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Re: Soy, isoflavones, and breast cancer risk in Japan.

The article by Yamamoto et al. (1) provides further evidence that isoflavones may play a role in reducing the risk of breast cancer. We are also conducting a cohort study (Japan Nurses’ Health Study) (2), with a baseline population of 39 713, and analyzing the association between phytoestrogen intake and breast cancer history among 4128 postmenopausal women. We identified 176 women who had a history of breast cancer and who answered a food frequency questionnaire in which we asked questions regarding intake of soy products (including intake of tofu, natto, and miso soup, separately) and history of female hormone use (including hormone replacement therapy). We computed the odds ratios (ORs) of breast cancer by using a logistic model. The following variables were included as potential confounders: age, body mass index, smoking history, number of pregnancies, age at menarche, hormone replacement therapy use, female hormone use, educational level, alcohol consumption, and food intake (three categories: 1 day/week, 2–5 days/week, and 6 days/week). Compared with women with a low intake of miso soup ( 1 day/week), women with a high intake ( 6 days/ week) had a statistically significantly reduced risk of breast cancer (OR 0.51, 95% confidence interval [CI] 0.30 to 0.84). This reduced risk remained statistically significant after adjusting for female hormone use and other variables. Natto intake was not statistically significantly associated with breast cancer (OR 1.07, 95% CI 0.61 to 2.00). However, women with a high intake of tofu had a statistically significantly increased risk of breast cancer (OR 1.73, 95% CI 1.02 to 3.02). Why the association between intake of natto or tofu and breast cancer history is different than the association between intake of miso soup and breast cancer history is unclear. However, one possibility involves the chemical structure of isoflavones and the method of cooking. Isoflavone glucoside is easily altered during extraction, processing, and cooking. Hot aqueous extraction to produce tofu results in the formation of -glucoside conjugates (3). Fermentation to produce miso and natto forms aglucones (4). Although the total isoflavones in food are not affected under usual cooking conditions, high temperature causes an increase in aglucones and a decrease in total isoflavones. Because aglucones are more potent and more rapidly absorbed than -glucoside conjugates, fermentation products such as miso soup and natto may have more anticarcinogenic effects than glucoside conjugates. A second possibility is that women with a history of breast cancer at menopause may ingest more tofu than women with no history of breast cancer. A history of breast cancer is associated with an increase in use of dietary soy for menopause symptoms (5), and a main source of soy products is tofu (6). We found an association between high tofu intake and a history of breast cancer among women aged 50–55 years (OR 2.09, 95% CI 1.07 to 4.38). However, we found no association between other soy products (natto and miso soup) and breast cancer history by subgroup analysis. Our finding regarding tofu intake and breast cancer may be explained by this temporal increase of tofu intake around menopause. We caution that when analyzing the effects of soy product consumption for women nearing menopause, attention to the type of soy product and the temporal increase of soy product consumption, especially tofu intake, is needed.