Originally published as JCO Early Release 10.1200/JCO.2008.16.8807 on November 17 2008

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Plasma Isoflavones and Subsequent Risk of Prostate Cancer in a Nested Case-Control Study: The Japan Public Health Center

Norie Kurahashi, Motoki Iwasaki, Manami Inoue, Shizuka Sasazuki, Shoichiro Tsugane

From the Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan

Corresponding author: Norie Kurahashi, 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: nkurahas{at}gan2.res.ncc.go.jp

	ABSTRACT

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Purpose The incidence of prostate cancer is much lower in Japanese than Western populations. Given the preventive effects of isoflavones on carcinogenesis in the prostate in many nonhuman studies and the high consumption of isoflavones in Japanese, this low incidence may be partly due to the effects of soy.

Patients and Methods We conducted a nested case-control study within the Japan Public Health Center–based Prospective Study. A total of 14,203 men aged 40 to 69 years who had returned the baseline questionnaire and provided blood samples were observed from 1990 to 2005. During a mean of 12.8 years of follow-up, 201 newly diagnosed prostate cancers were identified. Two matched controls for each case were selected from the cohort. Conditional logistic regression model was used to estimate the odds ratios (ORs) and 95% CIs for prostate cancer in relation to plasma levels of isoflavone.

Results Plasma genistein level tended to be inversely associated with the risk of total prostate cancer. Although plasma daidzein showed no association, the highest tertile for plasma equol, a metabolite of daidzein, was significantly associated with a decreased risk of total prostate cancer (OR = 0.60; 95% CI, 0.36 to 0.99; P_trend = .04). These inverse associations were strengthened after analysis was confined to localized cases, with ORs in the highest group of plasma genistein and equol compared with the lowest of 0.54 (95% CI, 0.29 to 1.01; P_trend = .03) and 0.43 (95% CI, 0.22 to 0.82; P_trend = .02), respectively. Plasma isoflavone levels were not statistically significantly associated with the risk of advanced prostate cancer.

Conclusion Isoflavones may prevent the development of prostate cancer.

	INTRODUCTION

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Although the incidence of prostate cancer has increased in Japan, it remains less than one fifth of that in Western countries.¹ Interestingly, however, the incidence of latent or clinically insignificant prostate cancer in autopsy studies among men from Japan and the United States is not substantially different.² Moreover, migration data show that incidence increases in men migrating from areas of low incidence to areas of higher incidence.^3,4 These results suggest that the etiology of prostate cancer may involve dietary, lifestyle, and environmental factors.^5-7

Isoflavones, which include genistein, daidzein, and glycitein, are found in soy and soy products.⁸ In some experimental studies, isoflavones have demonstrated protective effects against prostate cancer development as a result of their anticarcinogenic properties and estrogenic activity.⁹ Given that Asian populations consume more soy products than Western populations and that mean plasma concentrations of isoflavones are accordingly higher in Japanese than those in men from the United Kingdom¹⁰ and Finland,¹¹ this low incidence may partly reflect the influence of isoflavones.

Although experimental studies have consistently shown preventive effects of isoflavones on prostate cancer,⁹ data from epidemiologic studies have been inconsistent.^5,12-28 We previously reported an association between dietary isoflavones and prostate cancer risk among Japanese men using data from a 5-year follow-up questionnaire in the Japan Public Health Center (JPHC) –based Prospective Cohort Study.⁵ In that study, consumption of soy products, genistein, and daidzein was associated with a decreased risk of localized prostate cancer. However, we could not explore the association between equol, which is metabolized from daidzein by intestinal bacteria and known to have stronger estrogenic activity than daidzein,^29,30 and prostate cancer using a food frequency questionnaire (FFQ), because approximately 30% to 50% of adults lack the ability to metabolite daidzein to equol.⁸ Additionally, genistein and daidzein are absorbed as isoflavone aglycones after hydrolysis of the glycoside by beta-glucosidases present in not only human gut bacteria but also in foods. On this basis, the isoflavone aglycones in fermented foods, such as miso, natto, and so on, may be more bioavailable than their glucosides.⁸ Thus plasma data in Japanese, who consume various soy foods, both fermented and nonfermented, is useful with regard to bioavailability.

