Correspondence to: Timothy J. Key, DPhil, Endogenous Hormones and Breast Cancer Collaborative Group, Cancer Research U.K. Epidemiology Unit, University of Oxford, Gibson Bldg., Radcliffe Infirmary, Oxford OX2 6HE, U.K. (e-mail: Tim.Key{at}cancer.org.uk).
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ABSTRACT |
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INTRODUCTION |
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The Endogenous Hormones and Breast Cancer Collaborative Group was established to conduct pooled re-analyses of individual data from prospective studies of endogenous hormones and breast cancer. In an earlier article (6), we described the overall associations of sex hormones with breast cancer risk in postmenopausal women, and we observed that the largest increases in risk were associated with high serum concentrations of bioavailable estradiol, estimated as free estradiol and nonSHBG-bound estradiol. Here, we examine whether sex hormone levels could explain the relationship between BMI and breast cancer risk in postmenopausal women.
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SUBJECTS AND METHODS |
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Published studies were eligible for the re-analysis if they contained data on endogenous hormones and breast cancer risk using prospectively collected blood samples from postmenopausal women, as described previously (6). Nine eligible studies were identified: Columbia, MO (7,8); Guernsey, UK (9); Nurses Health Study, USA (10); New York University Womens Health Study (NYU WHS), USA (11,12); Study of Hormones and Diet in the Etiology of Breast Tumors (ORDET), Italy (13); Rancho Bernardo, USA (14,15); Radiation Effects Research Foundation (RERF), Japan (16); Study of Osteoporotic Fractures (SOF), USA (17); and Washington County, MD, USA (1820). Details of the recruitment of participants, informed consent, assay methods, and definitions of reproductive variables are in the original publications (720). Height and weight were measured by clinicians in three studies (Guernsey, ORDET, and Rancho Bernardo) and were self-reported in four studies (Columbia, Nurses Health Study, NYU WHS, and RERF), whereas weight was measured and height at age 25 was self-reported (because women had to be at least 65 years of age at recruitment and some may have experienced osteoporotic height loss secondary to vertebral fractures) in the SOF study. Height and weight were not available for women in the Washington County study; therefore, data from this study were excluded from the current analysis.
Collaborators were asked to provide data on concentrations of the hormones estradiol (total), free estradiol, nonSHBG-bound estradiol (free plus albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), testosterone, and SHBG, where available. Technically, SHBG is not a hormone, but for convenience it will be referred to as such throughout this paper. Collaborators also provided data on reproductive and anthropometric factors for each woman in their study. Women with missing data for any of the following factors were excluded from the analysis: date of diagnosis of case patients, date of birth, date of blood collection, height, and weight.
All studies that contributed data to the analysis were cohorts in which blood samples were collected from healthy women who were then followed to identify those subjects who developed breast cancer. Women who were using hormone replacement therapy or other exogenous sex hormones at the time of blood collection were excluded from our analysis.
Statistical Analysis
BMI was calculated as weight in kilograms divided by the square of height in meters and categorized as less than 22.5, 22.524.9, 25.027.4, 27.529.9, and greater than or equal to 30.0 kg/m2, respectively, on the basis of standard categories of BMI. Hormone concentrations were logarithmically transformed, and geometric mean concentrations by BMI category among control subjects, adjusted for study and age at blood collection (categorized as aged <55, 5559, 6064, 6569, and 70 years), were calculated using analysis of variance. The F test was used to test for linear trends in the geometric mean hormone concentrations between the BMI categories, with the BMI categories scored 1, 2, 3, 4, and 5.
Conditional logistic regression was used to calculate the relative risk (RR) of breast cancer by BMI category, relative to those with a BMI of less than 22.5 kg/m2 (category 1). For our analyses, we preserved the original matching in the six studies that used a nested matched casecontrol design [details of this matching are provided in the original publications (713,16)]. For two studies, which had a casecohort (17) or full cohort (14,15) design, nested casecontrol sets were generated from within the cohorts and matched as closely as possible for age and date of blood collection so that the same statistical analysis could be conducted across all eight studies, as described previously (6). Because matching was conducted within studies, only women from the same study are compared directly. Within this pooled dataset, there was no statistically significant heterogeneity between studies regarding the associations between serum hormone concentrations and breast cancer risk (6).
