Changes in Body Fat and Weight After a Breast Cancer Diagnosis: Influence of Demographic, Prognostic, and Lifestyle Factors
http://www.100md.com
《临床肿瘤学》
the Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, CT
The Fred Hutchinson Cancer Research Center, Seattle, WA
Cancer Research and Treatment Center, Department of Internal Medicine, University of New Mexico, Albuquerque, NM
Department of Preventive Medicine, University of Southern California, Los Angeles, CA
Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD
ABSTRACT
METHODS: Patients were participants in the Health, Eating, Activity, and Lifestyle (HEAL) study. Weight and body fat (via dual-energy x-ray absorptiometry scans) were measured during the baseline visit and 2 years later at a follow-up visit. Analysis of covariance methods were used to obtain mean weight and body fat changes adjusted for potential cofounders.
RESULTS: Women increased their weight and percent body fat by 1.7 ± 4.7 kg and 2.1% ± 3.9%, respectively, from during their first year of diagnosis to during their third year of diagnosis. A total of 68% and 74% of patients gained weight and body fat, respectively. Greater increases in weight were observed among women diagnosed with a higher disease stage, younger age, being postmenopausal, and women who decreased their physical activity from diagnosis to up to 3 years after diagnosis (P for trend < .05).
CONCLUSION: Weight and body fat increased in the postdiagnosis period. Future research should focus on the effect of physical activity on weight and fat loss and breast cancer prognosis.
INTRODUCTION
Multiple reasons for postdiagnosis weight gain in breast cancer survivors have been suggested, including receiving chemotherapy, being or becoming postmenopausal after diagnosis, decreased physical activity, and increased total caloric intake, although these explanations have not been extensively studied.1-6 Most studies that have examined changes in body weight after a diagnosis of breast cancer and factors associated with weight gain have been of short study duration (eg, only during treatment or within the first year) and with small sample sizes.2,3,5,20,21 Few studies have measured body weight (most rely on self-report) and even fewer studies have measured changes in body fat. Studies with a larger number of patients, with a longer follow-up, and using valid measures of body composition are necessary so as to better define the real prognostic impact of gains in body fat and weight in this setting.
To further investigate changes in body composition in the postdiagnosis period, we examined changes in body fat and weight from diagnosis to within 3 years after diagnosis in 514 breast cancer survivors enrolled onto the Health, Eating, Activity, and Lifestyle (HEAL) study, a population-based prospective cohort study. We also examined the associations of demographic, prognostic, and lifestyle factors with changes in body fat and weight.
METHODS
Briefly, in New Mexico, 654 women were recruited for the HEAL Study; they were aged 18 years or older, diagnosed with in situ to stage IIIA breast cancer between July 1996 and March 1999, and were living in Bernalillo, Sante Fe, Sandoval, Valencia, or Taos counties. In western Washington, 202 women were recruited; they were between the ages of 40 and 64 years, diagnosed with in situ to stage IIIA breast cancer between September 1997 and September 1998, and were living in King, Pierce, or Snohomish counties. In both New Mexico and Washington, stage of disease was based on the American Joint Committee on Cancer (AJCC) stage groupings 0 (or in situ), I, IIA, IIB, or IIIA, which are based on the TNM system.25 From 1996 through 1999 when these women were diagnosed, there were no major changes in the AJCC codes within SEER.
Participants completed in-person interviews at baseline (within their first year after diagnosis, 6 ± 2 months from diagnosis) and at 2 years after the baseline visit (within their third year after diagnosis, 31 ± 4 months from diagnosis). Among the 856 women enrolled at baseline, a total of 39 women had a previous breast cancer diagnosis, a total of 47 women did not have a baseline body weight measure, 220 women did not have a follow-up body weight measure, six women did not complete the physical activity questionnaire at baseline, and a total of 30 women had a recurrence of breast cancer between the two visits. Our analyses are based on the remaining 514 women. Analyses involving body fat include a reduced sample size of 132 women because of limited funds available to perform dual-energy x-ray absorptiometry (DEXA) scans. Women who had a DEXA scan were similar to the cohort of women included in the full analyses in terms of baseline characteristics. Written informed consent was obtained from each patient. 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
Trained staff measured weight and height in a standard manner at the clinic visit. 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, also without shoes, to the nearest 0.1 cm using a stadiometer. All measurements were performed and recorded twice in succession, and averaged for a final value for analyses. Body mass index (BMI) was computed as weight in kg divided by height in m2. Three mutually exclusive BMI groups were created: lean weight (BMI < 25 kg/m2), overweight (25 kg/m2 ≤ BMI < 30.0 kg/m2), and obese (BMI ≥ 30.0 kg/m2).26
Percent body fat was measured from whole-body scans using a DEXA scanner (New Mexico, Lunar model DPX, GE Medical Systems, Milwaukee, WI; Washington, Hologic model QDR 1500, Hologic Inc, Waltham, MA).
