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Originally published as JCO Early Release 10.1200/JCO.2007.13.9964 on March 3 2008 © 2008 American Society of Clinical Oncology. Plasma Isoflavone Level and Subsequent Risk of Breast Cancer Among Japanese Women: A Nested Case-Control Study From the Japan Public Health Center-Based Prospective Study Group
From the Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center; Department of Sport and Exercise Nutrition, School of Physical Education, Sendai University; and the Cancer Information Services and Surveillance Division, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan Corresponding author: Motoki Iwasaki, MD, PhD, Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; e-mail: moiwasak{at}gan2.res.ncc.go.jp
Purpose Because they have large variations in consumption, Asian countries are suitable settings for studies of the effect of relatively high-dose isoflavone intake on breast cancer risk. Nevertheless, no prospective study from Asia has assessed blood or urine levels as biomarkers of isoflavone intake. Patients and Methods A total of 24,226 women ages 40 to 69 years in the Japan Public Health Center–based prospective study who responded to the baseline questionnaire and provided blood in 1990 to 1995 were observed to December 2002. During a mean 10.6 years of follow-up, 144 patients newly diagnosed with breast cancer were identified. Two matched controls for each patient were selected from the cohort. Isoflavone levels were assessed by plasma level and food frequency questionnaire, and the odds ratio of breast cancer according to isoflavone level was estimated using a conditional logistic regression model. Results We found a statistically significant inverse association between plasma genistein and risk of breast cancer, but no association for plasma daidzein. Adjusted odds ratios for the highest versus lowest quartile of plasma level were 0.34 for genistein (95% CI, 0.16 to 0.74; P for trend, .02) and 0.71 for daidzein (95% CI, 0.35 to 1.44; P for trend, .54). Median plasma genistein values in the control group were 31.9 ng/mL for the lowest and 353.9 ng/mL for the highest quartile groups. Regarding dietary intake of isoflavones, nonsignificant inverse associations were observed for both genistein and daidzein. Conclusion This nested case-control study found an inverse association between plasma genistein and the risk of breast cancer in Japan.
Soy foods, a traditional staple dish in Asian countries, are a primary source of isoflavones, such as genistein and daidzein, which are classified as phytoestrogens. Because breast cancer risk is substantially lower in Asian than Western countries,1 the contribution of a high isoflavone intake to low breast cancer risk has been hypothesized.2 This hypothesis has been supported by in vitro studies at high genistein concentrations and in the majority of animal studies, which together have demonstrated various anticancer effects of isoflavones acting via both estrogen-dependent and -independent mechanisms.3,4 Estrogen-dependent mechanisms arise through the mediation of estrogen receptor  and β, owing to the similar chemical structure of isoflavones to the human estrogen hormone and their binding affinity to estrogen receptors.4,5 For this reason, they have been hypothesized to behave like selective estrogen receptor modulators. In contradiction to potential protective effects, however, genistein exhibits estrogenic properties at low concentrations, which could theoretically enhance breast cancer risk.3,4 In fact, some animal studies have reported that genistein stimulates tumor development and growth.6,7 Although a recent meta-analysis found that soy intake was associated with a small reduction in breast cancer risk, the authors concluded that in view of these risk-enhancing effects, recommendations for high-dose isoflavone supplementation to prevent breast cancer or its recurrence were premature.8 Phytoestrogen supplements, however, are commercially marketed for use by postmenopausal women as natural and safe alternatives to hormone replacement therapy. The effect of relatively high-dose isoflavone on breast cancer risk is now of concern. Because they have large variations in consumption among individuals, Asian countries serve as suitable venues for studies of the effect of relatively high-dose isoflavone intake on breast cancer risk. Despite this advantage, only a few epidemiological studies on soy or isoflavone intake and breast cancer risk from Asia have been reported.9 In particular, no prospective study on isoflavone levels in blood or urine samples has been reported, notwithstanding that, because they are partly determined by individual differences in absorption and metabolism, blood or urine levels might better reflect interperson differences than dietary assessment. The three nested case-control studies which have investigated this association in Western populations have been