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Original Investigation
December 6, 2018

Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index: A Secondary Analysis of a Randomized Clinical Trial and Observational Study

Author Affiliations
  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
  • 2Department of Medicine, Weill Cornell Medical College, New York, New York
  • 3Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
  • 4Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 5Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California
  • 6Division of Research, Kaiser Permanente, Oakland, California
  • 7Department of Medicine, Washington University in Saint Louis, St Louis, Missouri
  • 8Department of Epidemiology, University of Florida, Gainesville
  • 9Department of Family, Population and Preventive Medicine, Stony Brook University School of Medicine, Stony Brook, New York
  • 10Department of Epidemiology and Biostatistics, Indiana University, Indianapolis
  • 11Department of Biochemistry and Molecular Medicine, University of California, Davis
  • 12Los Angeles Biomedical Research Institute at Harbor-UCLA (University of California, Los Angeles) Medical Center, Los Angeles
JAMA Oncol. 2019;5(2):155-163. doi:10.1001/jamaoncol.2018.5327
Key Points

Question  Are increased levels of body fat in women with normal body mass index associated with an elevated risk of breast cancer?

Findings  In a cohort of 3460 postmenopausal women with normal body mass index enrolled in the Women’s Health Initiative randomized clinical trial and observational study, higher body fat levels measured by dual-energy x-ray absorptiometry were associated with increased risk of invasive breast cancer at a median follow-up of 16 years.

Meaning  Postmenopausal women with higher body fat levels are at elevated risk for breast cancer despite having a normal body mass index.


Importance  Obesity is associated with an increased risk of breast cancer, including the estrogen receptor (ER)–positive subtype in postmenopausal women. Whether excess adiposity is associated with increased risk in women with a normal body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown.

Objective  To investigate the association between body fat and breast cancer risk in women with normal BMI.

Design, Setting, and Participants  This ad hoc secondary analysis of the Women’s Health Initiative (WHI) clinical trial and observational study cohorts was restricted to postmenopausal participants with a BMI ranging from 18.5 to 24.9. Women aged 50 to 79 years were enrolled from October 1, 1993, through December 31, 1998. Of these, 3460 participants underwent body fat measurement with dual-energy x-ray absorptiometry (DXA) at 3 US designated centers with follow-up. At a median follow-up of 16 years (range, 9-20 years), 182 incident breast cancers had been ascertained, and 146 were ER positive. Follow-up was complete on September 30, 2016, and data from October 1, 1993, through September 30, 2016, was analyzed August 2, 2017, through August 21, 2018.

Main Outcomes and Measures  Body fat levels were measured at baseline and years 1, 3, 6, and 9 using DXA. Information on demographic data, medical history, and lifestyle factors was collected at baseline. Invasive breast cancers were confirmed via central review of medical records by physician adjudicators. Blood analyte levels were measured in subsets of participants.

Results  Among the 3460 women included in the analysis (mean [SD] age, 63.6 [7.6] years), multivariable-adjusted hazard ratios for the risk of invasive breast cancer were 1.89 (95% CI, 1.21-2.95) for the highest quartile of whole-body fat and 1.88 (95% CI, 1.18-2.98) for the highest quartile of trunk fat mass. The corresponding adjusted hazard ratios for ER-positive breast cancer were 2.21 (95% CI, 1.23-3.67) and 1.98 (95% CI, 1.18-3.31), respectively. Similar positive associations were observed for serial DXA measurements in time-dependent covariate analyses. Circulating levels of insulin, C-reactive protein, interleukin 6, leptin, and triglycerides were higher, whereas levels of high-density lipoprotein cholesterol and sex hormone–binding globulin were lower in those in the uppermost vs lowest quartiles of trunk fat mass.

Conclusions and Relevance  In postmenopausal women with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancer and altered levels of circulating metabolic and inflammatory factors. Normal BMI categorization may be an inadequate proxy for the risk of breast cancer in postmenopausal women.

Trial Registration  ClinicalTrials.gov identifier: NCT00000611