Physical Activity Assessment
We collected information on physical activity using an interview-administered questionnaire at a visit scheduled within the first and third years after diagnosis. The questionnaire was based on the Modifiable Activity Questionnaire developed by Kriska et al,27 which was designed to be easily modified for use with different populations, and which has been shown to be reliable and valid. The type, duration, and frequency of activities performed in the past year were assessed. The sports/recreation and household activity section of the questionnaire addressed 29 popular activities.
We then 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 activities. Each activity was also categorized as light (< 3 METs), moderate (3-6 METs), or vigorous (> 6 METs) -intensity based on Ainsworth et al's "Compendium of Physical Activities."28,29
Stage of Disease and Cancer Treatment
We obtained data on disease stage from the local SEER registries before recruiting women onto the HEAL Study.30 Adjuvant treatment was categorized into three mutually exclusive groups: surgery only (including those taking or not taking tamoxifen), surgery + radiation (including those taking or not taking tamoxifen), or any chemotherapy (including surgery, those taking or not taking tamoxifen, as well as those having radiation or not). We also were interested in looking at tamoxifen use (adjusted for treatment group), thus two mutually exclusive groups were created: patients not taking tamoxifen and patients taking tamoxifen.
Other Variables
Standardized questionnaire information was collected on medical history, reproductive history, family history of cancer, physician-diagnosed type 2 diabetes, smoking status, and selected demographic data. Information on diet was collected via a food frequency questionnaire.31
Statistical Analyses
Means and standard deviations of physiological and demographic characteristics of the study sample were calculated by study site, and differences in means were compared using t tests for continuous variables and {chi}2 analyses for categoric variables. We also examined the proportion of breast cancer survivors gaining or losing body weight or body fat over the 2-year follow-up period.
We used analysis of covariance methods to estimate least squares means and test for differences in body weight and body fat across categories of disease stage, adjuvant treatment, age, menopausal status, tamoxifen use, BMI, study site, ethnicity, smoking status, changes in total caloric intake, and changes in physical activity. Each analysis was adjusted for the other factors except the variable of interest; for example, in comparing body weight across disease stage, we adjusted for the other factors, but not disease stage. 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%.
RESULTS
The mean weight and percent body fat change of participants were 1.7 ± 4.7 kg and 2.1% ± 3.9%, respectively with 68% of the sample gaining weight (mean weight gain = 3.9 ± 3.7 kg) and 74% gaining percent body fat (mean percent body fat gain = 3.6% ± 3.0%; Fig 1). Among the 68% of women who gained weight, 31% gained less than 2.5 kg, 19% gained between 2.5 and 4.9 kg, and 18% gained 5 kg or more (Fig 2). Among the 74% of women who gained body fat, 36% gained less than 2.5%, 17% gained between 2.5 and 4.9%, and 21% of women gained 5% or more (Fig 3).
We observed a statistically significant trend of increasing gains in weight with increasing category of disease stage (P for trend = .0039), younger age groups (P for trend = .0001), postmenopausal women (P < .05), and decreasing sports/recreational physical activity from baseline to within 3 years after diagnosis (P for trend = .032; Table 2). Because of the observation of increasing weight gain among younger women, yet also with postmenopausal women, we further examined changes in body weight stratified by both age groups and menopausal status, and by age groups among only postmenopausal women (Table 3). Postmenopausal women had greater weight gain compared with premenopausal women and women who became postmenopausal after diagnosis for all age groups. When examining weight gain by age groups among only postmenopausal women, we observed a significant trend of greater weight gain among younger postmenopausal women compared with older postmenopausal women (P for trend = .0020; Table 3).
In unadjusted analyses, we observed greater weight gain among women receiving chemotherapy than women receiving just surgery or surgery plus radiation (P < .05). However, when we adjusted for potential confounders, weight gain was no longer greater among women receiving chemotherapy compared with the other two treatment groups. To determine which variables were the strongest confounders in the treatment and weight change association, we analyzed the treatment data by adding each adjustment variable, one at a time, as well as by examining the effect of treatment on weight change stratified by each adjustment variable. No one variable significantly changed the treatment–weight change association. However, when we stratified the analyses by menopausal status, in postmenopausal women we observed nonsignificantly greater weight gain among women receiving chemotherapy than women receiving just surgery or surgery plus radiation, but not among premenopausal women or women who became postmenopausal after diagnosis (data not shown). Further, when we stratified the analyses by change in sports/recreational physical activity from baseline to up to 3 years after diagnosis in women who did not increase their physical activity from baseline to up to 3 years after diagnosis, we observed greater weight gain among women receiving chemotherapy than women receiving just surgery or surgery plus radiation (P = .061 and P = .048, respectively), but not among women who increased their activity from baseline to up to 3 years after diagnosis (data not shown). This latter group actually had less weight gain among those receiving chemotherapy, compared with the two other treatment groups (P < .05). Thus, it appears that menopausal status and physical activity had the strongest effect on the treatment and weight change association. Lastly, we also examined the effect of type of chemotherapy (ie, those taking anthracycline-based chemotherapy versus those not taking anthracycline-based chemotherapy) on change in body weight. In unadjusted and adjusted analyses, we observed similar amounts of weight gain in both chemotherapy groups (P = .68).
