Waist-to-Hip Ratio and Breast Cancer Mortality

Marilyn J. Borugian1,2 , Samuel B. Sheps2, Charmaine Kim-Sing3, Ivo A. Olivotto4, Cheri Van Patten5, Bruce P. Dunn1, Andrew J. Coldman6, John D. Potter7,8, Richard P. Gallagher1,2 and T. Gregory Hislop1,2

1 Cancer Control Research Program, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
2 Department of Health Care and Epidemiology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
3 Vancouver Cancer Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
4 Vancouver Island Cancer Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
5 Nutrition Services, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
6 Population and Preventive Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
7 Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA.
8 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA.

Received for publication March 14, 2003; accepted for publication May 12, 2003.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
High insulin levels have been associated with increased risk of breast cancer and poorer survival after a breast cancer diagnosis. Waist-to-hip ratio (WHR) is a marker for insulin resistance and hyperinsulinemia. In this study, the authors tested the hypothesis that elevated WHR is directly related to breast cancer mortality. For identification of modifiable factors affecting survival, data were collected on 603 patients with incident breast cancer who visited the Vancouver Cancer Centre of the British Columbia Cancer Agency (Vancouver, British Columbia, Canada) in 1991–1992, including body measurements and information on demographic, medical, reproductive, and dietary factors. These patients were followed for up to 10 years. Cox proportional hazards regression models were used to relate the variables to breast cancer mortality (n = 112). After adjustment for age, body mass index, family history, estrogen receptor (ER) status, tumor stage at diagnosis, and systemic treatment (chemotherapy or tamoxifen), WHR was directly related to breast cancer mortality in postmenopausal women (for highest quartile vs. lowest, relative risk = 3.3, 95% confidence interval: 1.1, 10.4) but not in premenopausal women (relative risk = 1.2, 95% confidence interval: 0.4, 3.4). Stratification according to ER status showed that the increased mortality was restricted to ER-positive postmenopausal women. Elevated WHR was confirmed as a predictor of breast cancer mortality, with menopausal status and ER status at diagnosis found to be important modifiers of that relation.

body constitution; breast neoplasms; insulin resistance; mortality; receptors, estrogen

Abbreviations: Abbreviations: CI, confidence interval; ER, estrogen receptor; WHR, waist-to-hip ratio.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
There is a compelling need to identify modifiable factors that are related to breast cancer survival. Current evidence suggests that obesity, lack of physical activity, alcohol consumption, and a typical high-energy Western diet are all associated with the development of insulin resistance and hyperinsulinemia and that hyperinsulinemia may stimulate the growth of tumors, particularly breast and colorectal tumors (15). Hyperinsulinemia has also been associated with mortality among breast cancer patients (6). Elevated waist-to-hip ratio (WHR), representing a higher abdominal fat distribution, is a marker of insulin resistance and hyperinsulinemia (7, 8) and has been associated with both incidence of and mortality from several chronic diseases, including heart disease, hypertension, diabetes mellitus, and cancer (911).

WHR offers investigators a simple measure with which to identify people at greater risk of having or developing the "metabolic syndrome" (i.e., insulin resistance, hyperinsulinemia, hypertension, dyslipidemia, and atherosclerosis) (7, 8). WHR may also help clinicians identify high-risk breast cancer patients at diagnosis. Most importantly, WHR is potentially modifiable, so there may be an opportunity for risk reduction. In this study, we prospectively examined the relation between WHR and 10-year breast cancer mortality in a cohort of Canadian breast cancer patients.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Participants
The cohort included 603 women aged 19–75 years with in-situ or invasive incident breast cancer who visited the Vancouver Cancer Centre of the British Columbia Cancer Agency for a consultation between July 1991 and December 1992, an average of 2 months after surgery but before adjuvant treatment. The following women were excluded: patients for whom the referral tumor was not a new tumor; patients who had undergone any hormone, ablation, or chemotherapy treatment for breast cancer prior to referral; patients who did not speak English; and patients who were over age 75 years. Eligible consecutive patients were invited to participate during their initial assessment at the Vancouver Cancer Centre. A response rate of 87 percent was achieved (612 out of 700 eligible). These patients were followed for up to 10 years. For the current study, nine stage IV women were excluded. With the exception of menopausal status, subjects with missing data were excluded from analysis (n = 17 for WHR), leaving 586 subjects. Data on menopausal status, an important stratification variable, were missing for 50 (8 percent) of the cohort members. We imputed menopausal status for these patients using the median age at menopause (50 years) rather than excluding them, because of sample size considerations; we also performed analyses after excluding them to ensure that this did not change the results. The study was approved by the Ethics Committee of the University of British Columbia.

