Christy G Woolcott, Yurii B Shvetsov, Frank Z Stanczyk1, Lynne R Wilkens, Kami K White, Christian Caberto, Brian E Henderson1, Loïc Le Marchand, Laurence N Kolonel and Marc T Goodman
Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, 1236 Lauhala Street, Honolulu, Hawaii 96813, USA.
1Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
C G Woolcott; E-mail: : cwoolcott@crch.hawaii.edu.
Abstract
To add to the existing evidence that comes mostly from White populations, we conducted a nested case-control study to examine the association between sex hormones and breast cancer risk within the Multiethnic Cohort that includes Japanese American, White, Native Hawaiian, African American, and Latina women. Of the postmenopausal women for whom we had a plasma sample, 132 developed breast cancer during follow-up. Two controls per case, matched on study area (Hawaii, Los Angeles), ethnicity/race, birth year, date and time of blood draw and time fasting, were randomly selected from the women who had not developed breast cancer. Levels of estradiol (E2), estrone (E1), androstenedione, dehydroepiandrosterone (DHEA), and testosterone were quantified by RIA after organic extraction and Celite column partition chromatography. E1 sulfate, DHEA sulfate (DHEAS), and sex hormone-binding globulin (SHBG) were quantified by direct immunoassays. Based on conditional logistic regression, the sex hormones were positively associated and SHBG was negatively associated with breast cancer risk. All associations, except those with DHEAS and testosterone showed a significant linear trend. The odds ratio (OR) associated with a doubling of E2 levels was 2.26 (95% confidence interval (CI) 1.58-3.25), and the OR associated with a doubling of testosterone levels was 1.34 (95% CI 0.98-1.82). The associations in Japanese American women, who constituted 54% of our sample, were similar to or nonsignificantly stronger than in the overall group. This study provides the best evidence to date that the association between sex hormones and breast cancer risk is generalizable to an ethnically diverse population. Endocrine-Related Cancer (2010) 17 125-134.
Introduction
Many risk factors for postmenopausal breast cancer are thought to be mediated by a hormonal mechanism (Henderson & Feigelson 2000, Clemons & Goss 2001). The investigation of circulating sex hormones has provided evidence that is more direct. A pooled analysis published in 2002 (Key et al. 2002) of nine prospective studies of women not using hormone replacement therapy (HRT) found that all estrogenic and androgenic steroid sex hormones examined were associated with increased breast cancer risk, and that sex hormone-binding globulin (SHBG) was associated with decreased risk. Since the publication of this pooled analysis, these findings have been supported for the most part by analyses in some of the studies with extended follow-up (Missmer et al. 2004, Zeleniuch-Jacquotte et al. 2004, Cummings et al. 2005, Eliassen et al. 2006, Sieri et al. 2009) and additional large prospective studies (Cummings et al. 2002, Manjer et al. 2003, Onland-Moret et al. 2003, Kaaks et al. 2005, Beattie et al. 2006, Gunter et al. 2009).
With a single exception, all of these studies were conducted in largely White populations. Kabuto et al. (2000) investigated the association of breast cancer with estradiol (E2), SHBG, and dehydroepian-drosterone sulfate (DHEAS) in a prospective study of Japanese women in Japan, but had only 26 postmenopausal cases and did not investigate testosterone levels. The odds ratio (OR) for the association with a doubling of E2 levels was 0.90 (95% confidence interval (CI) 0.42-1.92) (reported in Key et al. (2002)) suggesting that the association may be different in women of Japanese ancestry. Two case-control studies conducted in China, on the other hand, found that breast cancer risk in non-Japanese Asian postmenopausal women was positively associated with estrogen and testosterone levels (Yu et al. 2003, Wang et al. 2009). This report examines the association between estrogens (E2, estrone (E1), and E1 sulfate), androgens (androstenedione, DHEA, DHEAS, and testosterone), and SHBG and breast cancer among postmenopausal women not using HRT within the Multiethnic Cohort (MEC) study. Because so few results are available from past studies in Asian populations, another objective was to examine these associations in the subgroup restricted to our Japanese American participants who comprise a large proportion of the MEC.