No significant associations were observed between changes in weight and family history of breast cancer, family history of type 2 diabetes, physician-diagnosed type 2 diabetes, cardiovascular disease, or education (data not shown).
We observed a statistically significant trend of increasing gains in body fat with decreasing categories of BMI (P for trend = .050) and sports/recreational physical activity from baseline to up to 3 years after diagnosis (P for trend = .051; Table 4). The trend of increasing gains in body fat associated with decreasing age approached significance (P for trend = .061). No statistically significant associations were observed between changes in body fat and disease stage, treatment, menopausal status, tamoxifen use, ethnicity, or change in total caloric intake.
DISCUSSION
The weight gain we and others have observed in breast cancer survivors is larger than that observed in other studies of healthy women. Williamson et al32 studied weight gain in 6,135 women who participated in the National Health and Nutrition Eamination Survey (NHANES I) study during a 10-year period in the 1970s. During a period of 10 years, women aged 45 to 55 years gained only 0.79 kg (0.08 kg/yr), whereas those aged 55 years and older lost weight. Our findings cannot be compared directly with the NHANES I study, however, women with breast cancer may experience a greater weight gain than women in the general population.
The effects of weight gain on breast cancer recurrence have been debated in the literature. Some,7-9 but not all33-37 investigators have associated weight gain with an earlier disease recurrence. Camoriano et al8 followed 646 breast cancer patients for a median of 6.6 years and found that premenopausal women who gained more than 5.9 kg were 1.5 times more likely to relapse and 1.6 times more likely to die of their breast cancer than were women gaining less weight.
Although it remains to be determined whether postdiagnosis weight gain influences risk for progressive disease, it is known that weight gain adversely affects risk for cardiovascular disease, hypertension, and diabetes.15-17 Furthermore, many studies have identified obesity as an important negative prognostic factor for breast cancer survival.10-14 In a review by Chlebowski et al,10 17 of 26 studies found increased weight to be a significant risk factor for recurrent disease and decreased survival, seven studies produced null findings, and two studies found an inverse association between weight and recurrence. In the studies that found a significant positive association between overweight and progressive disease, women categorized in the higher versus lower levels of obesity exhibited a 30% to 540% increased risk of death. Data from a study of 3,385 women by the National Surgical Adjuvant Breast and Bowel Project38 indicated that while obesity did not increase risk for breast cancer recurrence or death, obesity did increase risk of overall death, risk of other cancers, and death from cardiac disease. It is currently unknown whether postdiagnosis weight reduction modifies the relationship between obesity and breast cancer recurrence and mortality.
Several mechanisms have been proposed to explain the adverse effect of adiposity and weight gain on breast cancer prognosis. One mechanism rests on greater peripheral conversion of androstenedione to estradiol and inhibition of synthesis of sex hormone–binding globulin with an increase in free estradiol which stimulates neoplastic cells,39 especially in postmenopausal women.23 We have previously reported an association between increased adiposity and increased concentrations of estrone, estradiol, and free estradiol in the HEAL cohort of breast cancer survivors.23 Another mechanism relates to insulin and insulin-like growth factor (IGF) -I and the interactions of these hormones with adiposity.40 Insulin and IGFs exhibit mitogenic effects that influence both premalignant and cancerous stages of cell growth. Both insulin and IGF-I stimulate the synthesis of sex steroids, and thus, their cancer-promoting effects in the progression of breast cancer may be mediated by an effect on sex hormones. Another explanation for poorer survival may be associated with obese women failing to respond to treatment as a result of the common practice of chemotherapy capping at a body-surface area of 2 m2, which may offer suboptimal treatment benefit.41
In our study, higher disease stage, being postmenopausal, and less participation in physical activity were significantly related to gains in body weight. Receiving chemotherapy was also associated with greater weight gain, however this observation was limited to postmenopausal women and women who did not increase their physical activity from baseline to up to 3 years after diagnosis. Goodwin et al4 examined factors associated with weight gain during the subsequent year after diagnosis in 535 newly diagnosed breast cancer survivors. In multivariate analysis, onset of menopause and administration of chemotherapy were independent predictors of weight gain.
