The authors have declared that no competing interests exist.
Conceived and designed the experiments: HF DS DK KC RW SS DF. Performed the experiments: HF GF BS RF SV. Analyzed the data: HF GF KC ES DS DF. Contributed reagents/materials/analysis tools: DF ES. Wrote the manuscript: HF DS GF BS RF SV DK KC RW SS ES DF.
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.
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.
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.
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 (≥100mg) isoflavones can be recommended for breast cancer patients.
Breast cancer accounts for almost one third of cancers diagnosed among women. In the United States, there were approximately 288 thousand new cases expected for 2011 [
Soy, also known as
Like soy, red clover contains the isoflavones genistein, daidzein, biochanin A, and formononetin, however, soy contains higher amounts of genistein and daidzein, while the dominant isoflavones in red clover are biochanin A and formononetin [
To better elucidate the effect of soy, red clover, or isoflavones from these plants on breast cancer, we conducted a systematic review of soy and red clover as used by breast cancer patients or those at risk of breast cancer, assessing their impact on the risk of primary breast cancer or risk of recurrence. We also assessed the impact of isoflavones on surrogate endpoints for predicting breast cancer risk, including circulating estradiol and effects on estrogen responsive tissues such as the breast, endometrial, and vaginal tissues. Finally, we assessed the efficacy of isoflavones in treating menopausal symptoms in patients who have undergone breast cancer treatment.
Electronic search strategies were developed and tested through an iterative process by an experienced medical information specialist in consultation with the review team. Using the OVID platform, we searched Ovid MEDLINE®, Ovid MEDLINE®In-Process & Other Non-Indexed Citations, EmbaseClassic+Embase, and AMED (Allied and Complementary Medicine). We also searched the Cochrane Library on Wiley (including CENTRAL, Cochrane Database of Systematic Reviews, DARE, HTA, and NHS EED). The strategy was peer reviewed prior to execution by an experienced information specialist using the PRESS Checklist [
Strategies utilized a combination of controlled vocabulary (e.g., Soybeans, Phytoestrogens, Breast Neoplasms) and keywords (soy, plant estrogen, breast cancer). Vocabulary and syntax were adjusted across databases. Searches pertaining to soy and soy isoflavones were performed in May 2011 and updated in March 2013; there were no language or date restrictions on any of the searches. Searches pertaining to red clover and red clover isoflavones were performed in October 2011 and updated in December 2012. Additional references were also sought through hand-searching the bibliographies of relevant items. Specific details regarding the searches appear in
For inclusion, evidence had to come from clinical trials or observational studies in humans. Human trials had to: a) assess the safety and/ or efficacy of soy or red clover or isoflavones from these plants in breast cancer patients for the purposes of treatment or secondary prevention, or the reduction of side effects associated with chemo- or radiation- therapy; alternately, human trials had to: b) assess the effect of soy or red clover or isoflavones from these plants on risk of primary breast cancer among women without a history of previous breast cancer. Clinical surrogate studies were included if they examined endpoints directly related to breast cancer risk, pathogenesis, or objective markers assessing healthy bodily function such as hematological function in breast cancer patients. All types of breast cancers (carcinoma in situ, invasive breast cancer) were included.
Observational studies had to report on risk of primary breast cancer or breast cancer recurrence associated with soy or red clover consumption compared with non-consumption, in a prospective or retrospective design.
First pass record screening was based on title review with second pass conducted on abstracts and/or full texts where uncertainty existed. Reports published in English only were included for full analysis if they met inclusion criteria.
We piloted data extraction forms and conducted extraction independently in duplicate to assess inter-researcher reliability (HF, RF, GF, SV). No major inconsistencies in data extraction were found. Both quality and efficacy data were extracted. Extraction sheets were prepared based on the Consolidated Standards of Reporting Trials (CONSORT) statement for clinical trials and the Newcastle-Ottawa scale (NOS) for observational studies [
Data was collected on breast cancer incidence, recurrence, or death; impact on hot flashes in breast cancer patients; adverse events; and impact on blood or urinary hormone levels: estrone (E1), estradiol (E2), estriol (E3), progesterone (P), leutinizing hormone (LH), follicle stimulating hormone (FSH), and sex hormone binding globulin (SHBG). Data was also collected on the impact of soy on hormonally active tissues, including breast tissue, endometrial tissue, vaginal tissue, and cervical tissue, as well as on menstrual cycle length in premenopausal women.
