Solid curves indicates means; dashed curves, 95% CIs. BMI indicates body mass index, calculated as weight in kilograms divided by height in meters squared; SHBG, sex hormone binding globulin.
eFigure 1. Multivariable adjusted hazard ratios, compared to women of normal weight (BMI < 25 kg/m2), for total incident invasive breast cancer, breast cancer characteristics and other breast cancer outcomes in the WHI Clinical Trial
eFigure 2. Multivariable adjusted hazard ratios, compared to women of normal weight (BMI < 25 kg/m2), for total incident invasive breast cancer by select subgroups in the WHI Clinical Trial.
eFigure 3. Multivariate associations of BMI with breast cancer risk (a) and weight with breast cancer risk (b)
Customize your JAMA Network experience by selecting one or more topics from the list below.
Neuhouser ML, Aragaki AK, Prentice RL, et al. Overweight, Obesity, and Postmenopausal Invasive Breast Cancer RiskA Secondary Analysis of the Women’s Health Initiative Randomized Clinical Trials. JAMA Oncol. 2015;1(5):611–621. doi:10.1001/jamaoncol.2015.1546
Copyright 2015 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
More than two-thirds of US women are overweight or obese, placing them at increased risk for postmenopausal breast cancer.
To investigate in this secondary analysis the associations of overweight and obesity with risk of postmenopausal invasive breast cancer after extended follow-up in the Women’s Health Initiative (WHI) clinical trials.
Design, Setting, and Participants
The WHI clinical trial protocol incorporated measured height and weight, baseline and annual or biennial mammography, and adjudicated breast cancer end points in 67 142 postmenopausal women ages 50 to 79 years at 40 US clinical centers. The women were enrolled from 1993 to 1998 with a median of 13 years of follow-up through 2010; 3388 invasive breast cancers were observed.
Main Outcomes and Measures
Height and weight were measured at baseline, and weight was measured annually thereafter. Data were collected on demographic characteristics, personal and family medical history, and personal habits (smoking, physical activity). Women underwent annual or biennial mammograms. Breast cancers were verified by medical records reviewed by physician adjudicators.
Women who were overweight and obese had an increased invasive breast cancer risk vs women of normal weight. Risk was greatest for obesity grade 2 plus 3 (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, >35.0) (hazard ratio [HR] for invasive breast cancer, 1.58; 95% CI, 1.40-1.79). A BMI of 35.0 or higher was strongly associated with risk for estrogen receptor–positive and progesterone receptor–positive breast cancers (HR, 1.86; 95% CI, 1.60-2.17) but was not associated with estrogen receptor–negative cancers. Obesity grade 2 plus 3 was also associated with advanced disease, including larger tumor size (HR, 2.12; 95% CI, 1.67-2.69; P = .02), positive lymph nodes (HR, 1.89; 95% CI, 1.46-2.45; P = .06), regional and/or distant stage (HR, 1.94; 95% CI, 1.52-2.47; P = .05), and deaths after breast cancer (HR, 2.11; 95% CI, 1.57-2.84; P < .001). Women with a baseline BMI of less than 25.0 who gained more than 5% of body weight over the follow-up period had an increased breast cancer risk (HR, 1.36; 95% CI, 1.1-1.65), but among women already overweight or obese we found no association of weight change (gain or loss) with breast cancer during follow-up. There was no effect modification of the BMI-breast cancer relationship by postmenopausal hormone therapy, and the direction of association across BMI categories was similar for never, past, and current hormone therapy use.
Conclusions and Relevance
Obesity is associated with increased invasive breast cancer risk in postmenopausal women. These clinically meaningful findings should motivate programs for obesity prevention.
clinicaltrials.gov Identifier: NCT00000611
Obesity is a major public health problem in the United States. Recent data demonstrate that the age-adjusted obesity (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, ≥30.0) prevalence is 34.9% among all adults 20 years or older while that for overweight plus obesity (BMI ≥ 25.0) is 68.5%.1 Obesity has been associated with breast cancer risk in observational studies,2,3 systematic reviews, and meta-analyses.3-5 More recently, the 2012 Annual Report to the Nation on Cancer6 concluded that overweight and obese women have a relative risk for postmenopausal breast cancer of 1.13 and 1.25, respectively, vs women of normal weight.