A study by Demark-Wahnefried2 studied energy balance during the first year after breast cancer diagnosis in 53 premenopausal women. Weight gain during chemotherapy was associated with an increase in fat mass and decrease in lean body mass, a pattern consistent with sarcopenic obesity. This form of obesity is associated with reduced physical activity, aging, and menopause. A significantly lower level of physical activity throughout the year of observation was demonstrated. The authors conclude that reduced physical activity is the primary cause of weight gain during chemotherapy for breast cancer. Demark-Wahnefried et al's results are also consistent with a report by Rock et al1 stating that physical activity predicted weight stability in 1,116 breast cancer survivors participating in the WHEL study.
Despite strong evidence suggesting that regular physical activity can protect against gains in body fat and weight, only 32% of breast cancer survivors enrolled onto the HEAL study engaged in the recommended level of physical activity, defined as 150 minutes per week of moderate- to vigorous-intensity physical activity.24 This percentage is similar to the proportion of healthy US women (27%) meeting the current recommendation.29 Recently, we reported that women diagnosed with breast cancer were significantly less physically active during their first year after diagnosis than they were 1 year before diagnosis.22 While physical activity levels reported 3 years after diagnosis increased to prediagnosis levels for approximately 50% of the sample, this was mostly limited to nonobese women.24 Exercise interventions and physical activity programs focused on increasing physical activity among breast cancer survivors with the ultimate goal of testing the effects on prognosis are needed. Previous research42,43 has also shown beneficial effects of dietary interventions on breast cancer prognosis in breast cancer survivors. Studies examining the combination of diet and physical activity on prognosis are also needed.
The HEAL study has several strengths. It is one of a handful that has examined changes in measured body weight for a relatively long follow-up period, and is the largest study reporting changes in body fat measured via DEXA scans. However, a limitation of our study is that we were unable to measure weight and percent body fat at other time points (eg, within the second year after diagnosis). Women may have initially gained and then lost weight during this time. Thus, we are unable to report the maximal gains in body weight and body fat up to 3 years after a breast cancer diagnosis. Another limitation of the study is that some women were recruited onto the study while undergoing treatment, while others had not begun treatment or had completed treatment. Some women may have already experienced changes in weight or body fat after diagnosis, but before enrollment onto the study. Lastly, our sample was highly educated and mostly non-Hispanic white, therefore, we cannot be sure that these findings pertain to all breast cancer survivors.
Weight gain is a concern of many women after a diagnosis of breast cancer. In a community-based study,44 the majority of breast cancer survivors were dissatisfied with their weight and stated that they were ready to take steps necessary to reduce their weight. A study conducted among 531 breast cancer survivors found that 52% wanted nutritional guidance at the time of diagnosis or soon after, although few reported having ever received dietary recommendations from their physicians.45
In conclusion, more than two thirds of the women in our study gained weight and body fat during the first 3 years after a diagnosis of breast cancer, and to a greater degree than that previously reported in studies of healthy women. Weight and body fat gains were greatest in women who reported less participation in physical activity. Since higher levels of body fat are associated with increased breast cancer recurrence and decreased survival, it is imperative that research be conducted on the prognostic effect of physical activity and weight loss in overweight and obese breast cancer survivors.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported by National Cancer Institute contracts N01-CN-75036-20, NO1-CN-05228, NO1-PC-67010, and training grant T32 CA09661. A portion of this work was conducted through the Clinical Research Center at the University of Washington and supported by the National Institutes of Health Grant M01-RR-00037. Data collection for the Women's CARE Study at the University of Southern California was supported by contract N01-HD-3-3175 from the National Institute of Child Health and Human Development, and patient identification was supported in part by 050Q-8709-S1528 from the California Department of Health Services.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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13. Kumar NB, Cantor A, Allen K, et al: Android obesity at diagnosis and breast carcinoma survival: Evaluation of the effects of anthropometric variables at diagnosis, including body composition and body fat distribution and weight gain during lifespan, and survival from breast carcinoma. Cancer 88:2751-2757, 2000
14. Newman SC, Miller AB, Howe GR: A study of the effect of weight and dietary fat on breast cancer survival time. Am J Epidemiol 123:767-774, 1986
15. Willett WC, Manson JE, Stampfer MJ, et al: Weight, weight change, and coronary heart disease in women: Risk within the ‘normal’ weight range. JAMA 273:461-465, 1995
