Table 1.

Reported results of clinical trials on phytoestrogens and breast cancer (2008–2020).

Phytoestrogen	Trial Design	Sample Size/	Interventions	Results	NCT Number/
		Population Studied			References
Enterolactone and Genistein	Observational prospective cohort study	MARIE cohort of 1060–2105 postmenopausal breast cancer patients in Germany Aged 50–74 years	Lifestyle questionnaires and blood samples collected at recruitment 2002–2005 (baseline) and 2009 (follow-up)	Higher genistein concentrations were associated with lower Ki-67 expression in tumors showing >20% Ki-67 No associations between enterolactone or genistein and HER2 status Enterolactone concentration inversely associated with all- cause mortality, breast-cancer-specific mortality and distant disease-free survival, likely through mediation of C-reactive protein Higher enterolactone concentrations were associated with improved 5-year survival for postmenopausal breast cancer patients up to 4 years post-diagnosis Higher concentrations of genistein, resveratrol and luteolin at follow-up in long- term survivors were associated with poorer subsequent prognosis	NCT03401034 (Jaskulski et al., 2017 [209]) (Jaskulski et al., 2018 [225]) (Jaskulski et al., 2020 [226])
Estrogenic Botanical Supplements	Observational study	Up to 3159 women in the UK with invasive primary breast cancer at 9–15 months post-diagnosis Aged 18 to 75 years	Questionnaires (diet, lifestyle, use of complementary treatments) and blood/urine samples were collected annually for up to 5 years	Estrogenic botanical supplement usage doubled after diagnosis (8.4%) Flaxseed and soy/isoflavone were most commonly used Pre-diagnosis phytoestrogen intake was not associated with factors associated with improved breast cancer prognosis	NCT00701584 (Velentzis et al., 2011 [224]) (Swann et al., 2013 [227])
Red Clover Isoflavones	Double-blind, randomized intervention study	401 healthy women in the UK with at least one first-degree relative with breast cancer, in the UK Aged 35 to 70 years	Red clover isoflavones for 3 years	Red clover isoflavones were well tolerated in healthy women No significant differences in breast density, endometrial thickness, serum cholesterol, follicle stimulating hormone levels and bone mineral density	(Powles et al., 2008 [220])
Flaxseed Lignan Secoisolaricires inol Diglycoside (SDG)	Double-blind, randomized intervention study, phase IIB	152 premenopausal women who have a >2-fold relative risk of breast cancer compared to women in their age group, in USA Aged 21–49 years	50 mg of (SDG) capsule once daily for 12 months	No difference in breast epithelial cells’ Ki-67 expression between SDG and placebo	NCT01276704 (Fabian et al., 2020 [221])
Flaxseed (with aromatase inhibitor)	2 × 2 factorial, randomized interventional study	24 postmenopausal women with estrogen receptor positive (ER+) breast cancer receiving surgery at Roswell	25 g/day ground flaxseed +/−1 mg/day anastrozole for 13–16 days prior to breast surgery	No interaction between flaxseed and aromatase inhibitor anastrozole in serum hormone levels or prognostic breast tumor characteristics	NCT00612560 (McCann et al., 2014 [223])
		Park Cancer Institute, USA Aged 59–65 years		Anastrozole may reduce circulating lignans induced by flaxseed
S-equol	Open-label intervention study, early phase I	39 patients in Texas, USA, with invasive triple-negative breast cancer, confirmed by core needle biopsy Aged 18 and older	S-equol at a dose of 50 mg or 150 mG PO twice daily for 10–21 days	S-equol was well tolerated and inhibited proliferation of breast tumor cells, as measured by a decrease in Ki-67 (8% compared to baseline) Up to 20% decrease in Ki- 67 was observed in 28% of S-equol-treated patients	NCT02352025 (Lathrop et al., 2020 [208])
