Originally published as JCO Early Release 10.1200/JCO.2006.07.3965 on January 29 2007

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Physical Activity, Body Mass Index, and Mammographic Density in Postmenopausal Breast Cancer Survivors

Melinda L. Irwin, Erin J. Aiello, Anne McTiernan, Leslie Bernstein, Frank D. Gilliland, Richard N. Baumgartner, Kathy B. Baumgartner, Rachel Ballard-Barbash

From the Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, CT; Center for Health Studies, Group Health Cooperative; Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Preventive Medicine, University of Southern California, Los Angeles, CA; Cancer Research & Treatment Center, Department of Internal Medicine, University of New Mexico, Albuquerque, NM; and the Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD

Address reprint requests to Melinda L. Irwin, PhD, MPH, Department of Epidemiology and Public Health, Yale School of Medicine, PO Box 208034, New Haven, CT 06520-8034; e-mail: melinda.irwin{at}yale.edu

	ABSTRACT

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Purpose: To investigate the association between physical activity, body mass index (BMI), and mammographic density in a racially/ethnically diverse population-based sample of 522 postmenopausal women diagnosed with stage 0-IIIA breast cancer and enrolled in the Health, Eating, Activity, and Lifestyle Study.

Methods: We collected information on BMI and physical activity during a clinic visit 2 to 3 years after diagnosis. Weight and height were measured in a standard manner. Using an interview-administered questionnaire, participants recalled the type, duration, and frequency of physical activities they had performed in the last year. We estimated dense area and percentage density as a continuous measure using a computer-assisted software program from mammograms imaged approximately 1 to 2 years after diagnosis. Analysis of covariance methods were used to obtain mean density across WHO BMI categories and physical activity tertiles adjusted for confounders.

Results: We observed a statistically significant decline in percentage density (P for trend = .0001), and mammographic dense area (P for trend = .0052), with increasing level of BMI adjusted for potential covariates. We observed a statistically significant decline in mammographic dense area (P for trend = .036) with increasing level of sports/recreational physical activity in women with a BMI of at least 30 kg/m². Conversely, in women with a BMI less than 25 kg/m², we observed a non–statistically significant increase in mammographic dense area and percentage density with increasing level of sports/recreational physical activity.

Conclusion: Increasing physical activity among obese postmenopausal breast cancer survivors may be a reasonable intervention approach to reduce mammographic density.

	INTRODUCTION

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Mammographic density is a strong risk factor for breast cancer.¹ Dense tissue in more than 50% of the breast could account for approximately one third of breast cancers.¹ Mammographic density has also been associated with breast cancer tumor characteristics, including tumor size, lymph node status, and lymphatic or vascular invasion in screen-detected cancers.² A three-fold increased risk of second breast cancers has also been observed in women diagnosed with ductal carcinoma in situ who have highly dense breasts.³ Recently, Maskarinec et al⁴ observed higher percentage densities in women diagnosed with breast cancer than in age-matched controls.

Although inherited factors explain approximately 60% of the variance in the proportion of the breast occupied by dense tissue,¹ mammographic density is also modifiable.^5-7 Increases in mammographic density have been observed in women treated with hormone therapy,⁵ and decreases in mammographic density have been observed in women treated with tamoxifen⁶ or a low-fat diet.⁷ Factors that change mammographic density may also change breast cancer risk and prognosis.^1-3 Identification of sources of variation in mammographic density is likely to provide a better understanding of factors that cause breast cancer and new approaches to prevention and treatment.

Physical activity is associated with a reduced breast cancer risk.⁸ Changes in sex-hormone concentrations, menstrual patterns, and energy balance have been suggested as plausible explanations for the relationship between physical activity and breast cancer, although other mechanisms may account for the consistent data observed in epidemiologic studies.⁸ Physical activity may influence mammographic density by favorably changing certain hormones associated with mammographic density and breast cancer risk.⁹ We examined the relationship between physical activity and mammographic density in pre- and postmenopausal women, and observed a statistically significant inverse association between sports/recreational physical activity and prediagnostic mammographic density in obese postmenopausal breast cancer survivors.¹⁰ To further investigate the association between physical activity and mammographic density, we examined the association between physical activity, body mass index (BMI), and 1- to 2-years postdiagnosis mammographic density in a racially/ethnically diverse sample of postmenopausal breast cancer survivors. To our knowledge, no published studies have examined the associations among BMI, physical activity, and mammographic density in breast cancer survivors.