16. Calle EE, Thun MJ, Petrelli JM, et al: Body mass index and mortality in a prospective cohort of US adults. N Engl J Med 341:1097-1105, 1999
17. Kopelman P: Obesity as a medical problem. Nature 404:635-643, 2000
18. Aziz NM: Long-term survivorship: Late effects, in: Berger AM, Portenoyu RK, Weissman DE (ed): Principles and Practice of Palliative Care and Supportive Oncology (ed 2). Philadelphia, PA, Lippincott Williams & Wilkins, 2002, pp 1019-1033
19. Ganz PA: Cancer Survivors: Physiologic and psychosocial outcomes. ASCO Educational Book, Spring: 118-123, 1998
20. Harvie M, Campbell I, Baildman A, et al: Energy balance in early breast cancer patients receiving adjuvant chemotherapy. Breast Cancer Res Treat 83:201-210, 2004
21. Freedman R, Aziz N, Albanes D, et al: Weight and body composition changes during and after adjuvant chemotherapy in women with breast cancer. J Clin Endocrinol Metab 89:2248-2253, 2004
22. Irwin ML, Crumley D, McTiernan A, et al: Physical activity levels before and after a diagnosis of breast carcinoma: The Health, Eating, Activity, and Lifestyle (HEAL) Study. Cancer 97:1746-1757, 2003
23. McTiernan A, Rajan B, Tworoger S, et al: Adiposity and sex hormones in postmenopausal breast cancer survivors. J Clin Oncol 21:1961-1966, 2003
24. Irwin ML, McTiernan A, Bernstein L, et al: Physical activity levels among breast cancer survivors. Med Sci Sports Exerc 36:1484-1491, 2004
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37. Costa LJ, Varella PC, del Giglio A: Weight changes during chemotherapy for breast cancer. Sao Paulo Med J 120:113-117, 2002
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39. Kaye SA, Folsom AR, Soler JT, et al: Associations of body mass and fat distribution with sex hormone concentrations in postmenopausal women. Int J Epidemiol 20:151-156, 1991
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43. Rock CL, Demark-Wahnefried W: Can lifestyle modification increase survival in women diagnosed with breast cancer J Nutr 132:3504S-3509S, 2002 (suppl)
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The Fred Hutchinson Cancer Research Center, Seattle, WA
Cancer Research and Treatment Center, Department of Internal Medicine, University of New Mexico, Albuquerque, NM
Department of Preventive Medicine, University of Southern California, Los Angeles, CA
Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD
ABSTRACT
METHODS: Patients were participants in the Health, Eating, Activity, and Lifestyle (HEAL) study. Weight and body fat (via dual-energy x-ray absorptiometry scans) were measured during the baseline visit and 2 years later at a follow-up visit. Analysis of covariance methods were used to obtain mean weight and body fat changes adjusted for potential cofounders.
RESULTS: Women increased their weight and percent body fat by 1.7 ± 4.7 kg and 2.1% ± 3.9%, respectively, from during their first year of diagnosis to during their third year of diagnosis. A total of 68% and 74% of patients gained weight and body fat, respectively. Greater increases in weight were observed among women diagnosed with a higher disease stage, younger age, being postmenopausal, and women who decreased their physical activity from diagnosis to up to 3 years after diagnosis (P for trend < .05).
CONCLUSION: Weight and body fat increased in the postdiagnosis period. Future research should focus on the effect of physical activity on weight and fat loss and breast cancer prognosis.
INTRODUCTION
Multiple reasons for postdiagnosis weight gain in breast cancer survivors have been suggested, including receiving chemotherapy, being or becoming postmenopausal after diagnosis, decreased physical activity, and increased total caloric intake, although these explanations have not been extensively studied.1-6 Most studies that have examined changes in body weight after a diagnosis of breast cancer and factors associated with weight gain have been of short study duration (eg, only during treatment or within the first year) and with small sample sizes.2,3,5,20,21 Few studies have measured body weight (most rely on self-report) and even fewer studies have measured changes in body fat. Studies with a larger number of patients, with a longer follow-up, and using valid measures of body composition are necessary so as to better define the real prognostic impact of gains in body fat and weight in this setting.
To further investigate changes in body composition in the postdiagnosis period, we examined changes in body fat and weight from diagnosis to within 3 years after diagnosis in 514 breast cancer survivors enrolled onto the Health, Eating, Activity, and Lifestyle (HEAL) study, a population-based prospective cohort study. We also examined the associations of demographic, prognostic, and lifestyle factors with changes in body fat and weight.
METHODS
Briefly, in New Mexico, 654 women were recruited for the HEAL Study; they were aged 18 years or older, diagnosed with in situ to stage IIIA breast cancer between July 1996 and March 1999, and were living in Bernalillo, Sante Fe, Sandoval, Valencia, or Taos counties. In western Washington, 202 women were recruited; they were between the ages of 40 and 64 years, diagnosed with in situ to stage IIIA breast cancer between September 1997 and September 1998, and were living in King, Pierce, or Snohomish counties. In both New Mexico and Washington, stage of disease was based on the American Joint Committee on Cancer (AJCC) stage groupings 0 (or in situ), I, IIA, IIB, or IIIA, which are based on the TNM system.25 From 1996 through 1999 when these women were diagnosed, there were no major changes in the AJCC codes within SEER.