inconsistent, with one reporting an inverse association with plasma genistein in the Netherlands,10 the second showing no association with urinary genistein in the Netherlands,11 and the third finding a positive association with urine and serum phytoestrogens in the United Kingdom.12 This inconsistency might be in part explained by the apparently small variation in isoflavone levels in Western countries. For example, studies in the Netherlands, which has a high incidence of breast cancer (age-standardized rate per 100,000 world population, 86.7 in 2002),13 reported a median genistein intake of 0.14 mg/d in women ages 49 to 70 years,14 and a median plasma genistein level of 4.89 ng/mL in the control group of a nested-case control study.10 In contrast, a study in Japan, where the incidence of breast cancer is low (age-standardized rate per 100,000 world population, 32.7 in 2002),13 reported a median genistein intake of 22.3 mg/d and median serum level of 90.2 ng/mL.15 This substantial variation in isoflavone levels suggests that the Japanese population represents an ideal setting for determining whether an association exists at relatively high levels achievable from dietary intake only. Herein, to clarify the effect of relatively high-dose isoflavone exposure on breast cancer risk, we conducted a nested case-control study within a large-scale population-based prospective study in Japan.
Study Population The Japan Public Health Center–based prospective study, which began in 1990 for cohort I and in 1993 for cohort II, included 140,420 subjects (68,722 men and 71,698 women) living in the municipalities supervised by 11 public health centers (PHC). Details of the study design have been described elsewhere.16 The study protocol was approved by the institutional review board of the National Cancer Center, Tokyo, Japan. The study population comprised registered Japanese inhabitants living in each PHC area, ages 40 to 59 years in cohort I and 40 to 69 years in cohort II. In this analysis, one PHC area was excluded since data on cancer incidence were not available. We thus defined a population-based cohort of 67,426 women (27,389 in cohort I and 40,037 in cohort II) after the exclusion of ineligible subjects (n = 95).
Questionnaire Survey
Blood Collection
Follow-Up
Selection of Patients and Controls For each patient, two controls were selected using incidence density sampling from subjects who were not diagnosed with breast cancer during the follow-up period when the patient was diagnosed. Control selection was done without reference to incidence of other cancer sites. Controls were matched with each patient for age (within 3 years), PHC area, area (city or town and village), date of blood collection (within 90 days), time of day of blood collection (within 3 hours), fasting time at blood collection (within 3 hours), and baseline menopausal status.
Assessment of Dietary Intake
Laboratory Assay
Statistical Analysis
Case subjects and controls had significantly different distribution for number of births (Table 1). Other characteristics, such as age at menarche, age at first birth, body mass index (BMI), alcohol consumption, or dietary intake did not substantially differ between the two groups.
Plasma genistein was significantly lower among cases than controls whereas plasma daidzein values were similar (Table 2). No significant differences between the groups were seen for dietary genistein, daidzein, or isoflavone intake. Median isoflavone intake in the control group was 34.8 mg/d (36.1 in cohort I and 29.9 mg/d in cohort II). Genistein and daidzein were highly correlated for both plasma level (r = 0.72) and dietary intake (r = 0.99). Correlation coefficients between plasma and dietary levels were relatively low for both genistein (r = 0.23) and daidzein (r = 0.31).
We found a statistically significant inverse association between plasma genistein and the risk of breast cancer (P for trend, .02), but no statistically significant association for plasma daidzein (P for trend, .54; Table 3). Adjusted ORs for the highest versus lowest quartile of plasma level were 0.34 for genistein (95% CI, 0.16 to 0.74; P  .01) and 0.71 for daidzein (95% CI, 0.35 to 1.44; P = .34). Moreover, the results did not change substantially after adjustment for dietary intake of isoflavone or other potential confounders such as age at menarche, menopausal status at baseline, age at menopause, height, BMI, and alcohol consumption. Further, exclusion of cases diagnosed before the first 3 years of follow-up did not substantially change the results, nor did the exclusion of subjects who used vitamin supplements or who provided a nonfasting blood sample (ie, within 6 hours after a meal). Regarding dietary intake, we observed inverse associations for both genistein and daidzein but neither was statistically significant (Table 3). In addition, adjusted ORs by isoflavone intake were closely similar to those by genistein intake (data not shown).
