Breast Cancer Research and Treatment

, Volume 145, Issue 2, pp 545–552

Associations between anthropometric characteristics, physical activity, and breast cancer risk in a Canadian cohort

Authors

    • Department of Epidemiology and Population HealthAlbert Einstein College of Medicine
  • Victoria A. Kirsh
    • Prevention and Cancer ControlCancer Care Ontario
    • Dalla Lana School of Public HealthUniversity of Toronto
  • Colin L. Soskolne
    • University of Alberta
    • Faculty of HealthUniversity of Canberra
  • Nancy Kreiger
    • Prevention and Cancer ControlCancer Care Ontario
    • Dalla Lana School of Public HealthUniversity of Toronto
  • Erin Bruce
    • Faculty of MedicineUniversity of Calgary
  • Thi Ho
    • Prevention and Cancer ControlCancer Care Ontario
  • Scott T. Leatherdale
    • School of Public Health and Health SystemsUniversity of Waterloo
  • Thomas E. Rohan
    • Department of Epidemiology and Population HealthAlbert Einstein College of Medicine
Epidemiology

DOI: 10.1007/s10549-014-2973-z

Cite this article as:
Catsburg, C., Kirsh, V.A., Soskolne, C.L. et al. Breast Cancer Res Treat (2014) 145: 545. doi:10.1007/s10549-014-2973-z

Abstract

Obesity, physical inactivity, and sedentary behavior, concomitants of the modern environment, are potentially modifiable breast cancer risk factors. This study investigated the association of anthropometric measurements, physical activity and sedentary behavior, with the risk of incident, invasive breast cancer using a prospective cohort of women enrolled in the Canadian Study of Diet, Lifestyle and Health. Using a case-cohort design, an age-stratified subcohort of 3,320 women was created from 39,532 female participants who returned completed self-administered lifestyle and dietary questionnaires at baseline. A total of 1,097 incident breast cancer cases were identified from the entire cohort via linkage to the Canadian Cancer Registry. Cox regression models, modified to account for the case-cohort design, were used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association between anthropometric characteristics, physical activity, and the risk of breast cancer. Weight gain as an adult was positively associated with risk of post-menopausal breast cancer, with a 6 % increase in risk for every 5 kg gained since age 20 (HR 1.06; 95 % CI 1.01–1.11). Women who exercised more than 30.9 metabolic equivalent task (MET) hours per week had a 21 % decreased risk of breast cancer compared to women who exercised less than 3 MET hours per week (HR  0.79; 95 % CI 0.62–1.00), most evident in pre-menopausal women (HR  0.62; 95 % CI 0.43–0.90). As obesity reaches epidemic proportions and sedentary lifestyles have become more prevalent in modern populations, programs targeting adult weight gain and promoting physical activity may be beneficial with respect to reducing breast cancer morbidity.

Keywords

Physical activityObesityBreast cancerEpidemiologyAnthropometric measurements

Introduction

The current obesity epidemic can be attributed to a combination of declining levels of physical activity, increased sedentary behavior, and excessive food intake, with rates of obesity continuing to rise globally [1, 2]. Quantifying the adverse health consequences associated with physical inactivity and the attendant obesity has become increasingly important, as these behaviors are modifiable and thus potential targets for public health intervention. Coinciding with the rise in adult weight gain and decrease in physical activity has been a rise in the incidence of many chronic diseases, including cancer [3]. Specifically, it has been hypothesized that a positive energy balance may contribute to the etiology of breast cancer, particularly in post-menopausal women [4]. Individual positive energy balance occurs when the amount of energy intake exceeds the amount of energy expenditure, and manifests itself as weight gain. This balance can be reduced by reducing caloric intake and/or increasing physical activity. In this regard, maintaining a healthy body weight, physical activity promotion, and prevention of sedentary behavior represent promising modifiable targets for reducing the risk of breast cancer.