We investigated the effect of isoflavones as measured in plasma on subsequent prostate cancer in a nested case-control study within a large prospective cohort study.

	PATIENTS AND METHODS

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Study Population
The JPHC study was initiated in 1990 for cohort I and in 1993 for cohort II. Cohort I consisted of five Public Health Center (PHC) areas (Iwate, Akita, Nagano, Okinawa, and Tokyo), and cohort II consisted of six PHC areas (Ibaraki, Niigata, Kochi, Nagasaki, Okinawa, and Osaka) across Japan. The study design has been described in detail previously.³¹ This study was approved by the institutional review board of the National Cancer Center, Tokyo, Japan. The study population was defined as all residents aged 40 to 59 years in cohort I and 40 to 69 years in cohort II at the start of the respective baseline survey. In the present analysis, the Tokyo participants were not included in data analyses because incidence data for them were not available.³¹ After initiation of the study, 144 patients were found to be ineligible and were excluded because of non-Japanese nationality (n = 31), late report of emigration occurring before the start of the follow-up period (n = 107), incorrect birth data (n = 1), duplicate registration (n = 2), and self-reported history of prostate cancer (n = 3). Initially, we defined a population-based cohort of 65,657 men.

Questionnaire Survey
A self-administered questionnaire, which included personal and family medical history, smoking and drinking habits, diet, and other lifestyle factors, was distributed to all eligible residents who had registered their address in the respective PHC areas in 1990 to 1994. Completed questionnaires were received from 50,435 men (response rate, 77%). Dietary habits were assessed with an FFQ of 44 food items for cohort I and 52 food items for cohort II.³²

Blood Collection
Participants voluntarily provided 10 mL of blood during health check-ups in 1990 to 1995. Blood samples were divided into plasma and buffy layers, and preserved at –80°C until analysis. Among respondents to the baseline questionnaire, a total of 14,203 men (28%) donated blood.

Follow-Up
Participants were observed from the baseline survey until December 31, 2005. Changes in residence status, including survival, were identified annually through the residential registry in their PHC area. Among study participants, 749 patients (5.3%) moved out of their study area and 28 patients (0.2%) were lost to follow-up during the study period.

Selection of Cases and Controls
Incidence data on prostate cancer were identified by active patient notification from major local hospitals in the study area and data linkage with population-based cancer registries, with permission from the local governments responsible for the registries. Cases were coded using the International Classification of Diseases for Oncology, Third Edition. We identified 201 prostate cancer cases newly diagnosed after blood collection up to the end of the study period among men who had returned the baseline questionnaire, reported no history of prostate cancer, and provided blood samples. Ninety-seven percent of cases were pathologically confirmed, and 0.5% of cases were based on death certificate only. Among the 201 cases, advanced cases were defined by a diagnosis of extraprostatic or metastatic cancer involving lymph nodes or other organs at first diagnosis of prostate cancer. If this information was not available, they were defined as those with a high Gleason score (8 to 10) or poor differentiation. These criteria were selected to allow the identification of advanced cases with a high likelihood of poor prognosis. The remaining cases were organ-localized. A total of 48 advanced, 144 localized, and nine (4% of total) cases of undetermined stage were identified.

For each case, two controls were selected from among participants with no history of prostate cancer when the case was diagnosed. Controls were matched for each case by age (within 3 years), PHC area, area (city or town and village), date on which blood was obtained (within 60 days), time of day of blood collection (within 3 hours), and duration of fasting at blood collection (within 3 hours).

Laboratory Assays
Concentrations of isoflavones in the plasma samples, namely of genistein, daidzein, glycitein and equol, were measured using triple quadrupole tandem liquid chromatography-mass spectrometry.³³ The isoflavones assayed were genistein, daidzein, glycitein, and equol. Beta-glucuronidase/sulfatase was added to 0.1 mL of plasma. The aglycones of the isoflavones and their metabolites were recovered by diethyl ether extraction. The diethyl ether extract of the sample was dried under nitrogen flow and redissolved in acetonitrile. The ionizing method was electrospray using negative ions, and multiple reaction monitoring was used for mass analysis. To assure quality control (QC), laboratory precision in this measurement was assessed twice using two kinds of sample before and after each assay. Based on 40 replicated measurements of QC samples, interbatch coefficient of variations (CVs) were 6.08% for genistein, 4.06% for daidzein, 5.48% for glycitein, and 6.15% for equol. QC samples used blood pooled from healthy volunteers, for which mean concentrations were 60.1 and 103.4 ng/mL for genistein, 39.1 and 95.0 ng/mL for daidzein, 3.4 and 48.2 ng/mL for glycitein, and 15.7 and 57.1 ng/mL for equol. Cases and matched controls were assayed in the same batch. Detection limits were less than 1.0 ng/mL for all isoflavones. All samples were analyzed at a single laboratory (SRL, Tokyo, Japan) under blinding to case-control status.