A stratified analysis according to baseline menopausal status showed no remarkable difference between two strata for either genistein and daidzein, regardless of whether the values were assessed by plasma or questionnaire, although the inverse association between plasma genistein and risk of breast cancer tended to be more stable in postmenopausal than premenopausal women (Table 4).
In this study, we found a statistically significant inverse association between plasma genistein and the risk of breast cancer, but no association for plasma daidzein. This finding suggests that genistein may play a more important role in the etiology of breast cancer than daidzein. Our findings are in general agreement with those of a recent nested case-control study in the Netherlands,10 albeit that our inverse association occurred at substantially higher plasma concentrations. For example, median plasma genistein values in the control group of the Netherlands study were 3.75 ng/mL for premenopausal and 4.89 ng/mL for postmenopausal women.10 In contrast, the median value in our control group was 144.5 ng/mL, and only 3.2% of control subjects was under 5 ng/mL. This apparently high level is not surprising considering that the median value of 353.9 ng/mL in our highest plasma genistein quartile group, which had a significantly lower risk of breast cancer than the lowest group, corresponded to a median dietary intake of 28.5 mg/d for genistein and 46.5 mg/d for isoflavone, as estimated by the validation study data. Although some in vivo and in vitro studies have shown risk-enhancing effects of genistein, our study suggests that relatively high-dose isoflavones exposure achievable from dietary intake alone is associated with a decreased rather than increased risk. We observed an approximately 65% reduction in breast cancer risk in the highest plasma genistein quartile group but no decrease in the other quartiles, indicating that only the highest group benefited from risk reduction. The apparent lack of a dose-response relationship might imply the presence of a threshold level of effect. Interestingly, this idea contradicts findings in Western populations, in whom inverse associations are seen despite materially low levels of isoflavones. Given the differences in hormonal milieu between the two populations, the potential protective effect of isoflavones in breast cancer might act differently between Western and Asian populations: sex hormone levels are higher in Western than Asian women,19 for example, as is the prevalence of obesity.20,21 In this regard, a case-control study in Shanghai found that the inverse association between urinary isoflavone level and breast cancer risk was stronger among women in the high BMI, waist-hip ratio, and estradiol level groups and in the low sex hormone-binding globulin level group than in the respectively converse low and high groups.22 Alternatively, the apparent lack of a dose-response relationship might merely reflect uncontrolled confounding by other dietary characteristics or risk-lowering behaviors. The reason for a role for genistein but not daidzein in the etiology of breast cancer is unclear, but several possibilities can be speculated. Genistein possesses stronger binding affinity for estrogen receptor than daidzein.5 Further, a pharmacokinetic study showed higher plasma levels and a 1.5-fold longer half-life for genistein than daidzein after ingestion of baked soybean powder containing closely similar amounts of the two.23 Moreover, the absence of an association for plasma daidzein might be attributable to misclassification arising from the metabolization of this compound. Daidzein can be metabolized by intestinal bacteria to equol and O-desmethylangolites; because approximately only 30% to 50% of individuals are capable of equol production, probably due to differences in gut microflora, daidzein-to-equol metabolizers may have lower plasma daidzein levels than nonmetabolizers.24 Equol has been suggested to have greater biologic activity than daidzein,24 and an inverse association between equol level and breast cancer risk has been reported.25 Here, the lowest plasma daidzein quartile group might conversely have had a lower breast cancer risk