Breast Cancer Res Treat DOI 10.1007/s10549-016-4099-y
EPIDEMIOLOGY
Prognostic factors in early breast cancer associated with body mass index, physical functioning, physical activity, and comorbidity: data from a nationwide Danish cohort Trine L. Guldberg1 • Søren Christensen2 • Robert Zachariae2 • Anders Bonde Jensen1
Received: 27 December 2016 / Accepted: 28 December 2016 Ó Springer Science+Business Media New York 2017
Abstract Purpose To explore the associations between lifestyle-related factors and tumor-related prognostic factors in women treated for primary breast cancer, and to detect possible differences between the associations in pre- and postmenopausal women. Methods Associations between tumor-related prognostic factors, including the composite endpoint risk of recurrence (RoR), body mass index (BMI), comorbidity (Charlson comorbidity index), basic physical functioning (SF-36), physical activity, smoking, and alcohol consumption were examined with binary logistic regression analysis in a national cohort of 4917 women treated for primary breast cancer. In addition, statistical interactions between predictors and menopausal status were assessed in order to determine if their strength differed significantly as a function of menopausal status. Results Higher BMI, reduced physical function, reduced physical activity, and greater alcohol consumption were all statistically significantly associated with two or more tumor-related factors indicating a poorer prognosis. Interaction analysis revealed that BMI was significantly stronger associated with RoR among premenopausal women than among postmenopausal women (interaction ip = 0.048). Similarly, a significant association between RoR and physical function was only seen in the premenopausal population (ip = 0.008). This pattern was also & Trine L. Guldberg
[email protected] 1
Department of Oncology, Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark
2
Unit for Psychooncology and Health Psychology, Aarhus University Hospital, Aarhus, Denmark
seen between RoR and daily alcohol consumption, which only reached statistical significance in the total population and in premenopausal women (ip \ 0.001). Conclusion Premenopausal women who are overweight and have poorer physical function have poorer prognosis at the time of diagnosis, suggesting the possible relevance of stratifying adjuvant treatment according to guidelines, BMI, and menopausal status. Keywords Breast cancer Prognosis Lifestyle Menopausal status Risk assessment
Background Breast cancer is the most frequent cancer among women worldwide, representing 29% of all reported cancer cases diagnosed in 2012 [1]. In Denmark, breast cancer accounts for around 4500 new cases each year, 3800 of which are new primary breast cancer cases. The most recent data from 2008 on recurrence among Danish women suffering from early-stage breast cancer showed a risk of recurrence of 19% during a follow-up of 12 years. This included both loco-regional recurrence as well as distant metastasis [2]. At present, known tumor-related prognostic factors such as tumor size, grade of anaplasia, hormone and human epidermal growth factor receptor 2 (HER-2) status, and cancer cell involvement in the axillary nodes are used to determine the need for adjuvant treatment. If adjuvant treatment is found justified, the same tumor-related prognostic factors are used to establish the relevant treatment plan for the individual patient. Non-tumor-related factors such as lifestyle factors have also been shown to play a prognostic role in early-stage breast cancer. There appears to be a relationship between
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obesity (BMI [ 30) and poorer prognosis [3]. Concurrently, increased risk of breast cancer recurrence has been associated with lower levels of physical exercise [4]. Although women diagnosed with early-stage breast cancer generally do not suffer from higher levels of comorbidity than age-matched controls [5], comorbidity has been shown to have a considerable impact on both breast cancerspecific and non-specific outcomes in early-stage breast cancer and influence physicians’ choice of treatment strategy [6]. Age may also play an independent role in breast cancer pathology which is not yet fully understood. It is known that young women (\35 years) more often present with poorer tumor-related prognostic factors at the time of diagnosis than older women [7]. In addition, younger women have higher rates of recurrence both locoregionally and distant, often suffer from more aggressive disease, and have higher mortality from breast cancer than older women [8]. Furthermore, both medical treatment and radiotherapy may be less effective in younger than in older women with breast cancer [9]. For these reasons, it has been suggested that younger women may benefit from more aggressive adjuvant treatment than older women receive. This would call for an adjustment of the guidelines for adjuvant treatment for these women. It is therefore relevant to explore whether additional risk factors, e.g., lifestyle factors, play a different role in young and older patients. An additional aim of the ongoing research into risk and prognostic factors in breast cancer is to aid attempts to individualize therapy. The goal of individualized therapy is to achieve the optimal balance between sufficiently aggressive therapy to maintain the maximal effect and minimizing the toxicity of the treatment. The aim of the present study was to contribute to the search for optimal stratification of treatment regimens by exploring the associations between known tumor-related prognostic factors and non-tumor-related prognostic lifestyle factors. In the present study, we explored the role of non-tumor-related factors of comorbidity, BMI, physical function, activity level as well as health-related behaviors such as smoking and alcohol consumption with menopausal status used as a marker of young versus old age.
