Prevention Strategy for Pre-Menopausal Women at High Risk for Development of Breast Cancer

Study Overview
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Brief Summary
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The investigators will study the effect of 12 months of SDG (Brevail) vs placebo on women at increased risk for development of breast cancer.

Detailed Description
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The investigators would like to see if women at increased risk for breast cancer are likely to tolerate SDG daily for 12 months without significant side effects or changes in their menstrual cycles. The investigators would also like to determine if Brevail® can reduce breast cell proliferation in pre-menopausal women.

Official Title
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Flaxseed Lignan as a Prevention Strategy for Pre-Menopausal Women at High Risk for Development of Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Placebo
* Drug: secoisolariciresinol


Participation Criteria
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Eligibility Criteria
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PARTICIPANT SELECTION Risk Level Required for RPFNA Screening for Eligibility Given the low probability of side effects and the desire to be able to generalize results to a moderate as well as high risk population, the target cohort is pre-menopausal women who have a relative risk for breast cancer which is 2-fold or greater than that of the average woman in their age group by virtue of any one of the following conditions: A 1st or 2nd degree relative with breast cancer diagnosed under the age of 60 A prior biopsy indicating proliferative breast disease, atypical hyperplasia, or LCIS Multiple prior breast biopsies regardless of histology 50% or higher estimated mammographic density on visual inspection Prior or current RPFNA evidence of atypia Known carrier of a BRCA1 or 2 mutation. Age, Life-Style and Medical Eligibility Criteria for Tissue Screening Candidates for tissue screening for this study are pre-menopausal women who meet the risk criteria above and all of the following demographic and medical criteria: Age 21 to 49 (limiting the maximum age to 49 will reduce the possibility of reduction in Ki-67 due to entry into menopause transition during the study). Stable hormonal status for the previous 6 months (has not stopped or started oral contraceptives, or experienced lactation or pregnancy) and willing to maintain same status while on study. BMI < 40 kg/m2. Has had at least 4 menstrual cycles in past year If regularly undergoing screening mammography, must have been performed within 9 months prior to baseline RPFNA, and interpreted as not suspicious for breast cancer Breast exam interpreted as normal (not suspicious for cancer). Exclusion Criteria for Screening RPFNA and Study Participation Candidates are ineligible for tissue screening if they meet any of the following conditions: Consumption of systemic antibiotics during the 3 weeks prior to baseline RPFNA. Systemic antibiotics reduce intestinal bacteria and thus the ability to convert SECO to ENL. Consumption of supplements containing SDG (flaxseed or sesame seed) during the 3 weeks prior to baseline RPFNA. ( Consumption of foods containing flaxseed or sesame seed are OK.) Use of any selective estrogen receptor modulator or aromatase inhibitor (tamoxifen, raloxifene, arzoxifene, acolbifene, anastrozole, exemestane, letrozole) within the previous 6 months. Currently enrolled on an interventional investigational study. Bilateral breast implants. Invasive breast cancer or other invasive cancer diagnosis within five years. Metastatic malignancy of any kind.excluding Hodgkin's or non-Hodgkin's lymphoma. Current anticoagulant use. Consumption of coumadin, fish oil, or other anticoagulants during the 3 weeks prior to baseline RPFNA. Any other condition or intercurrent illness that in the opinion of the investigator makes the subject a poor candidate for RPFNA or the trial. Inclusion Criteria for Study Entry RPFNA performed in the follicular portion (day 1-10) of the menstrual cycle. Note that day 1 is defined as the first day of bleeding. RPFNA specimen exhibits hyperplasia +/- atypia (Masood score of ≥13) with ≥500 cells on the cytology slide. Ki-67 ≥2% positivity (≥500 cells). Willing to continue without oral contraceptives throughout the duration of the study participation (12 months). Non-oral contraceptives are permissible. If heterosexually active, must be agreeable to use some non-hormonal form of contraception during the trial or husband or partner must have had a vasectomy. (Safety of SDG during pregnancy has not been documented). Have reasonable organ function as documented by metabolic chemistry profile. Willing to undergo a history and physical at baseline and 12 months and be contacted periodically by the trial coordinator during the 12 month study period. Willing to have blood drawn at baseline and twelve months. Able to understand and willing to provide informed consent for the RPFNA's and study participation.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: flaxseed lignan, SDG<br>Secoisolariciresinol diglycoside | Drug: secoisolariciresinol<br>* 1 capsule daily of secoisolariciresinol diglycoside (SDG)50mg<br>* Other names: SDG;|
| Placebo Comparator: Placebo<br>Matched Placebo | Drug: Placebo<br>* The placebo contains same filler materials as commercially available Brevail® but without active SDG.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Percent of Breast Epithelial Cells With Ki-67 Immunocytochemical Expression | Change over the course of study in the percent of breast epithelial cells expressing the proliferation marker Ki- 67/MIB-1 in hyperplastic benign breast tissue acquired by random periareolar fine needle aspiration pre-study and post-study. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Gene Expression | Gene expression in breast epithelial cells assessed by RT-qPCR. Change in expression (fold-change for 12-months compared to baseline value) was evaluated by cluster analysis and used to define responders and non-responders based on favorable or non-favorable modulation of a set of 12 relevant genes. Specifically, data for change in ESR1 (codes for estrogen receptor alpha) are shown. | 12 months | 
| Breast Cancer Prevention Trial (BCPT) Symptom Checklist | Quality of life as measured by the Breast Cancer Prevention Trial (BCPT) Symptom Checklist, completed at baseline and end of study by each participant. Responses to 43 questions (with each question given a value from 0 to 4, higher score being worse) are clustered into seven domains to yield an average score per domain. These seven category scores are then averaged to provide a final average score (range by definition, 0 to 4). Change in score over the course of the intervention per individual is then assessed. By definition, change in score theoretically ranges from -4 to +4. | 12 months |