Despite relatively strong and consistent evidence that obesity may increase postmenopausal breast cancer risk, questions remain, including whether obesity is associated with breast cancer characteristics, such as tumor hormone receptor status and stage at diagnosis, or whether use of postmenopausal hormone therapy (HT) modifies the obesity–breast cancer association, because both obesity and HT alter a woman’s hormone profile. Questions also remain regarding any interaction of race/ethnicity and obesity and breast cancer risk. Black women in the United States have higher rates of obesity1 and lower breast cancer rates but higher mortality rates than non-Hispanic white women.4 In this secondary analysis, we examine the associations of overweight and obesity with postmenopausal breast cancer risk in the Women’s Health Initiative (WHI) clinical trials,7,8 in which the protocol requirements specified baseline and annual or biennial mammograms and measured weights.
Our research objective was to understand the relationship of obesity with breast cancer risk in the context of a clinical trial in which mammography and measured weights were part of the trial protocol, thus reducing the potential for ascertainment bias.
We found that overweight and obese postmenopausal women have a significantly increased risk for invasive breast cancer, particularly for estrogen receptor–positive cancers. The risk is greatest for women with a body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) greater than 35.0, in whom the risk is 1.58 times the risk for women of normal weight.
Obesity was also significantly associated with markers of poor prognosis; women with BMI greater than 35.0 were more likely to have tumors that were large, with evidence of nodal involvement and poorly differentiated tumors.
We found no evidence for modification of the obesity–breast cancer association by use of postmenopausal hormone therapy.
Design details of the 3 overlapping WHI clinical trials have been published.7 Briefly, women aged 50 to 79 years were recruited at 40 US clinical centers from 1993 to 1998. Women could be randomized to 1, 2, or all 3 clinical trials (1 of 2 hormone trials and trials of dietary modification (DM) and calcium and vitamin D supplementation). Eligibility criteria included being postmenopausal and anticipated 3 years’ survival. Exclusions included prior breast cancer, other prior cancer (except nonmelanoma skin cancer) within 10 years, and conditions related to adherence and safety. Trial protocols were reviewed and approved by the institutional review boards at each clinical center and the Clinical Coordinating Center. All women signed informed consent. Reconsents were required to continue follow-up through the posttrial WHI Extension periods (2005-2010 and 2011-2016). Participants were not compensated.
For the HT trials, women with an intact uterus (n = 16 608) were randomized to oral conjugated equine estrogen (CEE) (0.625 mg/d) plus medroxyprogesterone acetate (MPA) (Prempro) (2.5 mg/d) or placebo. Women with a prior hysterectomy (n = 10 739) were randomized to oral CEE (Premarin) (0.625 mg/d) or placebo. Dietary modification trial participants were randomized to an intervention (n = 19 541) to reduce fat intake and increase fruit, vegetable, and grain consumption or a comparison group (n = 29 294). After 1 year, women could participate in the calcium plus vitamin D (CaD) trial, with randomization to a daily dose of vitamin D3 (400 IU) and calcium (1000 mg) or placebo.
