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Original Investigation |

Overweight, Obesity, and Postmenopausal Invasive Breast Cancer Risk A Secondary Analysis of the Women’s Health Initiative Randomized Clinical Trials

Marian L. Neuhouser, PhD, RD1; Aaron K. Aragaki, MS1; Ross L. Prentice, PhD1; JoAnn E. Manson, MD, MPH, DrPH2; Rowan Chlebowski, MD, PhD3; Cara L. Carty, PhD4; Heather M. Ochs-Balcom, PhD5; Cynthia A. Thomson, PhD, RD6; Bette J. Caan, DrPH7; Lesley F. Tinker, PhD, RD1; Rachel Peragallo Urrutia, MD8; Jennifer Knudtson, MD9; Garnet L. Anderson, PhD1
[+] Author Affiliations
1Division of Public Health Sciences, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington
2Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
3Los Angeles Biomedical Research Institute at Harbor-UCLA, David Geffen School of Medicine, University of California, Los Angeles
4Department of Medicine, George Washington University School of Medicine, Washington, DC
5Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York
6Division of Health Promotion Sciences, University of Arizona, Tucson/Phoenix
7Division of Research, Kaiser Permanente, Oakland, California
8Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill
9Division of Reproductive Endocrinology and Fertility, University of Texas Health Science Center, San Antonio
JAMA Oncol. 2015;1(5):611-621. doi:10.1001/jamaoncol.2015.1546.
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Importance  More than two-thirds of US women are overweight or obese, placing them at increased risk for postmenopausal breast cancer.

Objective  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.

Results  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.

Trial Registration  clinicaltrials.gov Identifier: NCT00000611

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Figure.
Baseline Measurements of Estradiol, Estrone, and the Protein SHBG vs BMI at Baseline

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.

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