Flaxseed, Aromatase Inhibitors and Breast Tumor Characteristics

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.

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