We were unable to pool study findings due to heterogeneity between studies, however we display individual study results graphically via forest plots. Although we did not quantitatively calculate heterogeneity, an informal assessment indicated qualitative incoherence between studies on important parameters, most importantly the type and dose of intervention or exposure, as well as study populations and endpoints used.
A total of 4179 records were screened, and 131 records were included: from the soy literature search, 2867 records were screened, of which 127 were included for full analysis and review. From the red clover search, 1312 records were screened, of which four were included for full review.
A total of 44 case control studies pertaining to soy were included. These are described in
Overall, of the 44 case control studies, 32 showed that higher consumption of soy foods and/ or soy isoflavones was associated with lower risk for primary breast cancer [
Among studies reporting ORs with confidence intervals, 19 studies described breast cancer risk associated with soy food or soy protein intake [44-46,50,51,56,61,62,64,65,70-73,76-78,80,81], and 16 examined intake of soy isoflavones [
On subgroup analysis, there was no clear difference in effect based on the type of soy exposure (food / protein, or isoflavones), or according to study quality (NOS score), the measure of exposure (recall or measurement of blood or urinary isoflavone levels), or menopausal status (
Seven studies examined the effect of soy by receptor status; these findings were mixed. Three studies reported no modification of effect by ER/ PR status [
A total of 10 nested case control studies were included pertaining to soy, shown in
Of eight studies assessing risk of breast cancer, one showed significantly reduced risk associated with higher plasma genistein [
Five studies showed no significant effects in either direction. One study examined mammographic density as a surrogate of breast cancer risk, however with mixed findings [
A total of 24 prospective cohort studies were included, described in
Ref | Cohort Name | CohortN | Cases N | Geographic area | Menopause status | Tamoxifen Use? | Anastrozole Use? | Herceptin Use? | Exposure |
High quartile | Study duration | Years f/u |
Outcome |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Kang 2012 | Mongolia Medical College | 288 | 125 | China | Pre and post | Y: 206 | NR | NR | Soy protein & IF | >15.78g protein; >35.30mg IF | 2004-2011 | 5-7y | ↑Survival |
Woo 2012 | Korean cohort | 339 | 25 | Korea | Pre and post | Y: n=195 | NR | Y: n=28 | Soyfoods& soy IF | ≥65.7g soyfood; ≥15.2mg IF | 2007-2008+ | 32.6mo | ↔Recurrence |
Zhang 2012 | Mongolia Medical College | 616 | 79 (deaths) | China | Pre and post | 40-60% | NR | NR | Soy protein & IF | >13.03g protein; >28.83mg IF | 2004-2006+ | 52.1mo | ↑Survival |
Caan 2011 | WHEL | 2736 | 271 | USA | Pre and post | ~66% | NR | NR | Soy IF | >16.33mg IF | 1991-2006 | 7.3 | ↔Survival ↔Recurrence |
Kang 2010 | Harbin, China | 524 | 185 (recur) | China | Pre and post | 100% T or A | 100% T or A | NR | Soy IF | >42.3mg IF | 2002-2008 | 5.1 | ↔Survival ↓Recurrence (postM) |
Guha 2009 | LACE | 1954 | 282 | USA | Pre and post | 20-40% | NR | NR | Genistein intake | >13.02mg genistein | 2000-2008 | 6.31 | ↔Recurrence |
Shu 2009 | SBCSS | 5042 | 534 (recur) | Shanghai | Pre and post | Y: n=2622 | NR | NR | Soy protein & IF | >15.31g protein; >62.68mg IF | 2002-2009 | 3.9 | ↓Recurrence ↑Survival |
Fink 2007 | Long Island BrCa Study | 1210 | 113 (deaths) | USA | Pre and post | NR | NR | NR | Soy IF | ≥7.48mg IF | 1996-2002 | ~6 | ↑Survival |
Boyapati 2005 | Shanghai Breast Cancer study | 1459 | 216 (deaths) | Shanghai | Pre and post | NR | NR | NR | Soyfoods | NR | 1996-2002 | 5.2 | ↔Survival |
No significant effect; A anastrozole; IF isoflavones; LACE study Life After Cancer Epidemiology study; postM post-menopausal women; preM pre-menopausal women; SBCSS Shanghai Breast Cancer Survival Study; T tamoxifen; WHEL Women’s Healthy Eating & Living study
Exposure is dietary unless specified otherwise (ie. supplements)
Where (~) is used, the follow up period was not reported in the publication, but an estimate was calculated based the time between the end of the recruitment period and data censure/ end of follow-up.