Statistical Analysis
Baseline characteristics between cases and controls were evaluated by the Mantel-Haenszel procedure with matched set strata. Odds ratios (ORs) and 95% CIs for prostate cancer risk were estimated by tertile level of plasma genistein and daidzein using a conditional logistic regression model. Tertile cutoff points were based on the frequency distribution of controls. In analyses for glycitein and equol, the ORs were computed according to three levels: the first comprised study participants with amounts below the detection limits (< 1.0 ng/mL), whereas the middle and high level groups comprised those with detectable levels as equally bisected by the median detected amount. A total of 30.8% and 25.1% of cases and controls were under the detection limit for glycitein and 39.8% and 36.3% were under the detection limit for equol, respectively. In this study, we defined "equol producer" as a participant in whom plasma equol was detected ( 1.0 ng/mL).

ORs and 95% CIs were adjusted for the following variables as potential confounders: smoking status (never, former, and current), alcohol intake (almost never, one to three times per month, 1 times per week), marital status (yes/no), green tea intake (<1 cup/d, 1 to 2 cups/d, 3 to 4 cups/d, 5 cups/d), and intake of protein, fiber, green or yellow vegetables, and dairy food (continuous). These variables are either known or suspected risk factors for cancer or had previously been associated with the risk of prostate cancer.^6,7 A family history of prostate cancer was not to be evaluated as a potential confounding factor because there was only one participant who reported it. Because the questionnaires for cohorts I and II differed slightly with respect to food items, method of expression, and frequency categories, adjustment was done by calculating separate estimates for cohorts I and II and then analyzing the combined result using a fixed-effects model. The two cohorts were not heterogeneous.

Linear trends for OR were tested using the median values of isoflavones. All P values are two-sided, and statistical significance was determined at P < .05. Additionally, we estimated the OR of prostate cases stratified by stage as well as that for all cases. All statistical analyses were done with SAS software (version 9.1; SAS Institute Inc, Cary, NC).

	RESULTS

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Basic characteristics of case and matched controls at baseline are listed in Table 1. Cases tended to smoke less and to consume more protein, fiber, green or yellow vegetables, and dairy products. Further, Table 2 shows that there were no significant differences between cases and controls in median plasma levels of isoflavones.

	DISCUSSION

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In addition to these epidemiologic data, experimental studies in vivo and in vitro have also demonstrated protective effects of isoflavones against prostate cancer development. Among these effects, isoflavones possess weak estrogen activity, inhibit tyrosine protein kinases, angiogenesis, and reduce serum testosterone levels.^12,34,35 They also inhibit 5-reductase, an enzyme that metabolizes testosterone to dihydrotestosterone.³⁶ Any or all of these mechanisms may explain the inverse association between isoflavone and localized prostate cancer seen here. Moreover, these results are supported by incidence data, which show a much lower incidence of prostate cancer in Japanese, with a relatively high concentration of plasma isoflavones, than in Western men.¹

