Benign Breast Neoplasm, Ductal Breast Carcinoma In Situ, Invasive Breast Carcinoma, Lobular Breast Carcinoma In Situ, Paget Disease of the Breast, Stage IA Breast Cancer, Stage IB Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer
Conditions
Brief summary
This randomized phase II trial studies how well docosahexaenoic acid works in preventing recurrence in breast cancer survivors. Docosahexaenoic acid supplement may prevent recurrence in breast cancer survivors.
Detailed description
PRIMARY OBJECTIVES: I. To determine whether treatment with docosahexaenoic acid (DHA) for 12 weeks at 1000 mg twice daily as compared to placebo reduces normal breast tissue levels of tumor necrosis factor-alpha (TNF-alpha) in overweight and obese patients with a history of stage I-III invasive breast cancer, ductal carcinoma in situ (DCIS), Paget's disease, lobular carcinoma in situ (LCIS), or proliferative benign breast disease. SECONDARY OBJECTIVES: I. To investigate the effect of DHA at 1000 mg twice daily on tissue biomarkers * Change from the baseline in cyclooxygenase-2 (COX-2)/interleukin-1-beta (IL-1beta)/aromatase measured by quantitative real-time polymerase chain reaction (PCR). * Change from the baseline in crown-like structures of the breast (CLS-B) measured by immunohistochemical techniques for cluster of differentiation (CD)68. * Change from baseline in CLS-B index determined as follows: (\[number of slides with evidence of at least one CLS-B\]/\[total number of slides examined\]). * Change from baseline in CLS-B/cm\^2 defined as the number of CLS-B/cm\^2. II. Evaluate age as a predictor of CLS-B and inflammatory biomarkers (TNF-alpha/COX-2/IL-1beta) at baseline and over the time of treatment. III. Evaluate red blood cell (RBC) fatty acid level as a surrogate of compliance. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive docosahexaenoic acid orally (PO) twice daily (BID) for 12 weeks. ARM II: Patients receive placebo PO BID for 12 weeks.
Interventions
DRUGDocosahexaenoic Acid
Given PO
OTHERPlacebo
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have a history of histologically-confirmed stage I-III invasive breast cancer or ductal carcinoma in situ (DCIS), Paget's disease, lobular carcinoma in situ (LCIS), or proliferative benign breast disease * No evidence of disease (in situ or invasive cancer that would normally be treated by resection) at trial entry as determined by the investigator * \>= 6 months from all previous breast cancer treatment (including surgery for invasive cancer, chest wall radiotherapy, chemotherapy, trastuzumab and endocrine therapy) * Participants must have a body mass index (BMI) \>= 25, defined as (weight in kilograms/\[height in meters\]\^2) * Participants must have adequate accessible breast tissue as determined by the treating physician, consisting of one breast unaffected by invasive cancer, which has not been radiated; a history of prior pre-invasive breast cancer or benign biopsy of this breast will be permitted * Daily DHA consumption =\< 200 mg/day in the month prior to screening estimated by an abbreviated DHA food frequency questionnaire * Mammogram within no more than 6 months prior to the date of informed consent (normal/benign Breast Imaging-Reporting and Data System \[BI-RADS\] 1 or 2) and no further routine breast imaging planned during the course of the study (12 weeks DHA/placebo) * Eastern Cooperative Oncology Group (ECOG) performance status must be =\< 2 (Karnofsky \>= 60%) * Absolute neutrophil count \>= 1,500/uL * Platelets \>= 75,000/uL * White blood cells \>= 3,000/uL * Hemoglobin \>= 10 g/dL * Total bilirubin within 1.5 times the institution's upper limit of normal (ULN) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) within 1.5 times the institution's ULN * Serum creatinine within 1.5 times the institution's ULN * Pregnant women will be excluded; for women of childbearing potential; negative pregnancy testing within 72 hours prior to or on study visit #1 (day 0) and willingness to use adequate contraception during the study intervention OR post-menopausal defined as any one of the following 1) prior hysterectomy, 2) absence of menstrual period for 1 year in the absence of prior chemotherapy or 3) absence of menstrual period for 2 years in women with a prior history of chemotherapy exposure who were pre-menopausal prior to chemotherapy * Willingness to comply with all study interventions and follow-up procedures including the ability to swallow the study drug * Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
* Any type of active invasive cancer (excluding breast and non-melanoma skin cancer) within the preceding 18 months * A history of histologically-confirmed bilateral invasive breast cancer * Bilateral mastectomy * Prior history or evidence of metastatic breast cancer * Prior radiation therapy to the contralateral (unaffected) breast * Prior history of contralateral (unaffected) breast augmentation with breast implant placement * History of daily use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) in the week preceding study entry * History of DHA supplementation \> 200 mg/day in the month preceding study entry * History of autoimmune disorder or any illness that requires therapy with chronic steroids or immunomodulators * History of therapeutic doses of anticoagulants including warfarin and low molecular weight heparin (e.g. for prior deep venous thrombosis and pulmonary embolism) in the preceding year * Participants may not be receiving any other investigational agents during the study * Women who have received cancer surgery, chemotherapy, biological therapy (e.g., trastuzumab), or radiotherapy for the treatment of any cancer within 6 months of study participation * Women who are receiving endocrine therapy for breast cancer treatment or chemoprevention including tamoxifen, letrozole, anastrozole, fulvestrant, or exemestane at the time of screening * Individuals with severe underlying chronic illness, such as uncontrolled diabetes; ongoing or active infection, psychiatric illness or social situations which in the opinion of the investigator would interfere with study participation * History of allergic reactions attributed to compounds of similar chemical or biologic composition to DHA or corn/soy oil in placebo agent * Pregnant, breastfeeding, or women of childbearing potential unwilling to use a reliable contraceptive method
