Breast Cancer

Deborah Straub, MS, RD INTRODUCTION

Much interest exists about the role nutrition plays in the etiology, treatment, and recurrence of breast cancer. To date, hundreds of studies have been published on nutrition’s influence on the etiology of breast cancer, but much of this research is limited in scope and inconclusive. Nutrition care during breast cancer treatment should address not only the usual side effects associated with cancer treatment, but also the consequences of early menopause caused by treatment and the drug therapies that lower endogenous estrogen production. Many women treated for breast cancer use complementary and alternative medicine (CAM) to manage menopausal symptoms, and it is imperative that they obtain further knowledge about the risk versus benefit of supplementation. Data dealing with nutrition’s potential to prevent recurrence of breast cancer are very limited, although a few clinical trials in this area have been completed or are in progress.

Breast Cancer Incidence

Breast cancer is the most common cancer in women. In 2008, it is estimated that 184,460 new cases of invasive breast cancer will be diagnosed.1 During the period of 2001-2004, breast cancer incidence decreased by 3.5% per year. Breast cancer rates had been continuously increasing for more than two decades. This recent decrease may be due to the decline in the use of hormone replacement therapy (HRT) following publication of the results of the Women’s Health Initiative (WHI) in 2002, which linked HRT use with increased risk of breast cancer and heart disease. It may also reflect a slight decrease in mammography utilization.

An estimated 67,770 new cases of ductal carcinoma in situ (DCIS) are expected to be identified in 2008. Incidence rates of this noninvasive form of breast cancer have leveled off since the late 1990s, which may also reflect the decrease in mammography utilization.

Breast cancer is second only to lung cancer as the most common cause of cancer death in women. An estimated 40,930 breast cancer deaths are expected in 2008. Death from breast cancer has steadily declined since 1990—a trend attributable to a combination of early detection and advancements in treatment. Five-year survival rates for all races are 98% for localized cancer, 84% for regional cancer, and 27% for distant female breast cancer.

Breast Anatomy and Estrogen Metabolism

The anatomy of the breast consists of primarily fat, connective tissue, epithelial cells, and glandular tissue arranged into lobules and ducts. The lobules are the milk-producing glands of the breast. Ducts connect the lobules to the nipple. Epithelial cells line the lobules and the ducts. A variety of hormones—including estrogen, progesterone, insulin and growth factors—contribute to breast tissue development during puberty, pregnancy, and lactation. After menopause, the glandular tissue atrophies as estrogen and progesterone levels decline.

The female hormone estrogen is found in three forms: estradiol, estrone, and estriol. The most potent of these is estradiol. Estrogens circulate in the blood bound to sex-hormone-binding globulin (SHBG). Only unbound estrogens can enter target tissue cells and induce biological activity. Prior to menopause, estrogens are synthesized from cholesterol in the ovaries in response to pituitary hormones. The amount of estrogen produced after menopause, however, is significantly less than the amount produced prior to menopause. After menopause, estrogen is produced primarily by the aromatization of adrenal androstenedione to estrone in the peripheral tissues. Estrogens are also produced by the aromatization of androgens in fat cells. In postmenopausal women, the ovaries continue to make small amounts of testosterone, which is converted to estradiol.

The metabolism of estrogen takes place predominantly in the liver through Phase I (hydroxylation) and Phase II (methylation, glucuronidation, and sulfation) pathways. Estrogen is excreted in the urine and feces.

Estrogens have a wide range of actions, such that they affect almost all systems of the body in a tissue-specific manner. Estrogens bind with high affinity to estrogen receptors (ER) in target cells. When estrogen is bound to the receptor, it initiates transcription of the estrogen-responsive target gene. Two forms of estrogen receptors are distinguished—alpha and beta—that differ in terms of their tissue distribution, binding affinity, and biological function. Different target cells may respond differently to estrogen depending on the ratio of receptor subtypes. The actions of the selective estrogen modulators (SERMs) known as tamoxifen and raloxifene are examples of this phenomenon: These drugs act as estrogen in some tissue (bone) and block its action in other tissues (breast).

