Obesity and obesity-related metabolic disorders, such as diabetes and chronic inflammation, have been positively associated both with postmenopausal breast cancer and with resting energy expenditure (REE). However, there is limited epidemiologic evidence on the associations between REE and risk of postmenopausal breast cancer. We used multivariable Cox proportional hazards models to examine the association between predicted REE (calculated using the Ikeda, Livingston, and Mifflin equations) and risk of postmenopausal breast cancer overall and by subtypes, and by level of body fat) among 137,283 postmenopausal women in the Women's Health Initiative (WHI). All predicted REEs were positively associated with risk of invasive breast cancer [HRq5 vs. q1 = 1.69; 95% confidence interval (CI), 1.57–1.81; HR = 1.69; 95% CI, 1.57–1.82; and HR = 1.68; 95% CI, 1.56–1.80 for Ikeda, Livingston, and Mifflin, respectively]. These positive associations were observed irrespective of the hormone receptor subtype, grade, and stage of the tumors, but were most pronounced for estrogen receptor–positive/progesterone receptor–positive tumors. After additional adjustment for body mass index (BMI), the associations were mostly attenuated and remained statistically significant for most of the outcomes. We also observed an interaction between the predicted REEs and BMI, with the associations being somewhat stronger among normal weight and overweight women than among obese women (Pinteractions < 0.05). Our findings indicate that relatively high REE is associated with increased risk of invasive breast cancer among postmenopausal women (particularly for the obesity-related tumor subtypes), irrespective of the equation used. Further studies using more objective measures of REE are, however, needed to confirm our findings.

Prevention Relevance:

This study showed that higher resting energy expenditure (REE) was associated with higher postmenopausal breast cancer risk. REE provides energy to support cancer-associated disorders such as obesity and inflammation. Thus, studies on its association with breast cancer can help to improve our understanding of the pathophysiology of breast cancer.

Obesity is one of the key risk factors for postmenopausal breast cancer among women (1, 2). This metabolic disorder is thought to result partly from energy intake exceeding energy expenditure (3). Total energy expenditure (TEE) comprises three components, namely resting energy expenditure (REE), diet-induced thermogenesis, and activity-related energy expenditure (AREE; ref. 4). In a previous Women's Health Initiative (WHI) study, which investigated the association between the AREE component and postmenopausal breast cancer, higher AREE was inversely associated with risk (5).

REE, defined as the rate of energy production necessary for the body to perform important physiologic functions at rest (3, 6), is the primary component of TEE (accounting for approximately 60%–70% of TEE; ref. 7), but little is known about its association with risk of postmenopausal breast cancer. In a recent study conducted within The European Prospective Investigation into Cancer and Nutrition cohort, there was a 17% increase in the risk of postmenopausal breast cancer per one SD increase in predicted REE (8), and in an earlier study from the National Health and Nutrition Examination Survey (9), relative to women in the second quintile, predicted REE was associated with a two-fold increased risk of postmenopausal breast cancer among women in the highest quintile.

Higher REE is a compensatory physiologic change that typically occurs to meet the higher energy demand of obesity (10) and obesity-related metabolic dysfunctions including diabetes, impaired fasting glucose, reduced insulin sensitivity, and chronic inflammation (11–13). Obesity and the aforementioned metabolic dysfunctions have all been shown to enhance carcinogenic processes including cell growth, proliferation, and migration (14, 15) that can lead to breast cancer (16, 17). Given the role of energy expenditure in supporting cancer-associated metabolic aberrations, it is important to understand the association between REE and risk of postmenopausal breast cancer.

Indirect calorimetry (IC), performed using a metabolic cart, is regarded as the gold standard for determining REE (18). However, given the high cost of the metabolic cart, the need for highly trained staff, and the limited availability of equipment, its implementation in large-scale epidemiologic studies is currently impractical (19). Therefore, most epidemiologic studies have utilized various equations to predict REE, as this approach is less expensive and easier to incorporate in such studies than IC (19, 20). Previously, in a WHI ancillary study, which aimed to determine which equations that predicted REE yielded results that closely agreed with measured REE, the Ikeda, Livingston, and Mifflin equations, were found to perform the best (21). Hence, in this study, we utilized these three equations to assess the association of predicted REE with risk of postmenopausal invasive breast cancer overall, by tumor characteristics, and by anthropometric measures which are known to influence REE (3, 22).

Study population and design

A detailed description of the WHI design and study population have been previously published (23). The WHI is a prospective multicenter study comprising 161,808 postmenopausal women from diverse racial and ethnic groups aged 50 to 79 at enrollment who were recruited from 40 U.S. clinical centers throughout the United States between 1993 and 1998. Women participated in one of four clinical trials [hormone therapy (2 trials), low-fat diet modification, and calcium–vitamin D supplementation; n = 68,132] or an Observational Study (OS) group (n = 93,676; ref. 23). The study protocol was reviewed by ethics committees at all 40 clinical centers, by the coordinating center, and by a data and safety monitoring board. The WHI project was reviewed and approved by the Fred Hutchinson Cancer Research Center (Fred Hutch; Seattle, WA) Institutional Review Board (IRB) in accordance with the United States Department of Health and Human Services regulations at 45 Code of Federal Regulations 46 (approval number: IR# 3467-EXT). All participants provided written informed consent.

At recruitment, a self-administered questionnaire was used to collect information on sociodemographic characteristics, reproductive history, family history of breast cancer, medical history, medication use, and diet and lifestyle factors. Anthropometric measurements [weight, height, waist circumference (WC), hip circumference] were taken by trained clinic staff using a standardized protocol. Body mass index (BMI) was calculated by dividing weight (kg) by the square of standing height (m2). Waist circumference was measured to the nearest 0.1 centimeter at the narrowest part of the waist by trained staff using tape measures. Waist-to-hip-ratio (WHR) was calculated by dividing waist circumference by the corresponding hip circumference. Among a subgroup of participants (n = 11, 393), dual-energy x-ray absorptiometry (DXA)-derived whole body fat and lean body mass were measured by whole body DXA scans performed in fan-beam mode and obtained from Hologic QDR scanners (QDR 2000, 2000+, or 4500; Hologic, Inc.; ref. 24). For these participants, fat to lean body mass was calculated by dividing whole body fat mass by the corresponding lean body fat mass.

Analytic cohort

From the total cohort, we excluded women with missing information on all three predicted REEs (n = 532), those with a history of breast cancer or missing follow-up time (n = 670), and women with implausible dietary energy intake levels (<600 kcal or >5000 kcal; n = 4,239). We also excluded women with a history of thyroid disorders at baseline (n = 16,576) and those with follow-up time of 3 years or less (n = 23), to minimize the impact of preclinical disease and reverse causation. For each of the predicted equations, we excluded women with predicted REE values considered outliers (i.e., women with values less than the value at the first percentile or greater than the value at the 99th percentile; n = 2,988 for Ikeda and Livingston and 2,732 for Mifflin (there were also 842 women with missing values for Mifflin)]. After exclusion, the final analytic cohort comprised 136,780 women for the Ikeda and Livingston equations and 136,194 women for the Mifflin equation.

REE

For the main analyses, we utilized three predicted equations for REE, namely the Ikeda, Livingston, and Mifflin equations (21). Further information regarding the predicted REE equations is provided in Table 1. Among a subgroup of women from the WHI Nutrition and Physical Activity Assessment Study (N = 450), REE was measured by a trained technician using a VMAX 2900 indirect calorimeter (25). Three hundred and forty-eight of these women were included in the current analytic cohort.

Table 1.

REE equations.

REE equation (Kcal/day)
Ikeda 10 × [body weight (kg) − 3 × age (y)] + 750 
Livingston and Kohlstadt 48 × weight0.4356 − (5.09 × age) 
Mifflin St. Jeor (10 × weight) + (6.25 × height) − (5 × age) − 161 
REE equation (Kcal/day)
Ikeda 10 × [body weight (kg) − 3 × age (y)] + 750 
Livingston and Kohlstadt 48 × weight0.4356 − (5.09 × age) 
Mifflin St. Jeor (10 × weight) + (6.25 × height) − (5 × age) − 161 

Abbreviation: y, years.