Materials and methods
Study design and population
We conducted a case-control study nested within the MEC. This cohort includes over 215 000 men and women between the ages of 45 and 75 years at recruitment living in Hawaii and Los Angeles, California who returned a baseline questionnaire between 1993 and 1996 (Kolonel et al. 2000). From information in the questionnaire, participants were assigned to a single ethnic/racial group and if more than one group was reported, assignment was based on the following priority ranking: African American, Native Hawaiian, Latino, Japanese American, and White. More than 95% of all non-Hawaiians reported only one ethnic group. Body mass index (BMI) was calculated as weight divided by the square of height (kg/m2). Women were defined as postmenopausal if they reported cessation of menstrual periods naturally or due to bilateral oophorectomy, reported a hyster-ectomy without bilateral oophorectomy and use of HRT, or if this information was missing, were aged 55 years or older at blood draw.
Largely between 2001 and 2006, 67 594 MEC participants agreed to donate a biospecimen and complete a short questionnaire that updated infor-mation including HRT use and menopausal status. Fasting blood was drawn in the early morning at a clinical laboratory or in the participant’s home, processed, and separated into components. The plasma for the present hormone assays was stored in 2 ml aliquots at — 80 °C. Some women only had serum available in our repository and were excluded because the volume of serum that could be extracted from the 0.5 ml cryotubes in which it was stored was too low to reliably quantify the low hormone levels found in postmenopausal women. The MEC and this study were approved by the Institutional Review Boards of the University of Southern California and the University of Hawaii. All participants provided informed consent at the time of blood collection.
Cases and controls
Cases were women who had contributed a blood specimen before being diagnosed with a first primary breast cancer to the end of follow-up (December, 2006) and had plasma available for analysis. Diagnoses were identified by linkage of the MEC to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program that covers the entire population of the Hawaii and California. Deaths were identified by linkage with state vital statistics databases and the National Death Index. Two control women per case were randomly selected from a pool of subcohort members who were alive and not diagnosed with breast cancer at the same age as the case at diagnosis, and matched to the case by area (Hawaii, Los Angeles), ethnicity, birth year (±1 year), date of blood draw (± 6 months), time of blood draw (± 2 h), hours fasting before blood draw (0-<6, 6-<8, 8-< 10, ≥ 10), and HRT use at the time of blood draw. Only women not using HRT at the time of blood collection were included in this analysis.
Of the 326 cases who had a fasting blood sample available in the biorepository, 124 were currently using HRT and 70 had serum samples only. Thus, 132 incident breast cancer cases not using HRT had a plasma sample available for hormone measurement. Of the 264 controls matched to these cases, one did not have a plasma sample and two did not have sufficient sample for assays. Thus, a total of 132 cases and 261 controls had assay results for the analytes of primary interest (estrogens, testosterone, and DHEA). One control did not have sufficient sample to assay E1 sulfate and DHEAS.
Laboratory assays
Assays for sex hormones and SHBG were performed on plasma samples at the Reproductive Endocrine Research Laboratory at the University of Southern California (FZS). Each batch included matched case-control sets and pooled quality control samples, which were randomly ordered and were blinded to laboratory personnel, plus laboratory standards. Levels of the unconjugated steroid hormones were determined by RIA after organic extraction and partition chromatog-raphy on Celite columns (Goebelsmann et al. 1973, Stanczyk et al. 2007, 2009). Levels of E1 sulfate were determined by direct immunoassay using kits from Beckman-Coulter Diagnostic Systems Laboratories (Webster, TX, USA; Ranadive et al. 1998). Levels of DHEAS and SHBG were determined using a chemiluminescent immunoassay on an Immulite analyzer (Siemens Medical Solutions USA Inc., Malvern, PA, USA). The limits of detection were 5 pg/ml for E1, 0.01 ng/ml for E1 sulfate, 2 pg/ml for E2, 0.03 ng/ml for androstenedione, 0.04 ng/ml for DHEA, 15 mg/dl for DHEAS, 1.5 ng/dl for testosterone, and 1 nmol/l for SHBG. Seven women were below the limit for E2 and 57 women were below the limit for DHEAS. These women were assumed to have levels equal to half of the detection limit. Bioavailable testosterone and E2 were estimated with a validated algorithm using the measured concentrations of the sex hormones and SHBG and an assumed albumin concentration of 43 g/l (Sodergard et al. 1982, Vermeulen et al. 1999, Rinaldi et al. 2002). The intra-batch coefficients of variation (CV), based on 15 paired duplicates, were 10% forE1, 8.5% for E1 sulfate, 8.2% for E2, 5.9% for androstenedione, 3.9% for DHEA, 4.6% for DHEAS, 4.2% for testosterone, and 7.5% for SHBG.