	METHODS

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Study Setting, Participants, and Recruitment
The Health, Eating, Activity, and Lifestyle (HEAL) study is a population-based, multicenter, multiracial/-ethnic prospective cohort study that has enrolled 1,183 breast cancer patients who are being observed to determine whether weight, physical activity, diet, sex hormones, mammographic density, and other factors affect breast cancer prognosis.^11-13 Women were recruited into the HEAL study through Surveillance, Epidemiology, End Results (SEER) registries in New Mexico, Los Angeles County (CA), and western Washington. Names and contact information were retrieved from the SEER registries. Participants were contacted to determine interest and eligibility; approximately 41% of women with breast cancer who were eligible by age, stage, and county of residence were enrolled onto the study. Details of the aims, study design, and recruitment procedures have been published previously.^11-13

Briefly, in New Mexico, we recruited 615 women age 18 years or older diagnosed with in situ to stage IIIA breast cancer between July 1996 and March 1999 and living in Bernalillo, Sante Fe, Sandoval, Valencia, or Taos counties. In western Washington, we recruited 202 women between the age of 40 and 64 years diagnosed with in situ to stage IIIA breast cancer between September 1997 and September 1998 and living in King, Pierce, or Snohomish Counties. In Los Angeles county, 366 black women with stage 0 to IIIA breast cancer who had participated in the Los Angeles portion of the Women's Contraceptive and Reproductive Experiences (CARE) study, a case-control study of invasive breast cancer, or who had participated in a parallel case-control study of in situ breast cancer were recruited for the HEAL study. Eligible participants from these two studies were the subset of black women who were diagnosed with breast cancer between May 1995 and May 1998. Both studies restricted eligibility to women age 35 to 64 years at diagnosis who were English speaking and born in the United States.

Participants completed in-person interviews at baseline (within their first year after diagnosis, 6 ± 2 months from diagnosis) and follow-up (approximately 2.5 years after diagnosis). During the follow-up visit, participants also were approached for consent to retrieve their mammograms. Among the 1,183 women enrolled at baseline, 944 women returned for the follow-up visit (51 women died before the follow-up visit), and postdiagnosis mammograms were retrieved for 755 of the 944 participants. We were unable to retrieve mammograms for 189 participants because (1) the participant refused to consent to mammogram retrieval, (2) the mammogram facility would not release films for their patients, (3) the mammogram films were lost by another facility, or (4) participants were unable/unwilling to provide information regarding the location of the mammograms. Of the 755 postdiagnosis mammograms retrieved, 42 mammograms were of poor quality and could not be read accurately; thus, mammograms were read for 713 participants (76%). Among the 713 participants, 157 were premenopausal, five women did not complete the follow-up physical activity interview, and 29 did not have body weight measured at the follow-up visit. Our analyses are based on the remaining 522 women. Demographic and physiologic characteristics, including BMI and physical activity levels, of the 522 women included in this analysis and the 1,183 women enrolled onto the study did not differ. The study was performed with the approval of the institutional review boards of participating centers, in accord with an assurance filed with and approved by the US Department of Health and Human Services.