Height, weight, and waist and hip circumferences were measured at baseline and weight was measured at annual visits. Body mass index 2 was further defined as normal weight (BMI < 25.0); overweight (25.0 to < 30.0); obese, grade 1 (30.0 to < 35.0); and obese, grade 2 plus 3 (≥35.0).1 Weight change (in percentage) was defined as [(annual visit weight − baseline weight)]/baseline weight × 100]. Baseline data were collected on demographic characteristics, smoking, alcohol, physical activity, medical history, and family history of breast cancer. Mammograms and clinical breast examinations were required at baseline and annually for women in the HT trials and baseline and biennially in the DM trial. Baseline serum sex hormone levels were available for 200 randomly selected HT trial participants.9
Details of outcomes data collection, adjudication, and primary trial results have been published.10-15 Women were queried about new medical events every 6 months during the intervention and annually thereafter. Breast cancers and breast cancer characteristics (tumor hormone receptor status, histologic findings, stage, grade, tumor size, nodal involvement) were verified by medical records and pathology report review by physician adjudicators using the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) coding system. Vital status was collected through follow-up of participants and proxies and periodic searches of the National Death Index. Cause of death was determined by medical record and death certificate review.
Associations between obesity and breast cancer incidence and mortality are presented as hazard ratios (HRs) and 95% CIs from Cox models using event times measured as time from randomization. The proportional hazards assumption for the primary analysis was verified by Schoenfeld residuals (P > .38) and by visual inspection of linear time-varying coefficients. All analyses were stratified by baseline 5-year age groups, WHI clinical trial randomization assignment(s), hysterectomy status, and study phase (intervention vs postintervention) and adjusted for age (continuous), race/ethnicity, education, parity, age at first birth, bilateral oophorectomy, family history of breast cancer, prior estrogen use and duration, prior estrogen plus progestin use and duration, smoking, diabetes mellitus, and alcohol consumption. Because mammography use was required by the WHI clinical trial protocol and compliance was good,7,8 no additional adjustment for mammography use was applied. Breast cancer mortality data were collected as deaths attributed to breast cancer and as all deaths after breast cancer. Trend tests were computed using BMI categories as a continuous variable. When examining different breast cancer characteristics,16 heterogeneity in BMI trends was tested using competing risk methods. Graphical representation of the shape of the relative risk relationship across BMI categories was created by fitting nonparametric splines to the multivariable adjusted HRs in R software, version 2.15.3 (R Foundation).
Associations of weight change with breast cancer risk were examined with similar Cox regression models stratified by baseline BMI category and using a time-dependent weight change variable updated with annual weight measurements and displayed in 5 categories: weight stable (±2% of baseline weight), 2% to 5% weight gain, more than 5% weight gain, 2% to 5% weight loss, or more than 5% weight loss. The trend test was based on these weight change categories, and the test for heterogeneity in trends between baseline BMI category was based on interaction tests.
The relationship between BMI and breast cancer incidence within HT-use subgroups was examined using similar approaches, and the P values were based on interaction tests. The HT-use subgroups were determined compositely by baseline self-report of HT use and randomization into the WHI clinical trial HT trials. Specifically, participants randomized to HT were categorized as “current,” participants with no prior HT use were categorized as “never,” and all others were categorized as “past.” Finally, participants not randomized in the HT trial were categorized per their baseline HT use. In exploratory analyses, nonparametric fits (spline) of the multivariable association between invasive breast cancer risk and BMI were examined; smoothing parameter was chosen objectively via Akaike information criteria. Similar analyses also examined the nonparametric risk of weight and included height as a covariate. Unless otherwise noted, all analyses were conducted using SAS statistical software (version 9.3; SAS Institute Inc) and were not adjusted for multiple testing. Women with baseline weight (>135 kg or <35 kg) or BMI (>50.0 or <18.5) measurements were excluded; 67 142 of 68 132 participants and 3388 breast cancers were included in this study. See also the eMethods in the Supplement.
Participant characteristics differed by baseline BMI category (Table 1). Obese women were likely to be younger, nonwhite, less educated, have had a hysterectomy or bilateral oophorectomy, have been treated for diabetes mellitus, were less likely to have used HT, and have reported less recreational physical activity compared with women of normal weight.