than the higher groups due to its inclusion of equol metabolizers, and such misclassification, if present, would lead to a null result. Our study has several methodological advantages over previous studies of isoflavones and the risk of breast cancer. First, the direct measurement of plasma isoflavone levels provides not only an index of intake but also of the absorption and metabolism of isoflavone, an understanding of which is important to elucidating the mechanisms by which isoflavones might influence breast cancer development. Indirect measurement by dietary intake of genistein is likely a major reason for the present smaller and nonsignificant risk reduction of breast cancer than by plasma genistein. Exposure assessment using blood samples is therefore likely a more sophisticated means of detecting an association. Second, two case-control studies in Australia and China showed an inverse association between urinary isoflavones and breast cancer risk.25,26 In view of the retrospective design of these studies, however, blood or urine levels of isoflavones in breast cancer cases might have been influenced by metabolic changes after the breast cancer was detected or by altered eating habits among case subjects. In our nested case-control study within a prospective cohort, in contrast, blood samples were collected before cancer diagnosis, obviating any potential bias due to the presence of cancer. Third, cases and controls were selected from the same cohort, thereby avoiding the selection bias inherent to case-control studies. Several limitations of this study warrant mention. First, we measured plasma isoflavones only once for each individual. The consumption of soy foods is a personal dietary preference, and intake levels of most individuals are assumed to be relatively stable over time in Japan, as suggested by our validation study, which showed high reproducibility of repeated measurements of genistein intake by food frequency questionnaire (correlation coefficient = 0.72 for 1-year interval and 0.61 for 5-year interval).15,17 By comparison, plasma isoflavone levels may reflect short-term rather than long-term intake: isoflavones have short half-lives in blood (eg, 6 to 8 hours),23,27 and plasma levels are particularly affected by time elapsed since the last meal. To minimize the attenuation of risk estimates derived from random measurement errors, we matched fasting time between cases and controls. Second, despite a reasonably large cohort population (24,226 women) and long follow-up period (average, 10.6 years), the number of breast cancer cases was relatively small, reflecting the low incidence rate in Japan (age-standardized rate per 100,000 world population, 32.7 in 2002).13 The interpretability of our results might therefore be limited, particularly in stratified analyses. Third, although our cohort subjects were selected from the general population, subjects were restricted to the 24,226 women respondents (43%) to the baseline questionnaire who provided blood samples. Although health check-up examinees in our previous report had a different socioeconomic status than nonexaminees and a more favorable lifestyle profile,28 no apparent difference in isoflavone intake and breast cancer risk factors was found between subjects in the subcohort for this study and the original cohort; median isoflavone intake, for example, was 32.5 and 32.1 mg/d, respectively, and the average number of births was 2.8 and 2.7, respectively.29 Nevertheless, any extrapolation of the results to the general population should be done cautiously, particularly in view of a previous report showing the difficulty of extrapolating relative risk estimates for a subcohort to an entire cohort. This difficulty might in fact be inherent to prospective studies in general.30 Allowing for these methodological issues, we found an inverse association between plasma genistein and the risk of breast cancer in a nested case-control study in Japan. This finding suggests a risk-reducing rather than a risk-enhancing effect of isoflavones on breast cancer, even at relatively high concentrations within the range achievable from dietary intake alone.
The author(s) indicated no potential conflicts of interest.