Data Collection
Anthropometrics. Trained staff measured weight and height in a standard manner at the follow-up clinic visit (approximately 2.5 years after diagnosis). With the women wearing light indoor clothing and no shoes, weight was measured to the nearest 0.1 kg using a balance-beam laboratory scale. Height was measured, without shoes, to the nearest 0.1 cm using a stadiometer. All measurements were performed twice in succession, and averaged for a final value for analyses. BMI was computed as weight in kilograms divided by height in meters squared. Three BMI categories were created based on the WHO–National Institutes of Health cutoff for obesity: BMI less than 25 kg/m², 25.0 to 29.9, and 30 kg/m² or higher.¹⁴

Physical Activity Assessment
We collected information on physical activity using an interview-administered questionnaire at the follow-up visit scheduled within women's third year after diagnosis. Participants were asked to recall the type, duration, and frequency of physical activities performed during the last year. The questionnaire was based on the Modifiable Activity Questionnaire developed by Kriska et al, ¹⁵ which was designed to be easily modified for use with different populations, and which has been shown to be reliable and valid. The sports/recreation and household activities listed on the questionnaire addressed 29 popular activities.

We estimated hours per week for each activity by multiplying frequency and duration together. Two mutually exclusive groups were created based on type of activity, sports/recreation including walking or household/gardening. Each activity was also categorized by MET intensity (metabolic rate during activity divided by resting metabolic rate) as light (< 3 METs), moderate (3 to 6 METs), or vigorous (> 6 METs) intensity based on Ainsworth et al's "Compendium of Physical Activities."¹⁶

Mammographic Density
Mammographic films, corresponding to approximately 1.5 years after diagnosis, were retrieved from individual providers that each woman had specified. Each film was digitized using either an Epson 1680 scanner (Epson America Inc, Long Beach, CA; used in Washington) or Cobrascan CX-812 M large format 12-bit x-ray scanner (Radiographic Digital Imaging, Torrance, CA; used in New Mexico and Los Angeles). We measured the craniocaudal view contralateral to the breast diagnosed with breast cancer for mammographic percentage density and dense area (measured in thousands of pixels and converted to square millimeters by multiplying by 0.0676). The density readings were conducted by one of the authors (E.J.A.) using Cumulus 108, a computer-assisted mammogram-reading program developed at the University of Toronto (Ontario, Canada). This method has been described in detail elsewhere.¹⁷ Briefly, the reader uses a sliding scale to outline the breast edge and then the dense breast area based on pixel brightness. Percentage density is the proportion of dense breast area relative to the total area of the breast.

Other Variables
Standardized questionnaire information was collected at the baseline and follow-up visit on medical history and selected demographic data. Postmenopausal status, assessed at the follow-up interview, was defined as age 55 years or older or not menstruating in the last 12 months, surgery to remove ovaries, or a hysterectomy. Information on disease stage, adjuvant therapy, and hormonal therapy was collected from the participant's physician.

Statistical Analyses
Because of the known effects of BMI on mammographic density and breast cancer risk,¹ we decided to examine the physical activity and mammographic density association separately for women with a BMI less than 25, 25.0 to 29.9, and 30 kg/m² or higher. We calculated means and standard deviations of demographic and physiological characteristics of the study sample by BMI groups. Differences in means were compared using analysis of covariance methods. Categoric variables were compared using ² analysis.

We used analysis of covariance methods to estimate least-squares means and test for differences in the dense area and percentage density across categories of BMI, and total activity, moderate- to vigorous-intensity physical activity, and sports/recreational physical activity. The physical activity analyses were further stratified by BMI. Categories of physical activity were based on physical activity tertiles using the whole sample.

We adjusted for covariates associated with mammographic density including age (continuous), race/ethnicity, study site, education, parity (nulliparous v parous), disease stage, tamoxifen use, adjuvant therapy (no adjuvant therapy, radiation only, chemotherapy only, or radiation and chemotherapy), breast cancer recurrence, smoking, use of hormone therapy, and months from diagnosis to mammogram. We used Tukey's Honestly Significant Difference test to identify statistically significant differences between groups, with the overall level of statistical significance constrained to 5%. All analyses were conducted using SAS version 8.2 (SAS Institute, Cary, NC).

	RESULTS

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Among the 522 women included in this analysis, 197 had a BMI less than 25 kg/m², 168 had a BMI between 25.0 and 29.9 kg/m², and 157 had a BMI 30 kg/m² or higher (Table 1). Women who had a BMI 30 kg/m² or higher participated in significantly less physical activity than did women with a BMI less than 30 kg/m² (P < .05).