Women who were overweight; obese, grade 1; and obese, grade 2 plus 3 had an increased invasive breast cancer risk relative to women of normal weight (Table 2). The HRs increased as BMI increased and displayed a dose-response effect with the greatest risk for women with grade 2 plus 3 obesity (HR, 1.58; 95% CI, 1.40-1.79; P < .001 for trend). Tests of heterogeneity suggested that the association between BMI and breast cancer risk differed by hormone receptor status (P < .001). Body mass index was associated with an increased risk of estrogen- and progesterone-positive breast cancer, and the HRs increased at each BMI level, suggesting a dose-response relationship (HR, 1.86; 95% CI, 1.60-2.17 for BMI ≥ 35.0). In exploratory analyses, measures of central adiposity (waist circumference and waist-to-hip ratio) were added to the multivariable adjusted model of weight. Neither measure of central adiposity conferred any additional information (P > .40) beyond what was already explained by weight (data not shown).
Obesity was associated with more advanced disease, including larger tumor size (P = .02), positive lymph nodes (P = .06), and regional or distant stage at diagnosis (P = .05) (Table 2 and eFigure 1 in the Supplement). Body mass index was strongly associated with breast cancer mortality only for obesity grade 2 plus 3 (HR, 2.25; 95% CI, 1.51-3.36; P < .001) and mortality after invasive breast cancer for all obesity grades (grade 1, HR, 1.37; 95% CI, 1.04-1.79; and grade 2 plus 3, HR, 2.11; 95% CI, 1.57-2.84; P < .001).
Women who gained more than 5% of their baseline weight during follow-up had a modest increased risk (HR, 1.12; 95% CI, 1.00-1.25; P = .08 for trend) compared with women with stable weight, but there was no change in risk for women who lost weight (Table 3). Subgroup analyses suggested that associations between weight change and breast cancer risk was modified by baseline BMI (P = .05 for interaction). Women with normal BMI who gained more than 5% of their body weight during follow-up increased their breast cancer risk relative to women with stable weight (HR, 1.36; 95% CI, 1.11-1.65), but neither weight gain nor loss further changed risk for overweight and obese women.
A priori subgroup analyses investigated whether associations of BMI with invasive breast cancer risk varied by age, race/ethnicity, and HT use (Table 4 and eFigure 2 in the Supplement). Baseline age modified the association of BMI with cancer risk such that the associations seemed slightly weaker among the youngest women (P = .05 for interaction), but the overall obesity–breast cancer risk relationship remained strong. There was no evidence of effect modification of the BMI–invasive breast cancer relationship by race/ethnicity (P = .34 for interaction). Among women with an intact uterus, use of estrogen and progestin did not modify the association of BMI with cancer risk because the data support a similar trend between BMI and breast cancer risk across the estrogen and progestin use categories (P = .78 for interaction). Among women with a prior hysterectomy, data were suggestive, but not conclusive, of an interaction between estrogen use alone and BMI in relation to breast cancer risk (P = .11 for interaction). In particular, a low incidence rate for the referent normal weight group (annualized percentage, 0.23%) among women who never used estrogen alone was associated with linear, dose-response risk estimates for overweight (HR, 1.66; 95% CI, 1.06-2.60); obesity, grade 1 (HR, 2.16; 95% CI, 1.38-3.39); and obesity, grade 2 plus 3 (HR, 2.63; 95% CI, 1.32-2.00). For the subgroup defined as “current use” of estrogen alone, the BMI-associated risk was increased only for current users of estrogen alone who were obese, grade 1 (HR, 1.35 [95% CI, 1.07-1.71]), or obese, grade 2 plus 3 (HR, 1.47 [95% CI, 1.12-1.92]). A post hoc analysis that contrasted subgroups defined by never used estrogen alone and ever used estrogen alone (past or current use) was more suggestive of effect modification; HRs were 1.01 (95% CI, 0.83-1.22), 1.28 (95% CI, 1.04-1.58), and 1.44 (95% CI, 1.14-1.83) among women who ever used estrogen alone for overweight; obese, grade I; and obese, grade 2 plus 3, respectively (P = .04 for interaction). In a sensitivity analysis differentiating between prior estrogen and progestin use or estrogen use alone use among the posthysterectomy group, a similar association was observed between BMI and breast cancer among women who never used estrogen alone or estrogen and progestin. Specifically, HRs were 1.65 (95% CI, 1.02-2.68), 2.30 (95% CI, 1.42-3.73), and 2.80 (95% CI, 1.70-4.60) for overweight; obese, grade 1; and obese, grade 2 plus 3, respectively.