Questionnaire
A self-administered questionnaire was used to gather information on lifestyle factors, including diet, cigarette smoking, alcohol consumption, exercise, height, weight, hip and waist circumferences, education, ethnicity, and familial, medical, and reproductive history. It included the Block semiquantitative food frequency questionnaire (12). Items for which information was missing or unclear were clarified by telephone.

Variables
WHR was calculated as the ratio of self-reported waist measurement to hip measurement. Waist and hip measurements were made by the participant, with no specific instructions or tape measure being provided. Abstraction of clinical charts at enrollment provided patient and tumor information.

Covariates were defined as follows: age at diagnosis (continuous variable), reproductive status (premenopausal or postmenopausal), body mass index (weight (kg)/height (m)2), daily energy intake (kJ/day), employment status (yes or no), marital status (single, married, widowed, or divorced), family history of breast cancer in a first-degree relative (yes or no), physical activity (frequency of participation in exercise per week, month, or year), tumor size (0–1, 1.1–2.0, 2.1–5.0, or 5.1–9.9 cm), tumor grade (well-differentiated, moderately differentiated, or poorly differentiated), nodal status (positive or negative), estrogen receptor (ER) status (positive or negative), local treatment (lumpectomy, lumpectomy plus radiation, complete mastectomy, complete mastectomy plus radiation, or other), systemic treatment (chemotherapy alone, tamoxifen alone, both, or none), cigarette smoking (ever or never), alcohol consumption (g/day), age at menarche (continuous variable), number of livebirths (continuous variable), age at first birth (continuous variable), age at menopause (continuous variable), and ethnicity (Caucasian, Asian, East Indian, Black, or other). Both tumor size and nodal status were derived from the pathology report if it was available (>90 percent of cases). Covariates for access to care were not needed, because health care is universal in Canada.

Outcome variables
Data on outcome variables, including vital status, date of death, and primary and secondary cause of death (if applicable), were obtained from British Columbia Cancer Agency patient records, which are updated monthly with national death certificate information from Statistics Canada and the Canadian Cancer Registry. A patient was considered to have died of breast cancer if breast cancer was given as either the primary or the secondary cause of death.

Statistical analysis
Characteristics of participants were compared using an independent t test for continuous variables and a Pearson chi-square test for categorical variables. All-cause mortality and breast cancer-specific mortality were examined in relation to WHR using multivariate Cox proportional hazards regression models. The covariates listed above were tested in the regression model, and their significance was assessed using two criteria. Variables that both were significant predictors of breast cancer mortality (p < 0.05) and changed the WHR relative risk by more than 10 percent when added to the model were retained. All pairwise interactions with WHR (e.g., WHR and age) were tested by being added individually after the main effects.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
Of 146 deaths, breast cancer was the cause of death for 77 percent (n = 112). Mortality in the cohort (stage I—13.5 percent; stage II—31.2 percent; stage III—59.6 percent) was slightly lower than that for all cases referred to the British Columbia Cancer Agency in 1992 (stage I—14.8 percent; stage II—36.6 percent; stage III—68.7 percent). In table 1, selected characteristics of the study population are presented by menopausal status and WHR category (<0.8/>=0.8). By current standards (13), the average body mass index for the cohort, 26.0, would be classified as overweight. The cohort mean WHR, 0.8, was also the value generally considered in the literature to be the cutpoint above which the risk of obesity-related health problems in women increases (14). In this study, premenopausal women with a WHR of 0.8 or more had a significantly higher body mass index, had more children, were more likely to be non-Caucasian, and were likely to have a somewhat larger tumor than those with a WHR less than 0.8. Among postmenopausal women, those with a WHR of 0.8 or more were older, had a higher body mass index, and had a greater energy intake than women with a WHR less than 0.8. As expected, treatment did not vary significantly by WHR category. The postmenopausal group with a WHR of 0.8 or more appeared to have a higher proportion of women with a family history of breast cancer, but this result was not statistically significant.