Statistical analysis
Table 1. Characteristics of the cases and controls.
ORs for the association between breast cancer risk and hormone concentration in quartiles based on the distribution in controls were computed using conditional logistic regression with the matched sets as strata. Because levels of hormones and SHBG were positively skewed, they were logarithmically (base 2) transformed when used as continuous variables as was done in the pooled analysis (Key et al. 2002). The corresponding ORs represent the risk associated with a doubling of hormone concentration; these analyses also constituted our test for trend. Included in the models were two of the matching factors as continuous variables, age at blood draw and hours fasting, to control for any residual differences in these variables between cases and matched controls. We also evaluated a number of risk factors as potential confounders (listed in Table 1). None was retained as a confounder because when added to the models, they changed the ORs associated with a doubling of hormone concentration no more than 10% (Mickey & Greenland 1989). Analyses stratified by HRT use (past, never) and time between blood collection and diagnosis of the case in the set (< 1, ≥1 year) were done. These analyses used hormone levels as continuous variables; the product between the stratification variable and hormone variables was introduced into the models to assess the significance of any effect modification. An analysis stratified by ethnicity, using hormone levels as continuous variables, compared Japanese American women to the group of women of other ethnicities/ races combined. We did not have a sufficient number of women in any other single ethnic/racial group to compare directly to the group of Japanese American women. The analyses were done using SAS version 9.1 (SAS Institute, Cary, NC, USA). All statistical tests were two-sided with a 0.05 level of significance.
Results
Characteristics of all women (132 cases and 261 controls) and the subgroup of Japanese American women (72 cases and 142 controls) are shown in Table 1. The median age of all participants was 68 years, and over half of the women were Japanese American. About half of both cases and controls used HRT in the past. Levels of the sex hormones were uniformly higher in cases than controls, whereas the level of SHBG was lower in cases than controls (Table 2). Among controls, levels of the analytes were often significantly correlated. For example, the Pearson correlations (using log-transformed values) of E2 with E1, testosterone, and SHBG were 0.51, 0.33, and — 0.27 respectively (all P < 0.05). Among controls, the geometric mean E2 concentration adjusted for age and BMI varied significantly among the ethnic/racial groups (P = 0.03), with African American women having high average levels (39 pmol/l) and Latinas having low average levels (20 pmol/l) relative to the other three groups (28 pmol/l).
Table 2. Geometric mean (95% confidence interval) concentrations of sex hormones and SHBG in cases and controls.
Figure 1. Odds ratios (OR) and 95% confidence intervals (CI) for the association of hormone concentrations with the risk of breast cancer. aCases and controls were matched on area, ethnicity, birth year (±1 year), date of blood draw (±6 months), time of blood draw and hours fasting (in categories), and ORs were additionally adjusted for age at blood draw and hours fasting as continuous variables.
Sex hormones were positively associated with breast cancer risk, and SHBG was inversely associated with breast cancer risk (Fig. 1). All associations, except those with DHEAS and testosterone, showed a significant trend, the strongest of which were observed for E2 and free E2. Women who had E2 levels in the highest quartile had over sixfold increased risk of breast cancer relative to women in the lowest quartile (OR 6.43, 95% CI 2.78-14.9). We did not find that past HRT use significantly modified any of these associ-ations (all P for heterogeneity >0.05). Generally, the trends observed in the overall group were reflected in both past and never users of HRT but were larger in magnitude among the former group (data not shown). The ORs for the associations between a doubling of estrogen levels and breast cancer risk were slightly, but nonsignificantly, greater if blood was taken 1 year or more before diagnosis whereas the OR for the association between SHBG and breast cancer risk was slightly, but nonsignificantly, more protective if blood was taken < 1 year before diagnosis (data not shown). As depicted in Fig. 2, when the analysis was restricted to Japanese American women, all associ-ations except those with DHEAS and testosterone showed a significant trend and were nonsignificantly stronger than the associations in women of other ethnicity/race (all P for heterogeneity >0.05). For example, the OR for a doubling of E2 was 2.88 (95% CI 1.63-5.10) in Japanese American women as compared to 1.87 (95% CI 1.17-2.99) in women of other ethnicity/race.
