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

Neil M. Iyengar, Rhonda Arthur, Joann E. Manson, Rowan T. Chlebowski, Candyce H. Kroenke, Lindsay Peterson, Ting Yuan D. Cheng, Elizabeth C. Feliciano, Dorothy Lane, Juhua Luo, Rami Nassir, Kathy Pan, Sylvia Wassertheil-Smoller, Victor Kamensky, Thomas E. Rohan, Andrew J. Dannenberg

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalJAMA oncology
DOIs
StateAccepted/In press - Jan 1 2018

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Observational Studies
Adipose Tissue
Body Mass Index
Randomized Controlled Trials
Breast Neoplasms
Estrogen Receptors
X-Rays
Fats
Sex Hormone-Binding Globulin
Clinical Studies
Adiposity
Proxy
Women's Health
Leptin
C-Reactive Protein
HDL Cholesterol
Medical Records
Life Style
Interleukin-6
Triglycerides

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Iyengar, Neil M.; Arthur, Rhonda; Manson, Joann E.; Chlebowski, Rowan T.; Kroenke, Candyce H.; Peterson, Lindsay; Cheng, Ting Yuan D.; Feliciano, Elizabeth C.; Lane, Dorothy; Luo, Juhua; Nassir, Rami; Pan, Kathy; Wassertheil-Smoller, Sylvia; Kamensky, Victor; Rohan, Thomas E.; Dannenberg, Andrew J.

In: JAMA oncology, 01.01.2018.

Research output: Contribution to journalArticle

Iyengar, NM, Arthur, R, Manson, JE, Chlebowski, RT, Kroenke, CH, Peterson, L, Cheng, TYD, Feliciano, EC, Lane, D, Luo, J, Nassir, R, Pan, K, Wassertheil-Smoller, S, Kamensky, V, Rohan, TE & Dannenberg, AJ 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', JAMA oncology. https://doi.org/10.1001/jamaoncol.2018.5327
Iyengar, Neil M. ; Arthur, Rhonda ; Manson, Joann E. ; Chlebowski, Rowan T. ; Kroenke, Candyce H. ; Peterson, Lindsay ; Cheng, Ting Yuan D. ; Feliciano, Elizabeth C. ; Lane, Dorothy ; Luo, Juhua ; Nassir, Rami ; Pan, Kathy ; Wassertheil-Smoller, Sylvia ; Kamensky, Victor ; Rohan, Thomas E. ; Dannenberg, Andrew J. / 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. In: JAMA oncology. 2018.
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abstract = "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.",
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T1 - Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women with Normal Body Mass Index

T2 - A Secondary Analysis of a Randomized Clinical Trial and Observational Study

AU - Iyengar, Neil M.

AU - Arthur, Rhonda

AU - Manson, Joann E.

AU - Chlebowski, Rowan T.

AU - Kroenke, Candyce H.

AU - Peterson, Lindsay

AU - Cheng, Ting Yuan D.

AU - Feliciano, Elizabeth C.

AU - Lane, Dorothy

AU - Luo, Juhua

AU - Nassir, Rami

AU - Pan, Kathy

AU - Wassertheil-Smoller, Sylvia

AU - Kamensky, Victor

AU - Rohan, Thomas E.

AU - Dannenberg, Andrew J.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

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