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 wIn this stomen 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 bio-specimen 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.
Link to Full Text
Key Points
This research was a single arm pilot study in premenopausal women at increased risk for breast
cancer in which benign breast tissue was harvested in the follicular phase of the menstrual cycle by random periareolar fine needle aspiration (RPFNA) before and after 12 months of 50 mg/day of SDG given as the commercial product Brevail®. This was a placebo controlled multi-institutional trial with a 2:1 randomization of eligible women to 12 months of SDG (Brevail®) or placebo. The primary endpoint for comparison of randomization arms was change in Ki-67 over time, with a secondary endpoint of change in cytomorphology.
Reduction in breast tumor Ki-67 after short term treatment is used as a surrogate biomarker predictive of favorable disease-free survival in neoadjuvant endocrine therapy trials. As proliferation in hyperplasia is a risk factor for later development of breast cancer, change in Ki-67 in benign breast tissue has also been used in early phase primary prevention trials as an indicator of likely efficacy and a signal to progress to later phase cancer incidence trials. In this study, the change in Ki-67 in the SDG arm of the randomized trial was significant, but the borderline significant reduction of Ki-67 in the placebo arm resulted in no difference between arms and a null primary endpoint for the randomized trial as designed. The lack of any increase in Ki-67 relative to placebo suggests that at worst a moderate dose of flaxseed or SDG in supplements is unlikely to be associated with increased risk for breast cancer. This is important as flaxseed and/or SDG is often used as a dietary supplement to improve insulin sensitivity, promote cardiovascular health, and reduce inflammation, breast pain and vasomotor symptoms. In companion preclinical study of SDG in preventing development of carcinogen-induced mammary cancer in the ABI rat model using doses of SDG producing enterolactone levels similar to this pilot trial found reduction in dysplasia and Ki-67 at 3 months but little change in Esr1, Esr2, or Pgr mRNA. Twelve months of the lignan secoisolariciresinol diglucoside (SDG) significantly reduced proliferation in benign breast tissue of premenopausal women at increased risk for development of breast cancer; however, with the unanticipated reduction in proliferation in the placebo arm, there was no significant differences between the two groups. SDG in a dose of 50 mg/day is well tolerated and there is no evidence of adverse effects from this supplement.