However, when analyzed by stage, our data showed that isoflavones had no preventive effects against advanced prostate cancer. Our results thus were supported by the hypothesis that isoflavones may fail to protect against advanced prostate cancer via the complete or partial loss of estrogen receptor β (ERβ) expression,^37-39 on the basis that the effect of isoflavones on risk seems to involve ERβ in prostate tissue.⁹ Additionally, they are also supported by animal studies showing a beneficial role of a soy diet in the early stages of tumor development, but no effect in invasive prostate cancer.^40,41 On these bases, therefore, isoflavones may prevent the early stages of prostate cancer development, and then delay the progression of latent prostate cancer. This speculation is supported by the finding that the incidence of latent prostate cancer is the same in Japanese as in Western men, despite a lower incidence of prostate cancer.² Another possibility is that advanced prostate cancer may be different from localized prostate cancer. Consideration should also be given to the possibility of detection bias owing to the reduction in 5-reductase by isoflavone.³⁶ A reduction in 5-reductase will decrease the value of prostate-specific antigen⁴² and thus might mask the presence of prostate cancer. Isoflavones might therefore have no effect on the detection of advanced cases because of their substantially high prostate-specific antigen values. Nevertheless, because the number of advanced cases was small, the occurrence of this result by chance cannot be ruled out.

Of note, our present results for plasma isoflavone levels are similar to those we previously obtained in the JPHC Study using an FFQ.⁵ It is particularly meaningful that a similar association was shown between the long-term intake of isoflavones versus plasma concentrations obtained at a single time point, notwithstanding their short half lives of 8.4 hours for genistein and 5.8 hours for daidzein.⁴³ In a validation study using subsamples in the JPHC Study, Spearman's correlation coefficients for daidzein and genistein between intakes from the questionnaire and from serum concentrations were 0.31 and 0.33, respectively.⁴⁴ Further, our present results did not substantially change when we excluded participants who provided a nonfasting blood sample, within 6 hours of eating a meal (data not shown). Blood concentrations might be maintained in Japanese by frequent habitual intake of isoflavone-rich foods.

In this study, each isoflavone showed a different effect on prostate cancer. Several experimental studies have reported that genistein may have greater estrogenic activity than daidzein.^8,45 Daidzein is metabolized to equol, which is known to have more estrogenic potency and greater affinity for ERβ than daidzein.^29,30,46 A previous epidemiologic study reported that the highest serum equol level was associated with a statistically significant 60% decrease in total prostate cancer risk among Japanese men.²⁷ In contrast, our study showed no preventive effect of glycitein on prostate cancer, although several experimental studies have reported that glycitein has weak estrogenic activity⁴⁷ and plays a role in the modulation of tyrosine kinase activity.⁴⁸ Low et al²⁸ also reported that serum glycitein is not associated with prostate cancer (OR = 1.08). Nakamura et al⁴⁹ estimated daily intake of isoflavones from soy products by Japanese of 13.48 mg/d for genistein, 12.02 mg/d for daidzein, and 2.30 mg/d for glycitein. In our study, plasma glycitein levels were much lower than those of other isoflavones. Glycitein may fail to prevent prostate cancer because of its small amount in food or blood. These previous and present studies thus suggest it is plausible that isoflavones have different effects on prostate cancer.

Several limitations in the interpretation of our findings should be considered. First, plasma isoflavone levels were measured only once. As mentioned above, however, the frequent intake of isoflavone-rich foods by Japanese may keep plasma levels stable. In addition, because our study participants were restricted to those who participated in the baseline health check-up survey, any generalization of our results should be done with caution.⁵⁰

In summary, we found that plasma genistein and equol levels were inversely associated with the risk of localized prostate cancer in a nested case-control study in Japan. These findings suggest that these compounds may be protective against the development of prostate cancer.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Norie Kurahashi, Motoki Iwasaki, Manami Inoue, Shizuka Sasazuki, Shoichiro Tsugane

Collection and assembly of data: Norie Kurahashi, Motoki Iwasaki, Manami Inoue, Shizuka Sasazuki, Shoichiro Tsugane

Data analysis and interpretation: Norie Kurahashi, Motoki Iwasaki, Manami Inoue, Shizuka Sasazuki, Shoichiro Tsugane

Manuscript writing: Norie Kurahashi

Final approval of manuscript: Norie Kurahashi, Motoki Iwasaki, Manami Inoue, Shizuka Sasazuki, Shoichiro Tsugane