Outcome ascertainment

Incident invasive breast cancer was the primary outcome in this study. During follow-up, outcome information was collected semiannually in the CT group and annually in the OS using in-person, mailed, or telephone questionnaires. Incident breast cancer was confirmed via central review of medical records and pathology reports by trained physician adjudicators. Tumor hormone receptor status was coded using the NCI's Surveillance Epidemiology and End Results (SEER) coding system (26).

Statistical analysis

Predicted REE measures were analyzed after categorization by quintiles (for subgroup analyses by levels of the anthropometric measures, the predicted REE measures were categorized as tertiles). To summarize the population characteristics, we used the median and interquartile ranges for continuous variables and frequencies and percentages for categorical variables. We also examined the distribution of the predicted REEs by the measured REE (n = 348).

Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI) for the associations between the predicted REE measures and risk of breast cancer (overall, and by hormone receptor status, stage, and grade). Time to event was the underlying timescale. Participants were censored if they had not developed breast cancer by the end of the follow-up period (August 31, 2020) or if they died or withdrew from the study before the end of follow-up. Cases contributed person-time to the study from their date of enrollment until the date of breast cancer diagnosis, and noncases (participants who were censored) contributed person-time from their date of enrollment until the end of follow-up, date of death, or date of withdrawal from the study, whichever came first. The multivariable models were adjusted for age at enrollment (years; continuous), race and ethnicity (African-American, Asian, American Indian and Alaskan native, Native Hawaiian and other Pacific Islander, Spanish and Latina, White (not of Hispanic origin), missing), education (high school or less than postsecondary/some college, graduate school/some graduate school, missing), recreational physical activity (Met-hours/week; continuous), smoking status (never, former, current, missing), alcohol consumption (continuous; serving/week), randomization group/study arm (hormone therapy arm, low-fat diet modification arm, and calcium–vitamin D supplementation arm), ever use of unopposed estrogen therapy (yes/no), ever use of combined estrogen and progesterone therapy (yes/no), age at menopause (years; <45, 45–54, ≥55, missing), ever use of oral contraceptives (yes/no), age at menarche (years; <12, 12–13, ≥14, missing), age at first full‐term pregnancy (nulliparous, <20, 20–29, 30+, missing), parity (never been pregnant/no term pregnancy, 1, 2, 3, 4+, missing), ever breastfed (yes/no), family history of breast cancer in a first-degree relative (yes/no), mammogram ever (yes/no), and the healthy eating index 2015 (continuous). Further, given that fat mass and lean body mass influence REE (27, 28), in sensitivity analyses, we further adjusted for BMI and fat to lean body mass. Tests for trend were performed by modeling the ordinal variables as continuous variables.

We also assessed the association between the per SD increase in the predicted REEs and risk of invasive breast cancer by levels of the anthropometric measures. P values for heterogeneity were estimated by including an interaction term in the Cox regression models and using the Wald test to test its coefficient.

Finally, we performed sensitivity analyses by excluding persons with a history of cardiometabolic diseases [i.e., cardiovascular disease (CVD)/stroke, hypertension, and diabetes) at baseline, which can influence REE.

All analyses were conducted using Stata 17.0 (StataCorp). All P values were two-sided.

Data availability statement

This study was conducted using data from the Women's Health Initiative study. Information on data availability can be obtained at https://www.whi.org/.

After a median follow-up of 19 years (interquartile range: 9.0–22.8 years), a total of 9,396 incident invasive breast cancer cases had been ascertained. Cases had lower educational level, but were more likely to have a family history of breast cancer in a first-degree relative, to have an early age at menarche (<12 years), to be nulliparous, to have a higher BMI, to have a higher WC, and to have higher predicted REEs (Table 2).

Table 2.

Baseline characteristics of women from the WHI.

Breast cancer
YesNo
Characteristics(n = 9,396)(n = 127,887)
Age at entry, y 
 Median (IQR) 62 (57–68) 63 (57–69) 
Race and ethnicity, n (%) 
 African-American 594 (6.3) 11,282 (8.8) 
 Asian 180 (1.9) 2,721 (2.1) 
 American Indian and Alaskan native 66 (0.7) 1,007 (0.8) 
 Native Hawaiian and other Pacific Islander 82 (0.9) 1,400 (1.1) 
 Spanish and Latina 174 (1.9) 3,953 (3.1) 
 White (not of Hispanic origin) 8,156 (86.8) 104,174 (81.5) 
 Missing 144 (1.6) 3,350 (2.6) 
Education, n (%) 
 Graduate School/some graduate school 1,679 (17.9) 28,874 (22.6) 
Age at first live birth (y), n (%); <12 1,009 (10.7) 16,383 (12.8) 
Family history, n (%) 2,180 (23.2) 21,872 (17.1) 
Age at menarche (y), n (%); <12 2,162 (23.0) 27,413 (21.4) 
Parity, n (%) (nulliparous) 1,246 (13.3) 14,851 (11.6) 
Breastfed, n (%) 4,813 (51.2) 65,226 (51.0) 
Age at menopause (y), n (%); ≥55 1,307 (17.8) 16,405 (12.8) 
Ever had mammogram, n (%) 9,156 (97.5) 122,551 (95.8) 
Unopposed estrogen, n (%) 3.126 (33.3) 44,966 (35.2) 
Estrogen/progesterone combined therapy, n (%) 3,110 (33.1) 32,968 (25.8) 
Oral contraceptive, n (%) 4,175 (44.4) 53,352 (41.7) 
Alcohol serving/week 
 Median (IQR) 0.4 (0.0–3.4) 0.4 (0.0–2.7) 
Health eating index 
 Median (IQR) 65.8 (58.3–72.9) 65.6 (57.9–72.7) 
Physical activity, Met-hours/week 
 Median (IQR) 7.5 (1.5–17.3) 7.5 (1.5–17.5) 
BMI, kg/m2 
 Median (IQR) 27.0 (23.9–31.1) 26.8 (23.7–30.8) 
WC, cm 
 Median (IQR) 85.0 (76.5–95.0) 84.0 (76.0–94.2) 
WHR 
 Median (IQR) 0.80 (0.76–0.85) 0.80 (0.76–0.86) 
Smoking status, n (%) (current) 594 (6.3) 8,968 (7.0) 
Ikeda predicted REE 
 Median (IQR) 1,278 (1,191–1,387) 1,263 (1,177–1,374) 
Livingston predicted REE 
 Median (IQR) 1,276.5 (1,184.5–1,378.8) 1,260.3 (1,169.8–1,366.8) 
Mifflin predicted REE 
 Median (IQR) 1,262.5 (1,160.3–1,381.6) 1,241.5(1,138.6–1,363.0) 
Breast cancer
YesNo
Characteristics(n = 9,396)(n = 127,887)
Age at entry, y 
 Median (IQR) 62 (57–68) 63 (57–69) 
Race and ethnicity, n (%) 
 African-American 594 (6.3) 11,282 (8.8) 
 Asian 180 (1.9) 2,721 (2.1) 
 American Indian and Alaskan native 66 (0.7) 1,007 (0.8) 
 Native Hawaiian and other Pacific Islander 82 (0.9) 1,400 (1.1) 
 Spanish and Latina 174 (1.9) 3,953 (3.1) 
 White (not of Hispanic origin) 8,156 (86.8) 104,174 (81.5) 
 Missing 144 (1.6) 3,350 (2.6) 
Education, n (%) 
 Graduate School/some graduate school 1,679 (17.9) 28,874 (22.6) 
Age at first live birth (y), n (%); <12 1,009 (10.7) 16,383 (12.8) 
Family history, n (%) 2,180 (23.2) 21,872 (17.1) 
Age at menarche (y), n (%); <12 2,162 (23.0) 27,413 (21.4) 
Parity, n (%) (nulliparous) 1,246 (13.3) 14,851 (11.6) 
Breastfed, n (%) 4,813 (51.2) 65,226 (51.0) 
Age at menopause (y), n (%); ≥55 1,307 (17.8) 16,405 (12.8) 
Ever had mammogram, n (%) 9,156 (97.5) 122,551 (95.8) 
Unopposed estrogen, n (%) 3.126 (33.3) 44,966 (35.2) 
Estrogen/progesterone combined therapy, n (%) 3,110 (33.1) 32,968 (25.8) 
Oral contraceptive, n (%) 4,175 (44.4) 53,352 (41.7) 
Alcohol serving/week 
 Median (IQR) 0.4 (0.0–3.4) 0.4 (0.0–2.7) 
Health eating index 
 Median (IQR) 65.8 (58.3–72.9) 65.6 (57.9–72.7) 
Physical activity, Met-hours/week 
 Median (IQR) 7.5 (1.5–17.3) 7.5 (1.5–17.5) 
BMI, kg/m2 
 Median (IQR) 27.0 (23.9–31.1) 26.8 (23.7–30.8) 
WC, cm 
 Median (IQR) 85.0 (76.5–95.0) 84.0 (76.0–94.2) 
WHR 
 Median (IQR) 0.80 (0.76–0.85) 0.80 (0.76–0.86) 
Smoking status, n (%) (current) 594 (6.3) 8,968 (7.0) 
Ikeda predicted REE 
 Median (IQR) 1,278 (1,191–1,387) 1,263 (1,177–1,374) 
Livingston predicted REE 
 Median (IQR) 1,276.5 (1,184.5–1,378.8) 1,260.3 (1,169.8–1,366.8) 
Mifflin predicted REE 
 Median (IQR) 1,262.5 (1,160.3–1,381.6) 1,241.5(1,138.6–1,363.0) 