been published [10]. Eligible women were identified by the Danish Breast Cancer Cooperative Group (DBCG) and the surgical departments and informed about the study. The eligibility of the 4917 original PFAB cohort members were recently reassessed through a linkage to the DBCG registry. Two women were subsequently found to have disseminated disease at time of cohort enrollment, and 68 were not treated according to DBCG protocols leaving a total of 4847 eligible women. Of these, a total of 3301 (68%) also returned a mail-out follow-up questionnaire, 3-month post surgery. There were no differences between responders and non-responders for tumor- and treatmentrelated variables when adjusted for age (p [ 0.21) (data not shown). An estimated 97% of all eligible women in Denmark during the inclusion period were identified for the study. The study was approved by The Regional Science Ethical Committees and the Danish data protection agency. In brief, eligible patients were Danish residents aged 18–70 years, histological confirmed stage I, II, or III breast cancer, or T1-3, N0-3, and M0 according to the TNM classification. All patients were allocated to one of the at that time active DBCG standard treatment protocols: (A) No adjuvant therapy; (B) Seven courses of chemotherapy [Cyclophosphamide, Epirubicin, and 5-Fluorouracil (CEF)] followed by endocrine treatment for 5 years; (C) Endocrine treatment for 5 years; (D/E) seven courses of chemotherapy with either CEF or Cyclophosphamide, Methotrexate, and 5-Fluorouracil (CMF). Furthermore, women who met the DBCG criteria for adjuvant radiotherapy were allocated to radiotherapy according to standard DBCG protocols. The women included in the present study had no history of other cancers except non-melanoma skin cancer or carcinoma in situ of the cervix uteri. The women had to be able to read Danish and be physically and mentally capable of completing a questionnaire. Data concerning age, eligibility, comorbidity, tumor variables, and treatment-related variables were obtained from the DBCG registry and the surgical departments. For the present study, information regarding health behavior and health status was obtained from the 3-month follow-up questionnaire. Measures
Methods Physical function and activity Patients The study sample consisted of all participants of the nationwide psychosocial factors and breast cancer (PFAB) inception cohort of women treated for early-stage invasive breast cancer in Denmark between October 2001 and March 2004. Details concerning the cohort have previously
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Physical function refers to the basic physical ability of the patient (e.g., the ability to climb stairs and lift groceries) as measured by SF-36 physical functioning scale (PF-10) [11]. Physical activity refers to the activity level of the patient according to the physical activity scale of the elderly (PASE) [12].
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BMI was calculated as current weight (kg)/[height (m)]2. Obesity was defined according to the WHO criteria as BMI [ 30. Comorbidity was assessed for all eligible women at the surgical departments with The Charlson comorbidity index (CCI), and a total score was calculated [13]. Risk of recurrence (RoR) was assessed according to the DBCG guidelines of 2001. Patients were considered to have low risk of recurrence if they at the time of diagnosis fulfilled the following criteria: [35 years of age, tumor size B20 mm in diameter, estrogen receptor positive, malignancy grade 1 or non-ductal carcinoma, and no detected positive lymph nodes in the axilla [2]. The remaining women were defined as having high risk.
