For the Japan Public Health Center-Based Prospective Study on Cancer Cardiovascular Diseases (JPHC Study) Group
Affiliations of authors: S. Yamamoto, T. Sobue, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan; M. Kobayashi, S. Sasaki, S. Tsugane, Epidemiology and Biostatistics Division, National Cancer Center Research Institute, East, Kashiwa, Japan.
Correspondence to: Seiichiro Yamamoto, Ph.D., Cancer Information and Epidemiology Division, National Cancer Center Research Institute, 51-1, Tsukiji, Chuo-ku, Tokyo, Japan (e-mail: siyamamo{at}ncc.go.jp).
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ABSTRACT |
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INTRODUCTION |
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By contrast with results from experimental studies, results from epidemiologic studies that assessed associations between soy or isoflavone consumption and breast cancer risk have varied. To date, 13 studies have evaluated associations between soy or isoflavone consumption and breast cancer risk (Table 1). Among studies that reported results for premenopausal women, four casecontrol studies conducted among Singapore Chinese (6), Japanese (7), Asian American (8), and Chinese (9) populations found statistically significant inverse associations between soy consumption and breast cancer risk. However, one prospective American study (10) and four casecontrol studies conducted among Chinese (11), American and Canadian (12), non-Asian American (13), and Asian American (14) populations found no such association. Among studies that reported results for postmenopausal women, two casecontrol studies conducted among Chinese (9) and Asian American (14) populations found statistically significant inverse associations, whereas two prospective American studies (10,15) and five casecontrol studies conducted among Singapore Chinese (6), Japanese (7), Chinese (11), Asian American (8), and non-Asian American (13) populations found no such associations. Two other prospective studies and one casecontrol study conducted among Japanese populations (1618) reported combined results for pre- and postmenopausal women and found no statistically significant association between soy consumption and breast cancer risk. Thus, results were equivocal, even in studies using the same study design, geographic location, and menopausal status.
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SUBJECTS AND METHODS |
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The study cohort is a part of the Japan Public Health Center-Based Prospective Study on Cancer and Cardiovascular Diseases (JPHC Study) (2023). A detailed design of the study has been presented elsewhere (24). The JPHC Study Cohort I was established on January 1, 1990, and includes 27 435 women and 27 063 men aged 4059 years who registered their address in one of 14 administrative districts supervised by five public health centers (Ninohe Public Health Center in Iwate Prefecture, Yokote Public Health Center in Akita Prefecture, Saku Public Health Center in Nagano Prefecture, Ishikawa Public Health Center in Okinawa Prefecture, and Katsushika Public Health Center in the Tokyo metropolitan area) (25). The subjects from the Katsushika Public Health Center were not included in the analysis because incidence data were not collected. This study was approved by the institutional review board of the National Cancer Center, Tokyo, Japan.
Exposure Data
The study period was from January 1, 1990, through December 31, 1999. In 1990, a baseline survey was conducted in which the study participants completed a self-administered questionnaire. Participants answered questions regarding smoking status; habitual intake of foods and beverages, including alcohol; physical activity; personal and family history of diseases; occupation; educational level; personality; and reproductive history. Thirty-eight questions concerned the consumption of foods and nonalcoholic beverages, of which two items dealt specifically with consumption of soy and isoflavones. One item asked about consumption of "miso soup" and the other about consumption of "soybeans, tofu, deep-fried tofu, and natto," which are foods that have soybeans as the major ingredient. We refer to the latter items as "soyfoods" throughout this article.
