Body size, modifying factors, and postmenopausal breast cancer risk in a multiethnic population: the San Francisco Bay Area Breast Cancer Study

  • Esther M John1, 2Email author,

    Affiliated with

    • Amanda I Phipps3 and

      Affiliated with

      • Meera Sangaramoorthy1

        Affiliated with

        SpringerPlus20132:239

        DOI: 10.1186/2193-1801-2-239

        Received: 16 April 2013

        Accepted: 29 April 2013

        Published: 24 May 2013

        Abstract

        Data on body size and postmenopausal breast cancer in Hispanic and African American women are inconsistent, possibly due to the influence of modifying factors. We examined associations between adiposity and risk of breast cancer defined by hormone receptor status in a population-based case-control study conducted from 1995–2004 in the San Francisco Bay Area. Multivariate adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. Associations with body size were limited to women not currently using menopausal hormone therapy (801 cases, 1336 controls). High young-adult body mass index (BMI) was inversely associated with postmenopausal breast cancer risk, regardless of hormone receptor status, whereas high current BMI and high adult weight gain were associated with two-fold increased risk of estrogen receptor and progesterone receptor positive breast cancer, but only in women with a low young-adult BMI (≤22.4 kg/m2) or those with ≥15 years since menopause. Odds ratios were stronger among non-Hispanic Whites than Hispanics and African Americans. Waist circumference and waist-to-height ratio increased breast cancer risk in Hispanics and African Americans only, independent of BMI. These findings emphasize the importance of considering tumor hormone receptor status and other modifying factors in studies of racially/ethnically diverse populations.

        Keywords

        African Americans Body size Breast cancer Estrogen receptor Hispanics Progesterone receptor

        Introduction

        Obesity has long been recognized as a risk factor for postmenopausal breast cancer (BC) in studies of primarily non-Hispanic White (NHW) women (World Cancer Research Fund / American Institute for Cancer Research 2007). Only three studies in Hispanics (Wenten et al. 2002; Slattery et al. 2007; White et al. 2012) and eight studies in African Americans (AA) (White et al. 2012; Austin et al. 1979; Schatzkin et al. 1987; Adams-Campbell et al. 1996; Hall et al. 2000; Zhu et al. 2005; Palmer et al. 2007; Berstad et al. 2010) examined the relation between obesity and postmenopausal BC risk, and some of their findings contradict those reported for NHW women, suggesting differences in effects by racial/ethnic groups (Slattery et al. 2007; Sexton et al. 2011). In NHWs, BC risk is increased by 3-5% both per 2 kg/m2 increase in body mass index (BMI) and per 5 kg of weight gain (World Cancer Research Fund / American Institute for Cancer Research 2007). Young-adult obesity, on the other hand, has been associated with reduced postmenopausal BC risk, both in cohort (Barnes-Josiah et al. 1995; Huang et al. 1997; Morimoto et al. 2002; Ahn et al. 2007) and case–control (Berstad et al. 2010; Chu et al. 1991; Brinton & Swanson 1992; Magnusson et al. 1998) studies. A number of factors appear to modify the relation with body size. Increased risks associated with BMI and weight gain may be limited to women with a low young-adult BMI (Chu et al. 1991; Canchola et al. 2012). Stronger associations with body size have been found in women with estrogen receptor and progesterone receptor positive (ER+PR+) BC (Potter et al. 1995; Huang et al. 2000; Colditz et al. 2004; Suzuki et al. 2009), those not using menopausal hormone therapy (HT) (Morimoto et al. 2002; Friedenreich 2001; Feigelson et al. 2004), or with longer time since menopause (Chu et al. 1991; Magnusson et al. 1998; Macinnis et al. 2004). Data on abdominal obesity and BC risk in postmenopausal women are also inconsistent (World Cancer Research Fund / American Institute for Cancer Research 2007) and uncertainties remain whether associations are independent of overall obesity or differ by race/ethnicity.

        We report on the relation between overall and abdominal adiposity and risk of postmenopausal BC defined by hormone receptor status in a multiethnic population, and the role of modifying factors.

        Materials and methods

        Study population

        The San Francisco Bay Area Breast Cancer Study, a population-based case-control study (John et al. 2003; John et al. 2005), identified 17,581 women aged 35–79 years with newly diagnosed invasive BC through the Greater Bay Area Cancer Registry. Following telephone screening on study eligibility (83% participation), 2,571 cases were selected (all Hispanics diagnosed from 1995–2002, all AAs diagnosed from 1995–1999, and a 10% random sample of NHWs diagnosed from 1995–1999). An in-person interview was completed by 2,258 (88%) cases, including 1,119 (89%) Hispanics, 543 (87%) AAs, and 596 (86%) NHWs.

        Population controls, identified through random-digit dialing, were frequency-matched on race/ethnicity and 5-year age group (John et al. 2003). Of 3,170 eligible controls, 2,706 (85%) completed the in-person interview, including 1,462 (88%) Hispanics, 598 (82%) AAs, and 646 (83%) NHWs.

        This analysis was restricted to postmenopausal women (1,389 cases, 1,644 controls). Women were considered postmenopausal if their periods had stopped more than one year prior to diagnosis (cases) or selection into the study (controls), if they reported a bilateral oophorectomy, or if they were aged ≥55 years at the time of diagnosis/selection and had either started hormone therapy prior to the cessation of menses or had had a simple hysterectomy (without oophorectomy).

        Data collection

        Information on adult height, weight in the reference year (defined as the calendar year before diagnosis for cases or before selection into the study for controls), young-adult weight, and other BC risk factors was collected using a structured questionnaire, administered in English or Spanish. Young-adult weight was based on reported weight at age 25–30 years for cases diagnosed before May 1998 and their matched controls, and on reported weight at age 20–29 years for cases diagnosed in May 1998 or later and their matched controls. Interviewers also took measurements of weight, height, waist and hip circumference (described in (John et al. 2010)). Lifetime physical activity was assessed, as described elsewhere (John et al. 2003). Usual dietary intake and alcohol consumption during the reference year was assessed by a modified version of the Block food frequency questionnaire (Block et al. 1986). Cancer registry information on ER and PR status was available for 85% of cases. The study was approved by the Institutional Review Board of the Cancer Prevention Institute of California and participants provided written informed consent.

        Body size variables

        Current BMI was calculated as weight (kg) divided by height squared (m2), based on measured height at interview (or self-reported height for 10% of cases and 9% of controls who declined height measurements) and self-reported weight in the reference year (or measured weight at interview for 1% of cases and 3% of controls without self-report). BMI was classified as normal weight (<25.0 kg/m2), overweight (25.0-29.9 kg/m2) and obese (≥30.0 kg/m2) (WHO 2000). Underweight (BMI <18.5 kg/m2) women (9 cases, 16 controls) were grouped with normal weight women. Young-adult BMI was based on measured height at interview and self-reported weight in a woman’s twenties. Adult weight gain was calculated as the difference between self-reported young-adult weight and weight in the reference year. Waist-to-hip ratio (WHR) was calculated as a measure of body fat distribution reflecting both adipose tissue and muscle mass; waist-to-height ratio (WHtR) was calculated as a measure of visceral adiposity independent of height, which may more directly reflect abdominal adiposity (Molarius & Seidell 1998). WHR, WHtR, and waist and hip circumferences were categorized according to the tertile distribution among controls.

        Statistical analysis

        Unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) comparing cases to controls, both overall and separately for each racial/ethnic group. Polytomous logistic regression was used to compare ER+PR+ and ER-PR- case groups with a common control group. For all BCs combined and ER+PR+ BCs, multivariate analyses were adjusted for age (continuous) and factors significantly associated with BC risk in our study: birth place, education, first-degree family history of BC, personal history of benign breast disease, age at menarche, number of full-term pregnancies, age at first full-term pregnancy, lifetime breast-feeding, average lifetime physical activity, alcohol consumption, and caloric intake, categorized as shown in the tables. For ER-PR- BCs, analyses were adjusted for age, birth place, age at menarche, and lifetime breast-feeding. Analyses of all BCs combined were also adjusted for race/ethnicity. Analyses of current BMI, young-adult BMI and weight gain were mutually adjusted for each other. Linear trends were assessed across ordinal values of categorical variables. Significant differences in ORs between groups were tested using the Wald statistic P value. Two-sided P values are reported for tests of trend and interaction, with P values <0.05 considered statistically significant.

        We assessed associations with current BMI and weight change within strata defined by median young-adult BMI (≤22.4 kg/m2, >22.4 kg/m2), median time since menopause (<15, ≥15 years), and, in analyses of abdominal adiposity, by current BMI (<25.0 kg/m2, ≥25.0 kg/m2). Primary analyses were restricted to women not currently using menopausal HT, as previous studies have found no associations with body size among current HT users (Huang et al. 1997; Morimoto et al. 2002). Current HT use was defined as starting HT prior to the year of diagnosis/selection and reported use during the year of diagnosis/selection. All other women were classified as non-current HT users. Time since menopause was calculated as the difference between age at menopause and age at diagnosis/selection. Age at menopause was based on self-report for women with natural menopause and age at bilateral oophorectomy for women with surgical menopause.