A total of 12.1% suffered from one or more comorbidities (Charlson score C1). The comorbidities in the cohort are listed in Table 2. No significant associations were found between the Charlson score and any of the tumor-related variables included, neither in the entire cohort nor for pre- and postmenopausal women when analyzed separately (see Table 3).
Alcohol consumption
BMI
In the questionnaire, the women were asked to state their daily alcohol consumption. The categories were no alcohol consumption, 0–1, C1–2, C2–3, C3 units.
An overall statistically significant association was found between higher BMI and the composite risk of recurrence measure (RoR). Similar associations were also found between higher BMI and axillary involvement, higher grade of anaplasia, and larger tumor size. Concerning grade of anaplasia, a significant association was found between higher BMI and higher grade of anaplasia in the group of premenopausal women, but not in the postmenopausal group. The difference in the magnitude of associations between pre- and postmenopausal women reached statistical significance (interaction ip = 0.017). No statistically significant associations were found for estrogen receptor status. Although significant associations between higher BMI and higher RoR were found in both pre- and the postmenopausal women, the magnitude of the association differed between the two groups with BMI more strongly associated with RoR among premenopausal women than postmenopausal women (ip = 0.048). The same pattern was found for associations between BMI and tumor size, with BMI more strongly associated with tumor size among premenopausal women compared to postmenopausal women (ip = 0.045) (see Table 3).
Smoking In the questionnaire, the women were asked to report their smoking status. The categories were never-smoker, exsmoker, 1–9 cigarettes a day, 10–19 cigarettes a day, and C20 cigarettes a day. Statistics The data were analyzed with binary logistic regression analysis, with tumor variables as dependent variables coded according to their prognostic severity (low risk = ‘0’ and high risk = ‘1’). Results are presented for the total sample and stratified according to menopausal status. The independent variables were all treated as continuous variables, and results are presented as odds ratios (OR). In addition, statistical interactions between predictors and menopausal status were assessed in order to determine if their strength differed significantly as a function of menopausal status. The interactions are presented as p values (Table 3). Predictors and interaction effects were considered statistically significant (p \ 0.05) if confirmed by the Wald statistic. Analyses were conducted with SPSS 19.0.0.1 (IBM SPSS Inc., Chicago, USA).
Results Characteristics The characteristics of the cohort are shown in Table 1. At the time of diagnosis, 64.3% of the women were
postmenopausal, 81.0% of the women had estrogen receptor-positive disease, and 49.6% had tumor involvement of the axillary lymph nodes. Comorbidity
Physical function (PF) No association was found in the sample as a whole between women’s physical function (PF) and RoR. However, when looking at premenopausal women only, a significant association was found between RoR and PF. The corresponding association in the postmenopausal group did not reach statistical significance. The difference in magnitude of associations between the two groups reached statistical significance (interaction, p = 0.008), revealing that the association between RoR and PF applied only to premenopausal women When examining associations between the individual prognostic factors and PF, poorer PF was
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Breast Cancer Res Treat Table 1 Baseline characteristics of cohort
All
Questionnaire not filled
Questionnaire filled
4847
1546
3301
57.6
55.3
18–35 years
133 (3)
39 (3)
94 (3)
36–49 years
1201 (25)
305 (20)
896 (27)
50–59 years
1829 (38)
556 (36)
1273 (39)
60–70 years
1684 (35)
646 (42)
1038 (31)
Premenopausal
1728 (36)
444 (29)
1284 (39)
Postmenopausal
3115 (64)
1100 (71)
2015 (61)
0
4247 (88)
1306 (85)
2941 (89)
1
469 (10)
177 (12)
292 (9)
C2
114 (2)
56 (4)
59 (2)
Type of surgery Mastectomy
2620 (54)
833 (54)
1787 (54)
