Soy food consumption and breast cancer

Maturitas 76 (2013) 118–122

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Review

Soy food consumption and breast cancer Niki Mourouti, Demosthenes B. Panagiotakos ∗ Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece

a r t i c l e

i n f o

Article history: Received 30 June 2013 Accepted 7 July 2013

Keywords: Breast cancer Soy food Phytoestrogens Isoflavones

a b s t r a c t Breast cancer is the most frequently diagnosed cancer in female worldwide and occurs as an interaction of genes and diet. As regards diet numerous studies all over the world have associated the disease with many foods and nutrients including soy and its compounds. Soy food and soy products are rich in phytoestrogens, naturally occurring hormone-like compounds with weak estrogenic effects. Despite inconsistencies in the available data, an inverse association between soy food consumption and breast cancer is likely. However, it seems that this correlation is more obvious in Asian rather than Western populations, where the consumption of soy is already higher. Moreover, the vast majority of studies that demonstrate this inverse association are case–control studies, a fact that should be taken into account. In this review, the current scientific evidence relating breast cancer and soy consumption is reported through a systematic way. © 2013 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Selection of studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Studies on soy and breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females, worldwide, accounting for 23% (i.e., 1.38 million) of the total new cancer cases and 14% (458 400) of the total cancer deaths in 2008. About half the breast cancer cases and 60% of the deaths are estimated to occur in economically developing countries [1]. With respect to diet, only alcohol intake has been widely recognized as one of the behaviors most consistently associated with breast cancer risk [2]. However, it has to be underlined that during the last decades, several studies from all over the world have evaluated the relationship between consumption of specific foods, nutrients and the development of

∗ Corresponding author at: 46 Paleon Polemiston St., 16674 Glyfada, Greece. Tel.: +30 210 9603116; fax: +30 210 9600719. E-mail addresses: [email protected], [email protected] (D.B. Panagiotakos). 0378-5122/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.maturitas.2013.07.006

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the disease, including red and processed meat, dietary carbohydrates, dietary lipids, dietary fiber [3,4], as well as soy food and soy products [5]. Historical sources suggest that the Chinese first cultivated the soybean 3000 years ago. The migration of the soybean from China to the rest of the world was gradual. By the first century A.D. soybean was spread to central and south China, Korea, as well as Japan and South East Asia. It is believed that soybean arrived in Europe in the Sixteen Century. The role of soy food on human health, and particularly longevity, has long been studied, especially in Asian populations. Soy food and soy products are rich in phytoestrogens, naturally occurring hormone-like compounds that can be subdivided into coumestans, lignans and the most known isoflavones. The existence of isoflavones in plants was established for more than 100 years ago, even though their biological effects were not well known till the last 20 years [6]. The most important representatives of this phytoestrogen class are genistein, daidzein and glycitein. Genistein was the primary soybean isoflavone isolated in 1899, followed by daidzein 40 years later. The third one, glycitein, was not