The frequency of miso soup consumption was divided into four categories: almost never, one or two bowls per week, three or four bowls per week, and almost daily. Study participants who answered "almost daily" were then asked an additional question regarding the average number of bowls of miso soup consumed per day. The frequency of soyfood intake was divided into four categories: almost never, one or two times per week, three or four times per week, and almost daily. Isoflavone intake was calculated using these two items, with a portion size of 100 mL for miso soup (10 g of miso paste, 2.9 mg of genistein) and 55 g for soyfoods (17.3 mg of genistein). Among the isoflavones, we reported all the results for genistein as "isoflavones" because the intake estimates of genistein, daidzein, and total isoflavone (defined as the sum of genistein and daidzein intake) were highly correlated and the relative risk (RR) estimates for them were similar. This similarity among estimates came from the fact that all three were calculated using answers to questions about miso soup and soyfood consumption. The portion size and isoflavone content were estimated from the validation study (19,26). In the validation study, 247 subjects had provided 28-day dietary records and blood and urine samples between 1994 and 1995. The validation study showed that miso soup and soyfoods contributed more than 80% of the total isoflavone intake. The Spearmans correlation coefficients between the frequency of miso soup and soyfood consumption from the questionnaire and that from dietary records were 0.54 and 0.49, respectively, and between isoflavone intake estimated from the questionnaire and that from dietary records was 0.54. For reproducibility of estimation from the questionnaire, the correlation coefficients for the frequency of consumption of miso soup and of soyfoods, and estimated isoflavone intake between two questionnaires administered 5 years apart were 0.70, 0.53, and 0.61, respectively.
The questionnaire included an item regarding consumption of "vegetables other than yellow and green vegetables such as Chinese cabbage, radish, tomato, cucumber, and so on"; this item includes soybean sprouts, which also contain isoflavones. Isoflavone intake from this item is negligible (0.6% of total isoflavone intake) but was included in the analysis.
Follow-Up
On January 1, 1990, a specific cancer registry for the JPHC Study was established to collect cancer incidence data on the study subjects living within the study area via voluntary reports from local major hospitals, on-site visits to the hospitals, and records from the prefecturewide population-based cancer registry, if available (Akita prefecture does not have a prefecturewide cancer registry).
The site of origin and histologic type of all cancers were coded using the International Classification of Diseases for Oncology, second edition (ICD-O-2) (27). Among the 27 435 female study participants, 37 found to be ineligible after study entry and 12 diagnosed with breast cancer before study entrythe date of diagnosis was confirmed from death certificateswere excluded from the analysis. Of the remaining 27 386 participants, 225 participants were diagnosed with breast cancer during the study period. Eleven participants diagnosed with carcinoma in situ and two participants with uncertain diagnosis with regard to whether the tumor was benign or malignant were not considered as having breast cancers. A diagnosis of breast cancer was histologically confirmed for 97.4% of the patients by pathologists in local hospitals. The ratio of incidence to mortality was 5.4, and no cancer diagnoses were ascertained by death certificate alone, indicating that the completeness of cancer registration in this cohort was high.
Migration data were obtained from the residential registry. Among study participants, 1837 persons (6.7%) moved out of a study area and 34 persons (0.1%) were lost to follow-up during the study period.
Statistical Analysis
We excluded 4913 participants, of whom 33 were breast cancer patients, who did not answer the baseline questionnaire; 615 participants, of whom 13 were breast cancer patients, who answered a positive history of any cancer; and six participants, none of whom were breast cancer patients, who did not answer questions regarding dietary intake of foods and drinks. Thus, our analysis included 21 852 study participants, 179 of whom had breast cancer.
Person-years of follow-up were counted from the start of the study period (January 1, 1990) until the date of breast cancer diagnosis, the date of emigration from a study area, the date of death, or the end of the study period (December 31, 1999), whichever came first. For 34 participants who were lost to follow-up, the last confirmed date of their existence was used as the date of censoring. In total, 209 354 person-years were observed for 21 852 women. The crude incidence rate for breast cancer was calculated by dividing the number of breast cancer cases by the number of person-years. The incidence rates and the RRs of breast cancer are calculated for the categories of the frequency of miso soup consumption, soyfood consumption, and isoflavone intake in quartiles, with the lowest consumption category as the referent. Because most participants consumed miso soup daily, the frequency of miso soup consumption was categorized further into four groups using the information concerning average bowls per day as follows: not daily, one bowl per day, two bowls per day, and three or more bowls per day. Because few participants answered "almost never" to the questions on soyfood consumption, the frequency of soyfood consumption was also categorized further into three groups: less than two times per week, 34 times per week, and almost daily. RRs of breast cancer were estimated using the Cox proportional hazards model, with area (public health center) and 5-year age category at baseline (1990) as strata, by using the SAS PHREG procedure (version 8.02; SAS Institute, Cary, NC). This procedure allows for a different baseline hazard for each stratum. The assumptions for the Cox proportional hazards model were checked and found to hold.