	DISCUSSION

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Mammographic density was inversely related to sports/recreational physical activity among obese breast cancer survivors. Approximately 32% of breast cancer survivors do not participate in the recommended amounts of physical activity.¹² Physical inactivity and obesity have been associated with a recurrence of breast cancer and poor survival.^18,19 Mammographic density is a strong risk factor for breast cancer, and has been associated with breast cancer tumor characteristics.^1,2 Increasing physical activity among obese breast cancer survivors may be a reasonable intervention approach to reduce mammographic density, and, in turn, may improve breast cancer prognosis. However, until more physical activity and mammographic density studies are conducted, caution should be used in interpreting our findings.

Only four previous studies have examined the association between physical activity and mammographic density, all in healthy women. Vachon et al²⁰ investigated the association between physical activity and percentage mammographic density in 1,900 pre- and postmenopausal women. Physical activity was not associated with percentage mammographic density. However, their assessment of physical activity was limited to only one question. Gram et al²¹ examined the relationship between physical activity and mammographic density among 2,720 Norwegian pre- and postmenopausal women. Women who reported moderate physical activity (ie, more than 2 hours per week) were 20% less likely (odds ratio, 0.80, 95% CI, 0.60 to 1.10) to have high-risk mammographic patterns compared with those who reported being inactive. This relationship was consistent across strata of BMI and menopausal status. Recently, Suijkerbuijk et al²² examined physical activity in relation to mammographic density in the Dutch Prospect-European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. They observed, in 620 pre- and postmenopausal women, a slight trend of higher levels of physical activity and lower absolute density. Subgroup analysis for postmenopausal women showed similar results. Lastly, we recently reported a statistically significant inverse relationship between physical activity and prediagnostic mammographic density in obese postmenopausal breast cancer survivors.¹⁰

Physical activity may influence mammographic density by favorably changing certain hormones that may be associated with mammographic density, such as sex-steroid hormones. A recent study of US women enrolled on the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial observed strong associations between higher levels of endogenous estrone, estradiol, and bioavailable estradiol and greater mammographic density (P < .01)²³; however, two published studies that examined the association between mammographic density and endogenous estrogens observed no association between total estradiol and percentage density in both pre- and postmenopausal women.^24,25 The hypothesis that endogenous hormones may mediate the relationship between physical activity and mammographic density applies particularly to obese postmenopausal women whose major source of estrogen is the aromatization of androstenedione in body fat.^13,26,27 Thus, higher levels of physical activity may be associated with decreased mammographic density levels among obese postmenopausal women by directly or indirectly decreasing sex-hormone concentrations by reducing body fat.⁹ In a recently published yearlong randomized controlled trial, exercise had a favorable effect on decreasing circulating estrogen concentrations among overweight postmenopausal women; however, the effect was limited to women who lost body fat.⁹

Breast cancer incidence rates in the United States are lower among African American women than among non-Hispanic or Hispanic white women, yet mortality rates from breast cancer are higher.²⁸ Mammographic density may reflect these racial/ethnic differences in incidence or mortality. In our study, African American women had lower amounts of dense breast tissue than did non-Hispanic and Hispanic white women. Percentage breast density was similar among all three groups; however, after adjusting for potential covariates, percent breast density was higher in African American women than among non-Hispanic and Hispanic white women. African American women also had a higher BMI and reported less participation in physical activity than did non-Hispanic and Hispanic white women. Yet, the associations among BMI, physical activity, and mammographic density did not differ by racial/ethnic group. However, our sample of African American and Hispanic white women was small; thus, we had insufficient statistical power to determine whether race/ethnicity modified the associations.

The HEAL study has several limitations and strengths. Although the HEAL study is a prospective cohort study, this analysis is cross-sectional in design. Although mammographic density and physical activity were assessed at approximately the same time point (ie, 20 months postdiagnosis), BMI was measured, on average, 10 months later. However, it is unlikely that women would move into different BMI categories in the 10-month period (the correlation between BMI measured at approximately 6 months postdiagnosis and 30 months postdiagnosis was r = 0.96, P = .0001).

