Flaxseed, Aromatase Inhibitors and Breast Tumor Characteristics

Study Overview
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Brief Summary
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The proposed study plans to examine the effect of flaxseed consumption, a phytoestrogen rich food, compared to aromatase inhibitors as a complementary approach to treating estrogen receptor positive breast cancer, as well as the effect of combined flaxseed and aromatase inhibitor therapy on breast cancer treatment. Because of the increasing use of both complementary and alternative approaches to treatment, and the use of aromatase inhibitors in the treatment of breast cancer, the proposed study has potential to provide important clinical information about the effect of foods high in phytoestrogens on a common endocrine therapy used in breast cancer.

Detailed Description
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Although the 10 year survival rate for women with early stage breast cancer is very good, distant recurrence is still a serious concern, especially for estrogen receptor positive women. Consequently, breast cancer survivors are interested in therapies that might improve their recurrence free survival (RFS). Used in postmenopausal women, aromatase inhibitors (AI) block the peripheral conversion of androgens to estrogen, effectively lowering the estradiol available to promote breast tumor proliferation. However, use of AIs is associated with hot flashes, joint pain, bone loss, and an increase in cardiac events. Furthermore, many breast tumors eventually develop resistance to hormonal treatments. Complementary and alternative medicines (CAMs) are widely used by cancer survivors in an attempt to reduce disease recurrence with fewer side effects and potential health benefits, and use is particularly prevalent among breast cancer survivors. Flaxseed (FS) is a commonly available food often consumed as a dietary supplement and is the richest food source of lignans, a phytoestrogen. In experimental models, flaxseed consumption has been shown to exhibit a number of activities that suggest a potential benefit of flaxseed in the adjuvant setting. However, the majority of human studies investigating the biologic effects of flaxseed have involved healthy women. There is a paucity of clinical data regarding the efficacy and safety of use of flaxseed among women with breast cancer, especially among those receiving AIs. Because the phytoestrogens in flaxseed can influence many of the same biologic pathways affected by hormonal agents, diet-drug interactions are possible. Additionally, it is possible flaxseed could act through growth and signaling pathways, modifying the development of endocrine resistance. Potential synergistic or antagonistic effects between flaxseed and antiestrogens are of particular interest given the increasing use of AIs to treat postmenopausal women with hormone responsive disease. We propose to conduct a pilot 2x2 factorial randomized intervention study between tumor biopsy and resection, in postmenopausal women diagnosed with ER positive breast cancer, to assess the effects of flaxseed and AI on a number of steroid hormone and tumor-related characteristics associated with long-term survival, and to investigate the potential interaction between flaxseed and AI on tumor expression of Ki-67, caspase, ERα, ERβ, PgR, HER2, IGF1, IGFIR. The pre-surgical setting offers a unique opportunity to rapidly obtain information on intervention related effects on growth factor and signaling pathways related to tumor characteristics in a short time period without the interference of other treatments. We hypothesize that both flaxseed and AI interventions will independently favorably affect growth factor and signaling pathway protein expression resulting in reduced tumor proliferation and increased apoptosis. We further hypothesize that these improvements will be reflected in improved recurrence scores as estimated by the Mammostrat antibody panel (Applied Genomics Incorporated). The proposed study will provide important clinical data for future dietary intervention studies involving phytoestrogen lignans from flaxseed.

Official Title
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Flaxseed vs. Aromatase Inhibitors: Breast Tumor Characteristics and Prognosis

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Anastrozole
* Dietary Supplement: flaxseed
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 and ≤ 85 years Postmenopausal status defined as: no menstrual cycle in the past 12 months hysterectomy with bilateral oophorectomy hysterectomy with intact ovaries if age > 55 years Newly diagnosed with incident, primary, invasive, estrogen receptor positive clinical stage II or lower breast cancer ECOG performance status of 1 or less Willingness to comply with study guidelines and procedures Willingness and ability to provide informed consent Usual consumption of soy no more than 1 time per week and willingness to avoid whole soy foods or concentrated soy sources (soy milk, tofu, substitute meat products, meal replacement bars) during the intervention period Willingness to avoid herbal and dietary supplements (not including vitamins), aspirin, and ibuprofen during the intervention period No competing neoadjuvant or chemotherapy treatment Time between pre-surgical visit and surgery must be at least 2 weeks No chemotherapy in the past 12 months Exclusion Criteria: Inability to read and write English Previous invasive breast cancer Insulin dependent Type I or II diabetes diagnosed by physician History of coagulopathy, thrombocytopenia, or bleeding disorder Current (past 30 days) regular (at least once per week) use of reproductive hormone therapy, Tamoxifen, aromatase inhibitors, or other estrogen inhibitors, flaxseed, or antibiotics Current chemotherapy or neoadjuvant chemotherapy Allergies to flaxseed, nuts, or other seeds Renal dysfunction defined as creatinine > 1.5 mg/dl History of Crohns' disease, ulcerative colitis, irritable bowel syndrome, celiac sprue, or other malabsorption syndrome, diverticulitis, diverticulosis, or other bowel diagnosis which, in the opinion of the breast surgeon, would contraindicate large doses of dietary fiber or would impair nutrient absorption Current, regular (more than once weekly) use of prescription blood-thinning agents including coumadin, heparin and heparin related drugs, clopidogrel bisulfate

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2<br>Flaxseed 25 mg per day and 1 placebo pill per day | Dietary Supplement: flaxseed<br>* 25 g per day ground<br>|
| Experimental: 3<br>25 mg flaxseed per day and 1 mg anastrozole pill per day | Drug: Anastrozole<br>* 1 mg per day<br>* Other names: Arimidex;Dietary Supplement: flaxseed<br>* 25 g per day ground<br>|
| Placebo Comparator: 4<br>Placebo pill 1 per day | Drug: Placebo<br>* Placebo pill 1 per day<br>|
| Experimental: 1<br>Anastrozole 1 mg pill per day | Drug: Anastrozole<br>* 1 mg per day<br>* Other names: Arimidex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression of Estrogen Receptor (ER-beta) | Mean percentage of cells expressing estrogen receptor (ER-beta) | Biopsy/Week 1 and Surgical Resection/Week 2 | 
| Progesterone Receptor (PR) Expression | Mean percentage of cells expressing PR | Biopsy/Week 1 and Surgical Resection/Week 2 | 
| Human Epidermal Growth Factor Receptor 2 (Her2) Expression | Mean percentage of cells expressing human epidermal growth factor receptor 2 (Her2) | Biopsy/Week 1 and Surgical Resection/Week 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Growth Hormone Serum Levels IGF-1 | Mean serum level IGF-1(pg/ml) | Biopsy/Week 1 and Surgical Resection/Week 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2, breast neoplasms, phytoestrogens, tumor characteristics, proliferation, apoptosis, estrogen receptor