Participants completed in-person interviews at baseline (within their first year after diagnosis, 6 ± 2 months from diagnosis) and at 2 years after the baseline visit (within their third year after diagnosis, 31 ± 4 months from diagnosis). Among the 856 women enrolled at baseline, a total of 39 women had a previous breast cancer diagnosis, a total of 47 women did not have a baseline body weight measure, 220 women did not have a follow-up body weight measure, six women did not complete the physical activity questionnaire at baseline, and a total of 30 women had a recurrence of breast cancer between the two visits. Our analyses are based on the remaining 514 women. Analyses involving body fat include a reduced sample size of 132 women because of limited funds available to perform dual-energy x-ray absorptiometry (DEXA) scans. Women who had a DEXA scan were similar to the cohort of women included in the full analyses in terms of baseline characteristics. Written informed consent was obtained from each patient. 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
Trained staff measured weight and height in a standard manner at the clinic visit. 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, also without shoes, to the nearest 0.1 cm using a stadiometer. All measurements were performed and recorded twice in succession, and averaged for a final value for analyses. Body mass index (BMI) was computed as weight in kg divided by height in m2. Three mutually exclusive BMI groups were created: lean weight (BMI < 25 kg/m2), overweight (25 kg/m2 ≤ BMI < 30.0 kg/m2), and obese (BMI ≥ 30.0 kg/m2).26
Percent body fat was measured from whole-body scans using a DEXA scanner (New Mexico, Lunar model DPX, GE Medical Systems, Milwaukee, WI; Washington, Hologic model QDR 1500, Hologic Inc, Waltham, MA).
Physical Activity Assessment
We collected information on physical activity using an interview-administered questionnaire at a visit scheduled within the first and third years after diagnosis. The questionnaire was based on the Modifiable Activity Questionnaire developed by Kriska et al,27 which was designed to be easily modified for use with different populations, and which has been shown to be reliable and valid. The type, duration, and frequency of activities performed in the past year were assessed. The sports/recreation and household activity section of the questionnaire addressed 29 popular activities.
We then 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 activities. Each activity was also categorized as light (< 3 METs), moderate (3-6 METs), or vigorous (> 6 METs) -intensity based on Ainsworth et al's "Compendium of Physical Activities."28,29
Stage of Disease and Cancer Treatment
We obtained data on disease stage from the local SEER registries before recruiting women onto the HEAL Study.30 Adjuvant treatment was categorized into three mutually exclusive groups: surgery only (including those taking or not taking tamoxifen), surgery + radiation (including those taking or not taking tamoxifen), or any chemotherapy (including surgery, those taking or not taking tamoxifen, as well as those having radiation or not). We also were interested in looking at tamoxifen use (adjusted for treatment group), thus two mutually exclusive groups were created: patients not taking tamoxifen and patients taking tamoxifen.
Other Variables
Standardized questionnaire information was collected on medical history, reproductive history, family history of cancer, physician-diagnosed type 2 diabetes, smoking status, and selected demographic data. Information on diet was collected via a food frequency questionnaire.31
Statistical Analyses
Means and standard deviations of physiological and demographic characteristics of the study sample were calculated by study site, and differences in means were compared using t tests for continuous variables and {chi}2 analyses for categoric variables. We also examined the proportion of breast cancer survivors gaining or losing body weight or body fat over the 2-year follow-up period.
We used analysis of covariance methods to estimate least squares means and test for differences in body weight and body fat across categories of disease stage, adjuvant treatment, age, menopausal status, tamoxifen use, BMI, study site, ethnicity, smoking status, changes in total caloric intake, and changes in physical activity. Each analysis was adjusted for the other factors except the variable of interest; for example, in comparing body weight across disease stage, we adjusted for the other factors, but not disease stage. 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%.
RESULTS
The mean weight and percent body fat change of participants were 1.7 ± 4.7 kg and 2.1% ± 3.9%, respectively with 68% of the sample gaining weight (mean weight gain = 3.9 ± 3.7 kg) and 74% gaining percent body fat (mean percent body fat gain = 3.6% ± 3.0%; Fig 1). Among the 68% of women who gained weight, 31% gained less than 2.5 kg, 19% gained between 2.5 and 4.9 kg, and 18% gained 5 kg or more (Fig 2). Among the 74% of women who gained body fat, 36% gained less than 2.5%, 17% gained between 2.5 and 4.9%, and 21% of women gained 5% or more (Fig 3).
We observed a statistically significant trend of increasing gains in weight with increasing category of disease stage (P for trend = .0039), younger age groups (P for trend = .0001), postmenopausal women (P < .05), and decreasing sports/recreational physical activity from baseline to within 3 years after diagnosis (P for trend = .032; Table 2). Because of the observation of increasing weight gain among younger women, yet also with postmenopausal women, we further examined changes in body weight stratified by both age groups and menopausal status, and by age groups among only postmenopausal women (Table 3). Postmenopausal women had greater weight gain compared with premenopausal women and women who became postmenopausal after diagnosis for all age groups. When examining weight gain by age groups among only postmenopausal women, we observed a significant trend of greater weight gain among younger postmenopausal women compared with older postmenopausal women (P for trend = .0020; Table 3).
