Soy and Breast Cancer Risk and Recurrence:
Evidence, NOT Mythology
Constantine Kaniklidis·Sunday, October 23
Soy in relation to cancer, and especially breast cancer has been studied in hundreds and hundreds of studies for over 25 years since the key component of soy, isoflavones, was first explored as of potential chemopreventive value, via both estrogen-dependent (BUT NOT ESTROGENIC) and estrogen-independent mechanisms inhibiting the carcinogenesis and tumorigenesis of breast cancer, part of the triggering clue being the historically low breast cancer incidence and mortality rates in soy food-consuming Asian countries.
Dispelling the Concerns over Estrogenicity
Concerns arose that soy foods with their isoflavone component could both increase the probability of breast cancer development in high-risk women and possibly also compromise the prognosis of patients with breast cancer, especially based on preclinical studies in athymic ovariectomized mice implanted with estrogen-sensitive MCF-7 human breast cancer cells where it was observed that the growth of existing tumors was stimulated by isoflavones.
However, the concerns were unwarranted, these were in vivo animal data, contradicted by human clinical data. It has been decisively shown that mice metabolize isoflavones differently than humans [Setchell 2011], with in mice markedly higher circulating concentrations 20 to 150 times greater than in human of the biologically active (unconjugated) genistein isoflavone component. In addition, clinical evidence decisively shows that isoflavones are functionally and operationally different from estrogen: in direct contrast to estrogen, isoflavones do NOT stimulate vaginal tissue [Carmignani 2010].
Here it's important to remember that in the Women's Health Initiative (WHI) trial [Manson 2013] those in the estrogen group were LESS likely to develop invasive breast cancer in comparison to the women in the placebo group, regardless of when therapy was initiated, and at this juncture overwhelming evidence shows that it is combined estrogen PLUS PROGESTIN, rather than estrogen alone, that compromises breast cancer risk [Chlebowski 2012], soy itself having has no progestin activity.
But most importantly, these concerns have been decisively demonstrated to be unfounded in human clinical and epidemiologic data, which have consistently shown that isoflavone intake does NOT adversely affect critical markers of breast cancer risk such as cell proliferation and mammographic density, with prospective epidemiologic studies in a total of over 11,000 women (USA and China) finding the opposite, namely that postdiagnosis soy intake statistically significantly both reduces incidence of recurrence, as well as improves survival. Thus, clinical data [Messina 2015] establish that isoflavone exposure is safe for all women, while extensive prospective epidemiologic data [Chi 2013] go beyond safety, to establish that isoflavone exposure improves the prognosis of patients who already have breast cancer.
LESSON LEARNED: Do NOT feed athymic ovariectomized mice soy!
Evidence of Safety and Efficacy
[from Eakin 2015]
From prospective epidemiologic studies with over 11,000 breast cancer patients, we have evidence including that from the Shanghai Breast Cancer Survival Study that postdiagnosis soy intake favorably affects prognosis [Shu 2009], cross-confirmed in a pooled analysis of this and two additional prospective studies [Caan 2011] [Guha 2009] in the United States (n = 9,514) [Nechuta 2012]. Furthermore, a pooled meta-analysis (n = 11,206) [Chi 2013] of these 3 prospective studies plus 2 additional Chinese prospective studies [Kang 2010] [Zhang 2012] found soy food intake post-diagnosis was associated with BOTH reduced mortality AND reduced recurrence. And prospective data have shown that soy intake may enhance the efficacy of endocrine therapy, name of tamoxifen [Nechuta 2012] as well as the aromatase inhibitor, anastrozole (Arimidex) [Kang 2010].
Benefits Independent of Tumor Biology
And note that pooled analysis [Nechuta 2012] and meta-analysis [Chi 2013] has found that isoflavone intake is associated with protective effects in both ER-positive (ER+) AND ER-negative (ER-) breast cancer patients, so benefits are invariant to the biology / receptor status of the tumor. And as to triple negative breast cancer (TNBC) human data [Guo 2016] found that the tumor suppressors genes (TSGs) miR-29a-3p and IGF1R showed favorably overexpression for those women with high soy intake, in contrast with oncogenes KRAS and FGFR4 showing favorable underexpression, and with cell growth–related genes showing a predominantly underexpression pattern in women with high soy food intake, compared to women with lower soy food intake, suggesting that long-term prediagnosis soy intake may lead to increased expression of tumor suppressors and decreased expression of oncogenes, especially cell growth–related genes, in breast tumor tissues.
Regulatory Review Confirming Safety
The European Food Safety Authority (EFSA) has recently completed an extensive literature review of all critical data, concluding that in postmenopausal women, isoflavones do NOT adversely affect breast tissue, thyroid function, or the uterus [EFSA 2015], and that the human evidence does not support the hypothesis of an increased risk of breast cancer nor of an adverse effect on mammographic density, nor on proliferation marker (Ki-67) expression in interventional studies, with no effect on endometrial thickness and histopathological changes in the uterus, nor thryroid hormone levels, even with almost 3 years (30 months) of supplementation with high doses at 150 mg/day of soy isoflavones.