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TABLE 1. Selected characteristics of pre- and postmenopausal breast cancer patients at diagnosis, British Columbia, Canada, 1991–1992*
 
WHR and mortality
Baseline body shape, as measured by WHR, was found to predict breast cancer mortality for postmenopausal women but not for premenopausal women (table 2). Waist or hip measurement alone was not associated with mortality (data not shown), but for WHR as a continuous variable, we observed a statistically significant age and body mass index-adjusted relative risk of 1.5 (95 percent confidence interval (CI): 1.1, 2.1) for postmenopausal breast cancer mortality. This represents a 50 percent increase in risk of dying of breast cancer for each 0.1-unit increase in WHR (e.g., a WHR increase from 0.8 to 0.9). Adjustment for family history, ER status, stage at diagnosis, and systemic treatment resulted in some attenuation (relative risk = 1.4, 95 percent CI: 0.9, 2.1). Further adjustment for tumor grade did not alter the results. No significant risk from elevated WHR was observed in the premenopausal women (relative risk = 1.0, 95 percent CI: 0.6, 1.6). Analysis of WHR by quartile revealed an apparently nonlinear pattern for postmenopausal breast cancer mortality risk, with a decline in the third quartile. This pattern may have been due to chance, since the third-quartile relative risk did not reach statistical significance. The fully adjusted relative risk associated with being in the highest quartile of WHR compared with the lowest quartile was 3.3 (95 percent CI: 1.1, 10.4) for postmenopausal women and 1.2 (95 percent CI: 0.4, 3.4) for premenopausal women. All analyses were also performed with all-cause mortality as the outcome; similar results were obtained. Height, weight, and body mass index were examined separately and were not related to breast cancer mortality in this cohort (data not shown).


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TABLE 2. Relative risk of breast cancer mortality according to waist-to-hip ratio among pre- and postmenopausal breast cancer patients in British Columbia, Canada, 1991–2002*
 
Stratified analyses did not provide evidence of significant effect modification by age, body mass index, or family history of breast cancer; however, numbers of stratum-specific deaths became small, and our power to detect such effects was limited. Analysis by 10-year age category suggested that the difference between pre- and postmenopausal women was not solely due to the effects of advancing age. Although the number of subjects was small (n = 25), in premenopausal women aged 50–59 years at diagnosis, increasing WHR was not associated with increased breast cancer mortality (relative risk = 0.6, 95 percent CI: 0.2, 2.3), while postmenopausal women in the same age range at diagnosis (50–59 years) had a relative risk of 1.5 (95 percent CI: 0.9, 2.7) for a 0.1-unit increase in WHR.

Effect modification by ER status
In table 3, WHR is represented as a continuous variable stratified by ER status, with unstratified values given for comparison. The association of elevated WHR with postmenopausal breast cancer mortality was confined to women who were ER-positive (for ER-positive tumors, the relative risk was 1.6 (95 percent CI: 1.0, 2.4); for ER-negative tumors, the relative risk was 0.8 (95 percent CI: 0.3, 1.9)). No significant association was seen for premenopausal women, regardless of ER status.


