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From the Townsend Letter
April 2013

Breast Cancer Update: An Integrative Perspective
by Lise Alschuler, ND, FABNO
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Integrative Approaches
Perhaps the most important lifestyle intervention for women diagnosed with breast cancer is exercise. Many studies have indicated that exercise will help women with breast cancer, as it stimulates immune activity, enhances detoxification, encourages positive self-image, and helps prevent or reduce obesity. Exercise directly reduces risk factors for the development and progression of breast cancer, primarily via its effect on the body's metabolic processes. Women who obtain the equivalent of at least two to three hours of brisk walking each week in the year before they are diagnosed with breast cancer are 31% less likely to die of the disease than women who are sedentary before their diagnosis (HR = 0.69 [95% CI, 0.45 to 1.06; P = .045]). Additionally, compared with women who are inactive both before and after diagnosis, women who increase physical activity after diagnosis have a 45% lower risk of death (HR = 0.55; 95% CI, 0.22 to 1.38), whereas women who decrease physical activity after diagnosis have a fourfold greater risk of death (HR = 3.95; 95% CI, 1.45 to 10.50).14 The overall association between physical activity and breast cancer risk was further clarified in a meta-analysis and demonstrated a RR= 0.88 (CI=0.85–0.91). Stronger associations were found for subjects with BMI<25 kg/m2 [0.72 (0.65–0.81)], premenopausal women (0.77 [0.72–0.84]), and estrogen and progesterone receptor-negative breast cancer (0.80 [0.73–0.87]). Vigorous exercise reduced risk more than moderate activity (RR = 0.86 [0.82-0.89] vs. RR = 0.97 [0.94-0.99]).15

Increasing consumption of colorful fruits and vegetables is especially important in regard to breast cancer prevention and treatment. Many studies have demonstrated a link between breast cancer prevention and increased consumption of cruciferous vegetables and antioxidant-rich foods. In a secondary analysis of the Women's Healthy Eating and Living (WHEL) trial, researchers found in hot flash negative (indicative of higher circulating estrogen) women, increased consumption of vegetables, fruit, and fiber and reduced fat intake was associated with a 31% lower recurrence rate in premenopausal women and a 47% reduction of recurrence risk in postmenopausal women compared with this same diet in hot flash positive women.16 These results indicate that the benefits of a healthful diet may, in part, be due to the reduction in circulating estrogen. The role of fiber specifically has been assessed in this regard. A meta-analysis of 16 prospective studies on fiber intake and breast cancer risk concluded that the relative risk per 10gm per day of dietary fiber was 0.95 (95% CI 0.91–0.98, Pheterogeneity =0.82). In stratified analyses, the inverse association was only observed among studies with a large range (>13 g/day) or high level of intake (>25 g/day) of daily fiber. The intake of soluble fiber (seeds, legumes, oat, bran) but not insoluble fiber, fruit fiber, vegetable fiber, or cereal fiber was responsible for this inverse association. From a prevention standpoint, a prudent diet reduces risk of breast cancer. Prudent diets have high quantities of fruit, vegetables, poultry, fish, low-fat dairy, and whole grains. In a meta-analysis of 18 case-control and cohort studies, breast cancer risk is decreased in the highest compared with the lowest categories of prudent/healthful dietary patterns (OR = 0.89; 95% CI: 0.82, 0.99; P= 0.02) in all studies and in pooled cohort studies alone.17

A diet high in sugar should be avoided. A 2009 study featured in Cancer Causes and Control found that frequent consumption of sweets, particularly desserts, specifically in premenopausal women, doubled the risk of breast cancer development.18 High-sugar diets increase insulin resistance, which promotes breast cancer growth. Several studies have demonstrated a direct link between insulin resistance associated with the consumption of high glycemic index and high carbohydrate diets, and ER+/PR- breast cancer risk.