Cellular Classification of Breast Cancer

Breast cancers are primarily carcinomas of the epithelial cells. Breast cancer is classified based on whether the cancer arose from the epithelial cells of the ducts or the lobules and whether the cells infiltrated through the duct or the lobule into the fatty tissue of the breast. Invasive (or infiltrating) ductal carcinoma (IDC; see Figure 8.1) is the most common type of invasive breast cancer, accounting for 80% of invasive breast cancers. Invasive (infiltrating) lobular carcinoma (ILC; see Figure 8.2) represents 10% of invasive breast

Figure 8.1 Invasive Ductal Carcinoma (IDC)

Figure 8.2 Invasive Lobular Carcinoma (ILC)

cancers. Noninvasive breast cancers include DCIS (Figures 8.3, page 191, and 8.4, page 192) and lobular carcinoma in situ (LCIS). LCIS is not a true cancer, but it does increase a woman’s risk of developing invasive breast cancer in the ispsilateral or in the contralateral breast. Inflammatory breast cancer is a rare but aggressive type of breast cancer; it accounts for 1-5% of all breast cancer cases. Its symptoms may include redness, swelling, and warmth without a distinct tumor. Other less common ductal breast cancers include medullary, mucinous, papillary, and tubular carcinomas. Paget’s disease of the nipple is rare and is responsible for only 1% of all breast cancers.

Breast cancer subtypes with distinct gene expression profiles have been identified through the use of microarray analysis.2 The two major subtypes of the estrogen receptor-positive (ER-positive) tumors are luminal A and luminal B. Luminal A tumors tend to have a higher expression of ER-related genes and a lower expression of proliferative genes than do luminal B tumors. The major subtypes of the ER-negative tumors are those involving the human epidermal growth factor 2 (HER-2) and the basal-like subtype. Most ER-negative tumors tend to be HER-2 positive. The basal-like subtype

Figure 8.3 Ductal Carcinoma in Situ (DCIS)

tends to have a low expression of ER, progesterone receptor (PR), and HER-2. In general, HER-2-positive and basal-like subtypes are more aggressive than the luminal A tumors. The luminal A subtype appears to be associated with the best prognosis.

Breast Cancer Risk

As noted earlier, breast cancers are primarily carcinomas of the epithelial cells. Estrogen modulates the structure and growth of epithelial cells. Thus estrogen exposure is a well-established risk factor for breast cancer.3 Cumulative, excessive estrogen exposure over the course of a lifetime contributes to breast cancer risk and may be a cause of this disease. Early menarche, late menopause, not having children, or having children after age 30 all increase a woman‘s breast cancer risk.4 Such prolonged estrogen exposure can cause direct genotoxic effects by increasing breast cell proliferation and random genetic errors affecting cellular differentiation and gene expression. The mechanisms of carcinogenesis include the metabolism of estrogen to mutagenic

Figure 8.4 Range of Ductal Carcinoma in Situ (DCIS)

, genotoxic metabolites and the stimulation of tissue growth. These processes cause initiation, promotion, and progression of breast cancer.

Risk prediction models can be helpful in assessing a woman’s risk for breast cancer. The Breast Cancer Risk Assessment Tool (available at http://www.cancer.gov/bcrisktool) is a computer assessment tool developed by the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project (NSABP).5 It estimates breast cancer risk over the woman’s next five years and over a lifetime and is based on the Gail model. The risk factors included in this tool include age, age at menarche, age at first live birth, breast cancer among first-degree relatives, and breast biopsies. The Breast Cancer Risk Assessment Tool was developed and validated for primarily non-Hispanic white women in the United States who are age 35 or older. More research is needed to refine and validate this model for other racial and ethnic groups.