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isolated until 1976. At last, the isoflavan equol belongs also in the category of isoflavones, as it is a bacterially derived metabolite of daidzein [6]. Initially, the potential that soy food/soy products and its compounds can reduce cancer risk caught the attention of the researchers. During the last decades, they have been investigated for their ability to reduce the risk of chronic diseases (e.g. cerebral and myocardial infractions, coronary heart disease, osteoporosis) as well as certain types of cancer, like prostate cancer [6]. Nevertheless, most of the research focuses on breast cancer due to a simple reason. The consumption of soy food/soy products, which is rich in biologically active phytoestrogens, is traditionally high in Japan, where the annual breast cancer incidence rate is 33 per 100 000 women. In contrast, the corresponding breast cancer incidence rates in Western European countries and in the USA range from about 80 to 100 per 100 000 women [1]. So, it is reasonable to state a research hypothesis that soy may protects Asians form developing breast cancer. In a very recent meta-analysis regarding soy food intake and breast cancer risk, Zhong et al. [7], reported that soy food intake was inversely associated with the risk of breast cancer. This protective effect of soy food intake on the disease was observed only among studies conducted in Asian countries (odds ratio (OR) = 0.76, 95% confidence interval (CI) 0.67, 0.87), whereas no association was found in studies from Western countries (OR = 1.01, 95% CI 0.93, 1.09). Furthermore, the protective effect was only observed in case control studies but not in cohorts. The aim of this work was to present the current scientific evidence about the relationship between soy food/soy products and breast cancer risk, based on an extensive literature search. 2. Selection of studies The PRISMA guidelines for reporting systematic reviews were followed here. In particular, original-research studies that were published in English language between January 1st 2000 and April 30th 2013 were selected through a computer-assisted literature search (i.e., Medline via Pubmed and Scopus). Computer searcher used combinations of key words relating to breast cancer (i.e., breast cancer or breast neoplasm) and soy consumption (i.e., soy food intake, soy food consumption, soy intake, soy protein intake). In addition, the reference lists of the retrieved articles directed the search to relevant present articles that were not allocated through the searching procedure. Only studies published in English have been considered. Prospective cohorts, case–control studies, meta-analyses and clinical trials were included; whereas studies referring to dietary habits of women during adolescence and to consumption of supplements, as well as studies referring to polymorphisms related to soy consumption, were excluded. The endpoint was only breast cancer incidence and not recurrence or survival. 3. Studies on soy and breast cancer In the present review 29 studies, 10 cohorts, 3 nested case–controls and 16 case–controls were included. The smallest study included n = 375 women [8] whereas the largest study included n = 111 526 women [9]. The majority of the case–control studies demonstrated an inverse association between soy food/soy products or isoflavones and breast cancer risk [8,10–21]. Furthermore, in a nested case–control study performed within the Prospect cohort, one of the two Dutch cohorts participating in the European Prospective Investigation into Cancer and Nutrition (EPIC), plasma levels of isoflavones and lignans were measured in 383 case subjects and 383 controls. Verheus and its partners [22] observed that high levels of plasma genistein (which belongs to isoflavones) were

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associated with significantly lower risk of breast cancer development. Similarly, in a nested case–control study conducted in Japan this time, within the Japan Public Health Center-based prospective study, Iwasaki et al. [23], found an inverse association between plasma genistein and the risk of breast cancer in 144 breast cancer cases and 288 controls. More recently, Goodman et al. [24], conducted a nested-case control study within the Multiethnic Cohort Study which included 36 458 postmenopausal women. Researchers supported the hypothesis that a diet rich in isoflavones from soy products reduces the risk of postmenopausal breast cancer, particularly in populations with comparatively high excretion of phytoestrogens. In agreement with the results of the majority of case–control studies (as well as the nested case–control studies), in the Japan Public Health Center-Based Prospective Study on Cancer and Cardiovascular Diseases (JPHC Study) which included 21 852 Japanese female residents (aged 40–59 years) Yamamoto et al. [25], concluded that isoflavone consumption was associated with a reduced risk of breast cancer. Furthermore, in the Singapore Chinese Health Study, 35 303 Singapore Chinese women were enrolled during April 1993 to December 1998. After 338 242 person-years, Wu et al. [5], observed that relative to women with lower (below median) soy intake (<10.6 mg isoflavone per 1000 kcal), women with higher intake (above median) showed a significant 18% risk reduction (relative risk (RR) = 0.82, 95% CI = 0.70, 0.97). In this context, in a cohort of 73 223 Chinese women who participated in the Shanghai Women’s Health Study, Lee et al. [26], demonstrated that adult soy food consumption, measured either by soy protein or isoflavone intake, was inversely associated with the risk of premenopausal breast cancer, and the association was highly statistically significant (p for trend <0.001). Soy products are rich in phytoestrogens, which due to their properties, seem to be strong candidates for a role as natural cancerprotective compounds. One of the mechanisms by which they seem to exert their anticarcinogenic effects, is via their antioxidant capacity. More specifically, they have the ability to decrease lipid peroxidation as well as oxidative DNA damage, a property that can be attributed to their chemical structure which is similar to that of the human female hormone 17-␤ oestradiol [27–29]. Moreover, soy phytoestrogens seem to participate in the control of the cell cycle, by inhibiting cell proliferation [28,30,31] and inducing cell apoptosis [27,31]. As tumors require blood to develop and grow, they stimulate the production of new vessels from already existing blood vessels; a process termed angiogenesis. Soy phytoestrogens has been reported to inhibit angiogenesis [27,28,31]. Furthermore, other possible mechanisms through which soy consumption can be related to breast cancer prevention include aromatase enzyme inhibition [28,30] as well as reduction of the proportion of free oestrogens circulating in the plasma, by stimulating sex hormone-binding globulin (SHBG) levels [28,30,31]. Anyone of these mechanisms could explain the inverse association reported in the above mentioned studies. In contrary, there are some studies, i.e., three case–control studies [32–34] along with six cohorts [9,35–39], that reported no association between the intake of soy food/soy products or isoflavones and breast-cancer risk. In particular, Horn-Ross et al. [32], observed that phytoestrogen intake was not associated with breast cancer risk (OR = 1.0, 95% CI 0.80, 1.3 for the highest vs. lowest quartile), after assessing the usual intake of specific phytoestrogenic compounds in 1326 cases and 1657 controls in a Multiethnic population. Similarly, Shannon et al. [33], in a case–control study about diet and risk of breast cancer, showed no association of any of the soyfood categories with risk of breast cancer among Chinese women. Finally, Ward et al. [34], analyzed serum and urine samples for seven phytoestrogens, from 237 incident breast cancer cases and 952 control individuals in the European Prospective

