-Tello, A. Garzon, S. Alonso, A. Ferrero, C. Vargas, M. L. Larroder, F. Calero, A. Suarez, F. Pastrana, S. Chruchaga, C. Guzman, B Rodriguez, F. Cruz Caro, M. L. Marcos, M. A. Figueras, R. Huertas
Australian New Zealand Breast Cancer Trials Group (ANZ BCTG) Operations Office, University of Newcastle
J. F. Forbes, A. Wilson, D. Lindsay
Statistical Center, NHMRC CTC, University of Sydney (Sydney Australia)
R. J. Simes, E. Beller, C. Stone, V. Gebski
The Cancer Council Victoria (formerly Anti-Cancer Council of Victoria; Melbourne, Australia)
J. Collins, P. Gregory, P. Kitchen, S. Hart, S. Neil, M. Henderson, I. Russell, T. Gale, R. Snyder, R. McLennan, M. Schwarz, W. I. Burns, M. Green, R. Drummond, A. Rodger, J. McKendrick, R. Bennett, J. Funder, L. Harrison, V. Humenuik, P. Jeal, R. Reed, L. Sisely, R. Millar, J. Griffiths, J. Zalcberg, P. Briggs, A. Zimet, P. Brodie, P. Ellims
Flinders Medical Centre (Bedford Park, South Australia)
S. Birrell, M. Eaton, C. Hoffmann, B. Koczwara, C. Karapetis, T. Malden, W. McLeay, R. Seshadri
Newcastle Mater Misericordiae Hospital Waratah (Newcastle, Australia) and Gold Coast Hospital (Queensland, Australia)
J. F. Forbes, J. Stewart, D. Jackson, R. Gourlay, J. Bishop, S. Cox, S. Ackland, A. Bonaventura, C. Hamilton, J. Denham, P. O’Brien, M. Back, S. Brae, A. Price, Muragasu, H. Foster, D. Clarke, R. Sillar, I. MacDonald, R. Hitchins
Royal Adelaide Hospital (Adelaide, Australia)
I. N. Olver, A. Robertson, P. G. Gill, M. L. Carter, P. Malycha, E. Yeoh, G. Ward, A. S. Y. Leong, J. Lommax-Smith, D. Horsfall, R. D’Angelo, E. Abdi
Royal Perth Hospital (Perth, Australia)
E. Bayliss
Sir Charles Gairdner Hospital (Nedlands, Western Australia)
M. Byrne, G. van Hazel, J. Dewar, M. Buck, D. Ingram, G. Sterrett, P. M. Reynolds, H. J. Sheiner, K. B. Shilkin, R. Hahnel, S. Levitt, D. Kermode, H. Hahnel
University of Sydney, Dubbo Base Hospital and Royal Prince Alfred Hospital (Sydney, Australia)
M. H. N. Tattersall, A. Coates, F. Niesche, R. West, S. Renwick, J. Donovan, P. Duval, R. J. Simes, A. Ng, D. Glenn, R. A. North, J. Beith, R. G. O’Connor, M. Rice, G. Stevens, J. Grassby, S. Pendlebury, C. McLeod, M. Boyer, A. Sullivan, J. Hobbs, R. Fox, D. Hedley, D. Raghavan, D. Green, T. Foo, T. J. Nash, J. Grygiel
884 Appendix A. (Continued) Auckland Breast Cancer Study Group (Auckland, New Zealand)
R. G. Kay, I. M. Holdaway, V. J. Harvey, C. S. Benjamin, P. Thompson, A. Bierre, M. Miller, B. Hochstein, A. Lethaby, J. Webber, M. F. Jagusch, L. Neave, B. M. Mason, B. Evans, J. F. Carter, J. C. Gillman, D. Mack, D. Benson-Cooper, J. Probert, H. Wood, J. Anderson, L. Yee, G. C. Hitchcock
Wellington Hospital (Wellington, New Zealand)
J. S. Simpson, E. C. Watson, C. T. Collins, A. J. Gray, J. W. Logan, J. J. Landreth, W. Brander, P. Cairney, L. Holloway, I. M. Holdaway, C. Unsworth
SAKK (Swiss Group for Clinical Cancer Research) Inselspital; Bern) M. F. Fey, S. Aebi, E. Dreher, H. Schneider, K. Buser, J. Ludin, G. Beck, A. Haenel, J. M. Lüthi, H. J. Altermatt, M. Nandedkar, R. Joss, U. Herrmann, G. Berclaz, M. Castiglione-Gertsch Kantonsspital (St Gallen, Switzerland)
H. J. Senn, W. F. Jungi, B. Thürlimann, Ch. Oehlschlegel, G. Ries, M. Töpfer, U. Lorenz, O. Schiltknecht, B. Späti, W. W. Rittman, R. Amgwerd, M. Stanisic, U. Schmid, Th. Hardmeier, U. Lütolf, E. Hochuli, U. Haller, A. Ehrsam
Ospedale San Giovanni (Bellinzona, Switzerland)
F. Cavalli, O. Pagani, H. Neuenschwander, C. Sessa, G. Martinelli, M. Ghielmini, E. Zucca, J. Bernier, E. S. Pedrinis, T. Rusca, G. Losa, P. Luscieti, E. Passega, W. Müller, L. Bronz, P. Rey, M. Galfetti, W. Sanzeni, S. Martinoli, T. Gyr, L. Leidi, G. Pastorelli, M. Varini, M. Ginier, S. Longhi, A. Goldhirsch
Kantonsspital (Basel, Switzerland)
R. Herrmann, J. F. Harder, S. Bartens, U. Eppenberger, J. Torhorst, J. P. Obrecht, F. Harder, H. Stamm, U. Laffer, A. C. Almendral, C. F. Rochlitz, S. Baumann
Hôpital des Cadolles (Neuchâtel, Switzerland)
D. Piguet, P. Siegenthaler, V. Barrelet, R. P. Baumann
Kantonsspital (Zürich, Switzerland)
B. Pestalozzi, C. Sauter, V. Engeler, U. Haller, U. Metzger, P. Huguenin, R. Caduff, G. Martz
Centre Hôpitalier Universitaire (Lausanne, Switzerland)
L. Perey, S. Leyvraz, P. Anani, F. Gomez, D. Wellman, G. Chapuis, P. De Grandi, P. Reymond, M. Gillet, J. F. Delaloye
Hôpital Cantonal (Geneva, Switzerland)
P. Alberto, H. Bonnefoi, P. Schäfer, F. Krauer, M. Forni, M. Aapro, R. Egeli, R. Megevand, E. Jacot-des-Combes, A. Schindler, B. Borisch, S. Diebold, F. Misset
Kantonsspital Graubünden (Chur, Switzerland)
F. Egli, P. Forrer, A. Willi, R. Steiner, J. Allemann, T. Rüedi, A. Leutenegger, U. Dalla Torre
Swiss Cancer League (Bern, Switzerland)
U. Metzger, W. Weber, G. Noseda