Other risk factors for breast cancer have been identified but have not yet been incorporated into the Breast Cancer Risk Assessment Tool, as independent validation studies are lacking for these risk factors. In a large prospective study involving 1 million women who underwent screening mammography, researchers identified statistically significant risk factors for both premenopausal and postmenopausal women.6 In premenopausal women, risk of breast cancer diagnosis was significantly associated with age, breast density, number of first-degree relatives with breast cancer, and a prior breast procedure. A prior breast procedure was associated with an approximately 50% increase in risk even without knowledge of the type or result of the prior breast procedure. Breast density was strongly associated with increased risk among women with extremely dense breasts, with this characteristic conferring almost a fourfold greater risk than having breasts composed primarily of fat. In postmenopausal women, risk increased with age, breast density, family history of breast cancer, a prior breast procedure even without knowledge of the type of prior procedure or the outcome, hormonal therapy, age at natural menopause, and a prior false-positive mammogram. Other factors associated with increased risk in postmenopausal women included higher body mass index (BMI), late age at the birth of the first child or being nulliparous, and the use of hormone replacement therapy. The study did not distinguish among the various types of hormone therapy.

In another study, radiation exposure to the chest for treatment during childhood or young adulthood cancers was found to significantly increase the risk of breast cancer in adulthood.7 The risk was highest if the radiation was given during adolescence.

Genetic Breast Cancer

Genetic breast cancer, in which one dominant cancer gene is passed on to future generations, accounts for only 5-10% of all breast cancer cases. Most breast cancer cases are sporadic, meaning that there is no family history; indeed, 70-80% of women who get breast cancer do not have a family history of this disease.

A number of genetic mutations have been identified that increase the risk of breast cancer. Notably, mutations in the tumor suppression genes BRCA1

and BRAC2 confer up to a 50-80% lifetime chance of developing breast cancer. BRCA mutations are most often found in Jewish women of Ashkenazi (Eastern European) origin, but can appear in any racial or ethnic group.

Screening

The goal of screening is to detect breast cancer when it is more likely to be at an early stage, have a better prognosis, and be more successfully treated. Screen-detected breast cancers with or without clinical breast exams are associated with reduced morbidity and mortality. The American Cancer Society has established screening guidelines for breast cancer.8 Mammography screening is the primary tool for early detection and is recommended annually for women starting at age 40. Women who are at high risk of developing breast cancer (greater than 20% lifetime risk) should have an annual breast magnetic resonance imaging (MRI) scan in addition to an annual mammogram.9

Diagnosis

A diagnostic mammogram is performed when a suspicious finding is identi-lied on a screening mammogram. A breast ultrasound (US) and a breast MRI may be performed to obtain additional information. If imaging studies show suspicious findings, a biopsy will be performed.

The National Comprehensive Cancer Network (NCCN) has established diagnostic workup and treatment guidelines for breast cancer.10 The workup for invasive cancer includes a history and physical examination, complete blood count, platelets, liver function tests, chest imaging, diagnostic bilateral mammogram, US as necessary, optional breast MRI, and a pathology review, including the determination of tumor estrogen/progesterone receptor status (ER/PR), human epidermal growth factor receptor 2 (HER-2/neu) status, and surgical margins. A bone scan, abdominal computed tomography (CT) scan, or positron emission tomography (PET) scan may also be performed depending on the stage of the cancer and the laboratory findings.

Treatment

The treatment of local disease may consist of surgery, radiation therapy (RT), or both. The management of systemic disease, if present, may involve cytoxic chemotherapy, endocrine therapy, biologic therapies, or combinations of these modalities. Treatment is determined by numerous factors, including disease stage, tumor histology, clinical and pathologic characteristics of the tumor, axillary node status, tumor hormone receptor status, level of HER-2/neu expression, presence or absence of detectable metastatic disease, comorbid conditions, the patient’s age, and menopausal status. Molecular profiling of breast cancers using array technology has confirmed that breast cancer is a heterogeneous group of diseases that are marked by differences in prognosis and response to therapy.11 Molecular predictive models are beginning to influence treatment strategies.