We investigated the association between BMI and breast cancer risk after adjusting for various established risk factors for breast cancer: age at menarche (<12, 1213, 14 years); type of menopause (natural, surgical); age at menopause (<45, 4549, 5054,
55 years; natural postmenopausal women only); time since menopause (04, 514,
15 years; natural postmenopausal women only); parity (0, 1, 2, 3,
4 full-term pregnancies); age at first full-term pregnancy (<20, 2024, 2529,
30 years; parous women only); previous use of oral contraceptives (never, ever); and previous use of hormone replacement therapy (never, ever).
To assess the extent to which hormone concentrations might account for the association between BMI and breast cancer risk, the RR of breast cancer associated with BMI was calculated with and without adjustment for the within-study quintile of hormone concentration for each hormone in succession. To facilitate comparison of the adjusted and unadjusted RRs, the analysis for each hormone was restricted to informative matched sets of women with both BMI and hormone measurements. Unfortunately, not all of the hormones were measured in each of the studies, so that the comparisons for each hormone were made using data from different subsets of the studies.
All analyses were performed using STATA (21). Mean hormone concentrations and RRs were calculated with their 95% confidence intervals (CIs). Heterogeneity between RRs and linear trends in RRs (obtained by scoring the BMI categories from 1 to 5) were assessed by 2 tests. All statistical tests were two-sided.
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RESULTS |
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We next considered the geometric mean hormone concentrations among control subjects by BMI category, adjusted for study and age at blood collection (Table 2). Each of the estrogens (estradiol, free estradiol, nonSHBG-bound estradiol, estrone, and estrone sulfate) was strongly and statistically significantly positively associated with BMI, with the mean concentration in obese women (i.e., women with BMI
30.0 kg/m2) between 60% and 219% higher than that in thin women (i.e., women with BMI <22.5 kg/m2). There were no statistically significant associations between DHEA or DHEAS and BMI. There was a weak positive association between androstenedione and BMI, with the mean concentration in obese women being 12% higher than the mean concentration in thin women. Testosterone was positively associated with BMI, with the mean concentration in obese women being 20% higher than the mean concentration in thin women, whereas SHBG was strongly inversely associated with BMI, with the mean concentration in obese women being 44% lower than the mean concentration in thin women.
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Further analyses were conducted to examine whether the associations of the hormones with breast cancer risk would be altered by adjustment for BMI. Adjustment for BMI did not substantially change the associations between any hormone level and breast cancer risk, and all associations remained statistically significant. For example, the RR of breast cancer for women in the top quintile of total estradiol compared with those in the lowest quintile was 2.00 (95% CI = 1.47 to 2.71) without adjustment for BMI and 1.92 (95% CI = 1.37 to 2.67) after adjustment for BMI; for free estradiol, the RR of breast cancer for women in the top quintile compared with those in the lowest quintile was 2.62 (95% CI = 1.77 to 3.88) without adjustment for BMI and 2.73 (95% CI = 1.76 to 4.22) after adjustment for BMI.
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DISCUSSION |
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Consistent with other studies of postmenopausal women conducted in many parts of the world, breast cancer risk in the eight studies increased with increasing BMI. The magnitude of this association, an increase in risk of about 18% per 5 kg/m2 increase in BMI, is similar to the estimate from a recent meta-analysis of a 16% increase in risk per 5 kg/m2 increase in BMI (3). The association of BMI with breast cancer risk varied somewhat because not all studies included all hormones, but this variation may reasonably be attributed to chance. The only risk factor for breast cancer that appreciably confounded the relationship between BMI and breast cancer risk was parity; high parity is associated with reduced breast cancer risk and with higher BMI, and therefore adjustment for parity slightly strengthened the association of BMI with breast cancer risk.
