Fritz, H., Seely, D., Flower, G., Skidmore, B., Fernandes, R., Vadeboncoeur, S., Kennedy, D., Cooley, K., Wong, R., Sagar, S., Sabri, E., & Fergusson, D. (2013). Soy, red clover, and isoflavones and breast cancer: a systematic review. PloS One, 8(11), e81968

A Systematic Review

Article 1

Background:

Soy and red clover isoflavones are controversial due to purported estrogenic activity and possible effects on breast cancer. We conducted a systematic review of soy and red clover for efficacy in improving menopausal symptoms in women with breast cancer, and for potential impact on risk of breast cancer incidence or recurrence.

Methods:

We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to March 2013 for human interventional or observational data pertaining to the safety and efficacy of soy and red clover isoflavones in patients with or at risk of breast cancer.

Results:

Of 4179 records, we included a total of 131 articles: 40 RCTs, 11 uncontrolled trials, and 80 observational studies. Five RCTs reported on the efficacy of soy for hot flashes, showing no significant reductions in hot flashes compared to placebo. There is lack of evidence showing harm from use of soy with respect to risk of breast cancer or recurrence, based on long term observational data. Soy intake consistent with that of a traditional Japanese diet (2-3 servings daily, containing 25-50mg isoflavones) may be protective against breast cancer and recurrence. Human trials show that soy does not increase circulating estradiol or affect estrogen-responsive target tissues. Prospective data of soy use in women taking tamoxifen does not indicate increased risk of recurrence. Evidence on red clover is limited, however existing studies suggest that it may not possess breast cancer-promoting effects.

Conclusion:

Soy consumption may be associated with reduced risk of breast cancer incidence, recurrence, and mortality. Soy does not have estrogenic effects in humans. Soy intake consistent with a traditional Japanese diet appears safe for breast cancer survivors. While there is no clear evidence of harm, better evidence confirming safety is required before use of high dose (≥ 100 mg) isoflavones can be recommended for breast cancer patients.

·         It is a meta-analysis study that focuses on the association of soy isoflavones intake and breast cancer risk, recurrence, and mortality

·         Strength of this article is the search methodology they used, such as searching multiple citation databases and trial registries and hand searching of the gray literature.

Chen, M., Rao, Y., Zheng, Y., Wei, S., Li, Y., Guo, T., & Yin, P. (2014). Association between soy isoflavone intake and breast cancer risk for pre- and post-menopausal women: a meta-analysis of epidemiological studies. PloS One, 9(2), e89288.

A Meta-Analysis

Article 2

Background:

Conclusions drawn from meta-analyses on the association between soy isoflavone intake and breast cancer risk for pre- and post-menopausal women are not fully consistent. These meta-analyses did not explore the influence of different study designs on the pooled results on the basis of distinguishing between pre- and post-menopausal women.

Methodology and Principal Findings:

We performed a meta-analysis of 35 studies which reported results of association between soy isoflavone intake and breast cancer risk for pre- and/or post-menopausal women, calculated pooled odds ratios and their 95% confidence intervals of pre- and post-menopausal women respectively, and further explored soy isoflavone-breast cancer association on the basis of considering different study regions and designs.

Resutls:

Summary results suggested that soy isoflavone intake has a protective effect against breast cancer for both pre- and post-menopausal women. However, they are influenced by study design and region. Pooled ORs of studies carried out in Asian countries suggested that soy isoflavone’s protective effect exist in both pre- and post-menopausal women (OR = 0.59, 95%CI: 0.48-0.69 for premenopausal women; OR = 0.59, 95%CI: 0.44-0.74 for postmenopausal women). However, there are some differences between the results pooled from different study designs for women in Asian countries (test for consistency, P = 0.04). Pooled OR of studies on postmenopausal women in Western countries suggested that soy isoflavone intake has a marginally significant protective effect (OR = 0.92; 95%CI: 0.83 ∼ 1.00), but further analyses stratifying by study design found no statistically significant association.

Conclusions:

We meta-analyzed more and newer research results, and separated women according to menopausal status to explore soy isoflavone-breast cancer association. We founded that soy isoflavone intake could lower the risk of breast cancer for both pre- and post-menopausal women in Asian countries. However, for women in Western countries, pre- or post-menopausal, there is no evidence to suggest an association between intake of soy isoflavone and breast cancer.

·         This article focused the population which including both pre- and postmenopausal women.

·         The data is collected not only from the studies which conducted in Asia, but also in Western countries.

Wada, K., Nakamura, K., Tamai, Y., Tsuji, M., Kawachi, T., Hori, A., Takeyama, N., Tanabashi, S., Matsushita, S., Tokimitsu, N., & Nagata, C. (2013). Soy isoflavone intake and breast cancer risk in Japan: from the Takayama study. International Journal of Cancer, 133(4), 952–960.

Prospective Cohort Study

Article 3

Aim

The effects of soy or isoflavone intake on breast cancer need to be examined further in epidemiologic studies.

Method:

We assessed the associations of soy and isoflavone intake with breast cancer incidence in a population-based prospective cohort study in Japan. Participants were members from the Takayama study, aged 35 years or older in 1992. The follow-up was conducted from the time of the baseline study (September 1, 1992) to the end of March 2008. Cancer incidence was mainly confirmed through regional population-based cancer registries. Breast cancer was defined as code C50 according to ICD-10. Soy and isoflavone intakes were assessed with a validated food frequency questionnaire. Using the Cox proportional hazard models, the association of soy and isoflavone intake with breast cancer was assessed after adjustments for age, body mass index, physical activity, smoking, alcohol consumption, education, age at menarche, age at first delivery, menopausal status, number of children and history of hormone replacement therapy.