Staging

The American Joint Committee on Cancer’s (AJCC) TNM system is used to stage breast cancer. Five stages of breast cancer are distinguished based on the tumor (T) size and spread to the chest wall or skin; the degree of lymph node involvement (N) (Figures 8.5 and 8.6); and metastasis to distant organs (M).

Stage 0 includes DCIS and LCIS. DCIS is the earliest form of breast cancer, in which the cancer cells are still within the duct and have not invaded the surrounding fatty breast tissue. DCIS is usually treated with lumpectomy, RT, and tamoxifen citrate. LCIS is not considered true breast cancer by most oncologists, but is a marker for increased future risk and is treated with tamoxifen.

Figure 8.5 Axillary Lymph Nodes

Figure 8.6 Vascular and Lymphatic Invasions

Stages I—IV are classified by increasing tumor size, number of positive lymph nodes, and metastases to distant locations. The most common sites for metastatic breast cancer are the bone, liver, brain, or lung.

Local Treatment

Surgery Breast-conserving lumpectomy and mastectomy are the two types of surgery used to locally remove breast cancer. With lumpectomy, the tumor and healthy tissue surrounding the tumor are removed; the surgical procedure is then usually followed by RT. With mastectomy, the entire breast, including the nipple, is removed. Women may elect to have reconstruction surgery at the same time as mastectomy, after mastectomy, or not at all. Survival rates for breast-conserving surgery plus RT are equal to those for mastectomy in case of Stage I and Stage II breast cancers.

Sentinel node biopsy is the preferred method of determining lymph node involvement. If the sentinel node is positive, an axillary dissection is performed. Complications of surgery vary with the type of surgery performed and the number of lymph nodes removed. Side effects are less common and less severe with sentinel node dissection, but are more common and more severe with full axillary lymph node dissection. Side effects of lymph node dissection include nerve damage, limitation of arm and shoulder movement, and lymphedema of the arm.

Radiation Therapy Most women treated with breast-conserving surgery require follow-up treatment with RT. RT may also be indicated after mastectomy if the patient has extensive lymph node involvement. External-beam whole-breast radiation therapy with a boost to the tumor bed is the most common form of radiation employed. Brachytherapy or interstitial radiation involving the placement of radioactive seeds may be an option in some cases.

Side effects of radiation to the breast include swelling and heaviness in the breast, sunburn-like skin changes, hair loss in the treated area, and fatigue. Most symptoms occur during the second or third week of treatment and resolve within 2-4 weeks after RT completion. Changes in breast tissue and skin generally resolve in 6-12 months. Long-term risks associated with RT to the breast include rib fractures and secondary cancers caused by the radiation. Women treated with RT to the left breast are more likely than women treated with RT to the right breast to develop cardiac disease, including myocardial infarction and chest pain.12

Systemic Therapy

Chemotherapy The decision to initiate adjuvant polychemotherapy involves balancing the risk of recurrence from local therapy alone, the degree of benefit from chemotherapy (CT), the toxicity of the therapy, and existing comorbidities. Neoadjuvant CT may be given to reduce the size of the tumor prior to surgery. Chemotherapy is also used to treat metastatic breast cancer.

Multi-gene testing of the tumor to predict responsiveness to chemotherapy and prognosis is currently available. However, the NCCN believes that none of the available tests has been adequately studied to recommend its use in clinical practice.

The severity of side effects of chemotherapy depend on the specific agent used, the dose, the length of treatment, existing comorbidities, and individual tolerance.

Adjuvant Endocrine Therapy Adjuvant endocrine therapy is instituted for breast cancers that are estrogen or progesterone receptor-positive (ER-positive, PR-positive). The two SERMs used for treatment of breast cancer, tamoxifen and raloxifene (Evista), compete with estrogen for receptor sites in target tissues such as the breast.