Alcohol consumption has been clearly linked to an increased risk of breast cancer. The relationship between alcohol and breast cancer is linear. Women who drink between one and two alcoholic drinks per day increase their relative risk of breast cancer by 10% compared with light drinkers who drink less than one drink a day. The risk of breast cancer increases by 30% in women who drink more than three drinks a day. However, these are relative risks which translate into a very small absolute risk for the average woman. A typical 50-year-old woman, for example, has a 5-year breast cancer risk of about 3%, so a 10% increase would increase that 5-year risk to 3.3% and a 30% increase would increase that risk to 3.9%. Women who consume two or more drinks a day would see their 10-year risk of breast cancer climb to 4.1% from 2.8%.19 Additionally, dietary intake of folic acid may protect against the increased risk of breast cancer associated with alcohol consumption.20 Folic acid is found in various beans, asparagus, and spinach.

Sleep and Stress
In a prospective study of 23,995 Japanese women, short sleep duration was associated with higher risk of breast cancer (143 cases). Women who slept less than 6 hours per night had a 62% increased risk of developing breast cancer compared with women who slept 7 hours per night (multivariate hazard ratio 1.62 [95% confidence interval: 1.05–2.50; P for trend=0.03]).21 Stress impacts risk as well. A twofold increase in breast cancer risk is evident after disruption of marriage owing to divorce, separation, or death of a spouse.22 Cancer risk may increase in association with chronic depression that has lasts for at least 6 years.23 The combination of extreme stress and low social support was associated with a 9-fold increase in breast cancer incidence.24 However, of note, findings regarding the impact of psychological distress and breast cancer risk have been inconsistent. In general, stronger relationships have been observed between psychosocial factors and cancer progression than between psychosocial factors and cancer incidence.
Nutrients and Herbs
A wide variety of nutrients and herbs have been studied for preventing and treating breast cancer. While there are numerous natural compounds with significant preclinical research, there are relatively fewer with clinical evidence to support their use. The following nutrients and herbs have clinical evidence of efficacy.

•   Black cohosh: Preclinical studies have shown that black cohosh decreases cyclin D1, resulting in cell cycle arrest or slowing.25 This facilitates cell repair or apoptosis. In a case-control study conducted in Germany, ever-use of herbal preparations that included black cohosh was inversely associated with invasive breast cancer (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.63–0.87) in a dose-dependent manner (OR, 0.96 per year of use; P = 0.03). The benefit was evident irrespective of histologic type and receptor status. Two different observational studies involving breast cancer patients have demonstrated a significant protective effective on the rate of recurrence. An observational retrospective cohort study included 18,861 women with a previous diagnosis of breast cancer who were taking tamoxifen. The women were observed for an average of 3.6 years. After 2 years from diagnosis, 14% of control group developed recurrence. The black cohosh group took 6.5 years to reach 14% recurrence. After controlling for age, tamoxifen use and other confounders, black cohosh use demonstrated a protective effect on the rate of recurrence (hazard ratio 0.83, 95% CI 0.69–.099).26 Another population-based retrospective case control study with 949 breast cancer patients and 1524 controls from Philadelphia metropolitan area assessed the use of hormone related supplements (HRS) in association with breast cancer. The use of black cohosh (Remifemin) was associated with a significant cancer protective effect (adjusted odds ratio 0.47, 95% CI 0.27–0.82) in women as opposed to other HRS.27

•   Green tea: Several studies have demonstrated that green tea has a protective effect against breast cancer and can also inhibit breast cancer cell growth and invasion. A 7-year prospective trial of 472 Japanese premenopausal women with stage I to III invasive breast cancer found that an average consumption of 8 cups (4 oz size cup) of green tea daily was associated with a recurrence rate of 16.7% and a disease-free survival of 3.6 years in women with stages I and II cancer. These rates demonstrate improvement compared to non- or light green tea drinkers (less than 2 cups daily) with stages I and II cancers who have a recurrence rate of 24.3% and disease-free survival of 2.8 years. There was no benefit observed from green tea in stage III patients.28 In another prospective cohort study, women with a history of stage I–IV breast cancer were followed for an average of 4.5 years. Those women with stage I breast cancer who drank at least 5 cups of green tea daily had a 57% lower recurrence rate as well as decreased extent of recurrent disease. There was no effect noted in women with stage III and IV breast cancer.29 One 275–300 mg green tea extract capsule standardized to ³80% polyphenols and ³50% EGCG) is equal to two cups of green tea.