Discussion
In this study, estrogenic and androgenic hormones were positively associated, and SHBG was inversely associated with breast cancer risk. The pooled analysis done in 2002 (Key et al. 2002) and four prospective studies of circulating hormones done since then (Cummings et al. 2002, Manjer et al. 2003, Kaaks et al. 2005, Gunter et al. 2009) have also found such associations although a fifth prospective study did not (Beattie et al. 2006). In the current study, stronger associations than in other prospective studies were observed for some analytes such as E2, E1 sulfate, and SHBG. For example, the OR for a doubling of E2 concentration was 2.26 (95% CI 1.58-3.25), whereas in the pooled analysis, it was 1.29 (95% CI 1.15-1.44) with ORs ranging from 0.76 to 1.69 in the individual studies.
Figure 2. Odds ratios (OR) and 95% confidence intervals (CI) for the association between a doubling of hormone concentrations and the risk of breast cancer among Japanese American women and women of other race/ethnicity. aCases and controls were matched on area, ethnicity, birth year (±1 year), date of blood draw (±6 months), time of blood draw and hours fasting (in categories), and ORs were additionally adjusted for age at blood draw and hours fasting as continuous variables.
The impact of the short time between blood collection and diagnosis (median of 1 year), which could be construed as a limitation of our study, should be considered. Because mammary tumors express aromatase, they have the capability of producing estrogens from androgens (Pasqualini et al. 1996), and if the estrogens thus produced enter the circulation, reverse causality could be a concern. However, in breast cancer patients, breast tissue estrogens do not reflect circulating estrogens (Geisler 2003). Furthermore, in one study that collected two blood samples a mean of 31 months apart, the rate of change in most hormone levels was not significantly different between cases and controls, suggesting that the presence of an undetected tumor does not have a large effect on circulating hormone levels (Zeleniuch-Jacquotte et al. 2004).
The second sample, however, was collected on average 28 months before the diagnosis of the case, and the possibility still remains that tumors closer than this to diagnosis have an effect on circulating hormone levels. Additional information about the impact of the time between blood collection and diagnosis comes from prospective studies that have stratified on this factor, which had little effect on most associations (Dorgan etal. 1996, Zeleniuch-Jacquotte etal. 1997, Hankinson et al. 1998, Kabuto et al. 2000, Key et al. 2002, Sieri et al. 2009). Associations between a few of the hormones and breast cancer risk, however, were weaker (Toniolo et al. 1995, Dorgan et al. 1997, Hankinson et al. 1998, Onland-Moret et al. 2003) or stronger (Dorgan et al. 1996, Kabuto et al. 2000, Zeleniuch-Jacquotte et al. 2004) with less time between blood collection and diagnosis.
The strength of the association observed for circulating estrogen concentrations with breast cancer risk was notable in our multiethnic population. Some of these associations may have been stronger than in other prospective studies because our indirect assays have been shown to have high validity and reliability (Lee et al. 2006), perhaps leading to less attenuation of risk estimates due to nondifferential exposure misclassification. E2 measurements done in the laboratory in which our assays were performed correlate very well with the gold standard method gas chromatography tandem mass spectrometry (GC-MS/MS), whereas direct assays without an extraction step that reduces cross-reactivity with other hormone metabolites correlate less well (Lee et al. 2006). The CV of the assays done in this study, however, are not noticeably lower than those reported in other studies where case-control sets were placed in the same batch to eliminate the effect of inter-batch variability (Tworoger & Hankinson 2006). Also possibly contributing to the strength of our associations is the fact that Japanese American women comprised over half of our sample in whom the associations between most sex hormones and breast cancer risk appeared to be of greater magnitude than in women of other ethnicity/race. This difference, however, would not be enough to wholly explain our stronger results for E1, E2, and SHBG in comparison to previous prospective studies.
