The possible protective effect of soy and isoflavones originated from epidemiological studies which consistently showed lower rates of breast cancer among women in Eastern Asian countries than in the West (Parkin et al. 2002; Parkin et al. 2005). The most recent data available estimates that in Western Europe in 2008 the rate of breast cancer incidence (age standardized per 100 000 population) was 89.9 while in Eastern Asia the rate was 25.3 (Jemal et al. 2011). Evidence that this might be related to lifestyle rather than genes comes from numerous sources. Migration studies demonstrated that when Asian women moved to the West, their breast cancer rates increased quickly with each successive generation born in the new home country (Ziegler et al. 1993). This suggests that exposure to a Western lifestyle and environment, including reduced consumption of soy, is responsible. Additionally, since the 1970s many Eastern Asian countries such as South Korea, and more recently China, have rapidly become ‘Westernised’ in terms of their economies, lifestyle and diets. This has brought with it an increase in saturated fat intake, and a fall in use of cereals, with animal products replacing soy as the main dietary protein. In parallel, their breast cancer rates have quickly risen to near- Western levels (Kim et al. 2000; Popkin and Du 2003). It is important to note that in a Western lifestyle, soy is a marker for a healthier lifestyle, with lower energy intake, less saturated fat, and more fruit and vegetables, not smoking (Nechuta et al. 2012).
There have been many studies looking for an association between isoflavone intake and breast cancer. However, comparison is difficult, and should be interpreted with caution, since they are often highly variable in the population studied, exposure measures and the level of controlling for confounders. Study design varied, with some being prospective cohorts, some nested case-controls, and some population- or hospital-based case-controls. A number of the studies have stratified their results according to menopausal status or the oestrogen receptor status of the tumour, but this has been carried out inconsistently. In addition, in many of the studies the subgroups had relatively small numbers of breast cancer cases, meaning that the results may have occurred by chance.
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These studies have been collated in a meta-analysis carried out by Trock et al. (2006). This review of 23 studies reported an overall significant, although slight, inverse association between soy intake and breast cancer risk (odds ratio, OR = 0.86, 95% confidence interval (CI) = 0.75 to 0.99). They found that this inverse association was stronger for breast cancers diagnosed premenopausally (OR = 0.70, 95% CI = 0.58 to 0.85) than post menopausal women (OR = 0.77, 95% CI = 0.60 to 0.98), and similarly was stronger among women from Western countries (including two studies of Asian Americans; OR = 0.84, 95% CI = 0.70 to 1.00) than in Asian women (OR = 0.89, 95% CI = 0.71 to 1.12). However, the latter two odds ratios did not differ significantly. It is possible that the slightly greater inverse association between soy intake and breast cancer risk in Western women may be because soy intake in Asian countries is fairly universal, and that even low intake (which is similar to high Western intakes) may be enough to reduce risk. Alternately, in Western countries soy intake may act as a marker for other risk reducing behaviour.
A more recent publication described a separate meta-analysis for the Asian (n = 8) and Western (n = 11) studies (Wu et al. 2008), as each set of populations possess distinct lifestyle characteristics relating to breast cancer, and consume very different amounts and sources of soy, which may reduce the value of any direct comparison. Their findings contradicted those of Trock et al. by proposing a significant protective effect of consuming high levels of soy in Asian but not Western populations. Among Asian consumers, compared to the lowest level of soy food intake (≤ 5 mg/day isoflavones), breast cancer risk was intermediate (OR = 0.88, 95% CI = 0.78 – 0.98) for those with modest isoflavone intake (around 10 mg/day) and lowest (OR = 0.71, 95% CI = 0.60–0.85) among those with high isoflavone intake (≥20 mg/day). In contrast, the 11 Western populations (with average highest and lowest soy isoflavone intakes of 0.8 and 0.15 mg/day) included in the analysis demonstrated no relationship between isoflavone intake and breast cancer. However, it must be noted that this meta-analysis excluded much of the prospective cohort data available, on the grounds that they contained an insufficient level of detail about the soy foods consumed. Much of the remaining evidence came from case-control studies. Additionally, and perhaps significantly, Wu et al. included Asian American women in the Asian group, and not the Western group. The result is that while a relationship between soy intake and breast cancer risk can be proposed, inferences regarding the mechanism must be interpreted with caution.
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Although data is limited, where the results have been stratified according to the oestrogen receptor status of the tumour, protective effects of isoflavones have been limited to the ERα+ subgroup, having no effect on ERα- tumours, although individuals in this group may have tumours expressing ERβ (Linseisen et al. 2004; Suzuki et al. 2008).
Interestingly, these groups and a third meta-analysis reporting similar findings (Dong and Qin 2011) did not observe any dose-response relationship associated with soy intake and breast cancer risk, other than that reported as the difference between high and low intakes. This may relate to the study designs used, and a limited number of eligible studies for each meta-analysis, or it could imply a threshold isoflavone level is required for protective effects to be seen.
High intake of soy isoflavones has been associated not only with reduced risk of breast cancer, but also reduced breast cancer mortality (Zhang et al. 2012). Although they did not find a linear relationship between soy intake and mortality, they suggested that intakes above 17.3mg isoflavones per day might reduce mortality by 36% (n = 616 breast cancer cases), after adjusting for other factors which may have an influence such as age, smoking, alcohol consumption, physical activity and treatment regime.
In humans, there has only been one occasion where a significant relationship between high urinary and serum isoflavones (equol and daidzein) and increased breast cancer risk has been observed in a prospective (UK) cohort (Grace et al. 2004). They determined the log2 odds ratios (where the risk estimates represent a doubling in phytoestrogen exposure) to be 1.220 (1.005–1.481; p = 0.044) and 1.455 (1.051–2.017; p = 0.024) for serum daidzein and equol respectively. The effect of genistein did not achieve statistical significance. However, this study included a small number of breast cancer cases (n = 114 out of 333 women) increasing the chance that the results were coincidental.
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