Conception and design: Motoki Iwasaki, Manami Inoue, Tetsuya Otani, Shizuka Sasazuki, Seiichiro Yamamoto, Shoichiro Tsugane Financial support: Motoki Iwasaki, Shoichiro Tsugane Administrative support: Motoki Iwasaki, Manami Inoue, Tetsuya Otani, Shizuka Sasazuki, Norie Kurahashi, Tsutomu Miura, Seiichiro Yamamoto Collection and assembly of data: Motoki Iwasaki, Manami Inoue, Tetsuya Otani, Shizuka Sasazuki, Norie Kurahashi, Seiichiro Yamamoto, Shoichiro Tsugane Data analysis and interpretation: Motoki Iwasaki, Manami Inoue, Tetsuya Otani, Shizuka Sasazuki, Norie Kurahashi, Tsutomu Miura, Seiichiro Yamamoto, Shoichiro Tsugane Manuscript writing: Motoki Iwasaki Final approval of manuscript: Motoki Iwasaki, Manami Inoue, Tetsuya Otani, Shizuka Sasazuki, Norie Kurahashi, Tsutomu Miura, Seiichiro Yamamoto, Shoichiro Tsugane
Assessment of Dietary Intake. The cohort I questionnaire asked about average consumption during the previous month of 44 food items, including three items contributing to isoflavone intake, namely, (1) miso soup, (2) soybeans, tofu, deep-fried tofu, and natto, and (3) vegetables other than yellow and green vegetables, such as Chinese cabbage, radish, tomato, cucumber, and so on—whose items includes soybean sprouts. The cohort II questionnaire asked about average consumption during the previous month of 52 food items, including three items contributing to isoflavone intake: miso soup, tofu, and natto. The cohort I questionnaire had four frequency categories: rarely, 1 to 2 days/week, 3 to 4 days/week, and almost everyday, while the cohort II questionnaire had five frequency categories of never, less than 1 day/week, 1 to 2 days/week, 3 to 4 days/week, and almost everyday. Portion size and isoflavone content were estimated from a validation study (Yamamoto S, Sobue T, Sasaki S, et al: J Nutr 131:2741-2747, 2001; Tsubono Y, Kobayashi M, Sasaki S, et al: J Epidemiol 13:S125-133, 2003), in which 14- to 28-day dietary records and blood samples were collected from subsamples among the Japan Public Health Center cohort members, comprising 107 women in cohort I and 178 women in cohort II. Spearman's correlation coefficients between genistein and daidzein intake estimated from the questionnaire and from dietary records were 0.54 for genistein and 0.55 for daidzein in cohort I, respectively (Tsubono Y, Kobayashi M, Sasaki S, et al: J Epidemiol 13:S125-133, 2003), and 0.53 for genistein and 0.50 for daidzein in cohort II, respectively (unpublished data). To include intakes calculated from the two different questionnaires in the analysis, we estimated genistein and daidzein intake for each subject by cohort from the questionnaires based on a regression function derived from the validation study data.
Study Group Members:
We wish to thank all staff members in each study area and in the central offices for their cooperation and technical assistance. We also wish to thank the Iwate, Aomori, Ibaraki, Niigata, Osaka, Kochi, Nagasaki, and Okinawa Cancer Registries for their provision of incidence data.
published online ahead of print at www.jco.org on March 3, 2008. Supported by grants-in-aid for cancer research, for the Third Term Comprehensive Ten-Year Strategy for Cancer Control, and for Research on Risk of Chemical Substances from the Ministry of Health, Labour, and Welfare of Japan; and Grant-In-Aid No. 17015049 for Scientific Research on Priority Areas and Grant-In-Aid No. 17790378 for Young Scientists from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and Japan Society for the Promotion of Science. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Grace PB, Taylor JI, Low YL, et al: Phytoestrogen concentrations in serum and spot urine as biomarkers for dietary phytoestrogen intake and their relation to breast cancer risk in European prospective investigation of cancer and nutrition-norfolk. Cancer Epidemiol Biomarkers Prev 13:698-708, 2004 13. Ferlay J, Bray F, Pisani P, et al: GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide, IARC Cancer Base No. 5, version 2.0. Lyon, France, IARC Press, 2004 14. Keinan Boker L, van Der Schouw YT, Grobbee DE, et al: Dietary phytoestrogens and breast cancer risk. Am J Clin Nutr 79:282-288, 2004 15. Yamamoto S, Sobue T, Sasaki S, et al: Validity and reproducibility of a self-administered food-frequency questionnaire to assess isoflavone intake in a japanese population in comparison with dietary records and blood and urine isoflavones. J Nutr 131:2741-2747, 2001 16. Watanabe S, Tsugane S, Sobue T, et al: Study design and organization of the JPHC study. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
