Abstract 1120: Randomized clinical trial of a flaxseed lignan in pre-menopausal women at high risk for development of breast cancer
Authors: Fabian Carol J. , Khan Seema A. , Garber Judy E. , Dooley William C. , Yee Lisa D. , Zalles Carola M. , Metheny Trina , Phillips Teresa A. , Hu Jinxiang , Petroff Brian K. , Hursting Stephen D. , Kimler Bruce F. 
Published: September 2020

Abstract
Breast cancer prevention strategies for young pre-menopausal women must have minimal side effects and accommodate potential future child-bearing. Based on epidemiologic evidence and informed by a single-arm pilot study, we conducted a multi-institutional, placebo-controlled Phase IIB trial of the lignan secoisolariciresinol diglycoside (SDG) found in high concentrations in flaxseed. Benign breast tissue was acquired by random periareolar fine needle aspiration (RPFNA) from pre-menopausal women at increased risk for breast cancer during the follicular phase as estimated by dates. Those with cytologic hyperplasia and ≥2% positive cells by Ki-67 immunocytochemistry were eligible for randomization 2:1 to daily Brevail® (50 mg SDG) or placebo. After 12 months, RPFNA and blood for hormone assays were repeated. The primary endpoint was difference in change in Ki-67 between the randomization groups. A planned accrual of 230 was to provide an 80% power of detecting a 2.5% reduction in Ki-67 for the SDG group vs no reduction in the placebo group. Accrual was slower than anticipated and the study was closed with 180 enrollees at five sites. 152 (51 placebo, 101 SDG) sets of paired specimens were evaluable for the primary endpoint. Baseline Ki-67 was a median of 4.1% (range, 2.0 - 26.8%), with no difference between arms (Mann-Whitney nonparametric test, p=0.34). Both arms showed a decrease in percent Ki-67 over time (Wilcoxon signed rank test; p=0.034 for placebo, p=0.001 for SDG). Although Ki-67 reduction was greater in the SDG arm (median of -1.8% vs -1.2%), there was no statistically significant difference between the two arms (Mann-Whitney, p=0.72). Since luteal phase progesterone affects proliferation, we excluded 35 women that by serum progesterone levels could not be confirmed to be in the same phase of the menstrual cycle at baseline and off-study. Analyzing the remaining 117 for Ki-67 (42 placebo, 75 SDG), there was no significant change for the placebo arm (Wilcoxon, p=0.14) but the significant change in the SDG arm persisted (p=0.002). As an exploratory analysis, assessment of gene expression was performed by RT-qPCR on 77 pairs of non-bloody RPFNA specimens. 22 had significant ERα gene expression changes (defined &lt;0.5 or &gt;2.0 fold changes). There was no significant change over time for the placebo group (7/10 increases, Wilcoxon, p=0.16), but there was significant change for the SDG group (10/12 decreases, p=0.027). There was also a significant difference between the groups (Mann-Whitney, p=0.018). While the primary trial result is null, there is supportive evidence SDG may favorably affect cell proliferation and estrogen signaling in premenopausal women at high risk for development of breast cancer. Supported by Susan G. Komen Promise Grant KG101039. Study agent (Brevail®, placebo) provided by Lignan Research Inc. (later Barlean's Oils) which was otherwise not involved in the design, conduct, or analysis of the study.
Citation Format: Carol J. Fabian, Seema A. Khan, Judy E. Garber, William C. Dooley, Lisa D. Yee, Carola M. Zalles, Trina Metheny, Teresa A. Phillips, Jinxiang Hu, Brian K. Petroff, Stephen D. Hursting, Bruce F. Kimler. Randomized clinical trial of a flaxseed lignan in pre-menopausal women at high risk for development of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1120.