        The final analysis was based on 2,884 postmenopausal women (1,316 cases, 1,568 controls) after excluding 34 cases and 50 controls with missing information on confounding variables and 39 cases and 26 controls with unreliable caloric intake (<600 kcal/day or >5,000 kcal/day). Statistical analyses were conducted using SAS version 9.3 software (SAS Institute, Inc., Cary, North Carolina).

        Results

        Cases were more likely than controls to be U.S.-born, have a first-degree family history of BC, a personal history of benign breast disease, higher education, earlier menarche, fewer full-term pregnancies, a shorter duration of breast-feeding, lower lifetime physical activity, and higher alcohol consumption (Table 1).
        Table 1

        Characteristics of postmenopausal cases and controls

         

        Cases (n = 1,316)

        Controls (n = 1,568)

        P value

         

        n

        %a

        n

        %a

         

        Age (years)

             

         35–44

        20

        2

        25

        2

         

         45–54

        199

        15

        260

        17

         

         55–64

        531

        40

        625

        40

         

         65–74

        407

        31

        509

        33

         

         ≥75

        159

        12

        149

        10

         

        Race/ethnicity

             

         Hispanic

        614

        47

        804

        51

         

         Non-Hispanic White

        389

        30

        399

        26

         

         African American

        313

        24

        365

        23

         

        Joint ER/PR status

             

         ER+PR+

        714

        54

           

         ER+PR-

        168

        13

           

         ER-PR+

        21

        2

           

         ER-PR-

        204

        16

           

         Missing

        209

        16

           

        Menopausal hormone therapy use

            

        <0.01

         Never

        517

        39

        644

        41

         

         Former

        284

        22

        692

        44

         

         Current

        498

        38

        214

        14

         

         Missing

        17

        1

        18

        1

         

        Place of birth

            

        <0.01

         U.S.-bornb

        1,014

        77

        1,036

        66

         

         Foreign-born

        302

        23

        532

        34

         

        Education (years)

            

        <0.01

         Some high school or less

        398

        30

        600

        38

         

         High school or vocational/technical school graduate

        373

        28

        426

        27

         

         Some college

        297

        23

        297

        19

         

         College graduate

        248

        19

        245

        16

         

        Family history of breast cancer in first-degree relatives

            

        <0.01

         No

        1,089

        83

        1,371

        87

         

         Yes

        227

        17

        197

        13

         

        Personal history of biopsy-confirmed benign breast disease

            

        0.01

         No

        1,016

        77

        1,274

        81

         

         Yes

        300

        23

        294

        19

         

        Age at menarche

            

        <0.01

         ≤11

        304

        23

        327

        21

         

         12

        349

        27

        356

        23

         

         13

        319

        24

        387

        25

         

         ≥14

        344

        26

        498

        32

         

        Parity

            

        <0.01

         Nulliparous

        169

        13

        145

        9

         

         Parous

        1,147

        87

        1,423

        91

         

        Number of full-term pregnancies, parous women

            

        <0.01

         1

        162

        14

        177

        12

         

         2

        309

        27

        303

        21

         

         3

        263

        23

        349

        25

         

         ≥4

        413

        36

        594

        42

         

        Age at first full-term pregnancy (years), parous women

            

        <0.01

         ≤19

        302

        26

        415

        29

         

         20–24

        462

        40

        564

        40

         

         25–29

        235

        21

        298

        21

         

         ≥30

        148

        13

        146

        10

         

        Lifetime breast-feeding (months), parous women

            

        <0.01

         0

        541

        47

        547

        38

         

         ≤ 6

        250

        22

        294

        21

         

         7–12

        97

        8

        148

        10

         

         13–24

        126

        11

        184

        13

         

         ≥25

        133

        12

        250

        18

         

        Lifetime physical activityc (hours/week)

            

        0.04

         ≤ 6.9

        376

        29

        391

        25

         

         7.0-14.1

        342

        26

        390

        25

         

         14.2-25.4

        291

        22

        403

        26

         

         ≥25.5

        307

        23

        384

        25

         

        Alcohol consumptiond,e (g/day)

            

        <0.01

         0

        763

        58

        975

        62

         

         0.1-4.9

        262

        20

        312

        20

         

         5.0-9.9

        68

        5

        91

        6

         

         10.0-19.9

        115

        9

        107

        7

         

         ≥20

        108

        8

        83

        5

         

        Total caloric intakec,d,e (kcal/day)

            

        0.05

         ≤ 1362

        287

        22

        394

        25

         

         1363–1798

        343

        26

        385

        25

         

         1799–2435

        379

        29

        398

        25

         

         ≥2436

        307

        23

        391

        25

         

        Abbreviations: ER-, estrogen receptor–negative; ER+, estrogen receptor–positive; PR-, progesterone receptor–negative; PR+, progesterone receptor–positive.

        a Percentages may not add up to 100% due to rounding.

        b U.S.-born includes 43 cases and 34 controls born in westernized countries such as Canada, Europe, Australia, or New Zealand.

        c Quartiles among all postmenopausal controls.

        d In reference year.

        e Excludes 39 cases and 26 controls whose total caloric intake was <600 kcal/day or >5,000 kcal/day.

        Body size characteristics differed by race/ethnicity (Table 2). Among controls, the proportion of currently obese women (BMI ≥30.0 kg/m2) was higher in AAs and Hispanics than in NHWs. High young-adult BMI was twice as common in Hispanics as in NHWs, whereas the proportion of women with high weight gain was similar in the two groups. The prevalence of high weight gain, large waist and hip circumferences, and high WHR was lowest in NHWs, intermediate in Hispanics, and more than twice as high in AAs than in NHWs.
        Table 2

        Body size among control women by race/ethnicity

         

        Hispanics (n = 804)

        African Americans (n = 365)

        Non-Hispanic Whites (n = 399)

        P valuea

         

        n

        %b

        n

        %b

        n

        %b

         

        Current BMI (kg/m2) c

              

        * †

         <25.0

        147

        18

        80

        22

        185

        47

         25.0-29.9

        310

        39

        124

        34

        116

        29

         ≥30.0

        342

        43

        159

        44

        97

        24

        Young-adult BMI (kg/m2) d,e

              

        * ‡

         Q1: ≤20.6

        125

        17

        116

        32

        130

        33

         Q2: 20.7-22.4

        170

        23

        83

        23

        118

        30

         Q3: 22.5-24.7

        210

        29

        84

        23

        76

        19

         Q4: >24.7

        225

        31

        77

        21

        69

        18

        Weight gain (kg) f

              

        * † ‡

         Stable g

        80

        11

        31

        9

        65

        18

         Gain, 3.0-9.9

        176

        25

        66

        19

        113

        31

         Gain, 10.0-19.9

        234

        33

        91

        26

        96

        26

         Gain, 20.0-29.9

        142

        20

        83

        24

        63

        17

         Gain, ≥30.0

        74

        11

        76

        22

        34

        9

        Waist (cm) d

              

        * † ‡

         Q1: ≤ 82.3

        170

        22

        41

        14

        150

        43

         Q2: 82.4-90.5

        211

        27

        65

        22

        77

        22

         Q3: 90.6-99.8

        196

        25

        90

        30

        67

        19

         Q4: >99.8

        195

        25

        102

        34

        57

        16

        Hip (cm) d

              

        * † ‡

         Q1: ≤ 100.5

        206

        27

        48

        16

        103

        29

         Q2: 100.6-107.5

        186

        24

        60

        20

        107

        31

         Q3: 107.6-116.2

        183

        24

        85

        29

        87

        25

         Q4: >116.2

        196

        25

        105

        35

        54

        15

        Waist-to-hip ratio (WHR) d

              

        * † ‡

         Q1: ≤ 0.79

        172

        22

        52

        18

        163

        46

         Q2: 0.80-0.84

        224

        29

        70

        24

        83

        24

         Q3: 0.85-0.88

        190

        25

        83

        28

        53

        15

         Q4: >0.88

        185

        24

        92

        31

        52

        15

        Waist-to-height ratio (WHtR) d

              

        * †

         Q1: ≤ 0.52

        138

        18

        56

        19

        162

        46

         Q2: 0.53-0.58

        195

        25

        78

        26

        82

        23

         Q3: 0.59-0.64

        216

        28

        81

        27

        58

        17

         Q4: >0.64

        223

        29

        83

        28

        49

        14

        Abbreviation: BMI, body mass index.

        a Chi-square test for the difference between race/ethnicity; * = P <0.05 between non-Hispanic Whites and Hispanics; † = P <0.05 between non-Hispanic Whites and African Americans; ‡ = P <0.05 between Hispanics and African Americans.

        b Percentages may not add up to 100% due to rounding.

        c Based on self-reported adult weight and measured height at interview (if not available, then based on measured weight at interview and/or self-reported adult height).

        d Based on quartiles among all postmenopausal controls.

        e Based on self-reported young-adult weight and measured height at interview (or self-reported adult height when measured height not available).

        f Self-reported adult weight (or measured weight at interview if self-reported weight not available) minus self-reported young-adult weight; excludes 64 controls who lost >3 kg of weight.

        g Stable weight defined as +/- 3 kg.