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Normal Breast Tissue Expression of Tumor Necrosis Factor Alpha (TNF-alpha) Levels | Baseline to 12 weeks | Differences in normal breast tissue levels of TNF-α 12 weeks post-treatment relative to pre-treatment for active treatment and placebo arm, compared using analysis of covariance where the post-treatment measurements were used as a dependent variable and the pretreatment measurements were included as a covariate in the analysis. For the primary study end-point TNF-α levels will be measured by quantitative real-time PCR (mRNA essays) on extracted RNA from breast core biopsies. Relative expression determined using the Computed Tomography (ΔΔCT) analysis protocol. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Crown-like Structures of the Breast (CLS-B) at Baseline and Post-treatment | Baseline to 12 weeks | An indicator of whether a subject is detected with CLS-B or not. |
| Absolute Change in CLS-B/cm^2 Adjusted for the Pre-treatment Measurements | Baseline to 12 weeks | To assess the severity of CLS-B using the following formula: number of CLS-B/cm\^2. The absolute change in the CLS-B/cm\^2 calculated according to the formula; Change in CLS-B/cm\^2 = (post-treatment CLS-B/cm\^2) - (pre-treatment CLS-B/cm\^2). |
| Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Baseline and week 12 | Whole blood samples collected for red blood cell fatty acid analyses at baseline and week 12 (+ 2 weeks). RBC fatty acid composition analyzed by gas chromatography (GC) with flame ionization detection. |
| Mean Difference in the Breast Tissue IL- Beta mRNA Levels of Tissue Biomarkers | Baseline to 12 weeks | Biomarkers IL-1Beta are measured by quantitative real-time PCR. Differences between active treatment and placebo arm for each biomarker will be compared using analysis of covariance where the post treatment measurements will be used as a dependent variable and the pretreatment measurements will be included as a covariate in the analysis. |
| Mean Difference in the Breast Tissue Aromatase mRNA Levels of Tissue Biomarkers | Baseline and 12 weeks | Biomarkers Aromatase are measured by quantitative real-time PCR. Differences between active treatment and placebo arm for each biomarker will be compared using analysis of covariance where the post treatment measurements will be used as a dependent variable and the pretreatment measurements will be included as a covariate in the analysis. |
| Breast Tissue Cox 2 mRNA Levels at Baseline and 12 Weeks | Baseline to 12 weeks | Biomarkers COX-2 are measured by quantitative real-time PCR. Differences between active treatment and placebo arm for each biomarker will be compared using analysis of covariance where the post treatment measurements will be used as a dependent variable and the pretreatment measurements will be included as a covariate in the analysis. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: May 1 ,2013 to December 31, 2015. All recruitment done in medical settings.
Pre-assignment details
Of 65 participants enrolled, one was not eligible thus excluded from the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo orally twice a day for 12 weeks. | 32 |
| Docosahexaenoic Acid DHA 1000 mg orally twice a day for 12 weeks. | 32 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Not Evaluable | 5 | 3 |
| Overall Study | Screen Failure | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Docosahexaenoic Acid |
|---|---|---|---|
| Age, Continuous | 57 years | 59 years | 59.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 6 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 47 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 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 | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 55 Participants | 28 Participants |
| Region of Enrollment United States | 32 participants | 64 participants | 32 participants |
| Sex: Female, Male Female | 32 Participants | 64 Participants | 32 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 | 17 / 32 | 15 / 32 |
| serious Total, serious adverse events | 0 / 32 | 0 / 32 |
Outcome results
Primary
Normal Breast Tissue Expression of Tumor Necrosis Factor Alpha (TNF-alpha) Levels
Differences in normal breast tissue levels of TNF-α 12 weeks post-treatment relative to pre-treatment for active treatment and placebo arm, compared using analysis of covariance where the post-treatment measurements were used as a dependent variable and the pretreatment measurements were included as a covariate in the analysis. For the primary study end-point TNF-α levels will be measured by quantitative real-time PCR (mRNA essays) on extracted RNA from breast core biopsies. Relative expression determined using the Computed Tomography (ΔΔCT) analysis protocol.