Lumpectomy
2227 (46)
713 (46)
1514 (46)
Axillary lymph node dissection
3498 (73)
1106 (72)
2392 (73)
Sentinel lymph node procedure
1010 (21)
333 (22)
677 (21)
Not reported
339 (7)
107 (6)
232 (7)
Negative
2442 (50)
811 (53)
1631 (49)
Positive
2401 (50)
733 (48)
1668 (51)
B20 mm
2926 (61)
923 (60)
2003 (61)
[20 mm
1904 (39)
617 (40)
1287 (39)
Positive
3893 (81)
1230 (80)
2663 (81)
Negative
916 (19)
298 (20)
618 (19)
1169 (24)
385 (25)
784 (24)
II
1725 (36)
536 (35)
1189 (36)
III
1014 (21)
329 (21)
685 (21)
Non-ductal
893 (19)
280 (18)
613 (19)
Low
910 (19)
306 (20)
604 (18)
High
3937 (81)
1240 (80)
2697 (82)
N (%) Age Mean years
Menopause status
Charlson comorbidity Index
Axillary procedure
Nodal status
Tumor size
Estrogen receptor
Malignancy grade I
DBCGa Risk status
Body Mass Index B18.5
1896 (57)
C25–30
884 (27)
C30–35
288 (9)
C35
90 (3)
Missing
60 (2)
Smoker Non smoker
123
83 (3)
[18.5–25
2288 (69)
1–9 per day
174 (5)
10–19 per day
451 (14)
Breast Cancer Res Treat Table 1 continued
All
Questionnaire not filled
Questionnaire filled
C20
331 (10)
Missing
57 (2)
Daily alcohol consumption No alcohol
509 (15)
0–1
1338 (41)
C1–2
789 (24)
C2–3
382 (12)
C3 Missing
230 (7) 53 (1)
Missing observations \1% not shown a
Danish Breast Cancer Group
Table 2 Comorbidity characteristics of cohort (N = 4847) N (%) Chronic obstructive lung disease
202 (4)
Congestive heart failure
99 (2)
Diabetes—no late complications
86 (2)
Diabetes—with late complications
11 (0)
Connective tissue disease
77 (2)
Cerebrovascular disease
54 (1)
Gastric ulcer
49 (1)
Peripheral arterial disease
46 (1)
Myocardial Infarction
29 (1)
Liver disease (mild grade)
20 (0)
Liver disease (moderate/high grade) Hemiplegia
4 (1) 11 (0)
Othera
4 (1)
No of patients with diagnosis Patients may figure in more than one category if they have several diagnoses
not differ between pre- and postmenopausal women (ip = 0.60). Concerning known prognostic factors, higher levels of PA were statistically significantly associated with lower odds of having tumor-positive nodal status, lower malignancy grade, and smaller tumor size. Lower PA was statistically significantly associated with malignancy grade in premenopausal, while the association was not statistically significant in the postmenopausal women. The difference between the groups did not reach statistical significance (ip = 0.21). The same pattern was found for the association between PA and tumor size (ip = 0.34). Smoking No associations between smoking and known prognostic parameters reached statistical significance, neither in the entire group nor in pre- or postmenopausal group of women. Alcohol
A total of 584 women had more than one comorbid diseases a
AIDS or renal disease
associated with higher odds of presenting with tumorpositive nodal status and larger tumor size, but not with grade of anaplasia or estrogen receptor status (see Table 3). In the stratified analyses, poorer PF was significantly associated with larger tumor size and higher grade of anaplasia in premenopausal women, but not for postmenopausal women. However, the difference in magnitude of associations between the two groups did not reach statistical significance (ip = 0.07). Physical activity A statistically significant association was found between lower levels of physical activity (PA) and higher RoR both in the group as a whole and in premenopausal women alone (Table 3). The magnitude of the associations, however, did
Daily consumption of alcohol (DCA) was statistically significantly associated with RoR. Women with higher levels of DCA had lower RoR, less axillary node involvement, smaller tumor size, and higher frequency of estrogen receptor-positive tumors (see Table 3). The magnitude of the association between DCA and RoR differed significantly between pre- and postmenopausal women, and only reached statistical significance in premenopausal women (p \ 0.001, ip \ 0.001). The association between DCA and positive estrogen receptor status was similar in post- and premenopausal women (ip = 0.55). Statistically significant associations between higher DCA and fewer tumor-positive lymph nodes were found in both pre- and postmenopausal women, but the difference between menopausal groups did not reach statistical significance (p = 0.16). Higher DCA was not significantly associated with grade of anaplasia in neither the premenopausal nor the postmenopausal population;