In unadjusted analyses, we observed greater weight gain among women receiving chemotherapy than women receiving just surgery or surgery plus radiation (P < .05). However, when we adjusted for potential confounders, weight gain was no longer greater among women receiving chemotherapy compared with the other two treatment groups. To determine which variables were the strongest confounders in the treatment and weight change association, we analyzed the treatment data by adding each adjustment variable, one at a time, as well as by examining the effect of treatment on weight change stratified by each adjustment variable. No one variable significantly changed the treatment–weight change association. However, when we stratified the analyses by menopausal status, in postmenopausal women we observed nonsignificantly greater weight gain among women receiving chemotherapy than women receiving just surgery or surgery plus radiation, but not among premenopausal women or women who became postmenopausal after diagnosis (data not shown). Further, when we stratified the analyses by change in sports/recreational physical activity from baseline to up to 3 years after diagnosis in women who did not increase their physical activity from baseline to up to 3 years after diagnosis, we observed greater weight gain among women receiving chemotherapy than women receiving just surgery or surgery plus radiation (P = .061 and P = .048, respectively), but not among women who increased their activity from baseline to up to 3 years after diagnosis (data not shown). This latter group actually had less weight gain among those receiving chemotherapy, compared with the two other treatment groups (P < .05). Thus, it appears that menopausal status and physical activity had the strongest effect on the treatment and weight change association. Lastly, we also examined the effect of type of chemotherapy (ie, those taking anthracycline-based chemotherapy versus those not taking anthracycline-based chemotherapy) on change in body weight. In unadjusted and adjusted analyses, we observed similar amounts of weight gain in both chemotherapy groups (P = .68).
No significant associations were observed between changes in weight and family history of breast cancer, family history of type 2 diabetes, physician-diagnosed type 2 diabetes, cardiovascular disease, or education (data not shown).
We observed a statistically significant trend of increasing gains in body fat with decreasing categories of BMI (P for trend = .050) and sports/recreational physical activity from baseline to up to 3 years after diagnosis (P for trend = .051; Table 4). The trend of increasing gains in body fat associated with decreasing age approached significance (P for trend = .061). No statistically significant associations were observed between changes in body fat and disease stage, treatment, menopausal status, tamoxifen use, ethnicity, or change in total caloric intake.
DISCUSSION
The weight gain we and others have observed in breast cancer survivors is larger than that observed in other studies of healthy women. Williamson et al32 studied weight gain in 6,135 women who participated in the National Health and Nutrition Eamination Survey (NHANES I) study during a 10-year period in the 1970s. During a period of 10 years, women aged 45 to 55 years gained only 0.79 kg (0.08 kg/yr), whereas those aged 55 years and older lost weight. Our findings cannot be compared directly with the NHANES I study, however, women with breast cancer may experience a greater weight gain than women in the general population.
The effects of weight gain on breast cancer recurrence have been debated in the literature. Some,7-9 but not all33-37 investigators have associated weight gain with an earlier disease recurrence. Camoriano et al8 followed 646 breast cancer patients for a median of 6.6 years and found that premenopausal women who gained more than 5.9 kg were 1.5 times more likely to relapse and 1.6 times more likely to die of their breast cancer than were women gaining less weight.
Although it remains to be determined whether postdiagnosis weight gain influences risk for progressive disease, it is known that weight gain adversely affects risk for cardiovascular disease, hypertension, and diabetes.15-17 Furthermore, many studies have identified obesity as an important negative prognostic factor for breast cancer survival.10-14 In a review by Chlebowski et al,10 17 of 26 studies found increased weight to be a significant risk factor for recurrent disease and decreased survival, seven studies produced null findings, and two studies found an inverse association between weight and recurrence. In the studies that found a significant positive association between overweight and progressive disease, women categorized in the higher versus lower levels of obesity exhibited a 30% to 540% increased risk of death. Data from a study of 3,385 women by the National Surgical Adjuvant Breast and Bowel Project38 indicated that while obesity did not increase risk for breast cancer recurrence or death, obesity did increase risk of overall death, risk of other cancers, and death from cardiac disease. It is currently unknown whether postdiagnosis weight reduction modifies the relationship between obesity and breast cancer recurrence and mortality.
