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

Abstract

We conducted a multiinstitutional, 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 premenopausal 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) versus placebo for 12 months with repeat bio-specimen acquisition. The primary endpoint was difference in change in Ki-67 between randomization groups. A total of 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%). qRT-PCR was performed on 77 pairs of tissue specimens. Twenty-two had significant ERα gene expression changes (<0.5 or >2.0) with 7 of 10 increases in placebo and 10 of 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.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest: No potential conflicts of interest were disclosed.

©2020 American Association for Cancer Research.

Figures

Figure 1.

Schema for Phase IIB chemoprevention trial of flaxseed lignan in premenopausal women at high risk for development of breast cancer.

Figure 2.

Comparison of the distribution of change in Ki-67 over time for all evaluable subjects (panels A and C) and for those in the same phase of the cycle by progesterone levels at baseline and 12 months (panels B and D). Subjects in panels C and D received SDG; those in panels A and B were assigned to placebo.

Figure 3:

Representation of the results of analysis of modulation of gene expression. Panel A) Heat map demonstrating the results of unsupervised clustering analysis of RT‐qPCR data. For individual subjects, an increase in gene expression (fold‐change) >2 is indicated by purple and a decrease in gene expression TFF1,PGR, GREB1, AREG,ESR1, and ESR2. Panel B) Box plot demonstrating the difference in change in bioavailable estradiol levels between the four clusters identified for the entire cohort. Additional details are available in the Supplemental File.