SOY AND BREAST CANCER: THEN AND NOW

The relationship between soy and breast cancer has been rigorously investigated for 30 years. This relationship, more than any other, is responsible for the research attention soyfoods, in general, have received. It is also responsible for much of the confusion among health professionals and consumers about the healthfulness of soyfoods.

In the early 1990s, the historically low breast cancer incidence rates in soyfood-consuming countries,¹ along with animal research showing isoflavone-rich soy protein inhibited the development of chemically-induced mammary cancer in rats,² fueled speculation that the isoflavones in soybeans exerted anti-estrogenic effects thereby offering protection against breast cancer.³ National Cancer Institute funding aimed at understanding the role of soy in cancer prevention and treatment helped legitimize this speculation.

However, excitement about the possible breast cancer preventive properties of soy was relatively short lived. Primarily because in 1998, research showed that genistein (the main isoflavone in soybeans)⁴ and shortly thereafter, isoflavone-rich soy protein,⁵ stimulated the growth of existing estrogen receptor-positive (ER+) mammary tumors in ovariectomized athymic mice. These findings drew attention to the potential estrogenic properties of isoflavones and led to clinicians advising their patients with breast cancer, and women at high risk of this disease, to limit or avoid soyfoods.⁶

Since many women are understandably concerned about developing breast cancer regardless of their personal risk status, the 1998 mice research set a negative tone for the healthfulness of soy. These concerns were heightened throughout the 2000s because the laboratory responsible for the above-mentioned work in mice continued to publish results using their breast cancer model. For example, in 2002 isoflavones were shown to inhibit the efficacy of the breast cancer drug tamoxifen.⁷ Six years later, similar findings were reported for the breast cancer drug letrozole.⁸

It is possible for soy consumption to reduce risk of healthy women developing breast cancer but worsen the prognosis of women with this disease. However, the results of prevention-related research were not especially encouraging. The conclusion of a 2006 meta-analysis of 18 observational studies stated “Soy intake may be associated with a small reduction in breast cancer risk. However, this result should be interpreted with caution due to potential exposure misclassification, confounding, and lack of a dose response.”⁹ Several possible explanations exist for these lackluster results, as well as the results of a recently published meta-analysis,¹⁰ but in the opinion of this author, the most intriguing is that for soy to reduce breast cancer risk, it must be consumed early in life – that is, during childhood/adolescence.

Since this hypothesis was proposed in 1995,^11,12 it has gained support from both epidemiologic^13-16 and animal¹⁷ studies. In addition, several mechanisms have been proposed to explain why when cells in the developing breast are exposed to isoflavones, they are permanently changed in a way that makes them less likely to be transformed into cancer cells later in life.^18-21 Therefore, if adult soy intake poorly reflects childhood/adolescent soy intake, observational studies focusing on adult intake, which is typically the case, may greatly underestimate the potential value of soy for reducing breast cancer risk.

In contrast to the mouse studies that raised concern about carcinogenic effects, clinical studies that first began to be published in 1999,²² consistently show that neither soy nor isoflavones affect markers of breast cancer risk,²³ including mammographic density^24-26 and in vivo breast cell proliferation.^22,27-31 Cells that replicate more quickly are more likely to be transformed into cancer cells. These studies involved healthy women, women at high risk of breast cancer, and women with breast cancer. In some cases, the women were exposed to isoflavones in amounts greatly exceeding typical Japanese intake. This clinical research is strongly supportive of the safety of isoflavones but also argues against adult soy intake reducing breast cancer risk.

The lack of effect of isoflavones on cell proliferation contrasts with the proliferative effects of combined hormone therapy (CHT, estrogen plus progestin).^32,33 CHT, as opposed to estrogen only therapy, is known to increase breast cancer risk.³⁴ This observation is potentially relevant to soy since isoflavones have estrogen-like, but not progestin-like, properties.

After a decade of studies in mice raising concern, in 2009 the first prospective observational study to examine the impact of post-diagnosis soy intake on the prognosis of breast cancer patients was published.³⁵ Among women participating in the Shanghai Breast Cancer Survival Study, post-diagnosis soy consumption was associated with a significantly decreased risk of recurrence and breast cancer specific mortality.³⁵ Subsequently published observational studies conducted in the U.S.^36,37 and China^38,39 aligned with these findings as was summarized by meta-analyses published in 2013⁴⁰ and 2019^.41 Protective effects were observed in both ER+ and ER- patients. However, although there may be several mechanisms by which post-diagnosis soy intake could improve prognosis,^42-48 none have strong support.

Many of the world’s leading cancer organizations have concluded that women with breast cancer can safely consume soy (the American Cancer Society⁴⁹ and the American Institute for Cancer Research⁵⁰ in 2012, the World Cancer Research Fund International⁵¹ in 2014, and the Canadian Cancer Society⁵² in 2015). However, these conclusions were not based on extensive reviews of the literature as they were primarily limited to the observational data. In contrast, in 2015 after an extensive review of the pre-clinical, clinical, and observational data, the European Food Safety Authority concluded isoflavones do not adversely affect post-menopausal breast tissue.⁵³ A similar conclusion was reached in 2018 by the Permanent Senate Commission on Food Safety of the German Research Foundation.⁵⁴

There have been several twists and turns in the soy and breast cancer relationship story over the past 30 years. Evidence supporting the hypothesis that adult soy intake prevents breast cancer has been somewhat disappointing, whereas the notion that early life soy intake is protective against this disease has gained support. It is not possible to claim that the soy and breast cancer controversy has been definitively resolved; despite the extensive research on this subject, no clinical trial has examined the impact of soy on recurrence or mortality among women with breast cancer. On the other hand, studies in mice responsible for the controversy have been resoundingly contradicted by considerable clinical and observational data. The latter suggests soy is safe for women with breast cancer and also benefits them.

Despite these suggestive results, the observational data are not a sufficient basis for recommending breast cancer patients consume soy specifically for the purpose of improving prognosis. However, women with breast cancer need to focus on their overall diet, not just foods that potentially impact prognosis. Given the observational and clinical data, it is reasonable to conclude that women with breast cancer can make soy part of their diet. Soyfoods provide high quality protein^55,56 that modestly lowers LDL-cholesterol^57,58 (the U.S. Food and Drug Administration established 25g/d soy protein as the threshold intake for cholesterol reduction⁵⁹). In the clinical trials, many of the proposed benefits of isoflavones (e.g., hot flash alleviation,⁶⁰ improved arterial health,⁶¹ and memory⁶²) occur in response to an intake of 50-60mg/d, which is equivalent to approximately 2 servings of traditional soyfoods.

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