	Appendix

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Members of the JPHC Study Group include the following: S. Tsugane (principal investigator), M. Inoue, T. Sobue, and T. Hanaoka, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo; J. Ogata, S. Baba, T. Mannami, A. Okayama, and Y. Kokubo, National Cardiovascular Center, Suita; K. Miyakawa, F. Saito, A. Koizumi, Y. Sano, I. Hashimoto, and T. Ikuta, Iwate Prefectural Ninohe Public Health Center, Ninohe; Y. Miyajima, N. Suzuki, S. Nagasawa, Y. Furusugi, and N. Nagai, Akita Prefectural Yokote Public Health Center, Yokote; H. Sanada, Y. Hatayama, F. Kobayashi, H. Uchino, Y. Shirai, T. Kondo, R. Sasaki, Y. Watanabe, Y. Miyagawa, and Y. Kobayashi, Nagano Prefectural Saku Public Health Center, Saku; Y. Kishimoto, E. Takara, T. Fukuyama, M. Kinjo, M. Irei, and H. Sakiyama, Okinawa Prefectural Chubu Public Health Center, Okinawa; K. Imoto, H. Yazawa, T. Seo, A. Seiko, F. Ito, and F. Shoji, Katsushika Public Health Center, Tokyo; A. Murata, K. Minato, K. Motegi, and T. Fujieda, Ibaraki Prefectural Mito Public Health Center, Mito; T. Abe, M. Katagiri, M. Suzuki, and K. Matsui, Niigata Prefectural Kashiwazaki and Nagaoka Public Health Center, Kashiwazaki and Nagaoka; M. Doi, A. Terao, Y. Ishikawa, and T. Tagami, Kochi Prefectural Chuo-higashi Public Health Center, Tosayamada; H. Doi, M. Urata, N. Okamoto, F. Ide, and H. Sueta, Nagasaki Prefectural Kamigoto Public Health Center, Arikawa; H. Sakiyama, N. Onga, H. Takaesu, and M. Uehara, Okinawa Prefectural Miyako Public Health Center, Hirara; F. Horii, I. Asano, H. Yamaguchi, K. Aoki, S. Maruyama, M. Ichii, and M. Takano, Osaka Prefectural Suita Public Health Center, Suita; S. Matsushima and S. Natsukawa, Saku General Hospital, Usuda; M. Akabane, Tokyo University of Agriculture, Tokyo; M. Konishi, K. Okada, and I. Saito, Ehime University, Toon; H. Iso, Osaka University, Suita; Y. Honda, K. Yamagishi, and S. Sakurai, Tsukuba University, Tsukuba; H. Sugimura, Hamamatsu University, Hamamatsu; Y. Tsubono, Tohoku University, Sendai; M. Kabuto, National Institute for Environmental Studies, Tsukuba; S. Tominaga, Aichi Cancer Center Research Institute, Nagoya; M. Iida, W. Ajiki, and A. Ioka, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka; S. Sato, Osaka Medical Center for Health Science and Promotion, Osaka; N. Yasuda, Kochi University, Nankoku; K. Nakamura, Niigata University, Niigata; S. Kono, Kyushu University, Fukuoka; K. Suzuki, Research Institute for Brain and Blood Vessels Akita, Akita; Y. Takashima, Kyorin University, Mitaka; E. Maruyama, Kobe University, Kobe; M. Yamaguchi, Y. Matsumura, S. Sasaki, and S. Watanabe, National Institute of Health and Nutrition, Tokyo; T. Kadowaki, Tokyo University, Tokyo; M. Noda, International Medical Center of Japan, Tokyo; Y. Kawaguchi, Tokyo Medical and Dental University, Tokyo; and H. Shimizu, Sakihae Institute, Gifu.

	ACKNOWLEDGMENTS

 
We thank all staff members in each study area and in the central offices for their cooperation and technical assistance. We also thank the Iwate, Aomori, Ibaraki, Niigata, Osaka, Kochi, Nagasaki, and Okinawa Cancer Registries for their provision of incidence data.

	NOTES

 
published online ahead of print at www.jco.org on November 17, 2008.

Supported by Grants-in-Aid for Cancer Research (Grant No. 19shi-2), for the 3rd Term Comprehensive 10-Year Strategy for Cancer Control (Grant No. H18-sanjigan-ippan-001), and for Research on Risk of Chemical Substances (Grant No. H17-kagaku-ippan-014) from the Ministry of Health, Labour and Welfare of Japan, and Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology (Grant No. 17015049).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted February 20, 2008; accepted July 22, 2008.

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