Although being overweight or obese as an adult has consistently been associated with increased risk of post-menopausal breast cancer, recent evidence indicates that this association may be restricted to women who were not overweight in childhood or adolescence, suggesting that weight gain as an adult may be a more important risk factor than attained body mass [5]. These effects are not seen with pre-menopausal breast cancer, and in fact, there is evidence for a reduced risk of pre-menopausal breast cancer in association with obesity [6, 7]. One important difference between the two is that in post-menopausal women, estrogen is produced mainly by adipose tissue, where it is no longer under homeostatic regulation [7]. Epidemiological studies have related high circulating estrogen levels to an increased risk of breast cancer [8, 9]. In pre-menopause however, estrogen is produced mostly by the ovaries, with circulating estrogen levels under careful homeostatic regulation, and thus levels are not directly affected by excess adipose tissue [7]. Obese pre-menopausal women are also more likely to have irregular menstrual cycles and anovulation, thereby lowering pre-menopausal exposure to estrogen [10, 11].

Regular physical activity has been associated with a decreased risk of both pre- and post-menopausal breast cancer [12]. In post-menopausal women, at least part of this protective effect may arise from preventing weight gain and obesity; however, the fact that protective effects are also observed for pre-menopausal breast cancer suggests an effect of physical activity independent of weight control [9, 13]. Again, estrogen levels may come into play, as it has been demonstrated that high levels of physical activity can decrease circulating estrogen levels while also reducing insulin levels [14]. In addition, recent evidence has emerged that sedentary behavior, defined as prolonged periods of low physical activity, can contribute to breast cancer risk and needs to be considered independently of exercise levels [15, 16].

In the study described here, we evaluated the associations between body mass index (BMI), adult weight gain, and other measures of adiposity with the risk of breast cancer in a prospective cohort of Canadian women. We also investigated the associations of physical activity and estimates of sedentary lifestyles with risk of pre- and post-menopausal breast cancer in this population.

Methods

Study population

The Canadian Study of Diet, Lifestyle, and Health (CSDLH) is a prospective cohort study previously described in detail [17]. Briefly, the study recruited 73,909 Canadian male and female participants, predominantly from alumni of the Universities of Alberta, Toronto and Western Ontario between 1995 and 1998. A small contingent was also recruited through the Canadian Cancer Society, mostly in 1992. At recruitment, participants completed detailed self-administered dietary and lifestyle questionnaires. Incident cases of breast cancer (and other cancers) were ascertained via record linkage to the Canadian Cancer Registry and to the Ontario Cancer Registry. The CCR is a collaborative effort between the thirteen Canadian provincial and territorial cancer registries and the Health Statistics Division of Statistics Canada. Because each Canadian province and territory has a legislated responsibility for cancer collection and control, reporting is virtually complete (estimated at 97 %) [18]. Migration out of Canada was very low during this period (estimated to be less than 0.005 %) [19]. Deaths from all causes were ascertained by means of record linkage to the National Mortality Database, and this information was used as a censoring variable. Follow-up was continued through December 31st 2010 for participants who were resident in Ontario and through December 31st 2005 for participants residing in all other provinces of Canada.

Study design

The analysis reported here was conducted using a case-cohort design. The motivation for using a case-cohort approach was that where the outcomes of interest are relatively rare, as is the case here, this design represents a very cost-effective approach and loses little efficiency compared to a full cohort analysis [20, 21]. The study included a total of 1,097 incident, invasive breast cancer cases, and a subcohort of 3,320 women, which was created by selecting an age-stratified random sample of the entire female cohort at baseline. Given that we were to make comparisons between this selected subcohort and cancer cases, the subcohort was sampled with more weight for older participants. Thus, each 5-year age group had a different sampling fraction that increased with age, thereby attempting to approximate the anticipated distribution of age at diagnosis for all incident cancers.