Tamoxifen is used for adjuvant treatment for premenopausal breast cancer. It is also used to reduce the risk of breast cancer in women with LCIS and DCIS.13 This drug exerts estrogen-like activity on the skeletal and cardiovascular systems, reducing bone loss and improving lipid levels. Side effects of tamoxifen include hot flashes, night sweats, and vaginal dryness. Serious adverse effects include an increased risk of cataracts, endometrial cancer, and pulmonary embolism.

The U.S. Food and Drug Administration approved raloxifene for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer.14 Raloxifen has not been approved for use in decreasing breast cancer risk in women with DCIS.

Aromatase inhibitors (AIs) are used to decrease estrogen levels in postmenopausal women through aromatase inhibition. Members of this drug class include anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin), all of which are used only in postmenopausal women. Nutrition-related side effects of Als include loss of bone mineral density (BMD). Some agents may also have a negative effect on patients’ lipid profiles.15 For example, letrozole has been associated with increased total serum cholesterol, low-density cholesterol, apolipoprotein B, and serum-lipid risk ratios related to cardiovascular disease. An updated safety analysis of the Breast Cancer International Group (BIG) 1-98 study found that cardiovascular adverse events were relatively rare with letrozole, however.16 A large ongoing phase III trial comparing anastrozole with letrozole will provide head-to-head safety evaluations of the two drugs. Because most women presenting with early-stage breast cancer can expect long-term survival, the assessment of cardiovascular adverse effects of AIs is important.

Targeted Therapy

Trastuzumab (Herceptin) is used to treat HER-2/neu-positive tumors, which tend to be more aggressive. Overexpression of the HER-2/neu protein increases the rate of cell growth and division. Trastuzumab is a recombinant DNA-derived monoclonal antibody that selectively binds to HER-2, thereby inhibiting the proliferation of tumor cells that overexpress HER-2.

Ovarian Ablation

In an effort to decrease estrogen levels, premenopausal women may elect to have an oophorectomy. Side effects of this treatment include early menopause, which may be associated with hot flashes, night sweats, and bone loss.

Prognosis

The most significant prognostic factors predicting future recurrence or death from breast cancer include patient age, stage, comorbidity, tumor size, tumor grade, number of involved axillary lymph nodes, and possibly HER-2/neu level of expression. Algorithms are available that estimate rates of recurrence. A validated computer-based model, Adjuvant! Online, estimates 10-year disease-free and overall survival and is available at www.adjuvantonline.com.

Nutrition and Lifestyle Factors in the Etiology of Breast Cancer

All cancers start as a single cell that has lost control of its normal growth and replication processes. Carcinogenesis is a multistage process consisting of three phases: initiation, promotion, and progression. Initiation occurs when the cell has been exposed to an agent that results in the first genetic mutation, but by itself initiation is not sufficient for a cancer to develop. Instead, the initiated cell must be activated by a promoting agent that causes cellular proliferation—that is, the process called promotion. Initiated and promoted cells eventually form a tumor mass during the process of progression. At the end of the carcinogenesis process, the cell will have some or all of the characteristics of a cancer cell: growth signal autonomy, insensitivity to antigrowth signals, limitless replicative potential, evasion of apoptosis, sustained angiogenesis, tissue invasion, and metastasis. Factors related to food, nutrition, and physical activity can influence the various cellular processes involved in carcinogenesis.

In 2007, a joint panel of the World Cancer Research Fund (WCRF) and American Institute for Cancer Research published its findings on the role of food, nutrition, and physical activity in cancer prevention (Figure 8.7).17 In their report, the panel members judged the weight of the evidence for the role of nutrition and lifestyle factors in the etiology of breast cancer. Premenopausal and postmenopausal breast cancers were considered separately Postmenopausal

Figure 8.7 The Influences of Food, Nutrition, Obesity and Physical Activity on the Cellular Processes Linked to Breast Cancer in the report. Premenopausal cancers are thought to be mainly genetically driven, with the environment and nutrition playing smaller roles in their genesis. In the genetically associated cancers, a healthy diet may result in the delayed onset of the disease. Diet modulation is most likely to influence postmenopausal disease, which is more prolonged in onset. The panel’s findings related to breast cancer risk are summarized next.