Results:

Among the 15,607 women analyzed, 172 had developed breast cancer. The relative risks of postmenopausal breast cancer were lower among women with higher intakes of soy (trend p = 0.023) and isoflavone (trend p = 0.046), although the relative risks of premenopausal breast cancer were not associated with intakes of soy and isoflavone.

Conclusion:

Decreased risks of breast cancer were found even among women with a moderate intake of soy and isoflavone. These results suggested that soy and isoflavone intakes have a protective effect on postmenopausal breast cancer.

·         A good participation rate, a long follow-up and information on several confounders.

·         A large sample size (a cohort of 15,607 individuals), which is crucial in finding a statistically significant result.

Zhao, T.-T., Jin, F., Li, J.-G., Xu, Y.-Y., Dong, H.-T., Liu, Q., Xing, P., Zhu, G.-L., Xu, H., & Miao, Z.-F. (2019). Dietary isoflavones or isoflavone-rich food intake and breast cancer risk: A meta-analysis of prospective cohort studies. Clinical Nutrition (Edinburgh, Scotland), 38(1), 136–145.

A Meta-Analysis

Article 4

Background & Aims:

Previous studies implied that dietary isoflavone intake may reduce the risk of developing breast cancer, but some have shown ambiguous results. This study aimed to systematically evaluate and summarize available evidence on the effect dietary isoflavone intake has on the risk of developing breast cancer.

Methods:

PubMed, Embase, and the Cochrane Library were searched for prospective cohort studies published through April 2017 that evaluated the effect of dietary isoflavone intake on the development of breast cancer.

Results:

Sixteen prospective cohort studies, involving 11,169 breast cancer cases and 648,913 participants, were identified and included in our data analysis. The pooled relative risk (RR) of breast cancer was 0.99 for high versus low intake of isoflavones (95% confidence interval [CI], 0.91-1.09; P = 0.876) and 0.99 for moderate versus low intake of isoflavones (95%CI, 0.92-1.05; P = 0.653), with insignificant heterogeneity (P = 0.187 for high versus low, and P = 0.192 for moderate versus low). While a moderate consumption of soy-based foods did not significantly affect breast cancer risk, a high intake of soy-based foods associated with a lower risk of developing breast cancer. Considering specific foods, an increased the risk of developing breast cancer was seen with a moderate intake of formononetin, but no significant associations were found between breast cancer risk and other isoflavone-rich diets.

Conclusions:

The present meta-analysis indicates that women with a high dietary intake of soy foods may experience a statistically significant reduction in breast cancer risk. However, moderate formononetin consumption may increase the risk of developing breast cancer.

·         A meta-analysis study that provide highest level of evidence to explain my research question.

·         A large sample size, involving 11,169 breast cancer cases and 648,913 participants

(# of subjects/ studies, cohort definition etc. )

-Data was also collected on the impact of soy on hormonally active tissues, as well as on menstrual cycle length in premenopausal women.

-None of the studies showed evidence of harm from higher consumption of soy.

-Also found significantly decreased risk of breast cancer recurrence or longer disease-free survival associated with higher soy intake.

-Lack of long term interventional data assessing cancer risk.

-Need to more carefully assess the dose-response relationship between soy intake and risk of breast cancer in order to more clearly delineate the threshold of exposure needed for potential therapeutic effects.

-Evaluate the association with breast cancer risk, the priority order of isoflavone, soy protein, soy foods/soy products was taken in summary analyses.

-Test the homogeneity of results across studies, and quantify the heterogeneity among studies

-An inverse soy isoflavone-breast cancer association, while a weak but statistically significant inverse association was found among postmenopausal women living in Western nations.

-Exposure to soy isoflavone in early life and high intake level may be important contributing elements for its protective effect to Asian women.

-The incidence of cancer was mainly confirmed through two regional population-based cancer registries in Gifu.

-Information was also collected from a local base hospital, which had played a leading role in medical care for the residents in the study area.

-The causes of cancer were coded according to the International Classification of Diseases and Health Related Problems, 10th Revision (ICD-10).

-Migration data were obtained from the residential registers.

-The relative risks of postmenopausal breast cancer were lower among women with higher intakes of soy and isoflavone

-The inverse association between isoflavone and postmenopausal breast cancer tended to be somewhat stronger among women who were nonobese, physically active, never smokers and drinkers

-When soy or isoflavone intake was not controlled for the total energy intake, the associations between those and breast cancer were not substantially altered.

-Although the diet pattern might have changed because of the preclinical signs, the exclusion of cases during the first 2 years of follow-up did not change the results.

-Another limitation of this study was the lack of information on the estrogen receptor status of tumors and the equol-producer status.

-Data heterogeneity was assessed, with p-values <0.10 regarded as statistically significant.

-Sensitivity analysis was performed by excluding each individual study to determine its effect on the overall conclusions.

– A high consumption of soy foods associated with a lower risk of developing breast cancer as compared with a low intake of soy foods

-Moderate intake of soy foods did not significantly affect the risk of developing breast cancer

-In addition, the adjusted factors, which may play an important role in the progression of breast cancer, differ between the included studies.

-Finally, the criteria of dietary isoflavone intake level are different between Asia and Western countries, which might bias the relationship between dietary isoflavone intake and breast cancer.