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into Cancer-Norfolk cohort. They demonstrated that the association between phytoestrogen biomarkers and breast cancer risk was limited. Furthermore, six prospective studies reported no association between the intake of soy food/soy products or isoflavones and breast-cancer risk. First of all, Horn-Ross et al. [9], resulted that phytoestrogens were not associated with breast cancer risk, after following 111 526 women in the California Teachers Study. In this context, in a French cohort study with 26 868 participants, Touillaud et al. [38], found no evidence of an association between dietary intake of phytoestrogens and risk of premenopausal invasive breast cancer during 117 652 person-years of follow-up. Similarly, in a prospective population-based cohort study among 45 448 Swedish pre- and postmenopausal women, no inverse association between dietary intake of phytoestrogens and risk of breast cancer, either overall or by ER/PR status was found [35]. Furthermore, when Nishio et al. [37], analyzed the data from 30 454 women who participated in the Japan Collaborative Cohort (JACC) Study, they suggested that consumption of soyfood has no protective effects against breast cancer. In a Dutch cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC; 1993–1997), Keinan-Boker et al. [36], tried to study the effect of phytoestrogens on breast cancer risk in 15 555 women. The results showed no protective effects of isoflavones or lignans against breast cancer. More recently, in a cohort of 37 643 British women participating in the European Prospective Investigation into Cancer and Nutrition where the mean follow-up was 7.4 years, no evidence was found for a relationship of risk for breast cancer with dietary isoflavone intake [39]. At last, only 1 of the 29 studies included in this work revealed a possible positive association between phytoestrogen dietary intake and breast cancer risk. Specifically, Grace et al. [40], used a sample of 333 women drawn from a large United Kingdom prospective study of diet and cancer, the European Prospective Investigation of Cancer (EPIC) and Nutrition-Norfolk study. Seven phytoestrogens were measured in spot urines and serum samples from women who later developed breast cancer and from healthy controls matched by age and date of recruitment. The authors concluded that exposure to all isoflavones was associated with increased breast cancer risk, particularly daidzein and equol. In a very recent case–control study conducted in Greece [41] the researchers recruited 250 newly (within six months) diagnosed breast cancer patients, along with 250 subjects (controls), selected on a volunteer basis and age-matched (±3 years) with the cancer patients. A validated, semi-quantitative questionnaire (FFQ) [41] was used during the interviews to collect dietary information from the participants. Specifically for soy food consumption, data on frequency and quantity of intake were retrieved from all participants. Furthermore, detailed medical history, socio-demographic, dietary, lifestyle, psychological as well as environmental characteristics were also recorded through face-to-face interviews with the participants. It was found that compared with breast cancer patients, controls were more likely to be soy food consumers (32.8% vs. 19.8%, p = 0.001); specifically, 28.8% of the controls as compared with 18.2% of the patients reported consuming soy food and products at least 1 time per month (p = 0.04). It is of interest the very low frequency of soy food intake reported by both patients and controls. As regards the profile of the soy food consumers, they were more frequently younger participants (p < 0.001), with higher educational level (p < 0.001), with lower body mass index (BMI) (p = 0.04) and who were at postmenopausal status (p < 0.001). Results from the age-adjusted logistic regression revealed that consumption of soy food and its products was inversely associated with the likelihood of having breast cancer (OR = 0.49, 95% CI 0.32, 0.74). After adjusting for the common potential confounding factors including family history of breast cancer, BMI, physical activity