Abbreviations: IQR, interquartile range; Met, metabolic equivalent.

When we cross-classified the predicted REE measures by measured REE, 63.8%, 69.0%, and 60.3% of those in the highest tertile of measured REE were in the highest tertile for Ikeda, Livingston, and Mifflin predicted REE, respectively (Supplementary Table S1).

For the three predicted REEs, in multivariable models, we observed that those in the highest quintile had increased risk of invasive breast cancer (Tables 3,45). The HRs for the highest versus the lowest quintile were 1.69 (95% CI, 1.57–1.81), 1.69 (95% CI, 1.57–1.82), and 1.68 (95% CI, 1.56–1.80) for Ikeda, Livingston, and Mifflin, respectively. Generally, the positive associations were observed irrespective of hormone receptor subtype, stage, and grade of the tumors (Tables 3,45). The positive associations between the predicted REEs and risk of postmenopausal breast cancer were strongest for the hormone receptor–positive [(estrogen receptor—positive (ER+)/progesterone receptor–positive (PR+): HR = 1.96; 95% CI, 1.80–2.14; HR = 1.93, 95% CI, 1.77–2.12; and HR = 1.90; 95% CI: 1.73–2.08 for Ikeda, Livingston, and Mifflin-derived REE, respectively] and high-grade tumors (HR = 1.81; 95% CI, 1.56–2.10; HR = 1.81; 95% CI, 1.54–2.11; and HR = 1.78; 95% CI, 1.53–2.09 for Ikeda, Livingston, and Mifflin-derived REE, respectively). In analyses with additional adjustment for BMI, the associations between the predicted REEs were attenuated but still mostly statistically significant (HR = 1.39; 95% CI, 1.23–1.57; HR = 1.37; 95% CI, 1.21–1.55; and HR = 1.34; 95% CI, 1.21–1.48 for the associations between Ikeda, Livingston, and Mifflin derived-REE, respectively, and overall breast cancer risk; Tables 3,45). However, for ER+/PR-negative (PR) breast cancer and advanced breast cancers, these associations became null or borderline significant. In sensitivity analyses among the subgroup of women with available DXA measures, the associations between the predicted REEs and risk of invasive breast cancer were similar to those observed in the entire cohort, and were virtually unchanged after additional adjustment for the fat to lean body mass ratio (Supplementary Table S2).

Table 3.

HRs for the association of predicted REE (Ikeda) with risk of incident, invasive breast cancer in postmenopausal women, overall and by breast cancer subtype.