        For women not currently using HT, associations with current BMI and adult weight gain were limited to those with ER+PR+ tumors, although after adjustment for weight gain, no association remained with current BMI (Table 3). The positive association with weight gain was not altered by adjustment for current BMI (Table 3) or young-adult BMI (data not shown), and was largely driven by the increased risk found for NHW women. Young-adult BMI was associated with reduced risk of postmenopausal BC, with similar results for BC overall (>23.7 vs. ≤21.2 kg/m2: OR = 0.68, 95% CI:0.54-0.86, Ptrend < 0.01) and ER+PR+ BC (>23.7 vs. ≤21.2 kg/m2: OR = 0.73, 95% CI:0.54-0.98, Ptrend = 0.04). Inverse associations, however, were found only among Hispanic and NHW women.
        Table 3

        BMI and weight gain and breast cancer risk in postmenopausal women not currently using hormone therapy by race/ethnicity a and estrogen receptor and progesterone receptor status

         

        All race/ethnicities

        Hispanics

        African Americans

        Non-Hispanic Whites

        All breast cancer

        Cases (n = 801)

        Controls (n = 1,336)

        OR b 95% CI

        Cases (n = 377)

        Controls (n = 709)

        OR c 95% CI

        Cases (n = 243)

        Controls (n = 315)

        OR c 95% CI

        Cases (n = 181)

        Controls (n = 312)

        OR c 95% CI

        Current BMI (kg/m2) d

                    

         <25.0

        208

        329

        1.0

        81

        119

        1.0

        51

        70

        1.0

        76

        140

        1.0

         25.0-29.9

        278

        476

        0.95 0.74-1.21

        133

        273

        0.78 0.54-1.14

        90

        106

        1.19 0.74-1.94

        55

        97

        0.90 0.56-1.43

         ≥30.0

        312

        523

        0.94 0.74-1.20

        161

        312

        0.77 0.53-1.12

        101

        137

        1.07 0.66-1.73

        50

        74

        1.19 0.72-1.99

           

        Ptrend = 0.64

          

        Ptrend = 0.24

          

        Ptrend = 0.88

          

        Ptrend = 0.58

        Current BMI (kg/m2) –adjusted for weight gain d,e

                    

         <25.0

          

        1.0

          

        1.0

          

        1.0

          

        1.0

         25.0-29.9

          

        0.90 0.67-1.20

          

        0.80 0.52-1.25

          

        1.25 0.70-2.26

          

        0.63 0.34-1.16

         ≥30.0

          

        0.79 0.56-1.13

          

        0.73 0.43-1.24

          

        1.15 0.57-2.30

          

        0.52 0.22-1.22

           

        Ptrend = 0.75

          

        Ptrend = 0.26

          

        Ptrend = 0.77

          

        Ptrend = 0.11

        Young-adult BMI (kg/m2) f,g

                    

         T1: ≤21.2

        286

        402

        1.0

        109

        161

        1.0

        93

        122

        1.0

        84

        119

        1.0

         T2: 21.3-23.7

        259

        411

        0.87 0.69-1.09

        122

        209

        0.85 0.60-1.20

        77

        90

        1.17 0.76-1.79

        60

        112

        0.65 0.41-1.02

         T3: >23.7

        216

        445

        0.68 0.54-0.86

        115

        272

        0.63 0.45-0.90

        67

        98

        0.93 0.59-1.45

        34

        75

        0.52 0.30-0.90

           

        Ptrend < 0.01

          

        Ptrend = 0.01

          

        Ptrend = 0.80

          

        Ptrend = 0.01

        Weight gain (kg) h,i

        78

        140

                  

         Stable j

        180

        291

        1.0

        36

        65

        1.0

        18

        26

        1.0

        24

        49

        1.0

         Gain, 3.0-9.9

        217

        376

        1.15 0.82-1.63

        82

        149

        1.05 0.63-1.76

        50

        55

        1.27 0.59-2.73

        48

        87

        1.27 0.67-2.43

         Gain, 10.0-19.9

        142

        247

        1.06 0.76-1.48

        101

        217

        0.88 0.54-1.45

        68

        80

        1.18 0.57-2.44

        48

        79

        1.36 0.71-2.62

         Gain, 20.0-29.9

        111

        154

        1.03 0.72-1.48

        71

        125

        1.04 0.61-1.78

        44

        72

        0.91 0.43-1.93

        27

        50

        1.19 0.57-2.48

         Gain, ≥30.0

          

        1.19 0.81-1.75

        38

        67

        0.91 0.50-1.66

        51

        64

        1.13 0.54-2.39

        22

        23

        2.63 1.12-6.19

           

        Ptrend = 0.75

          

        Ptrend = 0.75

          

        Ptrend = 0.75

          

        Ptrend = 0.10

        Weight gain (kg) – adjusted for current BMI h,i,k

                    

         Stable j

          

        1.0

          

        1.0

          

        1.0

          

        1.0

         Gain, 3.0-9.9

          

        1.17 0.83-1.65

          

        1.07 0.64-1.80

          

        1.17 0.54-2.56

          

        1.38 0.71-2.67

         Gain, 10.0-19.9

          

        1.14 0.79-1.65

          

        1.00 0.58-1.70

          

        1.00 0.45-2.24

          

        1.92 0.89-4.15

         Gain, 20.0-29.9

          

        1.17 0.77-1.78

          

        1.22 0.66-2.25

          

        0.76 0.32-1.85

          

        1.94 0.75-5.03

         Gain, ≥30.0

          

        1.41 0.88-2.26

          

        1.12 0.55-2.27

          

        0.99 0.39-2.49

          

        4.70 1.48-14.97

           

        Ptrend = 0.24

          

        Ptrend = 0.67

          

        Ptrend = 0.68

          

        Ptrend = 0.02

        ER+PR+ breast cancer

        Cases (n = 415)

        Controls (n = 1,336)

        OR b 95% CI

        Cases (n = 191)

        Controls (n = 709)

        OR c 95% CI

        Cases (n = 108)

        Controls (n = 315)

        OR c 95% CI

        Cases (n = 116)

        Controls (n = 312)

        OR c 95% CI

        Current BMI (kg/m2) d

                    

         <25.0

        98

        329

        1.0

        34

        119

        1.0

        19

        70

        1.0

        45

        140

        1.0

         25.0-29.9

        141

        476

        1.09 0.80-1.49

        60

        273

        0.90 0.54-1.49

        44

        106

        1.76 0.89-3.47

        37

        97

        1.06 0.61-1.85

         ≥30.0

        175

        523

        1.30 0.95-1.78

        96

        312

        1.23 0.75-2.01

        45

        137

        1.46 0.74-2.89

        34

        74

        1.39 0.76-2.55

           

        Ptrend = 0.09

          

        Ptrend = 0.22

          

        Ptrend = 0.40

          

        Ptrend = 0.30

        Current BMI (kg/m2) – adjusted for weight gain d,e

                    

         <25.0

          

        1.0

          

        1.0

          

        1.0

          

        1.0

         25.0-29.9

          

        1.06 0.73-1.54

          

        1.01 0.56-1.84

          

        1.77 0.78-4.06

          

        0.74 0.35-1.56

         ≥30.0

          

        1.01 0.64-1.60

          

        1.17 0.58-2.35

          

        1.29 0.48-3.48

          

        0.64 0.23-1.76

           

        Ptrend = 0.99

          

        Ptrend = 0.62

          

        Ptrend = 0.78

          

        Ptrend = 0.37

        Young-adult BMI (kg/m2) f,g

                    

         T1: ≤21.2

        147

        402

        1.0

        51

        161

        1.0

        45

        122

        1.0

        51

        119

        1.0

         T2: 21.3-23.7

        133

        411

        0.87 0.65-1.15

        58

        209

        0.87 0.55-1.37

        35

        90

        1.23 0.69-2.20

        40

        112

        0.66 0.38-1.15

         T3: >23.7

        116

        445

        0.73 0.54-0.98

        65

        272

        0.80 0.51-1.25

        28

        98

        0.73 0.39-1.36

        23

        75

        0.52 0.27-1.00

           

        Ptrend = 0.04

          

        Ptrend = 0.33

          

        Ptrend = 0.39

          

        Ptrend = 0.04

        Weight gain (kg) h,l

                    

         Stable j

        44

        140

        1.0

        18

        65

        1.0

        9

        26

        1.0

        17

        49

        1.0

         Gain, 3.0-9.9

        79

        291

        0.94 0.61-1.46

        32

        149

        0.80 0.41-1.58

        20

        55

        1.11 0.40-3.14

        27

        87

        1.02 0.48-2.18

         Gain, 10.0-19.9

        114

        376

        1.07 0.71-1.62

        55

        217

        1.00 0.53-1.88

        26

        80

        0.96 0.36-2.57

        33

        79

        1.48 0.70-3.15

         Gain, 20.0-29.9

        77

        247

        1.12 0.72-1.74

        34

        125

        1.02 0.52-2.03

        25

        72

        1.19 0.44-3.18

        18

        50

        1.29 0.55-3.04

         Gain, ≥30.0

        67

        154

        1.53 0.96-2.45

        29

        67

        1.43 0.70-2.94

        24

        64

        1.27 0.47-3.42

        14

        23

        2.56 0.95-6.88

           