First, it is now well-established that isoflavones significantly alleviate hot flashes [Taku 2012]. Second, isoflavones help improve arterial cardiovascular health [Li 2010]. Third, isoflavones exert wrinkle reduction effects in women [Jenkins 2013]. And recent randoomized data has found that isoflavones increase bone calcium content and hence may be an aid against osteoporosis [Pawlowski 2015].
BOTTOM LINE: LESSONS LEARNED
It is clear that the most robust critically appraised high-level human clinical evidence aggregated to date demonstrates:
- No significant safety signals nor potential harms, neither for the general population nor for those at elevated cancer risk, nor for cancer patients.
- Regular soy consumption reduces the risk of breast cancer development.
- Regular soy consumption reduces the risk of recurrence of breast cancer.
- Soy do not adversely affect breast tissue, thyroid function, or uterine tissue or function.
- Regular soy consumption elevates levels of favorable tumor suppressors genes and decreases levels of adverse oncogenes.
- Regular soy consumption has additional health benefits, with positive effects on vasomotor symptoms (especially hot flashes), cardiovascular health, skin aging, and bone calcium content, among others.
[Caan 2011] Caan BJ, Natarajan L, Parker B, Gold EB, Thomson C, et al: Soy food consumption and breast cancer prognosis. Cancer Epidemiol Biomarkers Prev 2011;20:854-858.]
[Carmignani 2010] Carmignani LO, Pedro AO, Costa-Paiva LH, Pinto-Neto AM: The effect of dietary soy supplementation compared to estrogen and placebo on menopausal symptoms: a randomized controlled trial. Maturitas 2010;67:262-269.
[Chi 2013] Chi F, Wu R, Zeng YC, Xing R, Liu Y, Xu ZG: Post-diagnosis soy food intake and breast cancer survival: A meta-analysis of cohort studies. Asian Pac J Cancer Prev 2013;14:2407-2412.
[Chlebowski 2012] Chlebowski RT, Anderson GL: Changing concepts: Menopausal hormone therapy and breast cancer. J Natl Cancer Inst 2012;104:517-527.
[Eakin 2015] Eakin A, Kelsberg G, Safranek S. Clinical Inquiry: Does high dietary soy intake affect a woman's risk of primary or recurrent breast cancer? JFJ Fam Pract 2015; 64(10):660-2.
[EFSA 2015] EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to Food): Scientific opinion on the risk assessment for peri- and post-menopausal women taking food supplements containing isolated isoflavones. EFSA J 2015;13:4246.
[Guhu 2009] Guha N, Kwan ML, Quesenberry CP, Jr., Weltzien EK, Castillo AL, Caan BJ: Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the Life After Cancer Epidemiology study. Breast Cancer Res Treat 2009;118:395-405.
[Guo 2016] Guo X, Cai Q, Bao P, et al. Long-term soy consumption and tumor tissue MicroRNA and gene expression in triple-negative breast cancer. Cancer 2016 Aug 15; 122(16):2544-51.
[Jenkins 2013] Jenkins G, Wainwright LJ, Holland R, Barrett KE, Casey J: Wrinkle reduction in post-menopausal women consuming a novel oral supplement: a double-blind placebo-controlled randomised study. Int J Cosmet Sci 2013;36:22-31.
[Kang 2010] Kang X, Zhang Q, Wang S, Huang X, Jin S: Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. CMAJ 2010;182:1857-1862.
[Li 2010] Li SH, Liu XX, Bai YY, Wang XJ, Sun K, et al: Effect of oral isoflavone supplementation on vascular endothelial function in postmenopausal women: a meta-analysis of randomized placebo-controlled trials. Am J Clin Nutr 2010;91:480-486.
[Manson 2013] Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, et al: Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA 2013;310:1353-1368.
[Messina 2015] Messina M: Post-diagnosis soy isoflavone intake is not harmful to women with breast cancer. Breast Diseases: A Year Book Quarterly 2015;26:193-197.
[Nechuta 2012] Nechuta SJ, Caan BJ, Chen WY, Lu W, Chen Z, et al: Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women. Am J Clin Nutr 2012;96:123-132.
[Pawlowski 2015] Pawlowski JW, Martin BR, McCabe GP, McCabe L, Jackson GS, et al: Impact of equol-producing capacity and soy-isoflavone profiles of supplements on bone calcium retention in postmenopausal women: a randomized crossover trial. Am J Clin Nutr 2015;102:695-703.
[Setchell 2011] Setchell KD, Brown NM, Zhao X, Lindley SL, Heubi JE, et al: Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk. Am J Clin Nutr 2011;94:1284-1294.
[Shu 2009] Shu XO, Zheng Y, Cai H, Gu K, Chen Z, et al: Soy food intake and breast cancer survival. JAMA 2009;302:2437-2443.
[Taku 2012] Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M: Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause 2012;19:776-790.
[Zhang 2012] Zhang YF, Kang HB, Li BL, Zhang RM: Positive effects of soy isoflavone food on survival of breast cancer patients in China. Asian Pac J Cancer Prev 2012;13:479-482.
Constantine Kaniklidis Director, Medical Research,
No Surrender Breast Cancer Foundation (NSBCF)
Breast Cancer Reviewer, Current Oncology