Lifestyle and physical activity variables

The self-administered lifestyle questionnaire solicited information on a variety of demographic, lifestyle, and social factors including anthropometric measurements (participants were provided at baseline with tape measures and instructions on how to measure their waist and hip circumferences), current weight and weight at age 20, race/ethnicity, education, and medical history, including a detailed reproductive history section. Physical activity was queried extensively in the lifestyle questionnaire, including questions relating to amount of time per week spent walking, hiking, jogging, running, bicycling, in calisthenics or aerobics, playing tennis or squash, lap swimming, and in other aerobic recreation. Questions were also asked about flights of stairs climbed daily and about markers for sedentary lifestyle such as time spent sitting at home or at work and time spent sitting in front of a television screen. The physical activity duration portion of the questionnaire was developed by the Nurses’ Health Study (NHS) investigators [22], and has been validated in the NHS II study population [23]. To compare each activity by intensity, metabolic equivalent task (MET) values were assigned to each activity according to values listed in the Compendium of Physical Activities [24]. Total MET-hours per week were calculated for each individual by multiplying the number of hours per week spent in each activity by the MET score assigned to that activity. Subjects were also asked questions regarding times exercised per week long enough to perspire heavily, and flights of stairs climbed, as well as time spent per week standing/walking at home, standing/walking away from home, driving/sitting away from home, sitting watching television, and other sitting at home.

Statistical analysis

1,097 cases and 3,320 subcohort members contributed to the BMI (calculated as weight (kg)/height (m)2) and weight gain analyses. A total of 24 subjects (3 cases, and 21 subcohort members) were missing information on physical activity, and exclusion of these study subjects left 1,094 cases and 3,299 subcohort members contributing to the physical activity analyses. Hazard ratios for the association between the different exposures and risk of breast cancer were evaluated via Cox regression models, using a modification for case-cohort analysis as described by Langholz and Jiao [25]. Regarding BMI, participants were classified as underweight with a BMI less than 18.5 kg/m2, as normal with a BMI between 18.5 and 24.99 kg/m2, as overweight with a BMI between 25 and 29.99 kg/m2, and as obese with a BMI equal to or greater than 30 kg/m2, as per the WHO classification [26]. Models were adjusted for known breast cancer risk factors selected a priori. These included age (years) at menarche (≤12, 13, ≥14), use of oral contraceptives (never/ever), use of hormone therapy (never, estrogen only, estrogen plus progestin, missing or unspecified), number of live births (nulliparous or missing, 1–2, ≥3), age (years) at first live birth (<25, 25–29, ≥30, nulliparous or missing), family history of breast cancer (yes/no), menopausal status at baseline, alcohol intake in grams per day, BMI in kg/m2 as a continuous variable (for physical activity models) and physical activity in MET hours per week as a continuous variable (for BMI and weight models). Associations were assessed among the entire cohort and also stratified by menopausal status at baseline.

BMI and weight gain analyses were also stratified by use of hormone therapy (ever/never) in post-menopausal women. Physical activity analyses were also stratified by BMI (<25/≥25 kg/m2), and in post-menopausal women, by use of hormone therapy (ever/never).

Results

Cases were younger, had a shorter follow-up time, and were more likely to have a family history of breast cancer than members of the subcohort (Table 1). Among post-menopausal women only, cases had a higher BMI, higher alcohol intake, and were more likely to have used oral contraceptives and hormone replacement therapy. Among pre-menopausal women, cases had lower average physical activity than subcohort members (Table 1).
Table 1

Distribution of selected baseline characteristics in cases and women in the subcohort

 

Pre-menopausal women

Post-menopausal women

 

Cases (n = 556)

Subcohort (n = 1,110)

Cases (n = 541)

Subcohort (n = 2,210)

Lifestyle variables, mean (SD)

 Age at baseline (years)

44.8 (8.9)

45.8 (8.9)

63.7 (9.6)

67.9 (11.2)

 Follow-up (years)

7.7 (4.1)

14.0 (2.8)

6.7 (4.2)

12.2 (4.0)

 BMI (kg/m2)

24.0 (4.0)

24.1 (4.4)

25.0 (4.2)

24.5 (4.1)