        Ptrend = 0.04

          

        Ptrend = 0.16

          

        Ptrend = 0.58

          

        Ptrend = 0.07

        Weight gain (kg) – adjusted for current BMI h,k,l

                    

         Stable j

          

        1.0

          

        1.0

          

        1.0

          

        1.0

         Gain, 3.0-9.9

          

        0.93 0.60-1.44

          

        0.81 0.41-1.59

          

        0.92 0.31-2.67

          

        1.09 0.50-2.38

         Gain, 10.0-19.9

          

        1.04 0.66-1.65

          

        0.96 0.49-1.89

          

        0.67 0.22-2.04

          

        1.90 0.77-4.73

         Gain, 20.0-29.9

          

        1.10 0.65-1.86

          

        0.93 0.43-2.05

          

        0.85 0.26-2.77

          

        1.80 0.58-5.63

         Gain, ≥30.0

          

        1.53 0.85-2.73

          

        1.29 0.55-3.01

          

        1.02 0.29-3.58

          

        3.82 0.99-14.71

        Ptrend = 0.13

        Ptrend = 0.48

        Ptrend = 0.90

        Ptrend = 0.06

        Abbreviations: BMI, body mass index; CI, confidence interval; ER+, estrogen receptor–positive; OR, odds ratio; PR+, progesterone receptor–positive.

        a All P values for interaction by race/ethnicity were >0.05.

        b Adjusted for age (years, continuous), race/ethnicity (non-Hispanic White, African American, Hispanic), place of birth (U.S.-born, foreign-born), education (some high school or less, high school or vocational/technical school graduate, some college, college graduate), first-degree family history of breast cancer (no, yes), personal history of biopsy-confirmed benign breast disease (no, yes), age at menarche (≤11, 12, 13, ≥14 years), number of full-term pregnancies (nulliparous, 1, 2, 3, ≥4), age at first full-term pregnancy (nulliparous, ≤19, 20–24, 25–29, ≥30 years), lifetime breast-feeding (nulliparous, 0, ≤6, 7–12, 13–24, ≥25 months), lifetime physical activity (quartiles, hours/week), alcohol consumption in reference year (0, 0.1-4.9, 5–9.9, 10–19.9, ≥20 g/day), and total caloric intake (quartiles, kcal/day).

        c Not adjusted for race/ethnicity.

        d Based on self-reported weight and measured height at interview (if not available, then based on measured weight at interview and/or self-reported height).

        e Adjusted for above variables, and weight gain.

        f Based on tertiles among all postmenopausal controls.

        g Based on self-reported young-adult weight and measured height at interview (or self-reported adult height when measured height not available).

        h Self-reported weight (or measured weight at interview if self-reported weight not available) minus self-reported young-adult weight.

        i Excludes 34 cases and 55 controls who lost >3 kg of weight.

        j Stable weight defined as +/- 3 kg.

        k Adjusted for above variables, and current BMI.

        l Excludes 15 ER+PR+ cases and 55 controls who lost >3 kg of weight.

        Young-adult BMI was an important modifying factor (Table 4). For ER+PR+ BC, associations with high BMI (OR = 1.97, Ptrend = 0.01) and high weight gain (OR = 1.71, Ptrend = 0.03) were limited to women with a young-adult BMI ≤22.4 kg/m2. No increased risks were found among women with both high young-adult BMI and high current BMI. Associations were also influenced by time since menopause. High weight gain was associated with two-fold increased risks of BC overall (OR = 2.71, 95% CI:1.29-5.69, Ptrend = 0.01) and ER+PR+ BC (OR = 2.47, 95% CI:1.03-5.94, Ptrend = 0.03) only in women who had experienced menopause ≥15 years ago. Similarly, the inverse association of young-adult BMI with BC risk overall was seen only in women with ≥15 years since menopause (>23.7 vs. ≤21.2 kg/m2: OR = 0.59, 95% CI:0.41-0.85, Ptrend < 0.01).
        Table 4

        BMI and weight gain and breast cancer risk in postmenopausal women not currently using hormone therapy by young-adult BMI and time since menopause

         

        Young-adult BMI

        Young-adult BMI

         

        ≤22.4 kg/m2

        >22.4 kg/m2

        All breast cancer

        Cases (n = 413)

        Controls (n = 614)

        OR a 95% CI

        Cases (n = 348)

        Controls (n = 644)

        OR a 95% CI

        P interaction

        Current BMI (kg/m2) b

              

        0.01

         <25.0

        167

        243

        1.0

        38

        77

        1.0

         25.0-29.9

        131

        232

        0.77 0.56-1.06

        136

        217

        1.28 0.80-2.05

         ≥30.0

        115

        138

        1.22 0.86-1.74

        174

        350

        0.92 0.58-1.45

        Ptrend = 0.42

        Ptrend = 0.19

        Weight gain (kg) c,d

              

        0.12

         Stable e

        35

        52

        1.0

        43

        87

        1.0

         Gain, 3.0-9.9

        106

        142

        1.20 0.71-2.03

        74

        148

        1.03 0.64-1.66

         Gain, 10.0-19.9

        109

        198

        0.82 0.49-1.38

        108

        176

        1.26 0.80-1.99

         Gain, 20.0-29.9

        90

        126

        1.11 0.65-1.91

        51

        120

        0.81 0.48-1.36

         Gain, ≥30.0

        67

        84

        1.14 0.64-2.05

        44

        69

        1.08 0.62-1.90

         
           

        Ptrend = 0.84

          

        Ptrend = 0.81

         

        ER+PR+ breast cancer

        Cases (n = 209)

        Controls (n = 614)

        OR a 95% CI

        Cases (n = 187)

        Controls (n = 644)

        OR a 95% CI

        P interaction

        Current BMI (kg/m2) b

              

        0.01

         <25.0

        77

        243

        1.0

        19

        77

        1.0

         25.0-29.9

        63

        232

        0.87 0.57-1.32

        74

        217

        1.42 0.78-2.59

         ≥30.0

        69

        138

        1.97 1.26-3.09

        94

        350

        1.10 0.61-1.98

        Ptrend = 0.01

        Ptrend = 0.69

        Weight gain (kg) c,f

              

        0.08

        Stable e

        20

        52

        1.0

        24

        87

        1.0

         Gain, 3.0-9.9

        42

        142

        0.97 0.50-1.88

        37

        148

        0.99 0.54-1.80

         Gain, 10.0-19.9

        52

        198

        0.83 0.43-1.59

        62

        176

        1.44 0.82-2.54

         Gain, 20.0-29.9

        50

        126

        1.35 0.69-2.64

        27

        120

        0.88 0.46-1.69

         Gain, ≥30.0

        41

        84

        1.71 0.83-3.52

        26

        69

        1.48 0.75-2.94

         
           

        Ptrend = 0.03

          

        Ptrend = 0.42

         
         

        <15 Years Since Menopause g

        ≥15 Years Since Menopause g

         

        All breast cancer

        Cases (n = 335)

        Controls (n = 552)

        OR a 95% CI

        Cases (n = 352)

        Controls (n = 576)

        OR a 95% CI

        P interaction

        Current BMI (kg/m2) b

              

        0.09

         <25.0

        98

        134

        1.0

        82

        138

        1.0

         25.0-29.9

        115

        187

        0.85 0.57-1.26

        126

        229

        0.97 0.67-1.41

         ≥30.0

        120

        227

        0.70 0.47-1.03

        143

        205

        1.24 0.84-1.81

        Ptrend = 0.07

        Ptrend = 0.22

        Current BMI (kg/m2) –adjusted for weight gain b,h

              

        0.31

         <25.0

          

        1.0

          

        1.0

         25.0-29.9

        0.89 0.56-1.42

        0.73 0.46-1.15

         ≥30.0

        0.85 0.47-1.51

        0.68 0.39-1.18

        Ptrend = 0.58

        Ptrend = 0.20

        Young-adult BMI (kg/m2) i,j

              

        0.57

         T1: ≤21.2

        120

        181

        1.0

        127

        163

        1.0

         T2: 21.3-23.7

        112

        163

        1.03 0.72-1.48

        112

        174

        0.82 0.58-1.16

         T3: >23.7

        90

        181

        0.78 0.53-1.14

        92

        199

        0.59 0.41-0.85

        Ptrend = 0.22

        Ptrend < 0.01

        Weight gain (kg) c,k

              

        0.12

         Stable e

        33

        55

        1.0

        32

        68

        1.0

         Gain, 3.0-9.9

        85

        116

        1.13 0.65-1.96

        72

        133

        1.29 0.76-2.20

         Gain, 10.0-19.9

        101

        165

        0.89 0.53-1.52

        92

        152

        1.40 0.83-2.35

         Gain, 20.0-29.9

        52

        98

        0.82 0.46-1.48

        66

        105

        1.44 0.83-2.50

         Gain, ≥30.0

        40

        73

        0.69 0.37-1.30

        53

        55

        2.09 1.15-3.81

        Ptrend = 0.08

        Ptrend = 0.02

        Weight gain (kg) – adjusted for current BMI c,k,l

              

        0.12

         Stable e

          

        1.0

          

        1.0

         Gain, 3.0-9.9

          