Quintiles
12345Ptrend
Invasive breast cancer 
 Cases (n1,887 1,865 1,896 1,870 1,858  
 Age-adjusted HR (95% CI) 1.00 1.05 (0.99–1.12) 1.13 (1.06–1.20) 1.26 (1.18–1.35) 1.44 (1.35–1.54) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.11 (1.04–1.18) 1.23 (1.15–1.31) 1.43 (1.33–1.53) 1.69 (1.57–1.81) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.06 (0.99–1.14) 1.14 (1.06–1.23) 1.28 (1.17–1.39) 1.39 (1.23–1.57) <0.001 
ER+/PR+ breast cancer 
 Cases (n1,164 1,191 1,258 1,229 1,249  
 Age-adjusted HR (95% CI) 1.00 1.12 (1.03–1.22) 1.27 (1.17–1.37) 1.42 (1.31–1.54) 1.70 (1.57–1.85) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.16 (1.07–1.47) 1.58 (1.46–1.72) 1.96 (1.46–1.72) 1.96 (1.80–2.14) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.11 (1.02–1.21) 1.25 (1.14–1.37) 1.40 (1.25–1.56) 1.58 (1.36–1.84) 0.017 
ER+/PR breast cancer 
 Cases (n269 280 226 207 197  
 Age-adjusted HR (95% CI) 1.00 1.15 (0.98–1.37) 0.99 (0.83–1.19) 1.04 (0.87–1.26) 1.17 (0.97–1.41) 0.376 
 Multivariable-adjusteda HR (95% CI) 1.00 1.17 (0.99–1.39) 1.03 (0.86–1.23) 1.10 (0.91–1.33) 1.24 (1.02–1.52) 0.128 
 Multivariable-adjustedb HR (95% CI) 1.00 1.17 (0.98–1.40) 1.03 (0.83–1.27) 1.11 (0.86–1.43) 1.24 (0.87–1.78) 0.557 
ER/PR breast cancer 
 Cases (n231 229 218 235 202  
 Age-adjusted HR (95% CI) 1.00 1.05 (0.88–1.26) 1.05 (0.87–1.26) 1.28 (1.06–1.53) 1.24 (1.02–1.50) 0.004 
 Multivariable-adjusteda HR (95% CI) 1.00 1.05 (0.88–1.27) 1.04 (0.86–1.26) 1.25 (1.04–1.52) 1.17 (0.95–1.44) 0.035 
 Multivariable-adjustedb HR (95% CI) 1.00 1.01 (0.83–1.23) 0.97 (0.78–1.20) 1.11 (0.86–1.43) 0.95 (0.66–1.36) 0.746 
Localized 
 Cases (n1,434 1,423 1,452 1,378 1,355  
 Age-adjusted HR (95% CI) 1.00 1.09 (1.01–1.17) 1.18 (1.10–1.27) 1.29 (1.20–1.39) 1.49 (1.38–1.85) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.12 (1.04–1.21) 1.26 (1.17–1.35) 1.42 (1.32–1.54) 1.69 (1.56–1.84) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.09 (1.01–1.18) 1.19 (1.10–1.30) 1.31 (1.18–1.46) 1.47 (1.28–1.70) <0.001 
Advanced 
 Cases (n394 407 404 441 435  
 Age-adjusted HR (95% CI) 1.00 1.11 (0.96–1.27) 1.16 (1.01–1.33) 1.43 (1.25–1.64) 1.61 (1.40–1.87) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.12 (0.98–1.29) 1.19 (1.03–1.37) 1.48 (1.29–1.71) 1.68 (1.44–1.71) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.06 (0.91–1.22) 1.06 (0.90–1.25) 1.25 (1.03–1.50) 1.23 (0.95–1.59) 0.038 
Low grade 
 Cases (n528 500 499 468 434  
 Age-adjusted HR (95% CI) 1.00 1.02 (0.90–1.16) 1.09 (0.96–1.23) 1.17 (1.03–1.32) 1.27 (1.11–1.44) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.06 (0.94–1.20) 1.17 (1.03–1.33) 1.32 (1.16–1.51) 1.52 (1.32–1.74) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.03 (0.90–1.17) 1.10 (0.95–1.28) 1.20 (1.01–1.43) 1.28 (1.00–1.64) 0.024 
Intermediate grade 
 Cases (n811 775 807 778 796  
 Age-adjusted HR (95% CI) 1.00 1.04 (0.94–1.15) 1.16 (1.05–1.28) 1.28 (1.16–1.41) 1.53 (1.38–1.69) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.07 (0.97–1.19) 1.23 (1.11–1.36) 1.42 (1.28–1.57) 1.76 (1.58–1.95) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.04 (0.94–1.15) 1.16 (1.03–1.30) 1.29 (1.13–1.48) 1.49 (1.23–1.80) <0.001 
High grade 
 Cases (n375 415 398 440 448  
 Age-adjusted HR (95% CI) 1.00 1.20 (1.04–1.38) 1.22 (1.06–1.40) 1.53 (1.33–1.76) 1.79 (1.56–2.06) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.21 (1.05–1.40) 1.24 (1.07–1.43) 1.57 (1.36–1.81) 1.81 (1.56–2.10) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.17 (1.01–1.37) 1.16 (0.99–1.37) 1.43 (1.18–1.72) 1.54 (1.19–1.99) <0.001 
Quintiles
12345Ptrend
Invasive breast cancer 
 Cases (n1,887 1,865 1,896 1,870 1,858  
 Age-adjusted HR (95% CI) 1.00 1.05 (0.99–1.12) 1.13 (1.06–1.20) 1.26 (1.18–1.35) 1.44 (1.35–1.54) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.11 (1.04–1.18) 1.23 (1.15–1.31) 1.43 (1.33–1.53) 1.69 (1.57–1.81) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.06 (0.99–1.14) 1.14 (1.06–1.23) 1.28 (1.17–1.39) 1.39 (1.23–1.57) <0.001 
ER+/PR+ breast cancer 
 Cases (n1,164 1,191 1,258 1,229 1,249  
 Age-adjusted HR (95% CI) 1.00 1.12 (1.03–1.22) 1.27 (1.17–1.37) 1.42 (1.31–1.54) 1.70 (1.57–1.85) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.16 (1.07–1.47) 1.58 (1.46–1.72) 1.96 (1.46–1.72) 1.96 (1.80–2.14) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.11 (1.02–1.21) 1.25 (1.14–1.37) 1.40 (1.25–1.56) 1.58 (1.36–1.84) 0.017 
ER+/PR breast cancer 
 Cases (n269 280 226 207 197  
 Age-adjusted HR (95% CI) 1.00 1.15 (0.98–1.37) 0.99 (0.83–1.19) 1.04 (0.87–1.26) 1.17 (0.97–1.41) 0.376 
 Multivariable-adjusteda HR (95% CI) 1.00 1.17 (0.99–1.39) 1.03 (0.86–1.23) 1.10 (0.91–1.33) 1.24 (1.02–1.52) 0.128 
 Multivariable-adjustedb HR (95% CI) 1.00 1.17 (0.98–1.40) 1.03 (0.83–1.27) 1.11 (0.86–1.43) 1.24 (0.87–1.78) 0.557 
ER/PR breast cancer 
 Cases (n231 229 218 235 202  
 Age-adjusted HR (95% CI) 1.00 1.05 (0.88–1.26) 1.05 (0.87–1.26) 1.28 (1.06–1.53) 1.24 (1.02–1.50) 0.004 
 Multivariable-adjusteda HR (95% CI) 1.00 1.05 (0.88–1.27) 1.04 (0.86–1.26) 1.25 (1.04–1.52) 1.17 (0.95–1.44) 0.035 
 Multivariable-adjustedb HR (95% CI) 1.00 1.01 (0.83–1.23) 0.97 (0.78–1.20) 1.11 (0.86–1.43) 0.95 (0.66–1.36) 0.746 
Localized 
 Cases (n1,434 1,423 1,452 1,378 1,355  
 Age-adjusted HR (95% CI) 1.00 1.09 (1.01–1.17) 1.18 (1.10–1.27) 1.29 (1.20–1.39) 1.49 (1.38–1.85) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.12 (1.04–1.21) 1.26 (1.17–1.35) 1.42 (1.32–1.54) 1.69 (1.56–1.84) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.09 (1.01–1.18) 1.19 (1.10–1.30) 1.31 (1.18–1.46) 1.47 (1.28–1.70) <0.001 
Advanced 
 Cases (n394 407 404 441 435  
 Age-adjusted HR (95% CI) 1.00 1.11 (0.96–1.27) 1.16 (1.01–1.33) 1.43 (1.25–1.64) 1.61 (1.40–1.87) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.12 (0.98–1.29) 1.19 (1.03–1.37) 1.48 (1.29–1.71) 1.68 (1.44–1.71) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.06 (0.91–1.22) 1.06 (0.90–1.25) 1.25 (1.03–1.50) 1.23 (0.95–1.59) 0.038 
Low grade 
 Cases (n528 500 499 468 434  
 Age-adjusted HR (95% CI) 1.00 1.02 (0.90–1.16) 1.09 (0.96–1.23) 1.17 (1.03–1.32) 1.27 (1.11–1.44) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.06 (0.94–1.20) 1.17 (1.03–1.33) 1.32 (1.16–1.51) 1.52 (1.32–1.74) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.03 (0.90–1.17) 1.10 (0.95–1.28) 1.20 (1.01–1.43) 1.28 (1.00–1.64) 0.024 
Intermediate grade 
 Cases (n811 775 807 778 796  
 Age-adjusted HR (95% CI) 1.00 1.04 (0.94–1.15) 1.16 (1.05–1.28) 1.28 (1.16–1.41) 1.53 (1.38–1.69) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.07 (0.97–1.19) 1.23 (1.11–1.36) 1.42 (1.28–1.57) 1.76 (1.58–1.95) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.04 (0.94–1.15) 1.16 (1.03–1.30) 1.29 (1.13–1.48) 1.49 (1.23–1.80) <0.001 
High grade 
 Cases (n375 415 398 440 448  
 Age-adjusted HR (95% CI) 1.00 1.20 (1.04–1.38) 1.22 (1.06–1.40) 1.53 (1.33–1.76) 1.79 (1.56–2.06) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.21 (1.05–1.40) 1.24 (1.07–1.43) 1.57 (1.36–1.81) 1.81 (1.56–2.10) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.17 (1.01–1.37) 1.16 (0.99–1.37) 1.43 (1.18–1.72) 1.54 (1.19–1.99) <0.001 

aAlso adjusted for education, physical activity, smoking status, alcohol consumption, randomization group/study arm, unopposed estrogen therapy ever use, combined estrogen and progesterone therapy use ever, breastfed ever, age at menopause, oral contraceptive, healthy eating index 2015, age at menarche and age at first full‐term pregnancy, race, and ethnicity.

bAlso adjusted for BMI.

Table 4.

HRs for the association of predicted REE (Livingston) with risk of incident, invasive breast cancer in postmenopausal women, overall and by breast cancer subtype.