Although breast cancer risk increased with increasing BMI, risk did not increase further when BMI exceeded 30 kg/m2. Indeed, the RR was lower in women with the highest BMI than in those in the next lowest category (27.529.9 kg/m2). A similar pattern was observed in a pooled analysis of prospective studies (1), in which the authors noted that breast cancer risk among postmenopausal women statistically significantly increased with increasing BMI but did not increase further when BMI exceeded 28 kg/m2. One possible explanation for this apparent plateau in the relationship between BMI and breast cancer risk is that it might be associated with the residual effect of the lower RR for breast cancer among obese premenopausal women that has been observed in Western countries. The pooled analysis of prospective studies (1) and the recent review by the International Agency for Research on Cancer (2) observed that this reduction in risk in premenopausal women does not appear to be observed below a BMI of 28 kg/m2. Thus, postmenopausal women with a BMI of 30 kg/m2 and above, many of whom would also have been obese before menopause, may have only a moderate increase in breast cancer risk because of a residual reduction in postmenopausal risk accumulated during their premenopausal life (23,24).
The analyses among control women showed strong associations between BMI and serum concentrations of most hormones, as was expected from the results of previous studies (25,26). All of the estrogen measures increased with increasing BMI, with the largest proportional increases for free estradiol and nonSHBG-bound estradiol. First described by Siiteri et al. (5), the increase in free estradiol is the result of the dual effect of obesity in increasing estrogen production and depressing SHBG levels, leading to a marked increase in the amount of estradiol that is not bound to SHBG. Among the androgens, DHEA and DHEAS levels were not associated with BMI, whereas both androstenedione and testosterone levels were moderately higher in obese women than in thin women, but the magnitude of these associations was much smaller than those for estrogens.
The result of adjusting for serum hormones on the association of BMI with breast cancer risk showed large effects for the estrogens, a moderate effect for SHBG, and negligible impact for the androgens. The biggest impact was seen after adjusting for free estradiol, which reduced the excess risk for breast cancer associated with a 5 kg/m2 increase in BMI from 19% to 2%. Adjusting for nonSHBG-bound estradiol, or for total estradiol, also substantially reduced the association of BMI with breast cancer risk. The results do not allow us to determine which measure of estradiol is most important but strongly suggest that the increased breast cancer risk in obese postmenopausal women is largely due to the associated increase in bioavailable estradiol (as estimated by either free estradiol or nonSHBG-bound estradiol).
The analyses reported in this article were all based on single hormone measures for each woman. Measurements of hormone concentrations are subject to error associated with assay variation and short-term fluctuations in serum levels within individual women. These sources of variation are thought to be effectively random; therefore, it is likely that the observed associations between hormone concentrations and breast cancer risk are underestimates of the true associations (10). Furthermore, any change in the estimates of the risk associated with increasing BMI after adjustment for specific hormones would be related to the degree of measurement error in that hormone. Therefore, some of the differences in the apparent effect of hormones on the association of BMI with risk may be due not to intrinsic biologic effects but to artifacts of differences in the precision of hormone assays. Data were not available to allow us to estimate the impact of measurement error in hormone concentrations on the attenuation of the association between BMI and breast cancer risk caused by adjustment for estrogens. However, in one casecontrol study of endometrial cancer, endogenous hormones, and BMI, Potischman et al. (27) concluded that adjustment for measurement error in hormone determinations had only a small impact on the degree of attenuation of the association of BMI with risk effected by adjustment for estrone.
The possible role of serum androgens in the etiology of breast cancer remains unclear. We previously reported that androgens are associated with breast cancer risk in postmenopausal women (6), but the analyses here show that, by contrast with the impact of adjusting for estrogens, adjusting for androgens had little effect on the association between BMI and breast cancer risk. This is consistent with the absence of strong associations between BMI and serum androgen concentrations.
It is possible that the association between BMI and breast cancer risk might be partly explained by other biochemical variables that we did not measure. Other hormones that may be associated with breast cancer risk are prolactin, insulin-like growth factor-I, and insulin. Prolactin and insulin-like growth factor-I are poor candidates to explain this relationship, however, because neither is positively associated with BMI in postmenopausal women (28,29). Levels of insulin-like growth factor binding protein 1 decrease with increasing adiposity, which might increase the bioavailability of insulin-like growth factor-I (30), but available prospective data have not shown any definite association between insulin-like growth factor binding protein 1 and breast cancer risk (31,32). Insulin itself is strongly positively correlated with BMI and has been hypothesized to be an intermediate factor in the relationship between obesity and breast cancer risk (33). However, prospective data relating to this hypothesis involving insulin, C-peptide, and glucose have not shown any clear association with breast cancer risk in postmenopausal women (32,3436).