        1.16 0.67-2.01

          

        1.34 0.78-2.30

         Gain, 10.0-19.9

          

        0.96 0.54-1.71

          

        1.67 0.93-2.99

         Gain, 20.0-29.9

          

        0.91 0.46-1.82

          

        1.77 0.92-3.38

         Gain, ≥30.0

          

        0.78 0.36-1.68

          

        2.71 1.29-5.69

         
           

        Ptrend = 0.40

          

        Ptrend = 0.01

         

        ER+PR+ breast cancer

        Cases (n = 156)

        Controls (n = 552)

        OR a 95% CI

        Cases (n = 201)

        Controls (n = 576)

        OR a 95% CI

        P interaction

        Current BMI (kg/m2) b

              

        0.45

         <25.0

        42

        134

        1.0

        40

        138

        1.0

         25.0-29.9

        47

        187

        0.89 0.53-1.50

        77

        229

        1.26 0.79-2.02

         ≥30.0

        66

        227

        1.07 0.64-1.78

        84

        205

        1.63 1.00-2.65

        Ptrend = 0.71

        Ptrend = 0.05

        Current BMI (kg/m2) –adjusted for weight gain b,h

              

        0.43

         <25.0

          

        1.0

          

        1.0

         25.0-29.9

          

        0.97 0.52-1.81

          

        1.15 0.64-2.07

         ≥30.0

          

        1.35 0.63-2.87

          

        0.94 0.46-1.92

        Ptrend = 0.40

        Ptrend = 0.75

        Young-adult BMI (kg/m2) i,j

              

        0.76

         T1: ≤21.2

        56

        181

        1.0

        67

        163

        1.0

         T2: 21.3-23.7

        49

        163

        1.00 0.62-1.59

        66

        174

        0.89 0.58-1.37

         T3: >23.7

        45

        181

        0.89 0.54-1.46

        58

        199

        0.70 0.45-1.10

        Ptrend = 0.64

        Ptrend = 0.12

        Weight gain (kg) c,m

              

        0.51

         Stable e

        16

        55

        1.0

        22

        68

        1.0

         Gain, 3.0-9.9

        34

        116

        0.94 0.46-1.93

        34

        133

        0.93 0.48-1.77

         Gain, 10.0-19.9

        48

        165

        0.98 0.49-1.94

        53

        152

        1.25 0.68-2.30

         Gain, 20.0-29.9

        24

        98

        0.85 0.40-1.84

        40

        105

        1.38 0.72-2.64

         Gain, ≥30.0

        24

        73

        0.99 0.45-2.17

        33

        55

        2.32 1.15-4.69

        Ptrend = 0.91

        Ptrend = 0.01

        Weight gain (kg) – adjusted for current BMI c,l,m

              

        0.48

         Stable e

          

        1.0

          

        1.0

         Gain, 3.0-9.9

          

        0.95 0.46-1.95

          

        0.86 0.44-1.68

         Gain, 10.0-19.9

          

        0.94 0.44-1.97

          

        1.17 0.59-2.33

         Gain, 20.0-29.9

          

        0.70 0.28-1.73

          

        1.39 0.64-3.01

         Gain, ≥30.0

          

        0.76 0.29-1.99

          

        2.47 1.03-5.94

        Ptrend = 0.50

        Ptrend = 0.03

        Abbreviations: BMI, body mass index; CI, confidence interval; ER+, estrogen receptor–positive; OR, odds ratio; PR+, progesterone receptor–positive.

        a Adjusted for age (years, continuous), race/ethnicity (non-Hispanic White, African American, Hispanic), place of birth (U.S.-born, foreign-born), education (some high school or less, high school or vocational/technical school graduate, some college, college graduate), family history of breast cancer in first-degree relatives (no, yes), personal history of biopsy-confirmed benign breast disease (no, yes), age at menarche (≤11, 12, 13, ≥14 years), number of full-term pregnancies (nulliparous, 1, 2, 3, ≥4), age at first full-term pregnancy (nulliparous, ≤19, 20–24, 25–29, ≥30 years), lifetime breast-feeding (nulliparous, 0, ≤6, 7–12, 13–24, ≥25 months), lifetime physical activity (quartiles, hours/week), alcohol consumption in reference year (0, 0.1-4.9, 5–9.9, 10–19.9, ≥20 g/day), and total caloric intake (quartiles, kcal/day).

        b Based on self-reported weight and measured height at interview (if not available, then based on measured weight at interview and/or self-reported height).

        c Self-reported weight (or measured weight at interview if self-reported weight not available) minus self-reported young-adult weight.

        d Excludes 34 cases and 55 controls who lost >3 kg of weight.

        e Stable weight defined as +/- 3 kg.

        f Excludes 15 ER+PR+ cases and 55 controls who lost >3 kg of weight.

        g Among women with natural or surgical menopause only.

        h Adjusted for above variables, and weight gain.

        i Based on tertiles among all postmenopausal controls.

        j Based on self-reported young-adult weight and measured height at interview (or self-reported adult height when measured height not available).

        k Excludes 28 cases and 46 controls who lost >3 kg of weight.

        l Adjusted for above variables, and current BMI.

        m Excludes 13 ER+PR+ cases and 46 controls who lost >3 kg of weight.

        Waist circumference was associated with ER+PR+ BC in Hispanics (Ptrend = 0.01) and AAs (Ptrend = 0.05) only, with two- to three-fold increased ORs for large waist size that were independent of current BMI (Table 5). Associations were slightly stronger for ER+PR+ disease than BC overall. Large hip circumference was associated with elevated ORs in Hispanics and NHWs, with a significant trend in Hispanics (Ptrend = 0.01). There was no association with WHR (data not shown). High WHtR was associated with elevated ORs in Hispanics and AAs, with a significant trend in Hispanics (Ptrend = 0.01). For waist and hip circumferences and WHtR, associations did not vary by time since menopause (data not shown). Considering the joint effects of abdominal adiposity and overall adiposity (Table 6), we found that large waist circumference was associated with increased BC risk only in women with a BMI <25 kg/m2. A similar pattern was seen for WHtR. For ER+PR+ disease, ORs were elevated, regardless of BMI, but significant only in women with a BMI ≥25 kg/m2.
        Table 5

        Abdominal adiposity and breast cancer risk in postmenopausal women not currently using hormone therapy by race/ethnicity a

         

        All race/ethnicities

        Hispanics

        African Americans

        Non-Hispanic Whites

        All breast cancer

        Cases (n = 801)

        Controls (n = 1,336)

        OR b 95% CI

        Cases (n = 377)

        Controls (n = 709)

        OR c 95% CI

        Cases (n = 243)

        Controls (n = 315)

        OR c 95% CI

        Cases (n = 181)

        Controls (n = 312)

        OR c 95% CI

        Waist (cm) d

                    

         T1: ≤ 85.0

        198

        385

        1.0

        96

        201

        1.0

        30

        54

        1.0

        72

        130

        1.0

         T2: 85.1-96.4

        214

        407

        0.99 0.77-1.27

        113

        245

        0.90 0.63-1.27

        59

        78

        1.55 0.85-2.83

        42

        84

        0.91 0.55-1.52

         T3: >96.4

        293

        412

        1.32 1.03-1.69

        146

        232

        1.27 0.90-1.79

        102

        120

        1.83 1.04-3.21

        45

        60

        1.24 0.72-2.13

           

        Ptrend = 0.02

          

        Ptrend = 0.14

          

        Ptrend = 0.05

          

        Ptrend = 0.52

        Waist (cm) – adjusted for current BMI d,e

                    

         T1: ≤ 85.0

          

        1.0

          

        1.0

          

        1.0

          

        1.0

         T2: 85.1-96.4

          

        1.09 0.82-1.44

          

        1.08 0.73-1.60

          

        1.64 0.84-3.20

          

        0.80 0.44-1.47

         T3: >96.4

          

        1.59 1.15-2.19

          

        1.79 1.14-2.81

          

        2.17 1.05-4.49

          

        0.90 0.42-1.91

           

        Ptrend < 0.01

          

        Ptrend = 0.01

          

        Ptrend = 0.04

          

        Ptrend = 0.75

        Hip (cm) d

                    

         T1: ≤ 102.9

        194

        394

        1.0

        105

        224

        1.0

        39

        60

        1.0

        50

        110

        1.0

         T2: 103.0-112.7

        230

        402

        1.15 0.90-1.47

        119

        229

        1.13 0.80-1.58

        54

        77

        1.06 0.60-1.88

        57

        96

        1.46 0.87-2.43

         T3: >112.7

        281

        407

        1.36 1.07-1.73

        131

        224

        1.22 0.87-1.71

        98

        115

        1.51 0.89-2.56

        52

        68

        1.80 1.03-3.14

           

        Ptrend = 0.01

          

        Ptrend = 0.26

          

        Ptrend = 0.09

          

        Ptrend = 0.04

        Hip (cm) – adjusted for current BMI d,e

                    

         T1: ≤ 102.9

          

        1.0

          

        1.0

          

        1.0

          

        1.0

         T2: 103.0-112.7

          

        1.27 0.97-1.66

          

        1.34 0.92-1.94

          

        1.04 0.54-2.00

          

