1 Department of Epidemiology and Public Health, School of Medicine, Yale University, New Haven, CT.
2 Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC.
3 Current address: Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, Atlanta, GA.
4 School of Public Health, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia.
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ABSTRACT |
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anthropometry; blacks; breast neoplasms; mammography; neoplasm staging; obesity
Abbreviations: CI, confidence interval; OR, odds ratio; TNM, tumor-node-metastasis.
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INTRODUCTION |
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Racial differences in stage at diagnosis have often been attributed to differences in medical care or socioeconomic factors (5, 7
9
). However, one recent study suggested that the higher prevalence of severe obesity among African-American women as compared with White women was an important explanatory variable (10
). Specifically, in a study of breast cancer in Connecticut, Jones et al. (10
) reported that adjustment for the greater prevalence of severe obesity among African-American women explained almost one third of the observed racial difference in stage at diagnosis. Severe obesity remained an important explanatory variable when data were adjusted for socioeconomic status, history of breast cancer screening, and other demographic and lifestyle factors. The objectives of this investigation were to attempt to replicate these findings in a second and larger population-based study in North Carolina, and to extend the inquiry to include a measure of body fat distribution, the ratio of waist circumference to hip circumference (waist:hip ratio).
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MATERIALS AND METHODS |
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African-American women and women under age 50 years were oversampled using a modification of randomized recruitment (12). Women of all races were included in the study, but African-American women and White women comprised the vast majority of the subjects. Women of other races represented only 1.6 percent of the study population and were included with White women in the statistical analyses.
Permission to contact breast cancer patients was requested from the physician of record on the pathology report. Women for whom physician consent was obtained were contacted by a registered nurse, who scheduled an in-person interview. During the interview visit, the nurse administered a 1-hour questionnaire, took body measurements (height, weight, and waist and hip circumferences), and acquired the patient's signed consent for obtaining medical records related to the cancer. (Population-based controls were also selected and interviewed, but these analyses were restricted to cases only.) The study protocol was approved by the institutional review boards at the University of North Carolina School of Medicine and the participating hospitals. Medical records were requested from the hospitals, were abstracted by registered nurses, and were reviewed by one of the investigators (R. C. M.) to obtain relevant information, including tumor size, lymph node involvement, the presence of distant metastasis, and estrogen receptor status.
Of the 1,285 breast cancer patients sampled for the study, physician consent was not obtained for 5.7 percent; 6.1 percent were ineligible (usually because of a history of breast cancer), 0.9 percent died before being contacted, 3.3 percent could not be contacted, and 14.9 percent refused to participate. The overall response rate, calculated as the percentage of completed interviews among women who were located and eligible, was 77 percent for all cases. Response rates ranged from 83 percent among White case women younger than age 50 years to 68 percent among African-American case women aged 50 years or older (13). A total of 889 case women were interviewed. The analyses discussed in this paper were based on the 791 women (489 White and 302 African-American) for whom anthropometric data and medical record information on tumor stage were available.
Unconditional logistic regression analyses were used to obtain odds ratios and 95 percent confidence intervals. Modeling was performed using the GENMOD procedure of the SAS statistical software package (SAS Institute, Cary, North Carolina), which allows incorporation of an offset term to account for the sampling fractions used in the randomized recruitment study design. Variables related to tumor characteristics included stage (stage I vs. stage II or higher), determined using the tumor-node-metastasis (TNM) system (14); tumor size (<2 cm vs.
2 cm); lymph node status (positive vs. negative); and distant metastasis (present or absent). Severe obesity was defined as a body mass index (weight (kg)/height (m)2)
32.3, which was the cutpoint established by the National Center for Health Statistics (15
) and the one used in the earlier analyses by Jones et al. (10
). Tertiles of waist:hip ratio were based on the distribution among all cases and controls in the Carolina Breast Cancer Study (16
). Variables examined in the descriptive and multivariate analyses included age (as an 11-level ordinal variable reflecting 5-year age categories), education (less than high school graduation vs. high school graduation or higher), annual family income (<$30,000 vs.