Major strengths of our study are the quality of the physical activity data that were obtained using a reliable and valid 29-item interview-administered questionnaire; we measured weight and height, whereas many previous studies used self-reported measures; all measures were collected after the women completed adjuvant therapy; we recruited a multiracial/-ethnic cohort of breast cancer survivors; and we used a computer-assisted method to assess mammographic density, with assessments performed by a single reader. Measuring mammographic density on a continuous scale may provide more information than will the Breast Imaging Reporting and Data System (BIRADS; American College of Radiology, Reston, VA) or Wolfe categoric measures,^1,17 which most previous mammogram density studies have used. However, even though the computer-assisted continuous scale is considered the gold standard of assessing mammographic density, the currently available method used only a two-dimensional view. A more accurate method would involve a three-dimensional view, or volumetric approach, that captures overall volume. The need for volumetric measures is clearly reflected in the results observed in this study and others related to mammographic density and BMI. With two-dimensional views, one does not get a complete picture of the overall volume of the breast. Uncertainty regarding the overall volume is a problem for women with large breasts, which is common in women with a higher BMI. Although percentage mammographic density may be low for heavier women (because of fatty breasts), if they have a large breast volume, they may actually have more dense breast tissue than can be observed with two-dimensional views. Research is ongoing to develop a more precise volumetric method of assessing mammographic density.²⁹

Although it remains to be determined whether the effect of increasing physical activity decreases mammographic density, it is known that physical inactivity, obesity, and mammographic density are all independently associated with breast cancer risk and prognosis.^1,18,19 Increasing physical activity among obese breast cancer survivors may be a reasonable intervention approach to reduce mammographic density, and potentially influence breast cancer prognosis.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Melinda L. Irwin, Anne McTiernan, Leslie Bernstein, Frank D. Gilliland, Richard N. Baumgartner, Kathy Baumgartner

Financial support: Anne McTiernan, Leslie Bernstein, Frank D. Gilliland, Richard N. Baumgartner, Kathy Baumgartner

Administrative support: Rachel Ballard-Barbash

Provision of study materials or patients: Anne McTiernan, Leslie Bernstein, Frank D. Gilliland, Richard N. Baumgartner, Kathy Baumgartner

Collection and assembly of data: Melinda L. Irwin, Erin J. Aiello, Anne McTiernan, Leslie Bernstein, Frank D. Gilliland, Richard N. Baumgartner, Kathy Baumgartner, Rachel Ballard-Barbash

Data analysis and interpretation: Melinda L. Irwin, Erin J. Aiello, Anne McTiernan, Leslie Bernstein, Frank D. Gilliland, Richard N. Baumgartner, Kathy Baumgartner, Rachel Ballard-Barbash

Manuscript writing: Melinda L. Irwin, Erin J. Aiello, Anne McTiernan, Leslie Bernstein, Frank D. Gilliland, Richard N. Baumgartner, Kathy Baumgartner, Rachel Ballard-Barbash

Final approval of manuscript: Melinda L. Irwin, Erin J. Aiello, Anne McTiernan, Leslie Bernstein, Frank D. Gilliland, Richard N. Baumgartner, Kathy Baumgartner, Rachel Ballard-Barbash

	ACKNOWLEDGMENTS

 
We thank Kristin LaCroix, Shelley Tworoger, and Lynda McVarish for their contributions to the Health, Eating, Activity, and Lifestyle (HEAL) study, as well as the HEAL participants for their ongoing dedication to this study.

	NOTES

 
published online ahead of print at www.jco.org on January 29, 2007.

Supported by National Cancer Institute Grants No. N01-CN-75036-20, NO1-CN-05228, NO1-PC-67010, and training Grant No. T32 CA09661. A portion of this work was conducted through the Clinical Research Center at the University of Washington and supported by National Institutes of Health Grant No. M01-RR-00037, and University of New Mexico Grant No. NCRR M01-RR-0997.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted May 10, 2006; accepted December 12, 2006.

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