In addition, adjusted RRs were also calculated. The following variables were included as potential confounders: history of benign breast diseases; family history of breast cancer in female first-degree relatives; active smoking status (never smoker, previous smoker, current smoker); passive smoking history at home; leisure-time physical activity (almost never, 13 times per month, 12 times per week, 34 times per week, almost daily); educational level (junior high school, high school, junior college, university, or higher); alcohol consumption (almost never, 13 times per month, more than once per week with less than 100 g ethanol per week, and more than once per week with more than 100 g ethanol per week); total energy intake; consumption of meat, vegetables, and fruits; age at menarche; number of pregnancies; menopausal status at the baseline questionnaire; use of exogenous female hormones (never used, previously used, currently used); height; weight; body mass index (BMI); and age at first pregnancy. Study participants were not asked about oral contraceptive use, but use among this population is rare. We did not include miso soup, soyfoods, and isoflavone consumption in the same models because of their colinearity. We performed two separate analyses: one with all participants and one after excluding 45 participants who were diagnosed with breast cancer during the first 3 years of follow-up and the seven participants whose diagnoses were not based on microscopic evidence. We excluded the 45 participants to eliminate those who may have had breast cancer but were not diagnosed when they answered the questionnaire. Linear trends were tested in the Cox models by treating the consumption categories as ordinal variables (consecutive integers). All P values are two-sided.
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RESULTS |
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At the time of the baseline survey, 2.7% of all study participants almost never consumed miso soup, 7.1% consumed one or two bowls per week, 15.4% consumed three or four bowls per week, and 74.8% consumed miso soup almost daily. Among the participants who consumed miso soup almost daily, 22.8% consumed one bowl per day, 43.1% consumed two bowls per day, and 34.1% consumed three or more bowls per day. Also at baseline, 2.2% of all participants almost never consumed soyfoods, 17.3% consumed soyfoods one or two times per week, 35.1% consumed soyfoods three or four times per week, and 45.4% consumed soyfoods almost daily.
From this information, we calculated the isoflavone consumption. The characteristics of the participants according to quartile of isoflavone consumption are shown in Table 2. Participants with higher isoflavone consumption were slightly older, had fewer pregnancies, were more likely to be postmenopausal, were younger at first pregnancy, and had slightly less education than those with lower isoflavone consumption (Ptrend<.001 for all variables). Smoking status was associated with isoflavone consumption. Among those with higher isoflavone consumption, there were more never smokers and fewer past and current smokers than among those with lower isoflavone consumption (Ptrend<.001). Passive smoking history was slightly less common among those in the lowest quartile of isoflavone consumption than it was among those in the other quartiles. Participants with higher isoflavone consumption had higher total energy intake; higher consumption of fish, meat, vegetables, and fruits; and lower consumption of alcohol than participants with lower isoflavone consumption (Ptrend<.001 for all variables). Isoflavone intake was not linearly associated with a history of benign breast diseases, family history of breast cancer in female first-degree relatives, age at menarche, use of exogenous female hormones, height, weight, body mass index, or leisure time physical activity.
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We next determined whether there was an association between the consumption of miso soup, soyfoods, and isoflavones and risk of breast cancer. Area- and age-adjusted and fully adjusted RRs were not substantially changed. We found statistically significant inverse associations between breast cancer risk and consumption of miso soup (Ptrend = .042) and isoflavone consumption (Ptrend = .043) (Table 3). Compared with women in the lowest quartile of isoflavone consumption, those in the second, third, and highest quartiles of isoflavone consumption had adjusted RRs of breast cancer of 0.76 (95% CI = 0.47 to 1.2), 0.90 (95% CI = 0.56 to 1.5), and 0.46 (95% CI = 0.25 to 0.84), respectively. There was no statistically significant association between consumption of soyfoods and breast cancer risk (Ptrend = .44). Crude incidence rates varied from 57.2 to 109.7 per 100 000 person-years for miso soup consumption categories, which was a larger variation than those for soyfood categories (81.7 to 94.2 per 100 000 person-years) and those for isoflavone intake quartiles (61.6 to 99.2 per 100 000 person-years).