$30,000), occupational category of the woman or her spouse (professional, administrator, or executive vs. nonprofessional), alcohol consumption (ever vs. never), smoking status (ever a regular smoker vs. never), parity (nulliparous vs. parous), and menopausal status (postmenopausal vs. pre- or perimenopausal). Women were categorized as postmenopausal if they reported having undergone natural menopause, bilateral oophorectomy, or hysterectomy and were over 55 years of age. All other women were included in the pre-/perimenopausal category.
Limited information on mammographic screening was available, and there were no data on time since last mammogram prior to the breast cancer diagnosis. A variable addressing screening adequacy (inadequate vs. adequate) was created using information on age at first mammogram and total number of mammograms, taking into account age-specific screening recommendations. All women who were under age 40 years at diagnosis were considered to have had adequate screening, since routine mammograms were not recommended for this age group (17). For women aged 4049 years, the American Cancer Society recommended screening every 12 years and the National Cancer Institute had no specific recommendation during this time period (17
). If a woman in this age range reported undergoing any mammograms prior to her breast cancer diagnosis, she was categorized as having had adequate screening. For women aged 50 years or more at diagnosis, the difference between age at diagnosis and age at first mammogram was divided by the total number of mammograms. Women for whom this number was 2 or greater (implying that, on average, mammograms had been 2 or more years apart) and women who reported having no mammograms prior to the breast cancer diagnosis were categorized as having had inadequate screening.
The extent to which a variable explained the racial difference in stage at diagnosis was determined by change-in-estimate (18): We observed the change in the odds ratio for the relation of race to stage at diagnosis after adding a specific variable (e.g., severe obesity or waist:hip ratio) to the logistic regression model. The percentage change in the odds ratio (OR) was calculated according to the formula [(adjusted OR unadjusted OR)/(unadjusted OR - 1.00)] x 100.
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RESULTS |
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The associations between severe obesity and waist:hip ratio and tumor characteristics are shown in table 2. There were statistically significant relations between severe obesity (body mass index 32.3) and later stage at diagnosis, larger tumor size, and distant metastasis. Women with positive lymph nodes also were more likely to be severely obese than those with negative lymph node status, although this difference was not quite statistically significant. We repeated these analyses using both more extreme (
35) and less extreme (
30 or
27) body mass index cutpoints for obesity. The body mass index cutpoint of
32.3 showed the strongest association between obesity and stage at diagnosis. Analyses of the relation of waist:hip ratio to tumor stage and the three components of TNM staging showed that the odds ratios for later-stage disease, larger tumors, positive lymph nodes, and distant metastasis increased with increasing waist:hip ratio. These analyses were also performed separately for African-American and White women. There were no significant interactions by race (data not shown). When examining the joint effects of severe obesity and waist:hip ratio, we found that increasing waist:hip ratio was associated with increased risk of later-stage breast cancer among both women who were severely obese and those who were not. The odds ratio for women who were both severely obese and in the highest tertile of waist:hip ratio was 3.61 (95 percent CI: 2.02, 6.43), as compared with the reference category of lowest tertile of waist:hip ratio and not severely obese.
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We examined whether the relations between severe obesity or waist:hip ratio and later stage at diagnosis were modified by menopausal status, estrogen receptor status, or screening history. Because obesity is generally considered a risk factor for postmenopausal breast cancer but not premenopausal breast cancer (19), we hypothesized that the association between stage and severe obesity or waist:hip ratio would be stronger among postmenopausal women. We further hypothesized that the relation would be stronger among women with estrogen receptor-positive tumors, since heavier women have higher levels of bioavailable estrogen (19
). Finally, we expected that the association might be stronger among women who did not have adequate mammographic screening, since obesity may delay the discovery of self-detected tumors. Our data (not shown) supported none of these hypotheses. There were no important differences in the relation between severe obesity or waist:hip ratio and stage at diagnosis when data were stratified by menopausal status, estrogen receptor status, or mammography history, and none of the interaction terms were statistically significant.
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DISCUSSION |
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As has been observed in other populations (10, 15
, 23
), there were racial differences in a number of anthropometric measures. African-American women with breast cancer in this North Carolina population were more likely than White women to be obese, to be severely obese, and to have greater waist:hip ratios. They also were more likely to be diagnosed with later-stage breast cancer, larger tumors, positive lymph nodes, and distant metastases. Among both African-American women and White women, severely obese women and those with a waist:hip ratio in the highest tertile were more likely to be diagnosed with later-stage breast cancer.