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TABLE 3. Relative risk of breast cancer mortality according to waist-to-hip ratio (continuous variable), by estrogen receptor status, among pre- and postmenopausal breast cancer patients in British Columbia, Canada, 1991–2002*
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this cohort, WHR was strongly and positively related to risk of dying from breast cancer for postmenopausal breast cancer patients but not for premenopausal patients. Furthermore, the risk associated with WHR was restricted to women with ER-positive tumors.

The observed difference in WHR-associated relative risks between pre- and postmenopausal women may indicate important metabolic consequences of menopausal sex hormone changes, but overlap of confidence intervals means that it could also be a spurious finding. Another explanation may be differences in tumor subtype distributions for pre- and postmenopausal groups. Stratification by ER status made pre- and postmenopausal relative risks more similar, and it is possible that the addition of progesterone receptor data would further attenuate the observed difference by menopausal status.

If the risk associated with elevated WHR is due in part to insulin resistance and hyperinsulinemia, effect modification by ER status makes biologic sense, because insulin has been shown to stimulate ER-{alpha} in breast cancer cells (15). Women with a high WHR may also be at risk because insulin further stimulates the production of estrogens and androgens such as testosterone, adding to production by adipose tissue, and down-regulates sex hormone binding globulin, which controls the availability of the sex steroids (16). Some evidence has associated WHR with insulin resistance and hyperinsulinemia. In a prospective study of premenopausal women, Hollman et al. (8) found insulin resistance and hyperinsulinemia to be greater with increasing WHR. Serum C-peptide levels, a marker of insulin secretion, have also been associated with WHR by Bruning et al. (1). Our results are consistent with those of other studies, wherein WHR has been associated with both increased risk of developing breast cancer and increased risk of mortality from breast cancer. For example, WHR was associated with postmenopausal breast cancer risk in a large population-based case-control study (for highest quartile vs. lowest, odds ratio = 1.43, 95 percent CI: 1.07, 1.93) (11). Folsom et al. (10) reported a significant trend for increasing risk of mortality from all cancers with increasing WHR, and they found a positive association of WHR with breast cancer mortality in the Iowa Women’s Health Study cohort (9). In a prospective study by Kumar et al. (17), android body fat distribution was a statistically significant prognostic indicator for breast cancer survival.

The results of this study must be interpreted with caution. The data pertained to an urban, largely Caucasian cohort, and the results may not generalize to a more mixed population. The accuracy and reliability of self-measurement of body girth was not evaluated in this cohort, but it was examined by Kushi et al. (18) in postmenopausal women from the midwestern United States, a population not unlike our study cohort. Self-measurement was found to be both repeatable and accurate, although the protocol Kushi et al. used was different in that instructions and a tape measure were provided. WHR, a ratio, does not require standardized measurement units, because the units cancel each other out. Self-measurements may be underestimated as girth increases (18, 19), but this is also less of a problem with a ratio, since both components are likely to be underestimated. Potential misclassification of menopausal status may have attenuated observed differences between pre- and postmenopausal women. We lacked information on two potential confounders, use of hormone replacement therapy and progesterone receptor status. The strengths of this study include prospective data, 10 years of follow-up, a high rate of participant response, and access to detailed and actively updated patient records.

We conclude that elevated WHR is a predictor of mortality after a diagnosis of postmenopausal ER-positive breast cancer and that it may be useful clinically, both as a simple measurement with prognostic value and as a possible opportunity for risk reduction. It would be useful to undertake a larger study to confirm the observed relations and more precisely define the WHR value that should signal a need for intervention in specific populations.


    ACKNOWLEDGMENTS
 
This project was funded by the Canadian Breast Cancer Foundation (British Columbia/Yukon chapter) and the Lions Gate Healthcare Research Foundation.

The authors thank the Breast Outcomes Unit and the Breast Tumour Group of the British Columbia Cancer Agency for their assistance.


    NOTES
 
Reprint requests to Dr. Marilyn J. Borugian, Cancer Control Research Program, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada (e-mail: mborugia{at}bccancer.bc.ca). Back


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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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