 Physical activity, (MET h/week)

21.0 (32.5)

26.8 (46.8)

19.7 (31.4)

18.2 (24.7)

 Alcohol intake (gpd)

8.3 (11.3)

7.7 (10.5)

10.2 (14.4)

9.0 (12.7)

 Age at menarche (years)

12.6 (1.3)

12.8 (1.5)

12.7 (1.3)

12.7 (1.6)

 Parity, no. of children

1.6 (1.3)

1.7 (1.3)

2.0 (1.6)

2.1 (1.8)

 Age at first childbirth (years)

28.1 (4.7)

27.7 (4.4)

27.4 (4.8)

27.3 (4.7)

 Age at menopause (years)

48.3 (6.5)

48.3 (6.1)

Lifestyle variables, N (%)

   

 Race—White

522 (93.9)

1038 (93.5)

523 (96.7)

2141 (96.9)

 Family Hx of breast cancer

63 (11.3)

80 (7.2)

88 (16.3)

266 (12.0)

 Breastfed

355 (63.9)

713 (64.2)

323 (59.7)

1283 (58.1)

 Oral contraceptive use

467 (84.0)

940 (84.7)

279 (51.6)

939 (42.5)

 Hormone therapy (HT) use

260 (48.1)

955 (43.2)

Current BMI and BMI at age 20 were not associated with risk of breast cancer in this study population. Weight gain as an adult was associated with risk of post-menopausal breast cancer only, with a weight gain of greater than 15.9 kg since age 20 incurring a 39 % increase in risk (HR 1.39; 95 % CI 0.98–1.98; ptrend = 0.01) (Table 2). This equated to an approximate 6 % increase in risk of post-menopausal breast cancer with every 5 kg gained since age 20 (HR 1.06; 95 % CI 1.01–1.11). Other anthropometric measurements such as waist circumference, waist to hip ratio, and waist to height ratio were not associated with risk of breast cancer (Table 2). The associations of BMI and weight gain with post-menopausal breast cancer risk were not modified by use of hormone therapy (Supplementary Table 1).
Table 2

Body mass index (BMI), weight gain, and risk of breast cancer stratified by menopausal status

 

All subjects

Pre-menopausal

Post-menopausal

 

Cases

HRa (95 % CI)

Cases

HRa (95 % CI)

Cases

HRa (95 % CI)

BMI at baseline (kg/m2)

 Underweight

26

1.05 (0.65–1.68)

12

0.79 (0.39–1.61)

14

1.40 (0.75–2.62)

 Normal

665

1.0Ref.

372

1.0Ref.

293

1.0Ref.

 Overweight

296

1.15 (0.97–1.35)

124

1.06 (0.82–1.38)

172

1.22 (0.99–1.52)

 Obese

110

1.09 (0.85–1.39)

48

0.97 (0.66–1.43)

62

1.24 (0.90–1.71)

 P for trendb

 

0.22

 

0.88

 

0.08

BMI at age 20 (kg/m2)

 Underweight

152

1.19 (0.97–1.47)

80

1.09 (0.81–1.48)

72

1.32 (0.98–1.77)

 Normal

861

1.0Ref.

441

1.0Ref.

420

1.0Ref.

 Overweight

45

0.85 (0.60–1.21)

19

0.73 (0.42–1.25)

26

1.00 (0.63–1.59)

 Obese

6

0.59 (0.24–1.45)

5

0.96 (0.33–2.81)

1

0.21 (0.03–1.59)

 P for trendb

 

0.11

 

0.36

 

0.21

Adult Weight Gain (kg)

 None/lost

129

1.0Ref.

67

1.0Ref.

62

1.0Ref.