Time frame: Baseline to 12 weeks
Population: 6 participants in the Placebo group and 1 participant in the DHA group were not evaluable due to tissue was not available quantitative RT-PCR.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Normal Breast Tissue Expression of Tumor Necrosis Factor Alpha (TNF-alpha) Levels | Baseline | 0.26 Log Transformed Relative ExpressionLevel | Standard Deviation 0.93 |
| Placebo | Normal Breast Tissue Expression of Tumor Necrosis Factor Alpha (TNF-alpha) Levels | Post-Treatment | 0.06 Log Transformed Relative ExpressionLevel | Standard Deviation 0.92 |
| Placebo | Normal Breast Tissue Expression of Tumor Necrosis Factor Alpha (TNF-alpha) Levels | Post-treatment vs. Baseline Change | -0.22 Log Transformed Relative ExpressionLevel | Standard Deviation 1.19 |
| Docosahexaenoic Acid | Normal Breast Tissue Expression of Tumor Necrosis Factor Alpha (TNF-alpha) Levels | Baseline | 0.08 Log Transformed Relative ExpressionLevel | Standard Deviation 0.78 |
| Docosahexaenoic Acid | Normal Breast Tissue Expression of Tumor Necrosis Factor Alpha (TNF-alpha) Levels | Post-Treatment | 0.16 Log Transformed Relative ExpressionLevel | Standard Deviation 0.95 |
| Docosahexaenoic Acid | Normal Breast Tissue Expression of Tumor Necrosis Factor Alpha (TNF-alpha) Levels | Post-treatment vs. Baseline Change | 0.08 Log Transformed Relative ExpressionLevel | Standard Deviation 0.99 |
p-value: 0.5ANCOVA
Secondary
Absolute Change in CLS-B/cm^2 Adjusted for the Pre-treatment Measurements
To assess the severity of CLS-B using the following formula: number of CLS-B/cm\^2. The absolute change in the CLS-B/cm\^2 calculated according to the formula; Change in CLS-B/cm\^2 = (post-treatment CLS-B/cm\^2) - (pre-treatment CLS-B/cm\^2).
Time frame: Baseline to 12 weeks
Population: Data were not collected.
Secondary
Breast Tissue Cox 2 mRNA Levels at Baseline and 12 Weeks
Biomarkers COX-2 are measured by quantitative real-time PCR. Differences between active treatment and placebo arm for each biomarker will be compared using analysis of covariance where the post treatment measurements will be used as a dependent variable and the pretreatment measurements will be included as a covariate in the analysis.
Time frame: Baseline to 12 weeks
Population: Participants with adequate RNA available were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Breast Tissue Cox 2 mRNA Levels at Baseline and 12 Weeks | Baseline COX-2 | 0.49 relative expression level | Standard Deviation 1.35 |
| Placebo | Breast Tissue Cox 2 mRNA Levels at Baseline and 12 Weeks | Post-Treatment COX-2 | -0.11 relative expression level | Standard Deviation 1.3 |
| Docosahexaenoic Acid | Breast Tissue Cox 2 mRNA Levels at Baseline and 12 Weeks | Post-Treatment COX-2 | 0.22 relative expression level | Standard Deviation 1.16 |
| Docosahexaenoic Acid | Breast Tissue Cox 2 mRNA Levels at Baseline and 12 Weeks | Baseline COX-2 | 0.31 relative expression level | Standard Deviation 0.97 |
p-value: 0.19ANCOVA
Secondary
Mean Difference in the Breast Tissue Aromatase mRNA Levels of Tissue Biomarkers
Biomarkers Aromatase are measured by quantitative real-time PCR. Differences between active treatment and placebo arm for each biomarker will be compared using analysis of covariance where the post treatment measurements will be used as a dependent variable and the pretreatment measurements will be included as a covariate in the analysis.