In an age-adjusted model, inclusion of waist:hip ratio explained 20 percent of the later stage at diagnosis observed in African-American women. Together, waist:hip ratio and severe obesity explained 27 percent of the observed racial difference in stage at diagnosis of breast cancer, which suggests that anthropometric characteristics contribute substantially to this relation. The mammographic screening variable exerted a small, independent effect, increasing the explanatory effect of this model to 34.2 percent. After these factors were taken into account, other variables, including lifestyle characteristics and socioeconomic measures, had a minimal effect on the relation between race and stage at diagnosis.
There are several potential explanations for the association between obesity, waist:hip ratio, and stage at diagnosis. It is plausible that detection of tumors in large breasts is more difficult, leading to a delay in diagnosis. One would expect that this would be an issue primarily for women who were not receiving regular mammograms and whose tumors would be self-detected as palpable breast lumps. Among women receiving mammograms, tumors should not be more difficult to detect in heavier women, because larger breasts tend to be less dense and more radiolucent (24). Although one study reported a positive relation between body mass index and nonlocalized breast cancer only among women whose tumors were self-detected, not among women whose tumors were found by mammography (25
), other studies have found that the relations between obesity and stage at diagnosis were similar regardless of method of detection or screening history (10
, 26
). Our data are consistent with the latter studies, in that the relation between stage at diagnosis and obesity and waist:hip ratio was not stronger among women with an inadequate history of mammography. While delayed detection may contribute to the relation between obesity and stage at diagnosis, it is unlikely to fully explain the association.
Beyond detection issues, endocrinologic factors may be responsible for the association between obesity, high waist:hip ratio, and stage at diagnosis. A number of studies have found that breast cancer survival is poorer among heavier women, even when controlling for tumor size and stage of disease (2730
). This suggests that the growth and progression of breast tumors may be enhanced in obese women. Several mechanisms that could account for these observations have been proposed. Heavier women tend to have increased estrogen production due to conversion of androstenedione in adipose tissue (19
). Obesity and a high waist:hip ratio also have been shown to be associated with lower levels of sex hormone-binding globulin, resulting in higher levels of unbound, biologically active estrogen (31
, 32
). In addition, abdominal obesity is often associated with hyperinsulinemia and increased levels of insulin-like growth factor type I (33
, 34
). Insulin and insulin-like growth factor type I show mitogenic activity in mammary cancer cells, and insulin-like growth factor type I may act synergistically with estrogen to stimulate breast cancer cell growth (35
). Hyperinsulinemia has also been shown to be associated with lower levels of sex hormone-binding globulin (36
). Thus, several related endocrinologic factors may account for the observed relation between waist:hip ratio, obesity, and breast cancer stage.
The limitations in the available data and their possible effects on the association between race and later stage at diagnosis must be acknowledged. Information on mammographic screening was not optimal, and education may not have been an ideal measure of socioeconomic status. In addition, no data were available for factors such as access to health care or cultural beliefs and attitudes. To the extent that these factors are associated with body size, we may have overestimated the effect of increased waist:hip ratio or obesity in explaining racial differences in stage at diagnosis. Furthermore, the lack of information on brassiere size or method of discovery of the breast cancer limited us in examining the hypothesis that the association of obesity with later stage at diagnosis is due to delayed detection.
This investigation provides additional evidence that racial differences in anthropometric factors contribute to the observed difference between African-American women and White women in stage at diagnosis of breast cancer. Additional research is needed to determine whether these associations are mediated by detection issues or physiologic factors. Future studies in which measures of biomarkers (e.g., hormones or growth factors) are available or more detailed information on mammographic screening is available may help to elucidate the mechanisms. Regardless of the pathways by which body size influences stage at diagnosis, public health initiatives designed to reduce obesity and modify body fat distribution through diet and exercise may have important implications for changing disease course in some individuals, particularly African-American women.
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ACKNOWLEDGMENTS |
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The authors thank the Carolina Breast Cancer Study nurse-interviewers: Carolyn Dunmore, Dianne Mattingly, Theresa Nalevaiko, Patricia Plummer, and Cheryl Robinson.
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NOTES |
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REFERENCES |
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