Breast cancer-preventive effects of isoflavones have been examined in many epidemiologic studies – with encouraging results. Epidemiological data must always be carefully interpreted. Such findings cannot be regarded as a definitive proof of a given aspect, as epidemiological data are not facts, but correlations. As was stated with respect to the cancer risk inherent to gestagens, correlations do not represent real causal effects, but probabilities of coincidences (Kuhl 2008). This is of course also true for the epidemiology of soy and isoflavones. However, a correlation observed in many independent studies and found in hundreds of thousands of study participants under different conditions cannot be neglected, especially since the observations from epidemiology of the isoflavones have been confirmed in clinical trials.
Cancer-related epidemiological data on soy and isoflavones covers questions of benefits and safety. On the first glance the results appear somewhat inconsistent: Many studies show a correlation between isoflavone intake and a reduction of cancer incidence, whereas other studies do not show this effect. For the question of safety it is, however most important that none of the studies showed an increased incidence of cancer related to an intake of isoflavones as in the typical Asian diet. The majority of data point to a protective effect.
The correlation between soy/isoflavones and breast cancer is well-examined, with at least 40 studies including cohort studies, case control studies and nutrition surveys involving more than 400,000 women. The majority of these studies either demonstrated a cancer-protective effect of soy and/or isoflavones, or did otherwise not support the hypothesis of an increased rate of breast cancer formation under intake of isoflavones (Adebamowo et al. 2005; Cotterchio et al. 2008; Dai et al. 2001; Dai et al. 2002; Dai et al. 2003; den Tonkelaar et al. 2001; Do et al. 2007; dos Santos Silva et al. 2004; Fink et al. 2007; Hedelin et al. 2008; Hirose et al. 1995; Hirose et al. 2003; Hirose et al. 2005; Horn-Ross et al. 2001; Horn-Ross et al. 2002; Ingram et al. 1997; Iwasaki et al. 2008; Keinan-Boker et al. 2004; Key et al. 1999; Lampe et al. 2007; Lee et al. 1991; Lee et al. 1992; Lee et al. 2005; Li et al. 2005; Linseisen et al. 2004; Murkies et al. 2000; Nagata 2000; Nishio et al. 2007; Peterson et al. 2003; Piller et al. 2006; Sanderson et al. 2004; Shannon et al. 2005; Shu et al. 2001; Verheus et al. 2007; Witte et al. 1997; Wu et al. 1996; Wu et al. 2002; Wu et al. 2003; Yamamoto et al. 2003; Yuan et al. 1995; Zheng et al. 1999).
Not a single of these studies supports the hypothesis of an increased risk. A recent metaanalysis of 19 epidemiological studies reached the same result (Wu et al. 2008). The studies were analyzed according to the level of isoflavone intake and showed a statistically significant correlation between a higher intake of soy or isoflavones and a reduced incidence of breast cancer. Compared with the lower intake (≤5 mg isoflavones/day) a medium risk of breast cancer was found for women with low isoflavone consumption. The risk (odds ratio) at approximately 10 mg of isoflavones/day was 0.88 (95 % CI = 0.78–0.98). The lowest risk (OR 0.71, 95 % CI = 0.60–0.85) was found in the group of women with the highest isoflavone intake (≥ 20 mg per day). The risk reduction was calculated with approximately 16 % per 10 mg of isoflavones per day (Wu et al. 2008).
In two studies in populations with Western-style nutrition (low in soy) the daily intake of soy isoflavones was calculated with 0.8 and 0.15 mg of isoflavones per day, respectively. In these studies higher intakes of isoflavones did not increase breast cancer risk. According to Wu et al. (2008) the current knowledge from case-control studies supports the hypothesis of a protective effect of soy/isoflavone consumption against breast cancer, with daily doses corresponding to those typically encountered with Asian dietary habits (Wu et al. 2008).
The data presented by Wu et al. (2008) likewise do not confirm a positive correlation between breast cancer and the presence of equol or daidzein in serum or urine of women with Western style diet. These women had daily intakes of less than 1 mg of isoflavones per day (Wu et al. 2008).
Two frequently cited publications seemingly contradict this positive picture: the study of Grace et al. (2004), and more recently the examination of Ward et al. (2008). In both cases, however, the studies were performed in women who – according to the displayed data – had no soy consume to speak of (Grace et al. 2004; Ward et al. 2008). Both studies do therefore not support the hypothesis of a cancer risk by soy isoflavones. They might even be interpreted as a proof of the risks involved in isoflavone-free diet.
The study of Grace et al. (2004)
Grace et al. (2004) had reported on a correlation between breast cancer occurrence and equol levels in urine and serum, and between breast cancer and daidzein serum levels in a population of 333 women (114 cancer cases and 219 controls) (Grace et al. 2004). According to this publication, higher levels of isoflavones correlated with an increased breast cancer risk. In reality, however, the tested women were all non-soy consumers: the measured isoflavone levels in urine and serum were in the range of what is usually found in humans not consuming any soy. The extremely low serum and urine levels correspond to the background intake of isoflavones by industrially manufactured food and milk products.