status, as well as smoking habits, the inverse association of soy consumption with the likelihood of having breast cancer continued to exist (OR = 0.45, 95% CI 0.28, 0.70). However, when age of menarche, age of menopause and use of hormone replacement therapy were added in the model, these factors seemed to mask the beneficial association of soy consumption and breast cancer observed in previous analyses (OR = 0.62, 95% CI 0.34, 1.12). The later observation may be attributed to the long exposure to endogenous oestrogens, which may have masked the ability of soy phytoestrogens to antagonize the effect of these hormones and as a result tend to reduce breast cancer risk. Finally, when the MedDietScore (that evaluates adherence to a healthy dietary pattern, the Mediterranean) was taken into account, the beneficial effect of soy food consumption on breast cancer observed in previous models was further masked (OR = 0.67, 95% CI 0.36, 1.23). The previous observation could be explained by the fact that foods and nutrients are never eaten in isolation by individuals, and their effects are likely to interact within a diet. That is the basic reason of the adoption, in the last years, of a more holistic approach of dietary assessment through dietary patterns, so as to avoid confounding effects (due to the complex interaction of foods and nutrients) which may mask true associations.

4. Discussion The present work may state a basis for a strong scientific hypothesis for an inverse association between soy food intake and breast cancer risk. However, it is important to highlight the fact that the majority of the studies which demonstrated this inverse association refer to Asian and not Western populations (14 out of the 19 studies) (Table 1). The above finding could be largely attributed to the different amounts of soy food consumed between the two populations. Indeed, in Asians, the average intake of isoflavones is between 25 and 50 mg per day, while in Western populations intake of soy isoflavones is less than 1.0 mg per day [5]. In a recent metaanalysis of prospective studies [42] which aimed to examine the association between soy isoflavone consumption and breast cancer incidence, the protective effect of soy against the disease was only observed among studies conducted in Asian populations (RR = 0.76, 95% CI: 0.65, 0.86), but not in Western populations (RR = 0.97, 95% CI: 0.87, 1.06). Similarly, in a meta-analysis conducted lately, Zhong et al. [7], reported that the protective effect of soy food on breast cancer risk was observed among studies conducted in Asian countries (OR = 0.76, 95% CI 0.67, 0.87), whereas no association was found in studies from Western countries (OR = 1.01, 95% CI 0.93, 1.09). One more remarkable observation coming up from the above work refers to the fact that the majority of the studies demonstrating an inverse association between soy consumption and breast cancer risk are case–control studies (13 out of the 19), which may share several limitations, mainly recall bias. The variation in exposure measures used, in the amount and type of soy consumed, as well as the issue of the sample size, may have over- or under estimated the true effect size measures. Moreover, the potential dietary measurement errors usually occurred in nutritional surveys, the fact that the majority of the observational studies were not specifically designed to address the soy–breast cancer hypothesis, may also mask the true relationship. In conclusion, the inverse association between the consumption of soy and breast cancer incidence that arises from the majority of the studies conducted in the last years should taken into account with a critical eye, firstly due to the geographic concentration of the studies and secondly due to their limitations that can complicate interpretation of the results.