Quintiles
12345Ptrend
Invasive breast cancer 
 Cases (n1,875 1,878 1,876 1,871 1,876  
 Age-adjusted HR (95% CI) 1.00 1.06 (0.99–1.14) 1.17 (1.10–1.25) 1.31 (1.22–1.40) 1.52 (1.42–1.63) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.10 (1.03–1.17) 1.23 (1.15–1.31) 1.41 (1.32–1.51) 1.69 (1.57–1.82) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.05 (0.98–1.13) 1.14 (1.05–1.23) 1.25 (1.14–1.37) 1.37 (1.21–1.55) <0.001 
ER+/PR+ breast cancer 
 Cases (n1,173 1,186 1,237 1,250 1,247  
 Age-adjusted HR (95% CI) 1.00 1.08 (0.99–1.18) 1.25 (1.15–1.36) 1.42 (1.31–1.55) 1.66 (1.53–1.81) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.13 (1.04–1.22) 1.34 (1.23–1.45) 1.58 (1.46–1.73) 1.93 (1.77–2.12) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.07 (0.98–1.16) 1.21 (1.10–1.33) 1.36 (1.21–1.52) 1.48 (1.27–1.73) <0.001 
ER+/PR breast cancer 
 Cases (n268 274 233 200 201  
 Age-adjusted HR (95% CI) 1.00 1.11 (0.93–1.31) 1.04 (0.87–1.25) 1.01 (0.83–1.11) 1.18 (0.97–1.43) 0.325 
 Multivariable-adjusteda HR (95% CI) 1.00 1.14 (0.95–1.35) 1.08 (0.90–1.29) 1.06 (0.88–1.29) 1.27 (1.03–1.56) 0.101 
 Multivariable-adjustedb HR (95% CI) 1.00 1.16 (0.97–1.40) 1.12 (0.90–1.39) 1.13 (0.86–1.47) 1.40 (0.97–2.02) 0.277 
ER/PR breast cancer 
 Cases (n219 240 218 223 216  
 Age-adjusted HR (95% CI) 1.00 1.12 (0.93–1.35) 1.09 (0.90–1.32) 1.23 (1.01–1.49) 1.33 (1.10–1.63) 0.003 
 Multivariable-adjusteda HR (95% CI) 1.00 1.12 (0.93–1.35) 1.09 (0.89–1.32) 1.21 (0.99–1.47) 1.26 (1.02–1.56) 0.027 
 Multivariable-adjustedb HR (95% CI) 1.00 1.09 (0.90–1.33) 1.03 (0.82–1.29) 1.11 (0.85–1.44) 1.09 (0.75–1.57) 0.629 
Localized 
 Cases (n1,435 1,427 1,428 1,388 1,366  
 Age-adjusted HR (95% CI) 1.00 1.06 (0.99–1.14) 1.17 (1.09–1.26) 1.28 (1.19–1.38) 1.48 (1.36–1.60) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.10 (1.02–1.19) 1.25 (1.15–1.34) 1.41 (1.31–1.53) 1.69 (1.55–1.83) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.07 (0.99–1.15) 1.18 (1.08–1.28) 1.29 (1.16–1.43) 1.45 (1.25–1.67) <0.001 
Advanced 
 Cases (n384 411 405 434 446  
 Age-adjusted HR (95% CI) 1.00 1.11 (0.96–1.28) 1.19 (1.02–1.37) 1.40 (1.22–1.62) 1.64 (1.42–1.90) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.13 (0.98–1.30) 1.21 (1.05–1.40) 1.46 (1.26–1.69) 1.71 (1.47–1.99) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.06 (0.91–1.23) 1.08 (0.92–1.27) 1.22 (1.01–1.47) 1.25 (0.96–1.62) 0.049 
Low grade 
 Cases (n510 507 488 484 438  
 Age-adjusted HR (95% CI) 1.00 1.04 (0.92–1.18) 1.10 (0.97–1.25) 1.22 (1.07–1.39) 1.28 (1.12–1.47) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.08 (0.96–1.23) 1.19 (1.04–1.35) 1.39 (1.22–1.59) 1.55 (1.35–1.79) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.05 (0.92–1.20) 1.13 (0.97–1.31) 1.28 (1.07–1.53) 1.35 (1.05–1.74) 0.005 
Intermediate grade 
 Cases (n819 765 801 791 792  
 Age-adjusted HR (95% CI) 1.00 0.99 (0.90–1.09) 1.14 (1.03–1.26) 1.27 (1.14–1.40) 1.48 (1.33–1.64) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.03 (0.93–1.14) 1.22 (1.10–1.35) 1.40 (1.26–1.55) 1.70 (1.52–1.90) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 0.98 (0.88–1.09) 1.12 (0.99–1.25) 1.23 (1.07–1.41) 1.35 (1.12–1.64) <0.001 
High grade 
 Cases (n370 427 393 429 457  
 Age-adjusted HR (95% CI) 1.00 1.22 (1.06–1.40) 1.22 (1.06–1.41) 1.49 (1.29–1.71) 1.82 (1.57–2.10) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.23 (1.07–1.42) 1.23 (1.06–1.43) 1.50 (1.29–1.75) 1.81 (1.54–2.11) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.24 (1.07–1.43) 1.24 (1.07–1.44) 1.52 (1.31–1.76) 1.84 (1.58–2.14) <0.001 
Quintiles
12345Ptrend
Invasive breast cancer 
 Cases (n1,875 1,878 1,876 1,871 1,876  
 Age-adjusted HR (95% CI) 1.00 1.06 (0.99–1.14) 1.17 (1.10–1.25) 1.31 (1.22–1.40) 1.52 (1.42–1.63) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.10 (1.03–1.17) 1.23 (1.15–1.31) 1.41 (1.32–1.51) 1.69 (1.57–1.82) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.05 (0.98–1.13) 1.14 (1.05–1.23) 1.25 (1.14–1.37) 1.37 (1.21–1.55) <0.001 
ER+/PR+ breast cancer 
 Cases (n1,173 1,186 1,237 1,250 1,247  
 Age-adjusted HR (95% CI) 1.00 1.08 (0.99–1.18) 1.25 (1.15–1.36) 1.42 (1.31–1.55) 1.66 (1.53–1.81) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.13 (1.04–1.22) 1.34 (1.23–1.45) 1.58 (1.46–1.73) 1.93 (1.77–2.12) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.07 (0.98–1.16) 1.21 (1.10–1.33) 1.36 (1.21–1.52) 1.48 (1.27–1.73) <0.001 
ER+/PR breast cancer 
 Cases (n268 274 233 200 201  
 Age-adjusted HR (95% CI) 1.00 1.11 (0.93–1.31) 1.04 (0.87–1.25) 1.01 (0.83–1.11) 1.18 (0.97–1.43) 0.325 
 Multivariable-adjusteda HR (95% CI) 1.00 1.14 (0.95–1.35) 1.08 (0.90–1.29) 1.06 (0.88–1.29) 1.27 (1.03–1.56) 0.101 
 Multivariable-adjustedb HR (95% CI) 1.00 1.16 (0.97–1.40) 1.12 (0.90–1.39) 1.13 (0.86–1.47) 1.40 (0.97–2.02) 0.277 
ER/PR breast cancer 
 Cases (n219 240 218 223 216  
 Age-adjusted HR (95% CI) 1.00 1.12 (0.93–1.35) 1.09 (0.90–1.32) 1.23 (1.01–1.49) 1.33 (1.10–1.63) 0.003 
 Multivariable-adjusteda HR (95% CI) 1.00 1.12 (0.93–1.35) 1.09 (0.89–1.32) 1.21 (0.99–1.47) 1.26 (1.02–1.56) 0.027 
 Multivariable-adjustedb HR (95% CI) 1.00 1.09 (0.90–1.33) 1.03 (0.82–1.29) 1.11 (0.85–1.44) 1.09 (0.75–1.57) 0.629 
Localized 
 Cases (n1,435 1,427 1,428 1,388 1,366  
 Age-adjusted HR (95% CI) 1.00 1.06 (0.99–1.14) 1.17 (1.09–1.26) 1.28 (1.19–1.38) 1.48 (1.36–1.60) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.10 (1.02–1.19) 1.25 (1.15–1.34) 1.41 (1.31–1.53) 1.69 (1.55–1.83) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.07 (0.99–1.15) 1.18 (1.08–1.28) 1.29 (1.16–1.43) 1.45 (1.25–1.67) <0.001 
Advanced 
 Cases (n384 411 405 434 446  
 Age-adjusted HR (95% CI) 1.00 1.11 (0.96–1.28) 1.19 (1.02–1.37) 1.40 (1.22–1.62) 1.64 (1.42–1.90) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.13 (0.98–1.30) 1.21 (1.05–1.40) 1.46 (1.26–1.69) 1.71 (1.47–1.99) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.06 (0.91–1.23) 1.08 (0.92–1.27) 1.22 (1.01–1.47) 1.25 (0.96–1.62) 0.049 
Low grade 
 Cases (n510 507 488 484 438  
 Age-adjusted HR (95% CI) 1.00 1.04 (0.92–1.18) 1.10 (0.97–1.25) 1.22 (1.07–1.39) 1.28 (1.12–1.47) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.08 (0.96–1.23) 1.19 (1.04–1.35) 1.39 (1.22–1.59) 1.55 (1.35–1.79) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.05 (0.92–1.20) 1.13 (0.97–1.31) 1.28 (1.07–1.53) 1.35 (1.05–1.74) 0.005 
Intermediate grade 
 Cases (n819 765 801 791 792  
 Age-adjusted HR (95% CI) 1.00 0.99 (0.90–1.09) 1.14 (1.03–1.26) 1.27 (1.14–1.40) 1.48 (1.33–1.64) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.03 (0.93–1.14) 1.22 (1.10–1.35) 1.40 (1.26–1.55) 1.70 (1.52–1.90) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 0.98 (0.88–1.09) 1.12 (0.99–1.25) 1.23 (1.07–1.41) 1.35 (1.12–1.64) <0.001 
High grade 
 Cases (n370 427 393 429 457  
 Age-adjusted HR (95% CI) 1.00 1.22 (1.06–1.40) 1.22 (1.06–1.41) 1.49 (1.29–1.71) 1.82 (1.57–2.10) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.23 (1.07–1.42) 1.23 (1.06–1.43) 1.50 (1.29–1.75) 1.81 (1.54–2.11) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.24 (1.07–1.43) 1.24 (1.07–1.44) 1.52 (1.31–1.76) 1.84 (1.58–2.14) <0.001 