We next examined whether the interpretation of results varied by the type of obesity measure used: BMI or weight, including height as a covariate. The multivariable-adjusted risk for the BMI–invasive breast cancer association was mostly linear for most (middle 90%) of the distribution (eFigure 3A in the Supplement) and plateaued near 40.0; the 5th and 95th BMI percentiles were 21.3 and 39.3, respectively. However, the multivariable-adjusted risk associated with weight (kilograms) was nonlinear (eFigure 3B in the Supplement) even among the middle 90% of participants; the 5th and 95th percentiles were 54.5 kg and 104.5 kg, respectively.
To better understand the shapes of the curves for the BMI and weight models in which the breast cancer rates increase with both measures but are attenuated at the highest BMI levels (eFigure 3 in the Supplement), we explored the relationship between the sex hormones and BMI. Smoothed estimates of baseline mean levels of estradiol, estrone, and the protein SHBG in the available subset of 200 participants were plotted against BMI (Figure). Estradiol had a linear relationship with BMI, but the association between estrone and BMI dampens for grade 2 plus 3 obesity. Finally, the sharp decrease observed between mean serum SHBG concentrations and increasing BMI levels off for grade 2 plus 3 obesity.
The WHI clinical trial examined the association of overweight and obesity with invasive breast cancer risk in postmenopausal women. Unlike many observational studies, weight, height, and body circumferences were measured at baseline and annually using a standardized protocol throughout the trial; annual or biennial mammography was a required trial protocol element, thus minimizing ascertainment bias; and breast cancer outcomes (including details on breast cancer characteristics: tumor hormone receptor status, histologic characteristics, nodal involvement, tumor grade, and disease stage) were adjudicated by physician adjudicators. In this context, BMI was positively associated with increased risk of invasive breast cancer (P < .001). We observed a strong linear trend in which the risk progressively increased across the BMI categories. The strongest associations were observed for women with a BMI higher than 35.0; these women had a 58% increased risk of invasive breast cancer compared with women with a BMI lower than 25.0 . Breast cancer deaths were also more than 2-fold higher among those with grade 2 plus 3 obesity compared with those with normal BMI.
Obesity was associated with breast cancer characteristics, including tumor size, lymph node positivity, and regional and/or distant stage at diagnosis. In addition, women with estrogen receptor– and progesterone receptor–positive tumors who were obese, grade 1, or obese, grade 2 plus 3, had 52% and 86% increased risk of breast cancer, respectively, compared with women with normal BMI, respectively. The growth of estrogen receptor–positive tumors are under estrogen influence,17,18 and estrogen levels are higher in overweight and obese postmenopausal women owing to the aromatization of androstenedione and testosterone to estrogens in adipose tissue.19,20 Furthermore, obese individuals have larger and more abundant adipose tissue cells than those of normal weight, and these women typically have greater endogenous synthesis of estrogens in their adipose tissue. Leptin may also increase estrogen levels,21 and while leptin data are not available for study participants, leptin levels are higher in overweight and obese individuals than in those of normal weight.22,23 These biological relationships of BMI and altered hormone and cytokine profiles and the potential causal relationships with breast cancer risk are supported by our data showing a strong linear relationship between baseline BMI and both estradiol and estrone levels and are consistent with findings of a previous report24 on the role of serum hormone and breast carcinogenesis.