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We next stratified the data according to menopausal status at the time of the baseline questionnaire and examined associations between miso soup, soyfood, or isoflavone consumption and breast cancer risk, using participants in the lowest consumption category as the referent group. Among premenopausal and postmenopausal women considered separately, miso soup consumption was inversely associated with breast cancer risk. Consumption of soyfoods was inversely associated with breast cancer risk among postmenopausal women (Ptrend = .031). This inverse association led to a stronger inverse association found in postmenopausal women for isoflavone consumption (Ptrend = .006) than in premenopausal women (Table 4). Crude incidence rates varied from 49.1 to 123.6 per 100 000 person-years among isoflavone quartiles for premonopausal women, which was a larger variation than that for postmenopausal women.
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We next excluded the 45 participants who were diagnosed with breast cancer during the first 3 years of follow-up and the seven participants whose diagnoses were not made on the basis of histologic evidence. None of the results changed substantially.
The results for the multivariable analysis in Tables 3 and 4
show the RRs after adjusting for possible confounding variables that were associated with isoflavone consumption (P<.20 for all associations). None of the results substantially changed by using other multivariable models, such as those including all the potential confounding variables listed in Table 2
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DISCUSSION |
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The inverse association between isoflavone intake and breast cancer risk found in our epidemiologic study is consistent with results from ecologic and experimental studies (25). Lack of association between soy or isoflavone consumption and breast cancer risk in previous epidemiologic studies may be the result of recall bias in casecontrol studies, errors in exposure measurements, or small exposure variation in Western subjects.
Our study had several methodologic advantages over previous studies. First, we evaluated the association in a prospective cohort study of participants enrolled from the general population. A prospective study is free from recall bias, and the results from the general population are more applicable than those from a specific population, such as an occupational cohort or a cohort of a population with a specific characteristic. Second, we determined the risk for breast cancer incidence rather than breast cancer deaths using highly precise cancer incidence data. Incidence is a more direct measure of breast cancer risk than death because time to breast cancer death is greatly influenced by the treatment received. Third, we estimated isoflavone intake as well as soy intake by using a validated questionnaire. We could therefore investigate the association between breast cancer and isoflavone intake separately from other contents in soy. Fourth, we determined that there was a large variation in isoflavone consumption among participants. Associations between disease and exposure can be detected more easily when exposure has wide variability. Indeed, median isoflavone intake among all the study participants was seven times higher than that among Chinese in Singapore, 15 times higher than that among U.S. non-Asian (African American, Latina, and white) women, and 700 times higher than that among U.S. Caucasians (2830). Fifth, our cohort was established in 1990, thus reflecting present-day lifestyles and dietary habits and a large variation in the distribution of possible risk factors. Although consumption of isoflavones was high throughout Japan before World War II, the variation in intake levels is increasing with increasing westernization of the Japanese population. In addition, other risk factors for breast cancer, such as earlier age at menarche and high fat and meat consumption (31) are also becoming more common among the Japanese. This difference in the distribution of possible risk factors may explain the difference between our results and those of Japanese cohorts that were established in the 1960s and 1970s (16,17).
The highest incidence (99.2/100 000) of breast cancer in the present study was observed among women in the lowest quartile of isoflavone consumption. This incidence rate is lower than that among corresponding age groups (4069 years) in Western populations (1). Women in the lowest quartile of isoflavone consumption consumed approximately 6.9 mg/day of genistein, which is still 250 times more than the daily amount consumed by U.S. Caucasian women but only several times more than that consumed by U.S. non-Asian women. One hypothesis drawn from this comparison is that there may be a potential doseresponse relationship, even among those with lower intake levels of isoflavones observed among Western cohorts, although it may be difficult to detect because of small variations.
Our study has several limitations. First, the number of breast cancer cases was small. Possible associations between breast cancer risk and soyfoods that were not statistically significant in our study may be detected among larger sample sizes. For miso soup and isoflavones, although our study found a statistically significant association with breast cancer, more precise RR estimates can be derived from larger sample sizes. Second, our food-frequency questionnaire included only two items concerning soybean-ingredient foods (i.e., miso soup and soyfoods), making it impossible to investigate the difference in effects between types of soybean-ingredient foods. Third, although we adjusted for the consumption of dietary items other than soy as much as possible, we cannot exclude the possibility of residual confounding by other dietary characteristics.