The concentration of equol in cow milk can reach 3 to 4.5 µg/100 ml in summer, at the time of the flowering of red clover even more than 29µg/ml (Antignac et al. 2003; King et al. 1998). The quantities ingested by animals grazing on pastures with red clover are passed on through the food chain, and are one of the major reasons for the background exposure to isoflavones even in societies with no dietary habit for soy consumption. Other contributors to the background exposure are the use of soy preparations as excipients or protein source in food manufacturing. This background exposure should have been taken into account in a correlation. Grace et al. (2004) compared two groups which did not consume isoflavones in order to derive a risk inherent to isoflavone consumption – a rather questionable method. When the results of Grace et al. are compared to those of other groups examining women who really consumed soy, the data could also be interpreted as a hint to an increased risk of breast cancer by not consuming soy or isoflavones.
The study of Ward et al. (2008)
Recently, Ward et al. (2008) found a slightly increased risk of breast cancer (OR = 1.07, 95 % CI = 1.01 – 1.12) in women with estrogen-positive tumours and higher equol levels in urine. In contrast, the authors did not find a correlation with serum levels of equol, and they did likewise not find a correlation between breast cancer incidence and serum and urine levels of other isoflavones (Ward et al. 2008). Again, this study was already interpreted as a proof for the dangers inherent to soy consumption. As in the case of Grace et al. (2004) the measured values demonstrate that the participants of this study had no noteworthy soy consumption (Ward et al. 2008). Again, a risk is extrapolated from a study population which has to be classified as non-soy consumers.
Ward et al. (2008) themselves point out that the correlation between equol urine levels and the incidence of breast cancer „…should be interpreted with caution as it was not also observed in the analysis of serum equol.” Other biomarkers for isoflavones in urine and serum were not associated with breast cancer risk. Correspondingly, the authors point out that the study “…does not provide sufficient insight into the nature of the relationship between phytoestrogens and breast cancer to warrant modification of phytoestrogen intake among those at risk for breast cancer” (Ward et al. 2008).
This conclusion of the authors can unfortunately only be found when the full text is read, whereas the abstract is misleading to this point: It refers to the “…observation that some phytoestrogen biomarkers may be associated with greater risk of breast cancer”. This statement is clearly not reflected in the data, which – in view of the non-consumption of soy – does neither demonstrate a risk, nor would this risk refer to several biomarkers (“some”), but only to an isolated finding.
Special pitfalls with correlations of cancer incidence and serum/urine levels of isoflavones
The hypothesis that the results of Grace et al. (2004) and Ward et al. (2008) were due to chance is supported by a German case control study published in 2006. By analysis of plasma levels of enterolactone and genistein an inverse association between serum levels of enterolactone and the incidence of breast cancer was found, whereas there was no such association for genistein (Piller et al. 2006). Again, plasma genistein levels were very low in this study, with 4.5 nmol/l in cancer cases and 3.7 nmol/l in controls. Such low levels demonstrate that the study participants were non-soy consumers, as otherwise at least 1000-fold higher plasma levers would have been expected. Most interestingly the only (non-significant) hints to an association between plasma genistein and breast cancer risk came from a subgroup of study participants with low dietary intake of soy, but with relatively high plasma levels of genistein, with “relatively high” still representing an extremely low intake when compared with soy consumers.
This strange association (no dietary soy, but still higher plasma levels than in participants who indicated at least occasional soy consumption) underlines a general problem with the interpretation of random analyses of isoflavones in serum or urine (Piller et al. 2006). Random analyses of isoflavones in serum or plasma reflect the momentary status, and will only give information on the isoflavone content of the last meal, but not the average intake. Correspondingly, when compared with the seemingly exact laboratory measurements nutrition surveys are better suited for looking for correlations between breast cancer and isoflavone intake. Such a nutrition survey was presented by Linseisen in the same population for which Piller et al. (2006) had measured plasma and urine values. The nutrition survey did not show a correlation between higher soy intake and breast cancer incidence (Linseisen et al. 2004). Piller et al. (2006) had retrospectively added the laboratory values to the survey of Linseisen et al. (2004), and had likewise not found a correlation between genistein intake and breast cancer (Piller et al. 2006).
Although there is no evidence of isoflavones causing cancer, the association between isoflavones and breast cancer prevention is not always very clear (Gikas and Mokbel 2005; Qin et al. 2006; Tempfer et al. 2007; Trock et al. 2006; Wu et al. 2008). The overall available data allows concluding on a protection from hormonally induced cancer forms by an increased nutritional intake of isoflavones. With this background a recently published study in women with a family history of breast or ovarian cancer analyzed the dietary intake of isoflavones by 24 hour urine sampling. The authors concluded that random analyses, as performed by Ward et al. (2008) do not yield reproducible results (Tseng et al. 2008). The study also confirms a very low isoflavone intake by Western nutrition. When specifically asked for the reasons for avoiding soy food, a significant percentage of the women indicated to have been irritated by the running debate on risks of soy. Caused by misinformation the women therefore renounce to health benefits of an adequate nutritional intake of isoflavones, from which they might possible profit (Fang et al. 2005; Tseng et al. 2008).
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