Breast Cancer, Precancerous Condition
Conditions
Keywords
mammography, biopsy, ductal breast carcinoma in situ, atypical ductal breast hyperplasia
Brief summary
RATIONALE: Broccoli sprout extract supplements may slow the growth of tumor cells or abnormal cells and may be an effective treatment for ductal carcinoma in situ and/or atypical ductal hyperplasia. PURPOSE: This randomized phase II trial is studying how well broccoli sprout extract works in treating women with a diagnosis of breast cancer, ductal carcinoma in situ and/or atypical ductal hyperplasia.
Detailed description
OBJECTIVES: * To determine the correlation between supplemental sulforaphane (broccoli sprout extract) dose and concentrations of sulforaphane and its metabolites in blood and urine samples from women positive for cancer, ductal carcinoma in situ and/or atypical ductal hyperplasia. * To determine the effect of this supplement on biomarkers of prognosis in these patients. * To determine the effect of this supplement on HDAC inhibition in peripheral blood cell and normal and cancerous breast tissue samples from these patients. OUTLINE: Patients are randomized to 1 of 2 treatment arms. * Sulforaphane Supplement: Patients receive oral broccoli sprout extract supplementation three times daily for 2-8 weeks in the absence of unacceptable toxicity. * Placebo: Patients receive oral placebo supplementation three times daily for 2-8 weeks in the absence of unacceptable toxicity. Blood and urine samples are collected at baseline and after completion of study treatment for laboratory biomarker studies. Patients scheduled to undergo surgery (mastectomy or lumpectomy) also undergo breast tissue sample collection at baseline and at the time of surgery. Samples are analyzed for sulforaphane metabolism (isothiocyanate levels), HDAC activity (acetylated histone expression), cell proliferation (Ki-67 index by IHC), and apoptosis (TUNEL assay). Patients complete questionnaires at baseline and periodically during study about their dietary history, family history, cruciferous vegetable intake, adverse events, and dietary and medication changes. After completion of study therapy, patients are followed at/around 30 days.
Interventions
DIETARY_SUPPLEMENTbroccoli sprout extract
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
OHSU Knight Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
21 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Diagnostic mammogram * English speaking
Exclusion criteria
* Pregnancy (as determined by urine human chorionic gonadotropin (hCG) test) * No biopsy referral after diagnostic mammogram * Patient reported breast feeding * Significant active medical illness which in the opinion of the investigator would preclude protocol treatment * History of or active liver disease or baseline total bilirubin greater than institutional upper limit of normal * Patient reported allergy or sensitivity to cruciferous vegetables * Use of oral antibiotics within three months prior to randomization * Oral steroid therapy at enrollment * Current therapy with valproate acid or SAHA * Current use of nutrient supplements or herbal remedies containing sulforaphane and unwillingness or inability to quit 72 hours prior to randomization and for the duration of the trial * Radiation for currently-diagnosed disease prior to or during study supplementation * Chemotherapy for currently-diagnosed disease prior to or during study supplementation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Isothiocyanate in Urine Samples as Assessed at Baseline and After Completion of Study Therapy | Baseline and end of study (up to 8 weeks) | Isothiocyante including sulforaphane in micromolar (µM) concentration was measured following standard chemical measurement procedures and divided by the creatinine values in millimolar (mM) concentration. |
| Change in Ki-67 as Assessed at Baseline and After Completion of Study Therapy | Baseline and end of study (up to 8 weeks) | Ki-67 was measured through immunohistochemistry method. A modified H-score was recorded, which involved semi-quantitative assessment of both staining intensity (graded as 1-3 with 1 representing weak staining, 2 moderate staining, and 3 strong staining) and percentage of positive cells. The range of the H-score was 0-300. The maximum score indicates the strongest expression, the minimum score indicates no expression of positive tumor area. |
| Change in Histone Deacetylase (HDAC) Activity as Assessed in Peripheral Blood Mononuclear Cells (PBMC) at Baseline and After Completion of Study Therapy | Baseline and End of Study (up to 8 weeks) | PBMC HDAC activity was evaluated using the positive control, sodium butyrate.HDAC activity is expressed relative to PBMC protein content and negative control. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Compliance | Baseline and end of study (up to 8 weeks) | For treatment compliance, participants who take \>=80% of the prescribed pills will be considered to be treatment-compliant. |
Countries
United States
Participant flow
Recruitment details
This clinical trial was conducted between 12/23/2008 to 3/27/2013 at Oregon Health and Science University's (OHSU) Center for Women's Health Breast Center in Portland, OR. English-speaking women were recruited to participate in the study based on the following inclusion criteria: ≥ 21 years, diagnostic mammogram with results that require biopsy.