Soy Isoflavones	Randomized intervention study	31 healthy Belgian or Dutch women who were scheduled for an esthetic breast reduction Aged 18 to 62 years	Soy milk (16.98 mg genistein and 5.40 mg daidzein aglycone equivalents per dose) or soy supplement (5.27 mg genistein and 17.56 mg daidzein aglycone equivalents per dose), with three doses daily for 5 days before breast reduction	After soy product intake, genistein and total daidzein concentrations reached high levels in breast tissue, which could be sufficient to cause potential health effects	(Bolca et al., 2010 [219])
Soy Isoflavones	Double-blind, randomized intervention study	85 previously treated breast cancer women at high risk of breast cancer living in CA, USA Aged 30–75 years	Oral soy isoflavones (50 mg/day) for 12 months	Treatment increased plasma soy isoflavone levels with minimal adverse effect Soy supplementation did not decrease mammographic density	NCT01219075 (Wu et al., 2015 [215])
Soy Isoflavones	Double-blind, randomized	80 postmenopausal women with	250 mg of standardized soy extract corresponding to	Soy isoflavones did not affect breast density as measured by	(Delmanto et al., 2013 [216])
	intervention study	vasomotor symptoms in Brazil Aged >45 years	100 mg/day isoflavone for 10 months	mammography and ultrasound
Soy Isoflavones	Randomized, placebo-controlled intervention study	140 women with invasive breast adenocarcinoma in NY, USA Aged mean 56 ± 12 years	5.8 g soy protein powder twice a day for 7–30 days prior to breast surgery	Soy intake induced overexpression of FGFR2 and genes that drive cell cycle and proliferation pathways in breast tumor cells No significant changes in Ki67 or Caspase3	(Shike et al., 2014 [214])
Soy Isoflavones	Double-blind, randomized intervention study	200 healthy premenopausal women in TX, USA Aged 30 to 42 years	Soy isoflavone tablet (60 mg daidzein, 60 mg genistein and 16.6 mg glycitein) twice per day for five days per week for up to 2 years	Isoflavones tended to normalize systolic blood pressure via serum calcium moderation and decreased diastolic blood pressure, independent of calcium level Genistein significantly decreased whole-body bone mineral density at low serum calcium levels	NCT00204490 (Lu et al., 2020 [212]) (Nayeem et al., 2019 [211])
Soy Isoflavones/Genistein	Double-blind, randomized intervention study, phase IIB	126 healthy women who were at increased risk of developing breast cancer in IL, USA Aged 42–55 years	Oral PTI G-2535 pill (genistein 150 mg, daidzein 74 mg, glycitein 11 mg) once daily up to 6 months	Soy isoflavones in healthy, high-risk adult Western women did not reduce breast epithelial proliferation, as measured by Ki-67 In premenopausal women, soy induced a 27% increase in Ki-67 in breast epithelial cells post-intervention	NCT00290758 (Khan et al., 2012 [213])
Soy Isoflavones/Genistein/Soy Isoflavones/Genistein	Double-blind, randomized intervention study, phase	30 healthy non- obese postmenopausal women at no risk of breast cancer, living in NC, USA Aged 45–70 years	Oral genistein (PTI G-2535) twice daily for 84 days	High dose of soy isoflavones (900 mg) in postmenopausal women did not cause DNA damages, apoptosis or significant estrogenic effects	NCT00099008 (Pop et al., 2008 [217])
Soy Protein (with seaweed)	Double-blind, randomized with crossover intervention study	15 healthy postmenopausal European–American women living in central MA, USA Aged mean 58.8 ± 7.9 years	7 weeks of 5 g/day seaweed (Alaria), plus 2 mg isoflavones/kg body weight during week 7; crossover after 3-week washout	Soy and SeaSoy (seaweed plus soy) significantly decreased serum E1, increased urinary excretion of estrogen metabolites and altered phytoestrogen metabolism	NCT01204957 (Teas et al., 2009 [210])
Genistein (with Gemcitabine)	Open-label intervention study, phase II	17 women with metastatic stage IV breast cancer in MI, USA Aged 31 to 57	Oral genistein (100 mg) once daily on days −7 to 1, then twice daily from days 1 to 21; IV gemcitabine hydrochloride (1000 mg/m2) on days 1 and 8; course repeated up to 24 weeks	Study was closed early due to lack of efficacy	NCT00244933