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Breast Cancer Res Treat Table 3 Lifestyle factors associated with prognostic parametersa 3-month post surgery Total cohort OR
P value
95% CI
Premenopausal women
Postmenopausal women
Interaction
OR
OR
P value
P value
95% CI
P value
95% CI
Comorbidity (Charlson comorbidity index) Low vs high risk
1012
0.88
0.865–1.185
1.08
0.711
0.723–1.609
1.03
0.706
0.869–1.231
0.85
Nodal statusd
0.981
0.76
0.868–1.109
1071
0.63
0.809–1.418
0.984
0.81
0.857–1.129
0.59
Estrogen receptor statuse
1165
0.08
0.981–1.384
0.875
0.41
0.638–1.199
1263
0.02
1.031–1.546
0.06
Malignancy gradef
0.904
0.15
0.789–1.036
1150
0.46
0.790–1.674
0.881
0.10
0.758–1.025
0.86
Tumor sizeg
1115
0.09
0.985–1.261
1103
0.49
0.834–1.459
1122
0.10
0.977–1.290
0.91
Low vs high risk
1048
\0.001
1.025–1.072
1087
\0.001
1.043–1.133
1034
0.016
1.006–1.062
0.048 0.50
Body mass index Nodal status
1026
0.002
1.010–1.043
1035
0.010
1.008–1.062
1023
0.031
1.002–1.044
Estrogen receptor status
1004
0.73
0.983–1.024
1003
0.86
0.970–1.037
1004
0.79
0.977–1.031
0.98
Malignancy grade
1028
0.006
1.008–1.048
1043
0.014
1.008–1.078
1023
0.073
0.998–1.048
0.017
Tumor size
1084
\0.001
1.066–1.102
1110
\0.001
1.079–1.142
1071
\0.001
1.048–1.094
0.045
Basic physical functionb Low vs high risk
0.996
0.13
0.990–1.001
0.980
0.002
0.968–0.993
0.999
0.81
0.993–1.005
0.008
Nodal status
0.991
\0.001
0.986–0.995
0.991
0.027
0.983–0.999
0.990
\0.001
0.985–0.994
0.74
Estrogen receptor status
0.999
0.57
0.993–1.004
1001
0.85
0.0991–1.011
0.998
0.44
0.991–1.004
0.56
Malignancy grade
0.999
0.55
0.994–1.003
0.986
0.008
0.975–0.996
1002
0.50
0.996–1.007
0.12
Tumor size
0.995
0.015
0.991–0.999
0.989
0.004
0.981–0.996
0.997
0.24
0.992–1.002
0.07
Physical activity levelc Low vs high risk
0.998
0.007
0.997–1.000
0.998
0.028
0.996–1.000
0.998
0.06
0.997–1.000
0.60
Nodal status
0.998
\0.001
0.997–0.999
0.999
0.09
0.997–1.000
0.997
\0.001
0.996–0.998
0.14
Estrogen receptor status
1000
0.82
0.999–1.001
1000
1.0
0.998–1.002
1000
0.79
0.998–1.001
0.86
Malignancy grade
0.999
0.032
0.998–1.000
0.997
0.007
0.996–0.999
0.999
0.45
0.998–1.001
0.21
Tumor size
0.998
0.002
0.997–0.999
0.998
0.006
0.996–0.999
0.999
0.07
0.997–1.000
0.34
Low vs high risk
0.992
0.19
0.981–1.004
1000
0.97
0.981–1.019
0.988
0.11
0.975–1.002
0.36
Nodal status
0.994
0.19
0.985–1.003
0.998
0.83
0.984–1.013
0.991
0.10
0.980–1.003
0.43
Estrogen receptor status
1010
0.09
0.998–1.023
1009
0.38
0.990–1.028
1012
0.14
0.996–1.028
0.81
Malignancy grade
0.998
0.67
0.987–1.008
0.994
0.50
0.997–1.001
1000
0.98
0.987–1.013
0.82
Tumor size
0.996
0.36
0.986–1.005
1007
0.38
0.992–1.021
0.998
0.06
0.976–1.000
0.06 \0.001
Smoking
Alcohol consumption Low vs high risk
0.983
0.001
0.972–0.993
0.953
\0.001
0.934–0.972
0.996
0.58
0.983–1.009
Nodal status
0.983
\0.001
0.974–0.991
0.973
0.002
0.957–0.990
0.987
0.017
0.977–0.998
0.16
Estrogen receptor status
1027
\0.001
1.014–1.041
1022
0.07
0.999–1.045
1030
\0.001
1.014–1.047
0.55
Malignancy grade
0.999
0.86
0.989–1.009
0.982
0.058
0.963–1,001
1008
0.24
0.995–1.020
0.036
Tumor size
0.990
0.038
0.981–0.999
0.989
0.20
0.972–1.006
0.991
0.12
0.981–1.002
0.81
Significant associations (p \ 0.05) are presented in italics Combined and stratified according to menopausal status The independent variables were all treated as dependent variables in logistic regressions. The results are presented as odds ratios (OR) and 95% confidence intervals (CI) P values of the statistical interactions between menopausal status and lifestyle factors are presented for each prognostic parameter a b c
Logistic regression SF-36 physical functioning scale (PF-10) Physical activity scale of the elderly (PASE)
d
No tumor-positive nodes vs tumor-positive nodes
e
Negative vs positive
f
Grade I malignancy and non-ductal vs other
g
B20 vs [20 mm
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however, the difference in magnitude of associations between the two populations reached statistical significance with higher DCA more strongly associated with lower malignancy grade in premenopausal women compared with postmenopausal women (ip = 0.036).