Obesity is a modifiable risk factor for breast cancer, whereas several of the long-established risk factors are either fixed (family history and genotype) or not amenable to modification (age at menarche, number of pregnancies and ages at pregnancy, and age at menopause). The association between obesity and breast cancer risk is important because obesity may be the principal contributing factor for a substantial number of cases of breast cancer and because the prevalence of obesity is high and increasing. In the United States, for example, the estimated prevalence of obesity in women aged 6074 years increased from 29% in 19881994 to 40% in 19992000 (37). Furthermore, obesity is associated with poor survival among women with breast cancer, and the association of obesity with mortality from breast cancer appears to be stronger than the association with incidence (38). The results reported here suggest that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.
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APPENDIX: MEMBERS AND AFFILIATIONS OF THE ENDOGENOUS HORMONES AND BREAST CANCER COLLABORATIVE GROUP |
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Columbia, MO, United States: J. F. Dorgan, Fox Chase Cancer Center, Philadelphia, PA; C. Longcope, Departments of Obstetrics and Gynecology and Medicine, University of Massachusetts Medical School, Worcester; F. Z. Stanczyk, Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles; H. E. Stephenson, Jr., Department of Surgery, University of Missouri Health Sciences Center, Columbia; R. T. Falk, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; R. Miller, Cancer Screening Services, Ellis Fischel Cancer Center, Columbia, MO; A. Schatzkin, Division of Cancer Epidemiology and Genetics, National Cancer Institute.
Guernsey, United Kingdom: D. S. Allen, I. S. Fentiman, T. J. Key, D. Y. Wang, Cancer Research U.K., Oxford; M. Dowsett, Department of Academic Biochemistry, Royal Marsden Hospital, London; H. V. Thomas, Department of Psychological Medicine, University of Wales College of Medicine, Cardiff.
Nurses Health Study, United States: S. E. Hankinson for the Nurses Health Study Research Group, Channing Laboratory, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA; and Department of Epidemiology, Harvard School of Public Health, Boston.
NYU WHS, United States: P. Toniolo, A. Akhmedkhanov, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY; K. Koenig, R. E. Shore, A. Zeleniuch-Jacquotte, Nelson Institute of Environmental Medicine, New York University School of Medicine.
ORDET, Italy: F. Berrino, Division of Epidemiology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan; P. Muti, Department of Social and Preventive Medicine, University at Buffalo, State University of New York, and Istituto Nazionale per lo Studio e la Cura dei Tumori; A. Micheli, V. Krogh, S. Sieri, V. Pala, E. Venturelli, G. Secreto, Istituto Nazionale per lo Studio e la Cura dei Tumori.
Rancho Bernardo, United States: E. Barrett-Connor, G. A. Laughlin, Department of Family and Preventive Medicine, University of California at San Diego.
RERF, Japan: M. Kabuto, Environmental Risk Research Division, National Institute for Environmental Studies, Ibaraki; S. Akiba, Department of Public Health, Faculty of Medicine, Kagoshima University, Kagoshima; R. G. Stevens, Department of Community Medicine, University of Connecticut Health Center, Farmington; K. Neriishi, Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima; C. E. Land, Radiation Epidemiology Branch, National Cancer Institute, Bethesda, MD.
SOF, United States: J. A. Cauley, L. H. Kuller, Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA; S. R. Cummings, Departments of Medicine and Epidemiology and Biostatistics, University of California, San Francisco; and the Study of Osteoporotic Fractures Research Group.
Washington County (MD), United States: K. J. Helzlsouer, A. J. Alberg, T. L. Bush, G. W. Comstock, Department of Epidemiology, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD; G. B. Gordon, Oncology Center and Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine; S. R. Miller, Department of Health Policy and Management, The Johns Hopkins University School of Hygiene and Public Health; C. Longcope, Department of Obstetrics and Gynecology and Medicine, University of Massachusetts Medical School, Worcester.
We thank the women who participated, the research staff, the collaborating laboratories, and the funding agencies in each of the studies. The central pooling and analysis of these data was supported by Cancer Research U.K.
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Manuscript received December 13, 2002; revised May 27, 2003; accepted June 10, 2003.
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