 <4.6

221

1.21 (0.94–1.56)

132

1.38 (0.96–1.98)

89

1.03 (0.71–1.49)

 4.6–9.5

242

1.31 (1.02–1.69)

140

1.49 (1.04–2.14)

102

1.08 (0.76–1.55)

 9.5–15.9

276

1.52 (1.19–1.96)

128

1.70 (1.18–2.45)

148

1.37 (0.97–1.92)

 >15.9

204

1.23 (0.95–1.60)

81

1.05 (0.71–1.56)

123

1.39 (0.98–1.98)

 P for trend

 

0.12

 

0.88

 

0.01

Waist circumference (cm)

 <73

224

1.0Ref.

154

1.0Ref.

70

1.0Ref.

 73–78.7

226

1.16 (0.93–1.45)

135

1.11 (0.83–1.49)

91

1.20 (0.84–1.71)

 78.7–84.8

233

1.16 (0.93–1.45)

112

1.08 (0.80–1.47)

121

1.28 (0.91–1.78)

 84.8–92.7

212

1.32 (1.05–1.67)

85

1.50 (1.06–2.12)

127

1.29 (0.93–1.80)

 >92.7

183

1.06 (0.84–1.34)

62

0.84 (0.59–1.21)

121

1.30 (0.92–1.82)

 P for trend

 

0.12

 

0.51

 

0.09

Waist: hip ratio

 <0.76

275

1.0Ref.

180

1.0Ref.

95

1.0Ref.

 0.76–0.79

234

0.92 (0.74–1.14)

145

0.94 (0.71–1.25)

89

0.84 (0.60–1.17)

 0.79–0.83

210

0.93 (0.75–1.16)

105

1.02 (0.76–1.39)

105

0.86 (0.62–1.18)

 0.83–0.88

186

0.92 (0.73–1.15)

71

0.88 (0.62–1.24)

115

0.93 (0.67–1.28)

 >0.88

170

0.95 (0.75–1.20)

45

0.74 (0.49–1.11)

125

1.08 (0.78–1.49)

 P for trend

 

0.41

 

0.39

 

0.79

Waist: height ratio

 <0.45

253

1.0Ref.

179

1.0Ref.

74

1.0Ref.

 0.45–0.48

230

1.02 (0.82–1.27)

130

1.07 (0.80–1.43)

100

0.95 (0.67–1.34)

 0.48–0.52

193

0.96 (0.77–1.21)

98

0.97 (0.71–1.32)

95

0.96 (0.68–1.36)

 0.52–0.57

216

1.17 (0.94–1.47)

76

1.04 (0.74–1.46)

140

1.28 (0.92–1.78)

 >0.57

170

0.94 (0.74–1.19)

58

0.86 (0.59–1.23)

112

1.02 (0.72–1.43)

 P for trend

 

0.88

 

0.85

 

0.62

aModels adjusted for age (years) at menarche (≤12, 13, ≥14), use of oral contraceptives (never/ever), use of hormone therapy (never, estrogen only, estrogen plus progestin, missing or unspecified), number of live births (nulliparous or missing, 1–2, ≥3), age (years) at first live birth (<25, 25–29, ≥30, nulliparous or missing), family history of breast cancer (yes/no), menopausal status at baseline, alcohol intake (gpd), and physical activity in MET hours per week

bUnderweight subjects were included with normal subjects for calculation of trend

For all study subjects combined, physical activity was associated with a decrease in breast cancer risk when measured in either MET hours or total hours per week (Table 3). Women who exercised more than an average of 30.9 MET hours per week had a 21 % decreased risk of breast cancer (HR 0.79; 95 % CI 0.62–1.00; ptrend = 0.004). Similarly, women who exercised more than 7.5 h per week (all types of exercise combined) had a 23 % decreased risk of breast cancer (HR 0.77; 95 % CI 0.61–0.97; ptrend = 0.01). These associations were stronger among pre-menopausal women, where exercising >30.9 MET hours per week was associated with a 38 % decreased risk of pre-menopausal breast cancer (HR 0.62; 95 % CI 0.43–0.90; ptrend = 0.002). Among post-menopausal women, exercising >30.9 MET hours per week was associated with a non-significant 4 % decreased risk of post-menopausal breast cancer (HR 0.96; 95 % CI 0.69–1.32; ptrend = 0.42). The number of times performing physical activity per week long enough to perspire heavily was not associated with risk of breast cancer, nor was flights of stairs climbed daily (Table 3). The association between physical activity and breast cancer risk was stronger among normal weight women than those who were overweight or obese, although this difference was not statistically significant (Supplementary Table 2). Use of hormone therapy did not modify the association between physical activity and breast cancer risk (Supplementary Table 3). Sedentary activity, measured via time spent sitting and time spent in front of the television, was not associated with risk of breast cancer risk in this study population (Table 4).
Table 3