•   Indole-3-carbinol: A phase I trial of indole-3-carbinol (I3C) in 17 women (1 postmenopausal and 16 premenopausal) from a high-risk breast cancer cohort assessed the impact of I3C on hormonal risk factors. After a 4-week placebo run-in period, the subjects ingested 400 mg I3C daily for 4 weeks followed by 4 weeks of 800 mg I3C daily. All doses were tolerated well by all subjects. Comparing the results from the placebo with the 400mg and 800 mg daily dose periods, CYP1A2 was elevated by I3C in 94% of the subjects, with a mean increase of 4.1-fold. The increased activity of CYP1A2 was reflected in a 66% increase in the urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio in response to I3C. Additionally, lymphocyte glutathione S-transferase activity was increased by 69% in response to I3C. The maximal increase was observed with the 400 mg daily dose of I3C, with no further increase found at 800 mg daily.30 Similar results have obtained with 3,3'-diindolylmethane (DIM).31

•   Melatonin: At nocturnal levels, melatonin inhibits cell proliferation by delaying cells in the G1 phase of cell division. At pharmacological levels, melatonin exerts cytotoxic effects on cancer cells by stimulating apoptosis, altering adhesion molecule expression thus reducing invasiveness, regulating ER expression, inhibiting aromatase, and influencing kinase pathways.32,33 The effects of these mechanisms are demonstrated in human studies. In a prospective case-control study of 147 cases and 291 matched controls nested within the Nurses' Health Study II cohort, the relative risk of invasive breast cancer was 41% lower in those women with the highest concentration of a major melatonin metabolite (6-sulphatoxymelatonin) in the first morning urine.34 Additionally in a phase 2 study of tamoxifen and melatonin in metastatic breast cancer patients who were nonresponders to tamoxifen (progressed during tamoxifen treatment), the addition of 20 mg of melatonin caused a partial response to tamoxifen in 28% of the women.35

•   Mushrooms: A medicinal mushroom derivative known as polysaccharide krestin (PSK) has been shown in an adjuvant randomized trial of 914 women to increase disease-free survival in patients with node-negative, ER-negative, and stage IIA T2N1 cancer. The dosage used in the study was 3 g per day.36 Similar effects were observed in a randomized trial of 227 operable breast cancer patients with vascular invasion in the tumor and/or in the metastatic lymph node. The survival curve of the chemotherapy with 5-fluorouracil, cyclophosphamide, mitomycin C, and predonisolone (FEMP) and PSK group tended to be better than that of the chemotherapy group (logrank, P = 0.0706; generalized Wilcoxon, P = 0.0739).37 The dosage in this trial was also 3 gm daily.

•   Vitamin D: Although this vitamin has been studied primarily for its role in preventing breast cancer, newer research indicates that breast cancer prognosis may also be improved with vitamin D therapy. Studies indicate that women with low levels of vitamin D tend to have more advanced breast cancers while women with higher levels tend to have less advanced cancers.38

Some progress has been made in lowering the incidence of breast cancer among menopausal women, an effect attributed to the dramatic reduction of hormone replacement therapy in use by these women since 2003. Slight improvements have also been made in the prognosis for all women, primarily due to early detection followed by comprehensive treatment. Nonetheless, breast cancer remains the number one cause of death by cancer in women. An integrative approach to the entire spectrum of this disease – from prevention to treatment and including the reduction of recurrence risk – is indicated. Among the most promising components of an integrative approach are a healthful lifestyle that includes a balanced diet, exercise, stress management, and strong support systems. Additionally, supplementation with green tea, melatonin, PSK, I3C, and vitamin D are at the forefront of promising dietary supplementation.


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