Two studies reported on associations with mammographic density as a predictor of breast cancer risk [
Two studies reported on menopausal symptoms and quality of life among breast cancer patients [
Nine prospective studies reported on risk of breast cancer recurrence or mortality [
Of five studies reporting on recurrence [
Of seven studies examining survival [
We included 11 uncontrolled trials examining the effect of soy on safety outcomes relevant to breast cancer risk and progression [
In studies conducted among healthy women, there were no significant changes compared to baseline in endometrial thickness [
Of the 38 randomized controlled trials, five assessed the efficacy of soy for hot flashes among breast cancer survivors [
A total of 18 RCTs assessed circulating estrogens levels (E1, E2, and/ or E3) Fifteen of 18 studies found no significant impact from soy compared to the control group (p>0.05) [
A total of nine RCTs assessed the impact of soy consumption on estrogen metabolism as measured through urinary excretion of urinary metabolites. Of these, five reports of six studies found no significant change in 2-hydroxyestrone, 16α-hydroxyestrone, or 2:16α hydroxyestrone ratio compared to the control group (p>0.05 for all) [
None of the studies assessing endometrial thickness [
Three studies looked at molecular markers of breast cell proliferation or genetic markers of breast cancer risk. One study found no change in BRCA 1 and 2 mRNA level due to soy consumption, however there was a decrease over time in the placebo group, yielding a significant difference between groups (p<0.001) [
RCTs were assessed as having a moderate risk of bias, with inadequate reporting of random sequence generation and allocation concealment (selection bias) in 18 and 32 of 43 unique RCTs, respectively. The majority of RCTs showed low risk of performance bias, detection bias, attrition bias, and reporting bias; description of blinding of participants, blinding of outcome assessment, complete outcome data and reporting was adequate in over 88% of the studies. The risk of bias across studies is shown in
The most common adverse event associated with soy consumption was mild to moderate gastrointestinal discomfort, but this usually occurred with comparable frequency in both the soy and the placebo groups [
Seven studies included in our review investigated the effect of soy in combination with hormonal therapies: tamoxifen and aromatase inhibitors. Four cohort studies [
Of the cohort studies, the WHEL cohort exhibited relatively low soy isoflavone intake (≥6.3mg total isoflavones) and yielded null results: HR for recurrence among tamoxifen users was 0.59 (0.27-1.29) [
One cohort study examined soy consumption by post-menopausal women who were on anastrozole, and found decreased risk of recurrence among those with an intake of >42mg/d isoflavones, AHR 0.65 (0.47-0.85) [
Two RCTs pertaining to red clover were included [
In brief, Atkinson et al assessed the effect of red clover on mammographic density as well as a panel of other markers of estrogenic activity, in 205 women with an increased risk of breast cancer due to their breast density pattern (Wolfe P2 or DY mammographic breast patterns); there was also a secondary assessment of hot flashes [
Powles et al investigated the effect of red clover in 401 women with a family history of breast cancer (at least one first degree relative affected), assessing circulating FSH, endometrial thickness, mammographic density, and bone density [
Results of the study by Atkinson showed no significant changes in hot flash score (p=0.88) or mean number of daily hot flashes (p=0.41) when groups were compared [
Neither of the RCTs reported on breast cancer incidence rates, however surrogate markers of estrogenic activity were examined. Atkinson reported no significant changes in estradiol, FSH, or LH over the one year period: estradiol increased by 14.0 pmol/L in the red clover group compared to a decrease of 0.9 in the placebo group, however this was not significant, p=0.49); FSH decreased 4.2 IU/L in the red clover group compared to a decrease of 2.9 in the placebo group, p=0.83; LH decreased 4.0 IU/L in the red clover group compared to a decrease of 4.2 IU/L in the placebo group, p=0.71; and tyrosine kinase increased 1.62 units of activity/ µg protein in the red clover group compared to an increase of 0.90 in the placebo group, p=0.16 [
Neither of the two RCTs reported any significant changes in mammographic density among both pre- and post-menopausal women [
Atkinson did not report adverse events. Powles reported adverse effects, which most commonly included breast abnormality, “skin related symptoms” (not described), and other minor adverse events, however these were equally distributed between red clover and placebo groups [