        1.58 0.90-2.79

         T3: >112.7

          

        1.66 1.20-2.30

          

        1.64 1.05-2.58

          

        1.68 0.82-3.42

          

        1.88 0.86-4.10

           

        Ptrend < 0.01

          

        Ptrend = 0.03

          

        Ptrend = 0.10

          

        Ptrend = 0.09

        Waist-to-height ratio d

                    

         T1: ≤ 0.54

        200

        372

        1.0

        80

        153

        1.0

        42

        70

        1.0

        78

        149

        1.0

         T2: 0.55-0.61

        226

        410

        1.05 0.81-1.35

        117

        254

        0.88 0.61-1.28

        64

        85

        1.42 0.82-2.45

        45

        71

        1.27 0.76-2.12

         T3: >0.61

        279

        422

        1.27 0.98-1.64

        158

        271

        1.13 0.78-1.62

        85

        97

        1.74 1.02-2.96

        36

        54

        1.16 0.65-2.06

           

        Ptrend = 0.06

          

        Ptrend = 0.37

          

        Ptrend = 0.05

          

        Ptrend = 0.51

        Waist-to-height ratio – adjusted for current BMI d,e

                    

         T1: ≤ 0.54

          

        1.0

          

        1.0

          

        1.0

          

        1.0

         T2: 0.55-0.61

          

        1.14 0.86-1.52

          

        1.05 0.69-1.60

          

        1.55 0.82-2.91

          

        1.13 0.61-2.09

         T3: >0.61

          

        1.49 1.06-2.09

          

        1.55 0.96-2.50

          

        2.22 1.09-4.51

          

        0.85 0.39-1.84

           

        Ptrend = 0.02

          

        Ptrend = 0.05

          

        Ptrend = 0.03

          

        Ptrend = 0.72

        ER+PR+ breast cancer

        Cases (n = 415)

        Controls (n = 1,336)

        OR b 95% CI

        Cases (n = 191)

        Controls (n = 709)

        OR c 95% CI

        Cases (n = 108)

        Controls (n = 315)

        OR c 95% CI

        Cases (n = 116)

        Controls (n = 312)

        OR c 95% CI

        Waist (cm) d

                    

         T1: ≤ 85.0

        95

        385

        1.0

        42

        201

        1.0

        8

        54

        1.0

        45

        130

        1.0

         T2: 85.1-96.4

        106

        407

        1.11 0.80-1.54

        55

        245

        1.01 0.63-1.61

        26

        78

        2.70 1.01-7.17

        25

        84

        0.88 0.48-1.63

         T3: >96.4

        162

        412

        1.76 1.28-2.41

        84

        232

        1.79 1.14-2.81

        46

        120

        3.31 1.29-8.48

        32

        60

        1.38 0.75-2.56

           

        Ptrend < 0.01

          

        Ptrend = 0.01

          

        Ptrend = 0.02

          

        Ptrend = 0.33

        Waist (cm) – adjusted for current BMI d,e

                    

         T1: ≤ 85.0

          

        1.0

          

        1.0

          

        1.0

          

        1.0

         T2: 85.1-96.4

          

        1.13 0.78-1.63

          

        1.12 0.66-1.90

          

        2.48 0.86-7.19

          

        0.75 0.37-1.52

         T3: >96.4

          

        1.83 1.21-2.79

          

        2.03 1.11-3.70

          

        3.36 1.10-10.28

          

        0.98 0.41-2.32

           

        Ptrend < 0.01

          

        Ptrend = 0.01

          

        Ptrend = 0.05

          

        Ptrend = 0.93

        Hip (cm) d

                    

         T1: ≤ 102.9

        92

        394

        1.0

        46

        224

        1.0

        17

        60

        1.0

        29

        110

        1.0

         T2: 103.0-112.7

        118

        402

        1.32 0.96-1.81

        56

        229

        1.23 0.78-1.94

        23

        77

        1.04 0.48-2.28

        39

        96

        1.76 0.95-3.25

         T3: >112.7

        153

        407

        1.77 1.30-2.42

        79

        224

        1.85 1.19-2.85

        40

        115

        1.54 0.74-3.21

        34

        68

        2.06 1.07-3.97

           

        Ptrend < 0.01

          

        Ptrend = 0.01

          

        Ptrend = 0.20

          

        Ptrend = 0.03

        Hip (cm) – adjusted for current BMI d,e

                    

         T1: ≤ 102.9

          

        1.0

          

        1.0

          

        1.0

          

        1.0

         T2: 103.0-112.7

          

        1.36 0.96-1.93

          

        1.38 0.83-2.28

          

        0.77 0.31-1.88

          

        1.81 0.92-3.56

         T3: >112.7

          

        1.85 1.22-2.81

          

        2.12 1.17-3.84

          

        1.18 0.45-3.08

          

        1.96 0.78-4.91

           

        Ptrend < 0.01

          

        Ptrend = 0.01

          

        Ptrend = 0.57

          

        Ptrend = 0.12

        Waist-to-height ratio d

                    

         T1: ≤ 0.54

        98

        372

        1.0

        36

        153

        1.0

        14

        70

        1.0

        48

        149

        1.0

         T2: 0.55-0.61

        112

        410

        1.15 0.83-1.59

        51

        254

        0.88 0.53-1.46

        30

        85

        1.94 0.86-4.35

        31

        71

        1.44 0.79-2.65

         T3: >0.61

        153

        422

        1.61 1.16-2.23

        94

        271

        1.63 1.02-2.62

        36

        97

        2.19 0.99-4.82

        23

        54

        1.14 0.59-2.23

           

        Ptrend < 0.01

          

        Ptrend = 0.01

          

        Ptrend = 0.07

          

        Ptrend = 0.49

        Waist-to-height ratio –adjusted for current BMI d,e

                    

         T1: ≤ 0.54

          

        1.0

          

        1.0

          

        1.0

          

        1.0

         T2: 0.55-0.61

          

        1.13 0.77-1.64

          

        0.97 0.55-1.73

          

        1.75 0.72-4.26

          

        1.19 0.58-2.48

         T3: >0.61

          

        1.55 1.00-2.39

          

        1.83 0.97-3.47

          

        2.19 0.81-5.93

          

        0.74 0.30-1.85

        Ptrend = 0.04

        Ptrend = 0.02

        Ptrend = 0.14

        Ptrend = 0.62

        Abbreviations: BMI, body mass index; CI, confidence interval; ER+, estrogen receptor–positive; OR, odds ratio; PR+, progesterone receptor–positive.

        a All P values for interaction by race/ethnicity were >0.05.

        b Adjusted for age (years, continuous), race/ethnicity (non-Hispanic White, African American, Hispanic), place of birth (U.S.-born, foreign-born), education (some high school or less, high school or vocational/technical school graduate, some college, college graduate), first-degree family history of breast cancer (no, yes), personal history of biopsy-confirmed benign breast disease (no, yes), age at menarche (≤11, 12, 13, ≥14 years), number of full-term pregnancies (nulliparous, 1, 2, 3, ≥4), age at first full-term pregnancy (nulliparous, ≤19, 20–24, 25–29, ≥30 years), lifetime breast-feeding (nulliparous, 0, ≤6, 7–12, 13–24, ≥25 months), lifetime physical activity (quartiles, hours/week), alcohol consumption in reference year (0, 0.1-4.9, 5–9.9, 10–19.9, ≥20 g/day), and total caloric intake (quartiles, kcal/day).

        c Adjusted for above variables, except race/ethnicity.

        d Based on tertiles among all postmenopausal controls.

        e Adjusted for above variables, and current BMI.

        Table 6

        Abdominal adiposity and breast cancer risk in postmenopausal women not currently using hormone therapy by current BMI

         

        Current BMI < 25.0kg/m2

        Current BMI ≥ 25.0kg/m2

         

        All breast cancer

        Cases (n=396)

        Controls (n=648)

        OR a 95% CI

        Cases (n=402)

        Controls (n=680)

        OR a 95% CI

        P interaction

        Waist (cm) b

               

         M1: ≤ 90.5

        151

        272

        1.00

        140

        321

        0.87 0.65-1.18

        0.25

         M2: > 90.5

        27

        26

        1.90 1.05-3.44

        387

        585

        1.21 0.93-1.57

         

        Waist-to-height ratio b

               

         M1: ≤ 0.58

        156

        276

        1.00

        152

        310

        0.93 0.69-1.24

        0.93

         M2: > 0.58

        22

        22

        1.87 0.98-3.56

        375

        596

        1.17 0.90-1.52

         

        ER+PR+ breast cancer

        Cases (n=194)

        Controls (n=648)

        OR a 95% CI

        Cases (n=220)

        Controls (n=680)

        OR a 95% CI

        P interaction

        Waist (cm) b

               

         M1: ≤ 90.5

        73

        272

        1.00

        67

        321

        0.92 0.62-1.36

        0.16

         M2: > 90.5

        10

        26

        1.53 0.69-3.39

        213

        585

        1.55 1.11-2.17

         

        Waist-to-height ratio b

               

         M1: ≤ 0.58

        75

        276

        1.00

        75

        310

        1.02 0.70-1.50

        0.47

         M2: > 0.58

        8

        22

        1.53 0.63-3.68

        205

        596

        1.52 1.08-2.12

         

        Abbreviations: BMI, body mass index; CI, confidence interval; ER+, estrogen receptor–positive; OR, odds ratio; PR+, progesterone receptor–positive.

        a OR and 95% CI adjusted for age (years, continuous), race/ethnicity (non-Hispanic White, African American, Hispanic), place of birth (US-born, foreign-born), education (some high school or less, high school or vocational/technical school graduate, some college, college graduate), family history of breast cancer in first-degree relatives (no, yes), personal history of biopsy-confirmed benign breast disease (no, yes), age at menarche (≤11, 12, 13, ≥14 years), number of full-term pregnancies (nulliparous, 1, 2, 3, ≥4), age at first full-term pregnancy (nulliparous, ≤19, 20–24, 25–29, ≥30 years), lifetime breast-feeding (nulliparous, 0, ≤6, 7–12, 13–24, ≥25 months), lifetime physical activity (quartiles, hours/week), alcohol consumption in reference year (0, 0.1-4.9, 5–9.9, 10–19.9, ≥20 g/day), and total caloric intake (quartiles, kcal/day).

        b Based on median among all postmenopausal controls.