Physical activity and risk of breast cancer stratified by menopausal status

 

All subjects

Pre-menopausal

Post-menopausal

 

Cases

HRa (95 % CI)

Cases

HRa (95 % CI)

Cases

HRa (95 % CI)

Total MET hours per week

 <3

185

1.0Ref.

81

1.0Ref.

104

1.0Ref.

 3–8.5

227

1.07 (0.85–1.36)

118

0.97 (0.68–1.39)

109

1.09 (0.80–1.48)

 8.5–16.8

254

1.07 (0.85–1.35)

135

0.92 (0.64–1.31)

119

1.22 (0.89–1.65)

 16.8–30.9

213

0.93 (0.73–1.18)

112

0.82 (0.57–1.19)

101

1.00 (0.73–1.37)

 >30.9

195

0.79 (0.62–1.00)

100

0.62 (0.43–0.90)

95

0.96 (0.69–1.32)

 P for trend

 

0.004

 

0.002

 

0.42

Total hours per week

 <1

229

1.0Ref.

109

1.0Ref.

120

1.0Ref.

 1–2.3

196

1.03 (0.82–1.30)

105

0.89 (0.63–1.25)

91

1.14 (0.83–1.56)

 2.3–3.8

239

1.03 (0.82–1.29)

120

0.84 (0.60–1.18)

119

1.21 (0.90–1.64)

 3.8–7.5

241

0.92 (0.74–1.15)

128

0.83 (0.60–1.16)

113

0.99 (0.73–1.33)

 >7.5

169

0.77 (0.61–0.97)

84

0.62 (0.44–0.89)

85

0.91 (0.66–1.25)

 P for trend

 

0.01

 

0.01

 

0.21

Times per week

 <1

393

1.0Ref.

197

1.0Ref.

196

1.0Ref.

 1

164

1.07 (0.86–1.34)

88

1.09 (0.79–1.50)

76

1.01 (0.74–1.37)

 2–3

313

0.95 (0.80–1.14)

158

0.84 (0.65–1.09)

155

1.07 (0.84–1.38)

 4–6

157

0.99 (0.79–1.23)

92

1.05 (0.77–1.44)

65

0.89 (0.64–1.23)

 >7

20

0.77 (0.46–1.30)

5

0.38 (0.14–1.01)

15

1.27 (0.69–2.34)

 P for trend

 

0.43

 

0.34

 

0.92

Flights of stairs climbed daily

 <2

315

1.0Ref.

136

1.0Ref.

179

1.0Ref.

 3–4

208

1.01 (0.82–1.24)

111

0.93 (0.68–1.26)

97

1.12 (0.84–1.50)

 5–9

277

1.02 (0.83–1.24)

139

0.90 (0.67–1.22)

138

1.18 (0.91–1.54)

 10–14

169

1.02 (0.81–1.29)

96

0.97 (0.69–1.36)

73

1.03 (0.75–1.42)

 >15

89

0.88 (0.66–1.18)

58

0.89 (0.60–1.32)

31

0.83 (0.54–1.29)

 P for trend

 

0.87

 

0.52

 

0.24

aModels adjusted for age (years) at menarche (≤12, 13, ≥14), use of oral contraceptives (never/ever), use of hormone therapy (never, estrogen only, estrogen plus progestin, missing or unspecified), number of live births (nulliparous or missing, 1–2, ≥3), age (years) at first live birth (<25, 25–29, ≥30, nulliparous or missing), family history of breast cancer (yes/no), menopausal status at baseline, alcohol intake in grams per day, and BMI in kg/m2

Table 4

Sedentary behavior and risk of breast cancer stratified by menopausal status

 

All subjects

Pre-menopausal

Post-menopausal

 

Cases

HRa (95 % CI)

Cases

HRa (95 % CI)

Cases

HRa (95 % CI)

Time sent sitting

 <12.5

191

1.0Ref.