According to the Cochrane risk of bias tool, the trial reported by Powles was assessed as having low risk of bias in all of the categories, except one for which information about detection bias was not provided [
The results of our systematic review suggest that there is a lack of real evidence showing that soy increases risk of breast cancer or breast cancer recurrence. This is an important finding given the generally perceived controversial status of soy in relation to breast cancer [
Among studies included in our review, case control studies showed a stronger association between soy and reduced risk of breast cancer. As shown in
The effect of soy on hot flashes in breast cancer patients is not clear. RCTs noted some improvements over time, but not in comparison to placebo [
Several factors influence the biological activity of soy isoflavones in the body. First, soy isoflavones show selectivity toward ER-ß over ER-α [
Secondly, preclinical evidence has shown that under conditions of high estrogen concentration similar to premenopausal levels, soy isoflavones act as ER antagonists, while under conditions of low estrogen comparable to postmenopausal levels, they are ER agonists [
Placed in this context, the clinical data reviewed by our study, which demonstrates a lack of any clear pro-estrogenic effects from use of soy, is quite noteworthy. We found no effects on circulating estradiol, and no measurable effects on estrogen-sensitive target tissues, such as breast tissue (density) and endometrium. In addition, our findings are in agreement with those reported by Hooper et al in a 2009 meta analysis of 47 trials [
Despite this, and despite the fact that our study failed to show any clear estrogenic effects observable in humans overall, the possibility of soy having estrogen-like effects under some circumstances in certain subgroups of women cannot be ruled out [
Our review revealed no clear modification of soy’s effect based on menopausal status or ER+/- status in breast cancer patients in large observational studies. However we did find variation according to geographical locale; studies conducted in Asian countries more often reported chemopreventive effects compared to studies in Western countries, which more often reported null results. We attribute this to a difference in soy consumption between these areas. The traditional Japanese diet contains between 6-11g of soy protein and 25-50mg isoflavones; top percentiles of soy intake in Asian studies consume as much as 20g soy protein or 100mg isoflavones per day [
The suggestion has been made that the effect of soy depends on genetic variations present in Asian populations. Nechuta et al conducted an analysis of the effect of soy on breast cancer recurrence, investigating the possibility of ethnic variations [
Our review is broad in its scope, assessing soy in the context of breast cancer from several perspectives, including risk of breast cancer, risk of recurrence, estrogenic effects, and risk of interactions with tamoxifen and other hormonal therapies. Our findings are generally in agreement with those of the American Cancer Society, suggesting that moderate amounts of soy intake (up to 3 servings per day) is likely safe for consumption by women with breast cancer [
Although we included a large number of studies regarding soy and breast cancer risk, we were unable to pool data with respect to risk of breast cancer and risk of recurrence due to heterogeneity. There is a lack of long term interventional data assessing cancer risk. This is a particularly important shortcoming because RCTs of under 2 years duration are unlikely to reveal any serious adverse effects in breast cancer survivors, including possible interactions between soy and tamoxifen. This question deserves high priority for future research in this area. In addition, there is a 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.
Soy does not appear to influence levels of circulating estrogen or exert estrogen-like effects at target tissues. There is a lack of evidence showing clear effects of soy consumption or supplementation on reduction of hot flashes in breast cancer patients. Observational data suggest that higher soy intake, consistent with that of a traditional Japanese diet, may be protective against the development of breast cancer as well as breast cancer recurrence and mortality, although there is a need for clinical studies to confirm this relationship. Until there is more data supporting safety, caution is warranted with high dose isoflavone supplements in patients with breast cancer.
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