aAlso adjusted for education, physical activity, smoking status, alcohol consumption, randomization group/study arm, unopposed estrogen therapy ever use, combined estrogen and progesterone therapy use ever, breastfed ever, age at menopause, oral contraceptive, healthy eating index 2015, age at menarche and age at first full‐term pregnancy, race, and ethnicity.

bAlso adjusted for BMI.

Table 5.

HRs for the association of predicted REE (Mifflin) with risk of incident, invasive breast cancer in postmenopausal women, overall and by breast cancer subtype.

Quintiles
12345Ptrend
Invasive breast cancer 
 Cases (n1,497 1,753 1,940 2,043 2,093  
 Age-adjusted HR (95% CI) 1.00 1.08 (1.00–1.15) 1.21 (1.13–1.29) 1.34 (1.25–1.43) 1.54 (1.43–1.65) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.11 (1.03–1.19) 1.26 (1.17–1.35) 1.42 (1.32–1.53) 1.68 (1.56–1.80) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.16 (0.99–1.14) 1.16 (1.08–1.25) 1.26 (1.16–1.36) 1.34 (1.21–1.48) <0.001 
ER+/PR+ breast cancer 
 Cases (n930 1,127 1,257 1,354 1,384  
 Age-adjusted HR (95% CI) 1.00 1.12 (1.03–1.22) 1.28 (1.17–1.39) 1.45 (1.33–1.58) 1.69 (1.55–1.84) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.16 (1.06–1.27) 1.35 (1.24–1.47) 1.58 (1.44–1.72) 1.90 (1.73–2.08) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.10 (1.01–1.21) 1.22 (1.11–1.34) 1.34 (1.21–1.48) 1.41 (1.24–1.60) <0.001 
ER+/PR breast cancer 
 Cases (n195 269 255 225 226  
 Age-adjusted HR (95% CI) 1.00 1.30 (1.08–1.56) 1.26 (1.04–1.52) 1.17 (0.96–1.43) 1.34 (1.09–1.63) 0.053 
 Multivariable-adjusteda HR (95% CI) 1.00 1.32 (1.10–1.60) 1.28 (1.06–1.56) 1.22 (0.99–1.49) 1.40 (1.14–1.73) 0.023 
 Multivariable-adjustedb HR (95% CI) 1.00 1.34 (1.10–1.62) 1.30 (1.06–1.60) 1.25 (0.99–1.57) 1.46 (1.09–1.96) <0.001 
ER/PR breast cancer 
 Cases (n193 197 241 236 246  
 Age-adjusted HR (95% CI) 1.00 0.90 (0.74–1.10) 1.09 (0.89–1.32) 1.09 (0.90–1.33) 1.24 (1.02–1.52) 0.004 
 Multivariable-adjusteda HR (95% CI) 1.00 0.91 (0.74–1.11) 1.08 (0.89–1.32) 1.09 (0.89–1.33) 1.19 (0.96–1.46) 0.025 
 Multivariable-adjustedb HR (95% CI) 1.00 0.89 (0.72–1.09) 1.04 (0.84–1.28) 1.02 (0.81–1.28) 1.05 (0.78–1.40) 0.476 
Localized 
 Cases (n1,127 1,349 1,451 1,563 1,520  
 Age-adjusted HR (95% CI) 1.00 1.10 (1.02–1.20) 1.21 (1.12–1.31) 1.38 (1.27–1.49) 1.52 (1.40–1.65) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.14 (1.06–1.24) 1.27 (1.17–1.38) 1.48 (1.37–1.61) 1.69 (1.55–1.84) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.11 (1.02–1.20) 1.19 (1.10–1.30) 1.34 (1.22–1.47) 1.40 (1.24–1.57) <0.001 
Advanced 
 Cases (n322 363 436 439 504  
 Age-adjusted HR (95% CI) 1.00 1.01 (0.90–1.18) 1.21 (1.04–1.40) 1.26 (1.09–1.46) 1.60 (1.38–1.85) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.03 (0.88–1.19) 1.23 (1.06–1.43) 1.30 (1.12–1.51) 1.64 (1.41–1.92) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 0.97 (0.84–1.14) 1.12 (0.96–1.31) 1.11 (0.94–1.32) 1.24 (1.001–1.53) 0.027 
Low grade 
 Cases (n405 477 505 532 493  
 Age-adjusted HR (95% CI) 1.00 1.07 (0.93–1.22) 1.14 (0.99–1.30) 1.26 (1.10–1.44) 1.32 (1.15–1.52) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.11 (0.97–1.27) 1.21 (1.06–1.39) 1.39 (1.21–1.60) 1.54 (1.33–1.78) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.08 (0.94–1.24) 1.14 (0.99–1.32) 1.27 (1.08–1.48) 1.30 (1.06–1.59) 0.002 
Intermediate grade 
 Cases (n647 732 813 867 884  
 Age-adjusted HR (95% CI) 1.00 1.04 (0.93–1.15) 1.17 (1.05–1.30) 1.31 (1.18–1.46) 1.51 (1.36–1.68) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.07 (0.96–1.19) 1.23 (1.11–1.37) 1.42 (1.27–1.58) 1.69 (1.51–1.89) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.03 (0.92–1.15) 1.14 (1.02–1.27) 1.25 (1.11–1.41) 1.35 (1.15–1.57) <0.001 
High grade 
 Cases (n305 366 427 460 510  
 Age-adjusted HR (95% CI) 1.00 1.09 (0.94–1.28) 1.28 (1.11–1.49) 1.44 (1.24–1.68) 1.78 (1.53–2.07) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.11 (0.95–1.30) 1.30 (1.12–1.51) 1.47 (1.26–1.71) 1.78 (1.53–2.09) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.07 (0.91–1.25) 1.21 (1.03–1.32) 1.30 (1.10–1.55) 1.43 (1.16–1.77) <0.001 
Quintiles
12345Ptrend
Invasive breast cancer 
 Cases (n1,497 1,753 1,940 2,043 2,093  
 Age-adjusted HR (95% CI) 1.00 1.08 (1.00–1.15) 1.21 (1.13–1.29) 1.34 (1.25–1.43) 1.54 (1.43–1.65) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.11 (1.03–1.19) 1.26 (1.17–1.35) 1.42 (1.32–1.53) 1.68 (1.56–1.80) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.16 (0.99–1.14) 1.16 (1.08–1.25) 1.26 (1.16–1.36) 1.34 (1.21–1.48) <0.001 
ER+/PR+ breast cancer 
 Cases (n930 1,127 1,257 1,354 1,384  
 Age-adjusted HR (95% CI) 1.00 1.12 (1.03–1.22) 1.28 (1.17–1.39) 1.45 (1.33–1.58) 1.69 (1.55–1.84) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.16 (1.06–1.27) 1.35 (1.24–1.47) 1.58 (1.44–1.72) 1.90 (1.73–2.08) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.10 (1.01–1.21) 1.22 (1.11–1.34) 1.34 (1.21–1.48) 1.41 (1.24–1.60) <0.001 
ER+/PR breast cancer 
 Cases (n195 269 255 225 226  
 Age-adjusted HR (95% CI) 1.00 1.30 (1.08–1.56) 1.26 (1.04–1.52) 1.17 (0.96–1.43) 1.34 (1.09–1.63) 0.053 
 Multivariable-adjusteda HR (95% CI) 1.00 1.32 (1.10–1.60) 1.28 (1.06–1.56) 1.22 (0.99–1.49) 1.40 (1.14–1.73) 0.023 
 Multivariable-adjustedb HR (95% CI) 1.00 1.34 (1.10–1.62) 1.30 (1.06–1.60) 1.25 (0.99–1.57) 1.46 (1.09–1.96) <0.001 
ER/PR breast cancer 
 Cases (n193 197 241 236 246  
 Age-adjusted HR (95% CI) 1.00 0.90 (0.74–1.10) 1.09 (0.89–1.32) 1.09 (0.90–1.33) 1.24 (1.02–1.52) 0.004 
 Multivariable-adjusteda HR (95% CI) 1.00 0.91 (0.74–1.11) 1.08 (0.89–1.32) 1.09 (0.89–1.33) 1.19 (0.96–1.46) 0.025 
 Multivariable-adjustedb HR (95% CI) 1.00 0.89 (0.72–1.09) 1.04 (0.84–1.28) 1.02 (0.81–1.28) 1.05 (0.78–1.40) 0.476 
Localized 
 Cases (n1,127 1,349 1,451 1,563 1,520  
 Age-adjusted HR (95% CI) 1.00 1.10 (1.02–1.20) 1.21 (1.12–1.31) 1.38 (1.27–1.49) 1.52 (1.40–1.65) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.14 (1.06–1.24) 1.27 (1.17–1.38) 1.48 (1.37–1.61) 1.69 (1.55–1.84) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.11 (1.02–1.20) 1.19 (1.10–1.30) 1.34 (1.22–1.47) 1.40 (1.24–1.57) <0.001 
Advanced 
 Cases (n322 363 436 439 504  
 Age-adjusted HR (95% CI) 1.00 1.01 (0.90–1.18) 1.21 (1.04–1.40) 1.26 (1.09–1.46) 1.60 (1.38–1.85) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.03 (0.88–1.19) 1.23 (1.06–1.43) 1.30 (1.12–1.51) 1.64 (1.41–1.92) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 0.97 (0.84–1.14) 1.12 (0.96–1.31) 1.11 (0.94–1.32) 1.24 (1.001–1.53) 0.027 
Low grade 
 Cases (n405 477 505 532 493  
 Age-adjusted HR (95% CI) 1.00 1.07 (0.93–1.22) 1.14 (0.99–1.30) 1.26 (1.10–1.44) 1.32 (1.15–1.52) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.11 (0.97–1.27) 1.21 (1.06–1.39) 1.39 (1.21–1.60) 1.54 (1.33–1.78) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.08 (0.94–1.24) 1.14 (0.99–1.32) 1.27 (1.08–1.48) 1.30 (1.06–1.59) 0.002 
Intermediate grade 
 Cases (n647 732 813 867 884  
 Age-adjusted HR (95% CI) 1.00 1.04 (0.93–1.15) 1.17 (1.05–1.30) 1.31 (1.18–1.46) 1.51 (1.36–1.68) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.07 (0.96–1.19) 1.23 (1.11–1.37) 1.42 (1.27–1.58) 1.69 (1.51–1.89) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.03 (0.92–1.15) 1.14 (1.02–1.27) 1.25 (1.11–1.41) 1.35 (1.15–1.57) <0.001 
High grade 
 Cases (n305 366 427 460 510  
 Age-adjusted HR (95% CI) 1.00 1.09 (0.94–1.28) 1.28 (1.11–1.49) 1.44 (1.24–1.68) 1.78 (1.53–2.07) <0.001 
 Multivariable-adjusteda HR (95% CI) 1.00 1.11 (0.95–1.30) 1.30 (1.12–1.51) 1.47 (1.26–1.71) 1.78 (1.53–2.09) <0.001 
 Multivariable-adjustedb HR (95% CI) 1.00 1.07 (0.91–1.25) 1.21 (1.03–1.32) 1.30 (1.10–1.55) 1.43 (1.16–1.77) <0.001 