Breast Cancer

Convincing evidence: The consumption of alcoholic drinks, body fatness, and adult attained height increase risk; lactation decreases risk.

Probable evidence: Physical activity decreases risk; abdominal fatness and adult weight gain increase risk.

Limited suggestive evidence: Total fat intake increases risk.

Premenopausal Breast Cancer

Convincing evidence: Lactation decreases risk; consumption of alcoholic beverages increases risk.

Probable evidence: Body fatness decreases risk; adult-attained height and greater birth weight increase risk.

Limited suggestive evidence: Physical activity decreases risk.

The panel found limited evidence and could not draw a conclusion about other food and nutritional factors, including, but not limited to, soy, fiber, vegetables and fruits, tea, isoflavones, meat, folate, calcium, vitamin D, dietary patterns, culturally defined diets, and environmental chemicals. The lack of strong evidence for a relationship between diet and breast cancer may be real or it may reflect challenges related to study designs, including measurement errors in self-reporting intake by study participants, the focus on diet during adult life versus early life and puberty, follow-up periods that are too short to identify dietary factors, subgroups of women who are more susceptible to the influence of diet, or potential harmful effects of pesticides that negate the benefits of vegetable and fruit consumption.18 Few studies have focused on the role of diet during gestation, or before or during puberty, and the risk of breast cancer. The influence of diet on breast cancer risk may be most important during mammary gland development.

Lactation

There is convincing evidence that breastfeeding decreases the risk of breast cancer in both premenopausal and postmenopausal women, according to the WCRF panel. Most studies show a decreased risk with increased duration of breastfeeding. Specifically, pooled analysis from 47 epidemiological studies showed a decreased risk of 4.3% for each 12 months of breastfeeding.19

Protection may be conferred by the lower exposure to estrogen during the amenorrhea associated with breastfeeding, increased differentiation of breast cells, exfoliation of breast tissue during lactation, and massive epithelial apoptosis at the end of lactation, which may eliminate cells with potential DNA damage. Little is known about dietary exposures during pregnancy or lactation on future breast cancer risk in the mother or the infant.

In rodents, in utero exposure to a diet high in polyunsaturated fatty acids (n-6) or genistein increases ER-a receptors, causing an increase in unopposed cell proliferation and increased mammary tumorigenesis.20 In rodents, a diet high in genistein or n-6 fatty acids alters normal mammary gland development, which in turn may increase future breast cancer risk. It is unknown how these and other dietary exposures might modulate estrogen, estrogen receptor sites, or breast development during pregnancy or lactation, and what effects these changes might have on future breast cancer risk in women and their offspring.

Weight, Adult-Attained Height, and Postmenopausal Breast Cancer

As mentioned earlier, the WCRF panel determined that adult weight gain is a probable risk factor for postmenopausal breast cancer. The increased risk of breast cancer in this scenario may be due to higher estrogen levels: Circulating levels of estrogen are twice as high in overweight women. The higher estrogen levels are caused by the endogenous production of estrogen by the aromatization of adrenal androgens in the adipose tissue. Overweight women also have lower levels of SHBG as compared to normal weight women, and consequently have more bioavailable estrogen. Being overweight is also associated with increased levels of insulin and insulin-like growth factor 1 (IGF-1), which produces a hormonal environment that favors carcinogenesis and depresses apoptosis. Inflammation is also associated with overweight, especially abdominal adiposity. Chronic inflammation may be involved in the initiation and the progression of cancer by damaging DNA, increasing proliferation, inhibiting apoptosis, and increasing angiogenesis.

