Randomized Phase IIB Trial of the Lignan Secoisolariciresinol Diglucoside in Premenopausal Women at Increased Risk for Development of Breast Cancer

Abstract

We conducted a multi-institutional, placebo-controlled Phase IIB trial of the lignan secoisolariciresinol diglucoside (SDG) found in flaxseed. Benign breast tissue was acquired by random periareolar fine needle aspiration (RPFNA) from pre-menopausal women at increased risk for breast cancer. Those with hyperplasia and ≥2% Ki-67 positive cells were eligible for randomization 2:1 to 50 mg SDG/day (Brevail®) vs placebo for 12 months with repeat biospecimen acquisition. The primary endpoint was difference in change in Ki-67 between randomization groups. 180 women were randomized, with 152 ultimately evaluable for the primary endpoint. Median baseline Ki-67 was 4.1% with no difference between arms. Median Ki-67 change was-1.8% in the SDG arm (P=0.001) and-1.2% for placebo (P=0.034); with no significant difference between arms. As menstrual cycle phase affects proliferation, secondary analysis was performed for 117 women who by progesterone levels were in the same phase of the menstrual cycle at baseline and off-study tissue sampling. The significant Ki-67 decrease persisted for SDG (median-2.2%; P=0.002) but not placebo (median-1.0%). RT-qPCR was performed on 77 pairs of tissue specimens. 22 had significant ERα gene expression changes (<0.5 or >2.0) with 7/10 increases in placebo and 10/12 decreases for SDG (P=0.028), and a difference between arms (P =0.017). Adverse event incidence was similar in both groups, with no evidence that 50 mg/day SDG is harmful. Although the proliferation biomarker analysis showed no difference between the treatment group and the placebo, the trial demonstrated use of SDG is tolerable and safe.

Short‐term exposure to synthetic flaxseed lignan LGM2605 alters gut microbiota in mice

“…We therefore sought to determine how a 10‐day period of oral LGM2605 administration affects the gut microbial composition of mice. We utilized female mice for this study since SDG is of particular interest for breast cancer therapies (Bowers et al, 2019; Delman et al, 2015; Fabian et al, 2020) and analyzed 16S rRNA extracted from mouse cecums. The cecum is proportionately larger in mice as compared to humans due to its importance in the digestion of plant compounds within the mouse gut; thus, it is not a perfect homolog for humans (Hugenholtz & Vos, 2018).…”

“…Secoisolariciresinol diglucoside (SDG), a bioactive lignan highly concentrated in flaxseed, exhibits protective effects in a variety of systemic diseases, including cardiovascular and metabolic disorders (Kezimana et al, 2018). Several new studies also indicate protective effects of SDG in breast cancer with no adverse effects (Bowers et al, 2019;Delman et al, 2015;Fabian et al, 2020). The efficacy of SDG in a wide range of disease treatments is likely due to SDG's antioxidant properties (Kezimana et al, 2018).…”

Targeting Breast Cancer Stem Cells Using Naturally Occurring Phytoestrogens

“…Aside from soy isoflavones, red clover isoflavones were found to have no significant effects on breast density, endometrial thickness, serum cholesterol, follicle stimulating hormone levels and bone mineral density in a randomized trial of 401 healthy women in the United Kingdom [ 221 ]. Similarly, in a double-blinded, randomized trial of 152 premenopausal women at high risk of breast cancer, flaxseed Secoisolariciresinol Diglycoside (SDG) was reported to have no effect on Ki-67 expression in breast tissues [ 222 ].…”

Impact of Stilbenes as Epigenetic Modulators of Breast Cancer Risk and Associated Biomarkers

“…Lignans are phytochemicals that are obtained from sources like flaxseeds, that also show promise in reducing breast cancer risk, with minimal side effects [ 24 ]. Cruciferous vegetables such as broccoli, watercress, and cabbage harbor two of the most potent phytochemicals that prevent breast cancer—phenethyl isothiocyanate (PEITC) and sulforaphane.…”