aAlso adjusted for education, physical activity, smoking status, alcohol consumption, randomization group/study arm, unopposed estrogen therapy ever use, combined estrogen and progesterone therapy use ever, breastfed ever, age at menopause, oral contraceptive, healthy eating index 2015, age at menarche and age at first full‐term pregnancy, race, and ethnicity.

bAlso adjusted for BMI.

In analyses stratified by BMI category, we observed heterogeneity in the association between the predicted REEs and risk of invasive breast cancer (P < 0.05; Table 6). Specifically, all predicted REEs were positively associated with risk of invasive breast cancer in all BMI categories but the associations were stronger among overweight (BMI: 25.0–29.9 kg/m2) and in particular, normal weight women (BMI: 18.5–24.9 kg/m2) than among obese women (BMI: ≥30 kg/m2; Table 6). There was, however, no heterogeneity in the associations by WC or WHR categories (Table 6).

Table 6.

HRs for the association of predicted REE with risk of incident, invasive breast cancer in postmenopausal women stratified by anthropometric measures.

IkedaLivingstonMifflin
Per SD increase
BMI 
 18.5–24.9 kg/m2 1.28 (1.17–1.40) 1.24 (1.14–1.35) 1.22 (1.14–1.30) 
 25.0–29.9 kg/m2 1.26 (1.16–1.36) 1.26 (1.16–1.37) 1.18 (1.11–1.26) 
 ≥30 kg/m2 1.16 (1.10–1.22) 1.18 (1.11–1.25) 1.13 (1.08–1.19) 
Pinteraction 0.001 0.012 0.002 
WC 
 <80 cm 1.15 (1.06–1.24) 1.14 (1.06–1.22) 1.15 (1.08–1.23) 
 80–<88 cm 1.25 (1.14–1.37) 1.25 (1.14–1.37) 1.22 (1.13–1.32) 
 ≥88 cm 1.18 (1.13–1.22) 1.20 (1.15–1.25) 1.16 (1.12–1.21) 
Pinteraction 0.735 0.893 0.269 
WHR: <0.80 
 <0.80 1.22 (1.18–1.27) 1.22 (1.18–1.27) 1.23 (1.18–1.27) 
 0.80–0.85 1.17 (1.11–1.22) 1.17 (1.12–1.23) 1.15 (1.09–1.20) 
 >0.85 1.20 (1.15–1.25) 1.22 (1.16–1.28) 1.20 (1.15–1.25) 
Pinteraction 0.975 0.766 0.469 
IkedaLivingstonMifflin
Per SD increase
BMI 
 18.5–24.9 kg/m2 1.28 (1.17–1.40) 1.24 (1.14–1.35) 1.22 (1.14–1.30) 
 25.0–29.9 kg/m2 1.26 (1.16–1.36) 1.26 (1.16–1.37) 1.18 (1.11–1.26) 
 ≥30 kg/m2 1.16 (1.10–1.22) 1.18 (1.11–1.25) 1.13 (1.08–1.19) 
Pinteraction 0.001 0.012 0.002 
WC 
 <80 cm 1.15 (1.06–1.24) 1.14 (1.06–1.22) 1.15 (1.08–1.23) 
 80–<88 cm 1.25 (1.14–1.37) 1.25 (1.14–1.37) 1.22 (1.13–1.32) 
 ≥88 cm 1.18 (1.13–1.22) 1.20 (1.15–1.25) 1.16 (1.12–1.21) 
Pinteraction 0.735 0.893 0.269 
WHR: <0.80 
 <0.80 1.22 (1.18–1.27) 1.22 (1.18–1.27) 1.23 (1.18–1.27) 
 0.80–0.85 1.17 (1.11–1.22) 1.17 (1.12–1.23) 1.15 (1.09–1.20) 
 >0.85 1.20 (1.15–1.25) 1.22 (1.16–1.28) 1.20 (1.15–1.25) 
Pinteraction 0.975 0.766 0.469 

Note: Adjusted for education, physical activity, smoking status, alcohol consumption, randomization group/study arm, unopposed estrogen therapy ever use, combined estrogen and progesterone therapy use ever, breastfed ever, age at menopause, oral contraceptive, healthy eating index 2015, age at menarche and age at first full-term pregnancy, race and ethnicity.