Discussion The main finding of the present study was that lifestylerelated factors such as higher BMI and lower levels of physical functioning and activity were more strongly associated with a higher risk of presenting with poorer tumor-related prognostic factors among premenopausal than postmenopausal women. BMI was a convincing predictor of poor prognostic parameters at the time of diagnosis. The explanation for this finding may differ between pre- and postmenopausal women. In postmenopausal women, associations between the high levels of estradiol in obese women and a corresponding higher risk of estradiol-dependent breast cancer has been established [14]. In premenopausal women, the high prevalence of triple-negative tumors calls for another explanation. Higher levels of growth factors such as insulin and some adipokines in obese women have been suggested as mediators in triple-negative tumors [15]. Another possible explanation for the association between higher BMI and risk of presenting with poorer prognostic factors could be that obesity makes it difficult to detect a tumor in the breast at an early stage [16]. A tumor left undetected for longer time will have a greater risk of disseminating to the regional lymph nodes. One study has thus found that the rates of large invasive breast cancers and advanced-stage breast cancers increase 1.3- to 1.8-fold with each BMI category [17], a finding which has been supported by other studies [18]. Screening was not nationwide in DK at the time of the inception of the present study. Since the population investigated is by large unscreened, there may be an increased element of delay in detection among the obese women, causing them to present with poorer prognostic factors. In the present study, low levels of physical activity and physical functioning were both found to be related to poor prognostic factors at time of diagnosis. This finding is supported by previous research suggesting low physical activity levels to be predictive of poor prognosis and higher mortality in breast cancer [19]. The risk of recurrence was significantly associated with poorer physical function in premenopausal but not in postmenopausal women. It is known that higher levels of exercise in young adulthood reduce the risk of breast cancer [20]. Several hypotheses have been posted to explain the relation between physical activity and tumor growth. Reduced insulin sensitivity
provoked by physical inactivity may facilitate tumor growth because it produces a growth-promotional environment. Conversely, physical activity may improve nonspecific immunity, which is believed to play a role in preventing tumor growth. Finally, it is suggested that exercise probably reduces the exposure to estrogen levels, thereby reducing the risk of breast cancer [21]. A recent review has examined the influence of nutrition and physical activity on breast cancer incidence and outcome [22], and although the authors note a lack of randomized trials, the pattern found was in line with the results of the present study. Higher daily intake of alcohol was associated with lower RoR, and the significance of this association was carried by premenopausal women, as the association was small and non-significant in the group of postmenopausal women. This could be a coincidental finding, and we have no clear explanation. Alcohol increases estrogen levels in the blood, which could feed estrogen receptor-positive breast cancer cells [23]. However, since there was no statistically significant association between DCA and estrogen receptor status, neither in the premenopausal nor in the postmenopausal population, this explanation for the present findings is less likely. No statistically significant associations were found between comorbidity and tumor-related prognostic factors in the present study. One reason could be that, as expected with a mean age of 55.7 years, the rate of comorbidity was relatively low in this cohort of women. Of the 4847 women, only 12.1% reported any type of comorbidity. Studies have shown that women who expose themselves to risk factors for chronic disease, e.g., smoking, inactivity, and poor dietary choices, have a higher risk of developing breast cancer [24] and higher mortality from the disease [25]. Furthermore, women who have undergone any type of adjuvant therapy report significantly more new comorbidity 30-month post diagnosis, suggesting that receiving adjuvant treatment may influence the development of comorbidity [5]. Managing adjuvant treatment and comorbidity is thus a serious concern in early-stage breast cancer, and it is relevant to consider whether women with comorbidity receive relevant doses of adjuvant chemotherapy. The dose of adjuvant chemotherapy is generally adjusted according to body surface. However, in order to protect the women against unwanted and potentially lifethreatening side-effects from chemotherapy, dose capping is often used when the surface exceeds 2.0 m2. This cutoff is almost always met in women with BMI [ 30. Thus, the dosage/m2 is lower in the women with high BMI, and the American Society of Clinical Oncology (ASCO) recently argued against dose capping in a clinical practice guideline released in April 2012 [26]. However, dose
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capping is still practiced in many European countries, including Denmark. New data on the subject continues to emerge. The predominant message is that it is safe to avoid dose capping in obese women receiving adjuvant treatment for early-stage breast cancer, as they do not experience febrile neutropenia or hospital admissions more frequently than leaner women. However, in recognition of the fact that obese patients often suffer from other severe medical problems, clinicians are encouraged to use judgment when dosing [27, 28]. As a result of the continued practice of dose capping, obese patients frequently receive less, and potentially insufficient, therapy compared to women with lower BMI. This may be a reasonable decision in elderly obese patients who have developed comorbidity as a result of their obesity. In younger obese patients, however, the practice of dose capping seems more questionable. Younger women typically have more aggressive tumors with a more violent pattern of recurrence. In 2000, the results of a retrospective study suggested that young age alone should be criteria for more aggressive adjuvant therapy, even if other criteria may suggest low-risk disease [29]. The present results lend support to this conclusion and underscore the need to reconsider the practice of dose capping in younger obese patients. Among the strengths of the present study are that it is based on a large national cohort. This provides more robust results and greater statistical precision. Furthermore, the validation of the diagnosis of early-stage breast cancer by the DBCG increases the homogeneity and representativity of the sample. A possible limitation of our study may lie in the self-reported data on health behaviors, as self-reported data may be prone to information bias in clinical studies. The timing of the questionnaire also represents a concern, as the women receiving adjuvant chemotherapy could have been influenced by this at the time of answering the questionnaire. Thus, health behaviors could be biased, as side-effects of chemotherapy could cause the women to be less physically active, which, in turn, could influence their body weight. Overall, our results are in line with previous findings suggesting that lifestyle factors such as BMI and physical activity influence the prognostic profile of early-stage breast cancer, especially in the younger women. The results suggest that several lifestyle factors are related to a more unfavorable prognostic profile at the time of diagnosis, with the results for BMI being particularly convincing. Reconsidering the continued practice of dose capping seems appropriate, especially in the younger cohort with a higher risk of recurrence. Future data on this Danish cohort of women will reveal whether specific lifestyle patterns can add to the prediction of disease outcome.
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Compliance with Ethical Standards Conflict of interests The authors have no conflicts of interests to disclose. Informed consent Informed consent was obtained from all individual participants included in the study.
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