Time frame: Baseline and 12 weeks
Population: Participants with adequate RNA available were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Difference in the Breast Tissue Aromatase mRNA Levels of Tissue Biomarkers | Baseline Aromatase | -0.38 relative expression level | Standard Deviation 1.93 |
| Placebo | Mean Difference in the Breast Tissue Aromatase mRNA Levels of Tissue Biomarkers | Post-treatment Aromatase | -0.59 relative expression level | Standard Deviation 2.13 |
| Docosahexaenoic Acid | Mean Difference in the Breast Tissue Aromatase mRNA Levels of Tissue Biomarkers | Baseline Aromatase | 0.13 relative expression level | Standard Deviation 2.38 |
| Docosahexaenoic Acid | Mean Difference in the Breast Tissue Aromatase mRNA Levels of Tissue Biomarkers | Post-treatment Aromatase | 0.06 relative expression level | Standard Deviation 1.89 |
p-value: 0.12ANCOVA
Secondary
Mean Difference in the Breast Tissue IL- Beta mRNA Levels of Tissue Biomarkers
Biomarkers IL-1Beta are measured by quantitative real-time PCR. Differences between active treatment and placebo arm for each biomarker will be compared using analysis of covariance where the post treatment measurements will be used as a dependent variable and the pretreatment measurements will be included as a covariate in the analysis.
Time frame: Baseline to 12 weeks
Population: Participants with adequate RNA available were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Difference in the Breast Tissue IL- Beta mRNA Levels of Tissue Biomarkers | Baseline IL-Beta | 0.62 relative expression level | Standard Deviation 2 |
| Placebo | Mean Difference in the Breast Tissue IL- Beta mRNA Levels of Tissue Biomarkers | Post-treatment IL-Beta | 0.23 relative expression level | Standard Deviation 2.06 |
| Docosahexaenoic Acid | Mean Difference in the Breast Tissue IL- Beta mRNA Levels of Tissue Biomarkers | Baseline IL-Beta | 0.28 relative expression level | Standard Deviation 1.5 |
| Docosahexaenoic Acid | Mean Difference in the Breast Tissue IL- Beta mRNA Levels of Tissue Biomarkers | Post-treatment IL-Beta | 0.19 relative expression level | Standard Deviation 2.07 |
p-value: 0.52ANOVA
Secondary
Number of Participants With Crown-like Structures of the Breast (CLS-B) at Baseline and Post-treatment
An indicator of whether a subject is detected with CLS-B or not.
Time frame: Baseline to 12 weeks
Population: 4 participants on the placebo arm and 1 participant on the DHA arm did not have a post treatment biopsy.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Crown-like Structures of the Breast (CLS-B) at Baseline and Post-treatment | Baseline | 2 Participants |
| Placebo | Number of Participants With Crown-like Structures of the Breast (CLS-B) at Baseline and Post-treatment | Post-treatment | 3 Participants |
| Placebo | Number of Participants With Crown-like Structures of the Breast (CLS-B) at Baseline and Post-treatment | Positive both Baseline and Post-treatment | 2 Participants |
| Docosahexaenoic Acid | Number of Participants With Crown-like Structures of the Breast (CLS-B) at Baseline and Post-treatment | Baseline | 4 Participants |
| Docosahexaenoic Acid | Number of Participants With Crown-like Structures of the Breast (CLS-B) at Baseline and Post-treatment | Post-treatment | 3 Participants |
| Docosahexaenoic Acid | Number of Participants With Crown-like Structures of the Breast (CLS-B) at Baseline and Post-treatment | Positive both Baseline and Post-treatment | 0 Participants |
Secondary
Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance
Whole blood samples collected for red blood cell fatty acid analyses at baseline and week 12 (+ 2 weeks). RBC fatty acid composition analyzed by gas chromatography (GC) with flame ionization detection.
Time frame: Baseline and week 12
Population: Available blood samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Baseline Omega3 index | 5.03 percentage | Standard Deviation 1.65 |
| Placebo | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Baseline DHA level | 4.53 percentage | Standard Deviation 1.5 |
| Placebo | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Post-Treatment Omega3 index | 4.92 percentage | Standard Deviation 1.68 |
| Placebo | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Post-Treatment DHA level | 4.41 percentage | Standard Deviation 1.48 |
| Placebo | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Post Treatment v. Baseline Change Omega3 index | -0.10 percentage | Standard Deviation 0.068 |
| Placebo | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Post Treatment v. Baseline Change DHA level | -0.12 percentage | Standard Deviation 0.59 |
| Docosahexaenoic Acid | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Post Treatment v. Baseline Change Omega3 index | 6.99 percentage | Standard Deviation 1.43 |
| Docosahexaenoic Acid | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Baseline Omega3 index | 5.01 percentage | Standard Deviation 1.13 |
| Docosahexaenoic Acid | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Post-Treatment DHA level | 11.2 percentage | Standard Deviation 1.33 |
| Docosahexaenoic Acid | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Baseline DHA level | 4.47 percentage | Standard Deviation 0.98 |
| Docosahexaenoic Acid | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Post Treatment v. Baseline Change DHA level | 6.78 percentage | Standard Deviation 1.42 |
| Docosahexaenoic Acid | Red Blood Cell (RBC) Fatty Acid Level as a Surrogate of Compliance | Post-Treatment Omega3 index | 11.95 percentage | Standard Deviation 1.35 |