        For ER-PR- BC, there were no associations with current BMI and weight gain, whereas a strong inverse association was found with young-adult BMI (>23.7 vs. ≤21.2 kg/m2: OR = 0.61, 95% CI:0.38-0.97, Ptrend = 0.04) (Table 7). Modest positive associations with waist and hip circumferences were strengthened after adjustment for current BMI (Ptrend = 0.07 and 0.01, respectively). Sample sizes of ER-PR- cases were too small for further stratification by race/ethnicity (9 NHWs, 48 AAs, 79 Hispanics).
        Table 7

        Body size and risk of ER-PR- breast cancer in postmenopausal women not currently using hormone therapy

         

        Cases (n=135)

        Controls (n=1,336)

        ORa, 95% CI

        ORb95% CI

        ORc95% CI

        Current BMI(kg/m2) d

             

         <25.0

        34

        329

        1.00

         

        1.00

         25.0-29.9

        46

        476

        0.75 0.46-1.22

         

        0.62 0.36-1.08

         ≥30.0

        54

        523

        0.72 0.45-1.16

         

        0.58 0.30-1.14

        Ptrend = 0.21

        Ptrend = 0.13

        Young-adult BMI (kg/m2) e,f

             

         T1: ≤21.2

        46

        402

        1.00

          

         T2: 21.3-23.7

        43

        411

        0.82 0.52-1.29

          

         T3: >23.7

        37

        445

        0.61 0.38-0.97

          

        Ptrend = 0.04

        Weight gain (kg) g

             

         Stable h

        10

        140

        1.00

        1.00

         

         Gain, 3.0-9.9

        31

        291

        1.38 0.65-2.93

        1.47 0.69-3.16

         

         Gain, 10.0-19.9

        42

        376

        1.31 0.63-2.72

        1.67 0.76-3.65

         

         Gain, ≥20.0

        39

        401

        1.05 0.50-2.19

        1.45 0.60-3.48

         

        Ptrend = 0.63

        Ptrend = 0.48

        Waist (cm) e

             

         T1: ≤ 85.0

        28

        385

        1.00

        1.00

         

         T2: 85.1-96.4

        40

        407

        1.13 0.67-1.89

        1.43 0.80-5.54

         

         T3: >96.4

        48

        412

        1.24 0.75-2.06

        1.87 0.96-3.64

         

        Ptrend = 0.41

        Ptrend = 0.07

        Hip (cm) e

             

         T1: ≤ 102.9

        27

        394

        1.00

        1.00

         

         T2: 103.0-112.7

        41

        402

        1.40 0.84-2.34

        1.85 1.05-3.28

         

         T3: >112.7

        48

        407

        1.43 0.86-2.37

        2.35 1.20-4.59

         

        Ptrend = 0.19

        Ptrend = 0.01

        Waist-to-hip ratio

             

         T1: ≤ 0.81

        33

        434

        1.00

        1.00

         

         T2: 0.82-0.86

        34

        355

        1.14 0.68-1.90

        1.21 0.72-2.04

         

         T3: >0.86

        49

        413

        1.35 0.83-2.18

        1.46 0.88-2.39

         

        Ptrend = 0.22

        Ptrend = 0.14

        Waist-to-height ratio

             

         T1: ≤ 0.54

        30

        372

        1.00

        1.00

         

         T2: 0.55-0.61

        40

        410

        0.98 0.59-1.63

        1.19 0.66-2.17

         

         T3: >0.61

        46

        422

        1.05 0.63-1.73

        1.44 0.72-2.87

         

        Ptrend = 0.84

        Ptrend = 0.30

        Abbreviations: BMI, body mass index; CI, confidence interval; ER-, estrogen receptor–negative; OR, odds ratio; PR-, progesterone receptor–negative.

        a OR and 95% CI adjusted for age (years, continuous), race/ethnicity (non-Hispanic White, African American, Hispanic), place of birth (US-born, foreign-born), age at menarche (≤11, 12, 13, ≥14 years), and lifetime breast-feeding (nulliparous, 0, ≤6, 7–12, 13–24, ≥25 months).

        b Adjusted for above variables, and current BMI.

        c Adjusted for above variables, and weight gain.

        d Based on self-reported weight and measured height at interview (if not available, then based on measured weight at interview and/or self-reported height).

        e Based on tertiles among all postmenopausal controls.

        f Based on self-reported young-adult weight and measured height at interview (or self-reported adult height when measured height not available).

        g Self-reported weight (or measured weight at interview if self-reported weight not available) minus self-reported young-adult weight; excludes 5 cases and 55 controls who lost >3 kg of weight

        h Stable weight defined as +/- 3 kg.

        Among women currently using HT (289 cases, 498 controls), there was no evidence of significant associations between any of the body size measures examined and BC risk overall or ER+PR+ disease (data not shown).

        Discussion

        In postmenopausal women not currently using HT, weight gain was positively associated with risk of ER+PR+ BC and was a stronger predictor of risk than current BMI. The highest elevations in risks were found in subgroups of women with a low young-adult BMI or ≥15 years since menopause. Young-adult obesity was associated with reduced BC risk. High waist circumference and WHtR were associated with increased BC risk, independent of current BMI. Associations with weight gain and young-adult BMI were stronger for NHWs than Hispanics and AAs, whereas associations with waist and WHtR were present only in Hispanic and AA women.

        Consistent with other reports (White et al. 2012; Huang et al. 1997; Ahn et al. 2007; Feigelson et al. 2004), we found that weight gain was an important risk factor for postmenopausal BC, independent of current BMI. For current BMI no association remained after adjustment for weight gain. In agreement with other studies (Vrieling et al. 2010), we found that the relation with weight gain was limited to ER+PR+ BC. Risk was increased two-fold for currently obese women (BMI ≥30 kg/m2) who had a young-adult BMI <22.4 kg/m2, which is in agreement with other studies (Ahn et al. 2007; Canchola et al. 2012). We found modest effect modification by young adult BMI for weight gain, though some other studies did not (Barnes-Josiah et al. 1995; Feigelson et al. 2004; van den Brandt et al. 1997; Lahmann et al. 2005). In contrast, BC risk was not increased in women who were obese throughout their adult life, consistent with other (Ahn et al. 2007; Canchola et al. 2012), but not all reports (Barnes-Josiah et al. 1995). In agreement with other reports (Chu et al. 1991; Magnusson et al. 1998; Macinnis et al. 2004), we found time since menopause to be another important modifying factor, with two-fold increased risks of ER+PR+ BC with weight gain only among women with ≥15 years since menopause. Weight gain during adulthood largely reflects an increase in body fat which serves as an important source of estrogen production in postmenopausal women (Siiteri 1987). The role of an estrogen-related pathway is further supported by the observation that the associations with BMI and weight gain are limited to ER+PR+ tumors (Suzuki et al. 2009; Vrieling et al. 2010).

        Prior findings in AA and Hispanic women for BMI are inconsistent. In our study, OR estimates were increased only for ER+PR+ disease and were of similar magnitude in the three racial/ethnic groups. Two studies in AAs reported elevated risks of ER+PR+ disease (Palmer et al. 2007; Berstad et al. 2010), and, similar to our study, there was no evidence of an association with BMI for BC overall. Other studies did not consider hormone receptor status (White et al. 2012; Schatzkin et al. 1987; Adams-Campbell et al. 1996; Hall et al. 2000; Zhu et al. 2005), and not all found a positive association with BMI (White et al. 2012; Schatzkin et al. 1987; Zhu et al. 2005). In black women from Nigeria (Ogundiran et al. 2010; Okobia et al. 2006; Adebamowo et al. 2003) and Barbados (Nemesure et al. 2009), no associations with BMI were found. In Hispanic women, BMI was not associated with BC overall (Wenten et al. 2002; Slattery et al. 2007; White et al. 2012) and ER+ disease (Slattery et al. 2007), even among women not using HT (Slattery et al. 2007; White et al. 2012).