The only other prospective study done among postmenopausal Asian women, conducted in Japan, found no significant association between breast cancer risk and total E2, bioavailable E2, DHEAS, and SHBG; the point estimate for E2 was below 1.0 but the 95% CIs were wide due to a small sample size (Kabuto et al. 2000). Two case-control studies conducted in China, however, found positive associations between post-menopausal breast cancer risk and levels of estrogens and testosterone (Yu et al. 2003, Wang et al. 2009). The Japanese American women in the current study may have had higher levels of sex hormones than the Asian women in the other studies: higher sex hormone levels have been observed in Western Japanese as compared to Eastern Japanese populations in studies using the same assay techniques (Shimizu et al. 1990). Although this appears to be contradicted by the reported median or geometric mean E2 concentration being higher in the controls of two of these studies (Kabuto et al. 2000, Wang et al. 2009) than in the current study, comparing levels across studies is not possible when assay techniques are different (Key et al. 2002).
In the MEC, Japanese American women are at similar or slightly higher risk of breast cancer relative to White women (Pike et al. 2002, Woolcott et al. 2009). This result is compatible with observations made in the current study population and another within the MEC (Setiawan et al. 2006) that Japanese.
American women have sex hormone levels similar to or slightly higher than White women once age, BMI, and other factors are taken into account. Postmeno-pausal Japanese American women in the MEC, of whom 89% were born in the United States, may lead a fairly westernized lifestyle and thus may have a distribution similar to White women of lifestyle factors that affect sex hormone concentration. For example, indicators of a westernized diet, such as low vegetable and soy intake, are associated with lower SHBG concentrations (Wu et al. 2009) and higher testosterone concentrations (Setiawan et al. 2006). With respect to dietary patterns, however, Japanese Americans in the MEC are still likely to differ somewhat from Whites (Park et al. 2005).
In this study, we had sufficient statistical power with the whole sample to detect associations of the magnitude observed in other prospective studies of circulating hormones and breast cancer risk but our ability to detect differences in effect among subgroups was limited by our sample size. We had a larger number of women of Asian ancestry than in other published prospective studies, and we found significant associations in this group. Because the other ethnic/ racial groups each had few subjects, we compared the results in the Japanese American women to those in the other groups combined. As follow-up continues, we will be able to pursue analyses by each ethnic/ racial group separately. Although we relied on a single blood draw for our analysis, other studies have observed that hormone levels up to 5 years apart are moderately correlated suggesting that a single hormone measurement adequately characterizes levels over a longer period of time (Toniolo et al. 1995, Kim & Zeleniuch-Jacquotte 1997, Hankinson et al. 1998, Zeleniuch-Jacquotte et al. 2004). Our covariate information was largely derived from the baseline questionnaire, which was done an average of 9.3 years before the blood was drawn. This limitation only applies to time-dependent covariates, such as BMI, which are unlikely to change the conclusions in this study because in most other studies, covariates confound the associations between circulating sex hormones and breast cancer risk very little (Dorgan et al. 1996, Hankinson et al. 1998, Kabuto et al. 2000, Key et al. 2002, Endogenous Hormones and Breast Cancer Collaborative Group 2003, Onland-Moret et al. 2003, Zeleniuch-Jacquotte et al. 2004, Cummings et al. 2005, Kaaks et al. 2005).
In conclusion, this study supports previous evidence that sex hormone levels are associated with an increased risk of breast cancer, and SHBG levels are associated with a decreased risk among postmenopausal women. It demonstrates that these associations are generalizable to an ethnically diverse population, and furthermore, it suggests that these associations remain similar when restricted to Japanese American women.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work was supported in part by National Cancer Institute (grants P01 CA33619 and R37 CA54281), and by the National Institutes of Health, Department of Health and Human Services (contracts N01-PC-35137 and N01-PC-35139). C G Woolcott was supported by a postdoctoral fellowship on grant R25 CA90956.
Author contribution statement
C G Woolcott carried out the statistical analysis, interpreted the results, and wrote the manuscript. L R Wilkens and M T Goodman also helped to interpret the results. Y B Shvetsov and L R Wilkens provided statistical expertise. K K White and C Caberto were involved in data acquisition, management, and subject selection. B E Henderson and L N Kolonel are the Principal Investigators of the Multiethnic Cohort Study and with M T Goodman, L R Wilkens, and L Le Marchand were involved in the concept and procurement of funding for this particular project. F Z Stanczyk carried out the hormone assays and helped to interpret this data. All authors provided feedback on the initial draft of the manuscript and approved the final manuscript.
Acknowledgements
We thank Anne Tome for database management, and all participants and staff involved in the study.
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