The inverse association between isoflavone intake and breast cancer risk was stronger in postmenopausal women than premenopausal women. Although this result is somewhat surprising in that it is not consistent with previous epidemiologic studies (Table 1), experimental studies have shown effects of soy or isoflavones on hormone levels in postmenopausal women (3234). This stronger inverse association observed in postmenopausal women may explain the larger discrepancy in breast cancer incidence between Japan and Western countries in older age groups than in younger age groups (1). Although components of soy are known to affect menstrual cycles in different ways (3540) and late menopause is known to be associated with breast cancer risk (31), the link between soy, menopause, and breast cancer remains to be elucidated. Because a proportion of the premenopausal women at the baseline survey may have experienced menopause during the study period, our results for premenopausal women may be contaminated with those for the postmenopausal women. Regardless, our data suggest that menopausal status would be a confounder, an intermediate variable, or an effect modifier when analyzing the association between intake of isoflavones and breast cancer risk and should be taken into account in any analysis. In addition, the fact that the proportion of hormone receptor-positive breast cancers increases with age among U.S. women (41) may also explain the discrepancy between Japanese and Western countries in incidence among older age groups. This is consistent with evidence that the anticarcinogenic effect of isoflavones comes from the antiestrogenic or estrogenic activity through their affinity to estrogen receptors (42).
Monotonic inverse relationships were observed between breast cancer risk and miso soup consumption but were not clearly observed in soyfood and isoflavone consumption. This non-monotonicity may be a result of the relatively low validity of intake estimates from soyfood because they consist of four different types of soybean-ingredient foods (soybeans, tofu, deep-fried tofu, and natto). Indeed, the difference between subjects in the second and third quartiles of isoflavone intake was due mainly to a difference in the consumption frequency of soyfoods (Table 2). The difference in results for soyfoods and isoflavones may also be due to the composite nature of the question on soyfoods. More valid estimates of soyfood intake might reveal monotonic relationships between soyfood and isoflavone intake and breast cancer risk.
A reduced breast cancer risk was also associated with other Japanese eating habits including eating more rice, pickles, vegetables, fish, and less bread and butter (Yamamoto S: unpublished data). Among these, some (rice, pickles, vegetables, and fish) are commonly served with miso soup and soyfoods, whereas others (bread and butter) are less commonly served with them. Japanese eating habits, food items, or lifestyle might also help to explain the low risk of breast cancer among this population. Soy, however, showed the strongest associations after adjustment for other foods and lifestyles and, on the basis of experimental data, provides the most biologically plausible explanation for reducing breast cancer risk. The relationship between soy or isoflavone intake and breast cancer risk should be further investigated by collecting more cases, by more sophisticated analyses, and by using a more intensive food-frequency questionnaire such as that used in the 5-year follow-up survey of our cohort (19). This further investigation may clarify different roles for various soybean-ingredient foods on breast cancer risk, which was suggested by our stratified analysis by menopausal status in which a statistically significant relationship was observed between soyfoods and breast cancer risk for postmenopausal women. We plan to conduct a series of nested casecontrol studies using stored blood samples collected at the baseline survey and the 5-year follow-up survey (43) to elucidate the association between levels of serum isoflavones and the risk of breast cancer (44).
In conclusion, in a prospective cohort study in Japan, we found that frequent miso soup and isoflavone consumption reduced the risk of breast cancer. We found no evidence for such an association for intake of soyfoods.
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APPENDIX |
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NOTES |
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Supported by Grants-in-Aid for Cancer Research (13S-2) and by the Research on Food and Chemical Safety Health and Labour Sciences Research Grant (14120701), both from the Ministry of Health, Labour and Welfare of Japan.
We thank all staff members in each study area and in the central offices for their efforts in conducting the baseline survey and follow-up. We also wish to thank the Iwate, Aomori, and Okinawa cancer registries for providing incidence data.
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Manuscript received October 7, 2002; revised April 2, 2003; accepted April 15, 2003.
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