        We found that high weight gain was associated with a two-fold increased risk of ER+PR+ BC in NHW women. In AAs and Hispanics, the associations were much weaker, likely due to the higher prevalence of young-adult obesity in these groups. Of three studies in AAs that reported on weight gain and BC risk (White et al. 2012; Zhu et al. 2005; Palmer et al. 2007), only one found a significant association with BC risk overall (White et al. 2012). In Hispanic women from New Mexico, large weight gain was associated with a two-fold increased risk of ER+PR+ disease and, for BC overall, a significant trend with weight gain was limited to women with a BMI <22 kg/m2 at age 18 years (Wenten et al. 2002). Two other studies in Hispanics found no association with weight gain (Slattery et al. 2007; White et al. 2012). In order to address these inconsistent findings with BMI and weight gain for AA and Hispanic women, future studies should examine the modifying effect of young-adult obesity with larger sample sizes. This is particularly important since AA and Hispanic women have a higher prevalence of young-adult obesity than NHWs, as found in our study as well as others (Flegal et al. 2010).

        Our finding of a strong inverse association of postmenopausal BC risk with high young-adult BMI, which was independent of weight change or current BMI, is consistent with other reports (White et al. 2012; Palmer et al. 2007; Berstad et al. 2010; Barnes-Josiah et al. 1995; Huang et al. 1997; Morimoto et al. 2002; Ahn et al. 2007; Chu et al. 1991; Brinton & Swanson 1992; Magnusson et al. 1998), although in some studies there was no association with young-adult BMI (Canchola et al. 2012; Feigelson et al. 2004; Lahmann et al. 2005). In agreement with a large meta-analysis (Suzuki et al. 2009), we found that the inverse association with young-adult BMI did not differ by tumor hormone receptor status. We further found an inverse association, regardless of HT use, as reported by others (Morimoto et al. 2002; Ahn et al. 2007). These findings do not support an estrogen-related mechanism underlying the association with young-adult BMI.

        Abdominal adiposity has been proposed to be more important in estrogen production than adiposity at other body sites (Pinheiro et al. 2009). Studies in primarily NHW women, however, have produced inconsistent results (World Cancer Research Fund / American Institute for Cancer Research 2007). Not all studies considered HT use or ER/PR status, or adjusted for overall adiposity (Canchola et al. 2012; Potter et al. 1995; Huang et al. 2000). Our findings confirm previous reports of positive associations with waist circumference and WHtR only in women not currently using HT (Morimoto et al. 2002; Huang et al. 1999; Friedenreich et al. 2002) and stronger associations for ER+PR+ disease (Canchola et al. 2012; Potter et al. 1995; Huang et al. 2000). We found no association with WHR, whereas elevated WHtR was associated with increased risk, in agreement with another study (Canchola et al. 2012). Both waist circumference and WHtR may be better measures of abdominal adiposity than WHR (Molarius & Seidell 1998; Rankinen et al. 1999). In some studies, the association with abdominal adiposity was attenuated after adjustment for BMI (Morimoto et al. 2002; Lahmann et al. 2004; Tehard & Clavel-Chapelon 2006), whereas in our study associations became stronger after BMI-adjustment. Among women with BMI <25 kg/m2, large waist circumference and high WHtR were associated with two-fold increased risks of BC overall. Contrary to another study that reported an association between abdominal adiposity and ER+PR+ tumors only in normal-weight women (Canchola et al. 2012), we found elevated ORs for ER+PR+ tumors, regardless of BMI, with statistically significant estimates in overweight/obese women.

        Unlike NHW women, for whom we found no associations with waist circumference and WHtR, AAs and Hispanics had two- to three-fold increased risk of ER+PR+ BC. We found no association with WHR in any racial/ethnic group. This latter finding is consistent with two studies in AA women (Hall et al. 2000; Palmer et al. 2007), but contrasts with reports from Nigeria (Ogundiran et al. 2010) and Barbados (Nemesure et al. 2009), where large waist circumference and high WHR increased BC risk. Similarly, the two-fold increased risk of ER+PR+ disease associated with large hip circumference that we observed for NHW and Hispanic women was not seen in AAs, whereas previous studies from Nigeria (Ogundiran et al. 2012) and Barbados (Nemesure et al. 2009) reported inverse associations with hip circumference. In the Nigerian study, associations with abdominal adiposity were stronger or limited to women with a BMI <25 kg/m2 (Ogundiran et al. 2012), consistent with our findings. In the only study that examined abdominal adiposity in postmenopausal Hispanic women, hip circumference and WHR were not associated with BC risk in not recent HT users (Slattery et al. 2007), which differs from our finding. Given these conflicting reports, it remains to be determined whether there are true racial/ethnic differences in the effects of abdominal adiposity on BC risk. Abdominal fat comprises different fat stores, and AAs and NHWs differ in abdominal depot-specific body fat (e.g., visceral vs. subcutaneous adipose tissue) (Katzmarzyk et al. 2010). Whether different fat stores affect BC risk differentially has not been examined. Our results suggest that studies should assess multiple measures of adiposity in racially/ethnically diverse populations.

        Our analyses of body size and ER-PR- BC risk were limited by small numbers. Consistent with most other studies (Suzuki et al. 2009; Yang et al. 2011), we found no associations with current BMI and weight gain, although there are some reports of inverse (Berstad et al. 2010; Setiawan et al. 2009) or positive associations with BMI (Ritte et al. 2012) and positive associations with weight gain (Canchola et al. 2012). Unlike other studies (Canchola et al. 2012; Potter et al. 1995), we found a strong inverse association with young-adult BMI and ER-PR- disease. Adjustment for BMI strengthened the positive association between waist (Ptrend = 0.07) and hip (Ptrend = 0.01) circumferences and risk of ER-PR- BC, but, consistent with other studies (Canchola et al. 2012; Potter et al. 1995; Huang et al. 2000), we found no significant association with WHR or WHtR. The association between BMI, weight gain, and abdominal adiposity warrants further examination in studies with larger numbers of ER-PR- cases. This is particularly important since few risk factors have been identified for hormone receptor negative BC (Althuis et al. 2004; Ma et al. 2006), which disproportionately affects AA and Hispanic women (Ray & Polite 2010).

        Our findings should be considered in light of some limitations. Due to the concern that weight may be impacted by BC diagnosis and treatment, we relied on self-reported weight during the reference year. Although we cannot exclude the possibility of inaccurately recalled weight, among subjects for whom measured and self-reported weight was available, the correlation between the two measures was high (r = 0.85 for cases, r = 0.92 for controls). For waist and hip circumference we had to rely on measurements taken after diagnosis which may have also resulted in misclassification. Finally, some subgroup analyses were limited by small sample sizes, and analyses of potential modifying factors (young-adult BMI, time since menopause) could not be further stratified by race/ethnicity. Larger studies or analyses of pooled data will be necessary to further explore the role of these modifying factors in Hispanics and AAs.

        Our study also has several important strengths, including a population-based design, high participation rates among cases and controls in each racial/ethnic group, assessment of both overall and abdominal adiposity, detailed data on established BC risk factors, and availability of data on tumor hormone receptor status for most cases. The racial/ethnic diversity of the study population allowed us to assess associations with body size in Hispanic and AA women, thus contributing to the relatively sparse data in these two racial/ethnic populations that experience a greater burden of obesity than NHWs.

        It has been estimated that as many as one third of new postmenopausal BC cases may be attributable to adult weight gain (Huang et al. 1997). Given that a number of BC risk factors relate to events well before menopause (e.g., age at menarche, age at first birth) or characteristics that cannot easily be modified (e.g., BC family history), observed associations with body size suggest possible approaches to lowering BC risk in older women through weight maintenance, avoidance of further weight gain and abdominal adiposity, or weight loss. However, promoting overweight at a young age, as a means of reducing BC risk after menopause, should not be encouraged, given the many adverse health effects associated with obesity, including other cancers (Calle & Kaaks 2004; Chen et al. 2011).

        Abbreviations

        AA: 

        African American

        BC: 

        Breast cancer

        BMI: 

        Body mass index

        CI: 

        Confidence interval

        ER: 

        Estrogen receptor

        HT: 

        Hormone therapy

        OR: 

        Odds ratio

        NHW: 

        non-Hispanic white

        PR: 

        Progesterone receptor

        WHR: 

        Waist-to-hip ratio

        WHtR: 

        Waist-to-height ratio.

        Declarations

        Acknowledgments

        This work was supported by the National Cancer Institute (grant R03 CA121875). Data collection for the parent study was funded by National Cancer Institute (grants R01 CA63446 and R01 CA77305); the U.S. Department of Defense (grant DAMD17-96-1-6071); and the California Breast Cancer Research Program (grants 4JB-1106 and 7PB-0068). The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement U58DP003862-01 awarded to the California Department of Public Health. The ideas and opinions expressed herein are those of the authors and endorsement by the State of California, Department of Public Health the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors is not intended nor should be inferred.

        Authors’ Affiliations

        (1)
        Cancer Prevention Institute of California
        (2)
        Division of Epidemiology, Department of Health Research and Policy, and Stanford Cancer Institute, Stanford University School of Medicine
        (3)
        Division of Public Health Sciences, Fred Hutchinson Cancer Research Center

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        This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.