Epidemiologic data from the Nurses’ Health Study found a direct association between weight gain since age 18 and postmenopausal breast cancer risk, especially in women who had never used postmenopausal replacement therapy (PMT).21 In this prospective cohort, 49,514 women aged 30 to 55 years who were free of cancer were followed for as long as 26 years. Weight gain of 25 kg or more since age 18 was associated with an increased risk of breast cancer relative risk (RR) equal to 1.45, compared to women who maintained their weight. In women who never took PMT, the RR was 1.98. The data suggest that 15% of breast cancers could be attributed to weight gain of 2 kg or more since age 18 years and that 4.4% could be attributed to weight gain of 2.0 kg or more since menopause. Women who lost 10 kg or more since menopause and kept it off and never used PMT reduced their risk of breast cancer (RR = 0.45) compared to women who maintained their weight. The weaker association of weight gain in women who used PMT may be due to the high levels of circulating exogenous estrogens in these women, unrelated to their weight and adiposity.

The WCRF panel also found convincing evidence that postmenopausal breast cancer risk increases with adult-attained height. Tallness itself is probably not the cause of breast cancer. Rather, height acts as a surrogate for childhood nutritional factors affecting hormonal and metabolic systems that are related to cancer risk, including alterations in levels of growth hormone, insulin-like growth factors, sex hormone binding proteins, and the age of sexual maturation.

Body Fatness, Greater Weight at Birth, Greater Attained Height, and Premenopausal Risk

In premenopausal women, greater body fatness probably decreases the risk of breast cancer, according to the WCRF panel. The mechanism by which body fatness protects against breast cancer in premenopausal women is still speculative at this time. Proposed mechanisms include irregular menstrual cycles and ovulatory infertility in adulthood, with subsequent alteration in hormone levels.

Premenopausal breast cancer risk increases with greater weight at birth and greater adult-attained height. The mechanisms are speculative. The factors leading to greater birth weight and attained height may affect the long-term programming of hormonal systems. It is not likely that tallness itself is a risk factor, but rather the factors that promote growth during gestation and in childhood.

Alcohol

Convincing evidence exists that regular alcohol consumption increases the risk of breast cancer in both premenopausal and postmenopausal women in a dose-responsive manner. Pooled analysis of six prospective studies found a linear increase in breast cancer risk of 9% for each additional 10 g/day of alcohol consumed. The specific type of alcohol did not strongly influence risk.22 Another pooled analysis from 53 epidemiological studies found a similar linear increase in breast cancer risk of 7% for each 10 g of alcohol consumed per day.23 The risk was the same for ever-smokers and never-smokers. The authors estimated that 4% of breast cancers in developed countries could be attributed to alcohol consumption if the observed relationship is causal.

In one study, alcohol consumption was associated with ER-positive breast cancer in postmenopausal women but not with ER-negative breast cancer.24 A number of hormonal and nonhormonal mechanisms have been proposed to explain the positive association between alcohol and breast cancer. Alcohol may affect a number of hormone-dependent pathways by inducing the production of endogenous estrogens, decreasing the metabolic clearance of estradiol, stimulating the proliferation of ER-positive cells, and increasing ER-alpha activity through inactivation of the BRAC1 gene. Hormone-independent pathways include the induction of carcinogenesis and DNA damage by acetaldehyde (the reactive metabolite of ethanol), lipid peroxidation, and the production of reactive oxygen species.

Adequate folate status may partially mitigate the increased breast cancer risk associated with moderate alcohol consumption.25 Folate adequacy should be ensured in women who consume alcohol.

Dietary Fat

The relationship between dietary fat intake and breast cancer risk has been controversial, with mostly observational studies showing inconsistent results. The WCRF panel determined that there is limited evidence suggesting total dietary fat intake increases the risk of postmenopausal breast cancer, but not premenopausal breast cancer. The panel also decided that there is insufficient evidence to draw conclusions about the risk of breast cancer and the various types of fatty acids.

The National Institutes of Health/AARP’s (NIH-AARP) Diet and Health Study—a prospective study involving 188,736 postmenopausal women—did find a modest increase in the risk of breast cancer in women who were not using menopausal hormone therapy and who had higher total dietary fat intake.26 Women who consumed 40% of their total calories in the form of fat (90 g/day, highest quintile) had an 11% higher incidence of invasive breast cancer than women who consumed 20% of calories as fat (24.2g/day, lowest quintile).