Participants by arm
| Arm | Count |
|---|---|
| Sulforaphane Supplement Patients receive oral broccoli sprout extract supplementation three times daily for 2-8 weeks in the absence of unacceptable toxicity.
broccoli sprout extract: Given orally | 27 |
| Placebo Patients receive oral placebo supplementation three times daily for 2-8 weeks in the absence of unacceptable toxicity.
placebo: Given orally | 27 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period | Adverse Event | 1 | 5 |
| Treatment Period | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Sulforaphane Supplement |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 12 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 42 Participants | 24 Participants |
| Age, Continuous | 55.3 years STANDARD_DEVIATION 14.3 | 54.4 years STANDARD_DEVIATION 12.1 | 53.5 years STANDARD_DEVIATION 9.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 50 Participants | 26 Participants |
| Region of Enrollment United States | 27 participants | 54 participants | 27 participants |
| Sex: Female, Male Female | 27 Participants | 54 Participants | 27 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 | — / — | — / — |
| other Total, other adverse events | 8 / 27 | 9 / 27 |
| serious Total, serious adverse events | 0 / 27 | 0 / 27 |
Outcome results
Primary
Change in Histone Deacetylase (HDAC) Activity as Assessed in Peripheral Blood Mononuclear Cells (PBMC) at Baseline and After Completion of Study Therapy
PBMC HDAC activity was evaluated using the positive control, sodium butyrate.HDAC activity is expressed relative to PBMC protein content and negative control.
Time frame: Baseline and End of Study (up to 8 weeks)
Population: PBMCs available pre-/post-intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sulforaphane Supplement | Change in Histone Deacetylase (HDAC) Activity as Assessed in Peripheral Blood Mononuclear Cells (PBMC) at Baseline and After Completion of Study Therapy | -80.39 pmol/min/mg protein | Standard Error 48.53 |
| Placebo | Change in Histone Deacetylase (HDAC) Activity as Assessed in Peripheral Blood Mononuclear Cells (PBMC) at Baseline and After Completion of Study Therapy | 27.52 pmol/min/mg protein | Standard Error 32.58 |
Primary
Change in Isothiocyanate in Urine Samples as Assessed at Baseline and After Completion of Study Therapy
Isothiocyante including sulforaphane in micromolar (µM) concentration was measured following standard chemical measurement procedures and divided by the creatinine values in millimolar (mM) concentration.
Time frame: Baseline and end of study (up to 8 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sulforaphane Supplement | Change in Isothiocyanate in Urine Samples as Assessed at Baseline and After Completion of Study Therapy | 1.00 µM/mM creatinine | Standard Error 0.334 |
| Placebo | Change in Isothiocyanate in Urine Samples as Assessed at Baseline and After Completion of Study Therapy | -0.05 µM/mM creatinine | Standard Error 0.02 |
Primary
Change in Ki-67 as Assessed at Baseline and After Completion of Study Therapy
Ki-67 was measured through immunohistochemistry method. A modified H-score was recorded, which involved semi-quantitative assessment of both staining intensity (graded as 1-3 with 1 representing weak staining, 2 moderate staining, and 3 strong staining) and percentage of positive cells. The range of the H-score was 0-300. The maximum score indicates the strongest expression, the minimum score indicates no expression of positive tumor area.
Time frame: Baseline and end of study (up to 8 weeks)
Population: Maximum two observations (pre- and post- treatments) were expected per participant. Linear mixed effect models were used to calculate adjusted least square means (LSMEANS) and 95% confidence intervals,\& to test the statistical significance of the difference between pre- and post- treatments within each group, as well as between treatment groups.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Sulforaphane Supplement | Change in Ki-67 as Assessed at Baseline and After Completion of Study Therapy | Sulforaphane Supplement | -1.39 Log 2 (H-score) |
| Sulforaphane Supplement | Change in Ki-67 as Assessed at Baseline and After Completion of Study Therapy | Placebo | 0.23 Log 2 (H-score) |
| Placebo | Change in Ki-67 as Assessed at Baseline and After Completion of Study Therapy | Sulforaphane Supplement | 0.42 Log 2 (H-score) |
| Placebo | Change in Ki-67 as Assessed at Baseline and After Completion of Study Therapy | Placebo | -0.48 Log 2 (H-score) |
| Invasive Ductal Carcinoma Tissue; Ki-67 | Change in Ki-67 as Assessed at Baseline and After Completion of Study Therapy | Sulforaphane Supplement | 0.98 Log 2 (H-score) |
| Invasive Ductal Carcinoma Tissue; Ki-67 | Change in Ki-67 as Assessed at Baseline and After Completion of Study Therapy | Placebo | 0.28 Log 2 (H-score) |
Secondary
Treatment Compliance
For treatment compliance, participants who take \>=80% of the prescribed pills will be considered to be treatment-compliant.
Time frame: Baseline and end of study (up to 8 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sulforaphane Supplement | Treatment Compliance | 19 participants |
| Placebo | Treatment Compliance | 16 participants |