Breast Cancer
Conditions
Brief summary
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
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.
Interventions
DRUGPlacebo
The placebo contains same filler materials as commercially available Brevail® but without active SDG.
DRUGsecoisolariciresinol
1 capsule daily of secoisolariciresinol diglycoside (SDG)50mg
Sponsors
Lignan Research Inc.
Carol Fabian, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
21 Years to 49 Years
Healthy volunteers
Yes
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Percent of Breast Epithelial Cells With Ki-67 Immunocytochemical Expression | 12 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Gene Expression | 12 months | 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. |
| Breast Cancer Prevention Trial (BCPT) Symptom Checklist | 12 months | 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. |
Countries
United States
Participant flow
Pre-assignment details
180 participants were screened and found to be eligible. Two withdrew consent prior to being randomized. Of the 178 randomized, 116 were assigned to active agent; 62 to placebo. One active agent participant withdrew prior to receiving study agent. The 177 who received study agent constitute the analytic population.
Participants by arm
| Arm | Count |
|---|---|
| Flaxseed Lignan, SDG Secoisolariciresinol diglycoside
secoisolariciresinol: 1 capsule daily of secoisolariciresinol diglycoside (SDG)50mg | 115 |
| Placebo Matched Placebo
Placebo: The placebo contains same filler materials as commercially available Brevail® but without active SDG. | 62 |
| Total | 177 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Non-compliant | 2 | 2 |
| Overall Study | Physician Decision | 3 | 5 |
| Overall Study | Withdrawal by Subject | 7 | 1 |
Baseline characteristics
| Characteristic | Flaxseed Lignan, SDG | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 38.4 years STANDARD_DEVIATION 6.7 | 39.7 years STANDARD_DEVIATION 6.1 | 38.8 years STANDARD_DEVIATION 6.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 2 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 108 Participants | 60 Participants | 168 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Ki-67 expression | 6.1 percent of breast epithelial cells STANDARD_DEVIATION 0.4 | 5.4 percent of breast epithelial cells STANDARD_DEVIATION 4.2 | 5.9 percent of breast epithelial cells STANDARD_DEVIATION 4.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 3 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 103 Participants | 59 Participants | 162 Participants |
| Region of Enrollment United States | 115 participants | 62 participants | 177 participants |
| Sex: Female, Male Female | 115 Participants | 62 Participants | 177 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 115 | 0 / 62 |
| other Total, other adverse events | 84 / 115 | 45 / 62 |
| serious Total, serious adverse events | 2 / 115 | 4 / 62 |
Outcome results
Primary
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.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flaxseed Lignan, SDG | Change in Percent of Breast Epithelial Cells With Ki-67 Immunocytochemical Expression | -1.4 change in percent Ki-67 | Standard Deviation 5.3 |
| Placebo | Change in Percent of Breast Epithelial Cells With Ki-67 Immunocytochemical Expression | -1.4 change in percent Ki-67 | Standard Deviation 5.3 |
Comparison: 83% power to detect an absolute 2.5% reduction in Ki-67 for the treatment group compared with no reduction in the control group.p-value: 0.72Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Flaxseed Lignan, SDG | Breast Cancer Prevention Trial (BCPT) Symptom Checklist | -0.05 Change in score on a scale |
| Placebo | Breast Cancer Prevention Trial (BCPT) Symptom Checklist | 0.21 Change in score on a scale |
p-value: 0.036Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: 12 months
Population: Adequate residual material available from baseline and 12-month specimens for post-hoc analysis of change in gene expression.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Flaxseed Lignan, SDG | Change in Gene Expression | > 2-fold increase | 3 Participants |
| Flaxseed Lignan, SDG | Change in Gene Expression | No substantial change | 36 Participants |
| Flaxseed Lignan, SDG | Change in Gene Expression | < 0.5 fold change | 10 Participants |
| Placebo | Change in Gene Expression | > 2-fold increase | 7 Participants |
| Placebo | Change in Gene Expression | No substantial change | 19 Participants |
| Placebo | Change in Gene Expression | < 0.5 fold change | 2 Participants |
p-value: 0.018Wilcoxon (Mann-Whitney)