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Table 1 Characteristics of published epidemiological studies on soyfood consumption and breast cancer in women in high-consuming populations. Authors

Country or Region

Study design

Subjects

Items

Results (95% CI)

Adjustments

Dai (2001)

China

Case–control

1459 cases, 1556 controls

Soy food Soy protein

0.78 (0.52, 1.16) 0.46 (0.28, 0.75)

Wu (2002)

USA

Case–control

501 case, 594 controls

Tofu Isoflavones

0.65 (0.38, 1.10) 0.61 (0.39, 0.97)

Yamamoto (2003)

Japan

Cohort

179 cases

Isoflavones

0.46 (0.25, 0.84)

Dos Santos Silva (2004)

England

Case–control

240 cases, 477 controls

Do (2007)

Korea

Case–control

359 case, 708 controls

Genistein Daidzein Isoflavones Soybeans

0.62 (0.36, 1.06) 0.57 (0.33, 0.99) 0.58 (0.33, 1.00) 0.67 (0.45, 0.91)

Iwasaki (2008)

Japan

Nested case–control

144 cases

Dietary genistein

0.58 (0.29, 1.18)

Wu (2008)

Singapore

Cohort

629 cases

Soy isoflavones

0.82 (0.70, 0.97)

Iwasaki (2009)

Japan/Brazil

Case–control

850 case, 850 controls

Soy isoflavones

0.45 (0.26, 0.77)

Korde (2009)

USA

Case–control

597 cases, 966 controls

Soy intake

0.76 (0.56, 1.02)

Lee (2009)

China

Cohort

592 cases

Isoflavones

0.81 (0.61, 1.07)

Zhang (2010)

China

Case–control

438 cases, 438 controls

Soy isoflavones Soy protein

0.54 (0.34, 0.84) 0.62 (0.40, 0.96)

Zhu (2011)

China

Case–control

183 case, 192 controls

Soy isoflavones Soy protein

0.42 (0.22, 0.80) 0.46 (0.24, 0.88)

Age, age at menarche, age at birth of first child, parity, menopausal status, age at menopause, family history of breast cancer, history of breast disease, education, energy intake, physical activity, some dietary factors, waist-to-hip ratio Age, age at menarche, parity, menopausal status, family history of breast cancer, ethnicity, education, body mass index, physical activity, alcohol consumption, smoking history, some dietary factors, hormone replacement therapy Age, age at menarche, age at first pregnancy, parity, menopausal status, smoking, alcohol, physical activity, education, energy, consumption of meat, fish, vegetables and fruit Age, age at menarche, age at birth of first child, parity, menopausal status, lactation, family history of breast cancer, energy intake Age, education, income, age at menarche, parity, age at first live birth, history of breastfeeding, use of hormones (oral contraceptives and hormone replacement), family history of breast cancer in a first-degree relative, frequency of exercise, physical activity, cigarette smoking, alcohol consumption, total energy intake Age, years of interview, dialect, education, family history of breast cancer, parity, age when period became regular, menopausal status, BMI, and n-3 fatty acid BMI, menopausal status, parity, HRT, smoking, family history of breast cancer, and saturated fat intake Menopausal status, number of births, family history of breast cancer, smoking status, moderate physical activity in past 5 years, vitamin supplement use Age at diagnosis, ethnicity, study center, parity/age at first live birth, menopausal status at diagnosis, age at menarche, family history of breast cancer, personal history of benign breast disease Age, location, race ethnicity, date and time of urine collection, HRT use, and fasting hours BMI, alcohol use, parity, and family history of breast cancer age at menarche, body mass index (BMI), history of benign breast disease, mother/sister/daughter with breast cancer, physical activity, passive smoking, total energy, total vegetable, and total fruit intake Age, smoking, passive smoking, drinking, family history of cancer, history of breast disease, vegetables and fruit

Contributors DBP contributed in the writing, and critically reviewed the paper, NM contributed to the writing, the interpretation of the studies’ findings and reviewed the paper.

Competing interests None to declare.

Funding None.

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