99

1.0Ref.

92

1.0Ref.

 12.5–24

190

0.90 (0.71–1.15)

103

0.92 (0.65–1.31)

87

0.88 (0.63–1.23)

 24–39

265

1.08 (0.86–1.35)

140

1.08 (0.78–1.50)

125

1.09 (0.80–1.49)

 39–54

227

1.10 (0.87–1.38)

110

1.05 (0.74–1.48)

117

1.17 (0.85–1.62)

 >54

167

0.98 (0.76–1.25)

86

0.99 (0.68–1.43)

81

0.98 (0.69–1.39)

 P for trend

 

0.63

 

0.82

 

0.54

Time spent in front of the television

 ≤1

152

1.0Ref.

86

1.0Ref.

66

1.0Ref.

 2–5

343

1.07 (0.85–1.35)

200

1.29 (0.93–1.78)

143

0.88 (0.63–1.23)

 6–10

267

1.04 (0.82–1.33)

131

1.06 (0.74–1.50)

136

1.03 (0.73–1.45)

 11–20

202

0.98 (0.76–1.27)

91

1.13 (0.77–1.66)

111

0.87 (0.61–1.23)

 ≥21

105

1.17 (0.86–1.59)

35

1.08 (0.65–1.79)

70

1.20 (0.81–1.80)

 P for trend

 

0.62

 

0.74

 

0.27

aModels adjusted for age (years) at menarche (≤12, 13, ≥14), use of oral contraceptives (never/ever), use of hormone therapy (never, estrogen only, estrogen plus progestin, missing or unspecified), number of live births (nulliparous or missing, 1–2, ≥3), age (years) at first live birth (<25, 25–29, ≥30, nulliparous or missing), family history of breast cancer (yes/no), menopausal status at baseline, alcohol intake in grams per day, and BMI in kg/m2

Discussion

We found an increased risk of post-menopausal breast cancer with adult weight gain, even in the absence of a direct association between BMI or other anthropometric measures and breast cancer risk. We also found that increasing levels of physical activity were associated with a decreased risk of breast cancer, particularly in pre-menopausal women. Sedentary behavior was not associated with risk in either pre-menopausal or post-menopausal women.

Adipose tissue has the capacity to synthesize estrogen and can contribute significantly to circulating estrogen levels in post-menopausal women [27, 28]. In turn, adiposity-related changes in insulin can inhibit the synthesis of sex hormone-binding globulin (SHBG), resulting in increased bioavailability of estrogen [29]. Measures of obesity, such as BMI and waist circumference, have consistently been associated with post-menopausal breast cancer risk, while consistently showing a null or even decreased risk with pre-menopausal breast cancer [30]. The differential effect of menopausal status on estrogen exposure is most likely responsible for this heterogeneity. Pre-menopausal obese women often have lower exposure to estrogen via irregular menstrual cycles and anovulation [10, 11], and they are also more likely to have low mammographic density [31], one of the strongest known risk factors for breast cancer. Currently, the most commonly used measure of obesity and adiposity is BMI. However, adult weight gain has recently gained recognition as a more direct indicator of adiposity and obesity-associated metabolic changes. The reasoning behind this is that where BMI reflects both lean mass and adipose tissue, weight gained as an adult is more likely to be due predominantly to an increase in adipose tissue [5, 32, 33]. There is also epidemiological evidence that adult weight gain is a more predictive factor for post-menopausal breast cancer than BMI [34, 35]. Results from our study are consistent with this, given that, although we found no evidence for an increased risk of post-menopausal breast cancer with increasing BMI, we found that adult weight gain was strongly associated with post-menopausal breast cancer risk. This study estimated a 6 % increase in post-menopausal breast cancer risk with every 5 kg gained since age 20, consistent with previous studies which have estimated a 4–15 % increase in risk per 5 kg weight gain [32, 33, 36]. Considering recent evidence that the body weight of a typical 45-year-old Canadian woman has increased on average by 5.2 kg between 1981 and 2009 [1], this suggests that the future burden from obesity-related breast cancer is likely to continue to increase.