The WHI clinical trial results differ from findings in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (NSABP P-1) and the Study of Tamoxifen and Raloxifene (STAR).25-28 In contrast to the findings of the WHI clinical trial reported herein, the NSABP P-1 and STAR results showed a modest but nonsignificant, increased risk for postmenopausal breast cancer (relative risk [RR], 1.14; 95% CI, 0.94-1.38) for women with a BMI of at least 30.0 compared with women with a BMI lower than 25.0.25 Similar to the WHI clinical trial , the NSABP P-1 trials had baseline breast cancer risk assessment, baseline and serial mammography, and adjudicated breast cancer outcomes. However, the NSABP P-1 results are not directly comparable with those reported herein because nearly 75% of NSABP P-1 participants were randomized to tamoxifen or raloxifene, agents that decrease breast cancer incidence by almost 50%.26-28 As a result, there were fewer than 3200 postmenopausal women who were randomized to placebo for whom findings could reasonably be compared with those in the WHI clinical trial . The HRs for breast cancer risk in obese, grade 1, and obese, grade 2 plus 3, NSABP P-1 postmenopausal-placebo participants were 1.77 and 1.28, respectively (P = .36). However, the limited sample size precludes reliable generation of information regarding BMI influence on breast cancer risk in women not receiving these effective chemoprevention agents.
Several observational studies have reported that the relationship between obesity and breast cancer risk is modified by postmenopausal HT use.29-32 Huang et al30 found that higher vs lower BMI was associated with an increased postmenopausal breast cancer risk (RR, 1.59; 95% CI, 1.09-2.32; P < .001 for trend), except among current and past HT users. Subsequent observational studies from the Carolina Breast Cancer Study,31 a follow-up analysis from the Nurses’ Health Study,29 the Breast Cancer Surveillance Consortium,32 the WHI Observational Study,33 and others34-37 have similarly reported apparent effect modification of the obesity–breast cancer relationship by HT use. Many investigators reporting interactions of HT and obesity in relation to breast cancer risk have posited that HT use obscures the effects of obesity, particularly in relation to their effects on circulating hormone levels. To our knowledge, a biological mechanism to explain these associations has not been identified nor have results been confirmed with evidence from randomized clinical trials. Of note, 2 previous reports38,39 from the WHI clinical trial did not find an interaction between BMI and CEE alone or CEE plus MPA, and in this report we found no effect modification, and similar directions of associations were observed across BMI categories for never, past, and current HT use. While we did find attenuations of the risk estimates for ever-users of estrogen alone among women with a prior hysterectomy, the association between obesity and breast cancer remained. Differences in findings may be due to observational studies’ reliance on self-reported height, weight, and HT and may be subject to mammography screening and ascertainment bias when outcomes are collected by self-report. Notably, there are higher rates of routine screening mammograms for women receiving postmenopausal HT; the larger detection rates from screening mammograms could introduce bias in the observational studies if obese women underwent screening mammography at a different rate than women of normal weight.40
The WHI clinical trial findings of consistent dose-response risks across the BMI categories regardless of postmenopausal HT use have clinical implications. One report32 suggested that since the obesity–breast cancer risk was attenuated or not observed among HT users, obese women may benefit from HT use because they observed no excess breast cancer risk for these women. However, the preponderance of evidence suggests that postmenopausal HT is not beneficial for multiple health outcomes, including breast cancer, and the risks outweigh the benefits.41
One intriguing finding was that women in the WHI clinical trial who began the study with a BMI lower than 25.0 and gained more than 5% of body weight over the follow-up period had a breast cancer HR of 1.36 (95% CI, 1.1-1.65) compared with women of stable weight. After menopause, the breast tissue evolves toward a higher adipose content. Breast tissue adipocytes serve as a source of inflammatory cytokines as well as local estrogen production.19,20 It is possible that a weight gain–induced sudden and steep rise in breast adipocytes and exposure to cytokines and estrogens could explain why women of normal weight who gained more than 5% bodyweight had an increased risk for breast cancer compared with women of stable weight. These results suggest that prevention of weight gain may be an important public health strategy for reducing breast cancer risk.