In sensitivity analyses, the associations between the predicted REEs and risk of invasive breast cancer were mostly unchanged after excluding women with a history of chronic diseases at baseline (Supplementary Table S3).

In this large prospective study, regardless of which formula was used, the predicted REEs showed similar positive associations with risk of invasive breast cancer among postmenopausal women, overall, and irrespective of hormone receptor status, stage, and grade of the tumors. Most of these associations remained after additional adjustment for BMI or for the ratio of fat mass to lean body mass. Further, except for heterogeneity in the association between the predicted REEs and risk of invasive breast cancer by BMI category, there was no evidence of heterogeneity by levels of central adiposity.

Physical activity is inversely associated with cancer-related metabolic disorders such as overweight/obesity, insulin resistance, diabetes, and chronic inflammation (16, 17). Therefore, it is not surprising that previously in this cohort, AREE was shown to be inversely associated with risk of breast cancer among postmenopausal women (5). In contrast to the activity-related component of TEE, in the current study and in previous studies (8, 9), predicted REE was positively associated with risk of postmenopausal invasive breast cancer.

In this study, the first to assess the association between REE and risk of postmenopausal breast cancer by hormone receptor subtype, stage, and grade, predicted REEs were positively associated with risk irrespective of these tumor characteristics. REE tends to be higher in overweight or obese individuals because a large body mass requires more kilocalories for movement and to perform other basic energy utilizing functions (10). Moreover, excess adiposity is more strongly associated with the hormone receptor–positive breast tumors (1, 29) and higher-grade breast tumors (1, 30, 31). In keeping with this, in the current study, we observed that among postmenopausal women, the positive associations between the predicted REEs and risk of breast cancer were most pronounced for the hormone receptor–positive and higher grade tumors. Further, in analyses in which we adjusted for BMI, the associations between the predicted REEs and risk of invasive breast cancer (i.e., overall and by subtype) were attenuated, suggesting that body fat level partly explains the association between the predicted REEs and risk of invasive breast cancer.

We also showed positive associations between the predicted REEs and risk of postmenopausal invasive breast cancer irrespective of the categories of anthropometric measures. In this study, the positive associations between the predicted REEs and risk of breast cancer were more prominent among normal weight and overweight women than among obese women. Similar findings were observed in the study by Kliemann and colleagues (8), which utilized the World Health Organization/The Food and Agriculture Organization of the United Nations (WHO/FAO) predicted REE equation (8). When we examined the associations between the predicted REEs and risk of postmenopausal invasive breast cancer by level of central adiposity (i.e., based on WC and WHR categories), we did not find any evidence of heterogeneity in the associations. These findings suggest that higher REE may be associated with higher risk of invasive breast cancer even among postmenopausal women with low to moderate levels of general or central adiposity.

Mechanisms underlying the association between REE and breast cancer are unclear. Nonetheless, our findings are consistent with the notion that various metabolic dysfunctions including impaired fasting glucose, reduced insulin sensitivity, and chronic inflammation (11–13) are energy-demanding and result in increased energy expenditure (10–13). Chronic inflammation, for example, increases energy expenditure by 10% (13). The aforementioned metabolic dysfunctions can contribute to breast carcinogenesis by triggering oxidative stress and DNA damage, and by enhancing tumor cell growth, proliferation, survival, and migration (14, 15). Further experimental studies are needed to determine whether REE indirectly induces breast carcinogenesis by providing energy for dysregulated metabolic pathways and their associated carcinogenic processes (32, 33).

In this large prospective study, with long-term follow-up and information on a wide range of potential confounding variables, we were able to investigate the associations between the predicted REEs and risk of postmenopausal invasive breast cancer by selected tumor characteristics. Due to the relatively high number of invasive breast cancer cases, we were also able to perform analyses stratified by various anthropometric measures. However, this study has several limitations. First, we used equations to predict REE and therefore it is likely that there was some misclassification of the exposure of interest. The gold standard for measuring REE is indirect calorimetry (18) but there were too few women with available measured REE values to allow examination of the association between measured REE and risk. Nevertheless, in cross-classified analyses among a subgroup of women with measured REE, 60% or more of the participants with measured REEs in the highest tertile were also in the highest tertile of the predicted REEs. As this study was restricted to postmenopausal women, our findings may not be generalizable to premenopausal women.

Our findings suggest that relatively high REE is positively associated with risk of invasive breast cancer among postmenopausal women, independent of BMI or fat to lean body mass and other confounders. Moreover, the association between the predicted REEs and risk appeared to be most pronounced for tumor subtypes which are more strongly associated with excess adiposity, namely hormone receptor–positive subtypes and intermediate and high-grade breast tumors. Given the role of energy expenditure in supporting cancer-associated metabolic processes, further studies should be conducted to improve our understanding of the role of REE in the pathogenesis of breast cancer among postmenopausal women. If our findings are confirmed in future studies, predicted REE may provide a cheap, noninvasive means for predicting risk of breast cancer, and in particular, risk of the obesity-related subtypes, among postmenopausal women within a clinical setting and may be valuable in the development of nutritional interventions aimed at reducing risk of breast cancer.

Y. Mossavar-Rahmani reports grants from NIH during the conduct of the study. R.L. Prentice reports grants from NIH during the conduct of the study. Q. Qi reports grants from NIH outside the submitted work. G.L. Anderson reports grants from National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study. S. Wassertheil-Smoller reports grants from NIH during the conduct of the study. No disclosures were reported by the other authors.

R.S. Arthur: Conceptualization, formal analysis, methodology, writing–original draft, writing–review and editing. Y. Mossavar-Rahmani: Conceptualization, writing–review and editing. R.L. Prentice: Writing–review and editing. A.H. Shadyab: Writing–review and editing. J. Luo: Writing–review and editing. M. Sattari: Writing–review and editing. X. Xue: Formal analysis, writing–review and editing. V. Kamensky: Data curation, writing–review and editing. G.-C. Chen: Writing–review and editing. Q. Qi: Writing–review and editing. G.L. Anderson: Writing–review and editing. S. Wassertheil-Smoller: Writing–review and editing. M.L. Neuhouser: Conceptualization, supervision, writing–review and editing. T.E. Rohan: Conceptualization, supervision, funding acquisition, writing–review and editing.

T.E. Rohan is supported by the Breast Cancer Research Foundation (BCRF-16–140). We thank the WHI investigators, staff, and the trial participants for their outstanding dedication and commitment.

WHI investigators:

Program Office: (National Heart, Lung, and Blood Institute, Bethesda, MD) Jacques Roscoe, Shari Ludlum, Dale Burden, Joan McGowan, Leslie Ford, and Nancy Geller.

Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kopperberg.

Investigators and Academic Centers: (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (City of Hope Comprehensive Cancer Center, Duarte, CA) Rowan T. Chlebowski; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker.

WHI Memory Study: (Wake Forest University School of Medicine, Winston Salem, NC) Sally Shumaker.

Additional information: A full list of all the investigators who have contributed to WHI science appears at: https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.p.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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