Many observational epidemiologic studies have been published on the role of physical activity in the etiology of breast cancer, indicating a clear inverse dose–response association between physical activity and breast cancer risk [15]. Most studies have found a 20–40 % decrease in risk of breast cancer among the most physically active, observed in both pre- and post-menopausal women [15]. The study reported here is at least partially consistent with the literature, in that we found those in the highest category of MET hours (>30.9 per week; roughly equivalent to 10 h brisk walking per week) had a 21 % decrease in breast cancer risk in all study subjects combined, and a 38 % decrease in risk when considering pre-menopausal women only. Although the protective effect of physical activity is probably due, at least in part, to direct control of weight gain, the effects of high levels of physical exercise may be mediated by other mechanisms, particularly for pre-menopausal women [12]. Intense physical activity has long been shown to increase irregular menstrual cycles and anovulation in young women, and thus lower pre-menopausal estrogen exposure [37, 38]. There is evidence that these same preventive effects may be evident even at low to moderate levels of exercise [9, 39]. Moreover, in both pre- and post-menopausal women, physical activity may reduce breast cancer risk by improving insulin sensitivity and decreasing levels of insulin and insulin-like growth factor [40, 41], thereby increasing SHBG and lowering estrogen bioavailability [14], and improving immune defense [42, 43].

Sedentary behavior, defined as prolonged periods of low (≤1.5 MET hours) physical activity, has recently emerged as a potential risk factor for breast cancer, independent of physical activity levels [15, 16]. We found no association between markers for a sedentary lifestyle and risk of breast cancer in this study population. However, sedentary lifestyle is inherently difficult to assess via questionnaire, and the markers that we used (i.e., time spent sitting and time spent in front of the television) may not accurately reflect the degree of sedentary activity. A further limitation of this study is that menopausal status was assessed only at baseline, so that many of those who were pre-menopausal at enrolment would have become post-menopausal during the course of follow-up. As a result, our sub-group of women classified as having pre-menopausal breast cancer may be a mix of women with pre- and post-menopausal breast cancers. As the majority of participants were recruited from alumni associations, the women in our study were generally well-educated, and may not be representative of the physical activity patterns of the general Canadian population. There is, however, no biologic rationale to suggest that the effect of physical activity on the risk of cancer would differ between university alumni and other sub-populations. Strengths of this study include the large sample size, and the near complete follow-up, resulting in a large number of breast cancer cases. Further strengths were the prospective study design, helping to limit the effects of recall bias, and the detailed information collected on both physical activity exposures and potential confounders.

In summary, this study provides evidence that adult weight gain may be more predictive of post-menopausal breast cancer risk than other measures of obesity such as BMI or waist circumference. We also found that physical activity was associated with reduced risk of breast cancer, particularly in pre-menopausal women, suggesting mechanisms independent of weight control. As obesity reaches epidemic proportions and sedentary lifestyles have become more prevalent in modern populations, programs targeting minimization of adult weight gain and promoting physical activity may be beneficial with respect to reducing breast cancer morbidity.

Acknowledgments

Drs. Rohan and Catsburg are supported by the Breast Cancer Research Foundation. Financial support partially provided by the Canadian Tobacco Control Research Initiative (Grant 016025 awarded to S. Leatherdale).

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

10549_2014_2973_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 22 kb)

Copyright information

© Springer Science+Business Media New York 2014