In contrast, women who were overweight or obese at baseline had no change in risk by weight gain or loss during follow-up relative to weight stability. It is important to note that the WHI clinical trial was not a weight loss trial, and the weight change data we present may reflect both intentional and unintentional weight loss. Well-designed clinical trials are needed to definitively test whether weight loss and body composition changes in overweight and obese women or obesity prevention in women of normal weight will reduce breast cancer risk. In addition, it is not clear at what stage in life excess weight confers the greatest risk. For example, during adolescence and pregnancy, breast epithelial cells undergo rapid division and differentiation. It is possible that obesity superimposed on this rapid cell growth may set the stage for aberrant cell growth and biological susceptibility to breast cancer.5,42 Another susceptible time point may be the menopause, when breast tissue is undergoing further changes.
Strengths of this WHI-CT report include the large sample size, standardized data collection, adjudicated breast cancers, protocol-required mammography, and limited loss to follow-up. Limitations include fewer participants of minority race/ethnic groups, lack of data on tumor molecular characteristics,43 and fewer data on longer-term weight and body composition changes and inability to distinguish from unintentional weight loss. Death from breast cancer was not common, so the elevated mortality risk for women with grade 2 plus 3 obesity should be viewed with caution. Finally, we had insufficient power to examine risk for distant stage only owing to very few cases presenting with distant stage at diagnosis.
Obesity is associated with a dose-response increased postmenopausal breast cancer risk, particularly for estrogen receptor– and progesterone receptor–positive disease, but risk does not vary by HT use or race/ethnicity. These clinically meaningful findings support the need for trials clinical trials evaluating the role of obesity prevention and treatment on breast cancer risk.
Corresponding Author: Marian L. Neuhouser, PhD, RD, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave North, M4B402, Seattle, WA 98109-1024 (firstname.lastname@example.org).
Accepted for Publication: April 24, 2015.
Published Online: June 11, 2015. doi:10.1001/jamaoncol.2015.1546.
Author Contributions: Dr Neuhouser and Mr Aragaki had full access to the data and take full responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Neuhouser, Prentice, Manson, Thomson, Anderson.
Acquisition, analysis, or interpretation of data: Neuhouser, Aragaki, Prentice, Manson, Chlebowski, Carty, Ochs-Balcom, Caan, Tinker, Urrutia, Knudtson, Anderson.
Drafting of the manuscript: Neuhouser, Aragaki, Chlebowski, Thomson, Anderson.
Critical revision of the manuscript for important intellectual content: Neuhouser, Aragaki, Prentice, Manson, Carty, Ochs-Balcom, Caan, Tinker, Urrutia, Knudtson, Anderson.
Statistical analysis: Neuhouser, Aragaki, Prentice, Carty, Caan.
Obtained funding: Prentice.
Administrative, technical, or material support: Manson, Chlebowski, Thomson, Knudtson.
Study supervision: Neuhouser, Manson, Chlebowski, Ochs-Balcom, Anderson.
Conflict of Interest Disclosures: Dr Chlebowski has received speaker’s fees and honorarium from Novartis; honorarium for advisory boards and consulting for Novartis, Novo Nordisk, Pfizer, Genetech, and Amgen. No other disclosures are reported.
Funding/Support: The Women’s Health Initiative (WHI) programs are funded by the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, US Department of Health and Human Services through contracts, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.
Role of the Funder/Sponsor: The WHI project office at the NHLBI, which was the sponsor of WHI, had a role in the overall design and conduct of the WHI, but no direct role in this manuscript with regards to design, interpretation of the data, review and approval of the manuscript and decision to submit the manuscript for publication. Decisions concerning the above, as well as overall data collection, management, and analysis resided, with committees composed of WHI investigators and included NHLBI representatives.
Additional Information: A complete list of WHI investigators can be found at https://www.whi.org.