Several mechanisms have been proposed to explain the adverse effect of adiposity and weight gain on breast cancer prognosis. One mechanism rests on greater peripheral conversion of androstenedione to estradiol and inhibition of synthesis of sex hormone–binding globulin with an increase in free estradiol which stimulates neoplastic cells,39 especially in postmenopausal women.23 We have previously reported an association between increased adiposity and increased concentrations of estrone, estradiol, and free estradiol in the HEAL cohort of breast cancer survivors.23 Another mechanism relates to insulin and insulin-like growth factor (IGF) -I and the interactions of these hormones with adiposity.40 Insulin and IGFs exhibit mitogenic effects that influence both premalignant and cancerous stages of cell growth. Both insulin and IGF-I stimulate the synthesis of sex steroids, and thus, their cancer-promoting effects in the progression of breast cancer may be mediated by an effect on sex hormones. Another explanation for poorer survival may be associated with obese women failing to respond to treatment as a result of the common practice of chemotherapy capping at a body-surface area of 2 m2, which may offer suboptimal treatment benefit.41
In our study, higher disease stage, being postmenopausal, and less participation in physical activity were significantly related to gains in body weight. Receiving chemotherapy was also associated with greater weight gain, however this observation was limited to postmenopausal women and women who did not increase their physical activity from baseline to up to 3 years after diagnosis. Goodwin et al4 examined factors associated with weight gain during the subsequent year after diagnosis in 535 newly diagnosed breast cancer survivors. In multivariate analysis, onset of menopause and administration of chemotherapy were independent predictors of weight gain.
A study by Demark-Wahnefried2 studied energy balance during the first year after breast cancer diagnosis in 53 premenopausal women. Weight gain during chemotherapy was associated with an increase in fat mass and decrease in lean body mass, a pattern consistent with sarcopenic obesity. This form of obesity is associated with reduced physical activity, aging, and menopause. A significantly lower level of physical activity throughout the year of observation was demonstrated. The authors conclude that reduced physical activity is the primary cause of weight gain during chemotherapy for breast cancer. Demark-Wahnefried et al's results are also consistent with a report by Rock et al1 stating that physical activity predicted weight stability in 1,116 breast cancer survivors participating in the WHEL study.
Despite strong evidence suggesting that regular physical activity can protect against gains in body fat and weight, only 32% of breast cancer survivors enrolled onto the HEAL study engaged in the recommended level of physical activity, defined as 150 minutes per week of moderate- to vigorous-intensity physical activity.24 This percentage is similar to the proportion of healthy US women (27%) meeting the current recommendation.29 Recently, we reported that women diagnosed with breast cancer were significantly less physically active during their first year after diagnosis than they were 1 year before diagnosis.22 While physical activity levels reported 3 years after diagnosis increased to prediagnosis levels for approximately 50% of the sample, this was mostly limited to nonobese women.24 Exercise interventions and physical activity programs focused on increasing physical activity among breast cancer survivors with the ultimate goal of testing the effects on prognosis are needed. Previous research42,43 has also shown beneficial effects of dietary interventions on breast cancer prognosis in breast cancer survivors. Studies examining the combination of diet and physical activity on prognosis are also needed.
The HEAL study has several strengths. It is one of a handful that has examined changes in measured body weight for a relatively long follow-up period, and is the largest study reporting changes in body fat measured via DEXA scans. However, a limitation of our study is that we were unable to measure weight and percent body fat at other time points (eg, within the second year after diagnosis). Women may have initially gained and then lost weight during this time. Thus, we are unable to report the maximal gains in body weight and body fat up to 3 years after a breast cancer diagnosis. Another limitation of the study is that some women were recruited onto the study while undergoing treatment, while others had not begun treatment or had completed treatment. Some women may have already experienced changes in weight or body fat after diagnosis, but before enrollment onto the study. Lastly, our sample was highly educated and mostly non-Hispanic white, therefore, we cannot be sure that these findings pertain to all breast cancer survivors.
Weight gain is a concern of many women after a diagnosis of breast cancer. In a community-based study,44 the majority of breast cancer survivors were dissatisfied with their weight and stated that they were ready to take steps necessary to reduce their weight. A study conducted among 531 breast cancer survivors found that 52% wanted nutritional guidance at the time of diagnosis or soon after, although few reported having ever received dietary recommendations from their physicians.45
In conclusion, more than two thirds of the women in our study gained weight and body fat during the first 3 years after a diagnosis of breast cancer, and to a greater degree than that previously reported in studies of healthy women. Weight and body fat gains were greatest in women who reported less participation in physical activity. Since higher levels of body fat are associated with increased breast cancer recurrence and decreased survival, it is imperative that research be conducted on the prognostic effect of physical activity and weight loss in overweight and obese breast cancer survivors.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported by National Cancer Institute contracts N01-CN-75036-20, NO1-CN-05228, NO1-PC-67010, and training grant T32 CA09661. A portion of this work was conducted through the Clinical Research Center at the University of Washington and supported by the National Institutes of Health Grant M01-RR-00037. Data collection for the Women's CARE Study at the University of Southern California was supported by contract N01-HD-3-3175 from the National Institute of Child Health and Human Development, and patient identification was supported in part by 050Q-8709-S1528 from the California Department of Health Services.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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