In the Women’s Health Initiative (WHI)—a randomized, controlled, primary prevention trial involving 48,835 postmenopausal women, ages 50 to 70—reducing the total fat consumed to 20% of total calories did not result in a statistically significant reduction in invasive breast cancer over an 8.1-year follow-up period.27 However, those women in the intervention group who consumed the highest percentage of energy in the form of fat at baseline (>36.8% of calories from fat, >76 g/day) did see a significant reduction in their risk of invasive breast cancer risk (hazard ratio = 78) when compared to the comparison group. It may be that a subgroup of women with very-high-fat diets would benefit the most from switching to a low-fat dietary pattern.

If a causal relationship between breast cancer risk and dietary fat does exist, it may reflect any of several mechanisms that affect the initiation and growth of breast cancer. These include increased endogenous production of estrogen with higher-fat diets, an increase in bioavailable estrogen with higher-fat diets, modulation of the immune system, and regulation of gene function.

Red Meat, Processed Meat, and Heterocyclic Amines

Studies of meat consumption, red meat consumption, heterocyclic amines, and breast cancer risk have produced conflicting results. The WCRF has determined that there is limited evidence to support the relationship between these dietary factors and cancer risk, but a definitive conclusion cannot be reached. Nevertheless, it seems prudent to advise women to decrease red meat and processed meat consumption, as some evidence supports a link between intake of these foods and breast cancer.

In a prospective study involving 90,659 premenopausal women (Nurses’ Health Study II), red meat intake was strongly associated with an elevated risk of ER-positive, PR-positive breast cancer, but not ER-negative, PR-negative breast cancer.28 Compared with the practice of eating three or fewer servings of red meat per week, RR increased with increased consumption as follows: 1.14 for more than 3—5 servings per week, 1.42 for more than 5 servings per week to 1 or fewer servings per day, and 1.97 for more than 1.5 servings per day.

In the UK Women’s Cohort Study, which enrolled 35,371 participants, women with the highest total meat consumption (poultry, red meat, and processed meat) had the highest risk of both premenopausal and postmenopausal breast cancer.29 High total meat consumption (>103 g/day) compared with no meat consumption was associated with a premenopausal cancer hazard ratio (HR) of 1.20, high processed meat consumption (>20 g/day) compared with no meat consumption was associated with a HR of 1.45, and high red meat consumption (>57 g/day) compared with no meat consumption was associated with a HR of 1.32. The effect was larger in postmenopausal women for all types of meat, including red and processed meat. High total meat consumption (57 g/day) compared with no meat consumption was associated with a HR of 1.63, high processed meat consumption (>20 g/day) compared with no meat consumption was associated with a HR of 1.64, and high red meat consumption (>57 g/day) compared with no meat consumption was associated with a HR of 1.56.

Several mechanisms have been proposed to explain the positive association between meat consumption and breast cancer. In particular, heterocyclic amines, which are produced when meats are charbroiled, fried, or cooked until well done, have been implicated in increasing cancer risk. Heterocyclic amines are estrogenic and stimulate ER and PR gene expression in vitro. Processed meats contain nitroso compounds, which are known carcinogens and may also be involved in breast cancer etiology.

It has been suggested that individuals who have inherited polymorphisms in N-acetyltransferase 1 and 2 (NAT1, NAT2) genes and in glutathione S-transferase M1 and T1 genes (GSTM1, GSTT1), and who consume meat (especially charbroiled meat) are at increased risk for breast cancer. NAT1 and NAT2 are involved in phase II acetylation of heterocyclic amines.

GSTM1 and GSTT1 confer protection against oxidative stress by reducing hydrogen peroxide levels and by regenerating vitamins C and E. A study in the Netherlands found that the GSTM1 null genotype (i.e., absence of the gene on the chromosome) increases breast cancer risk irrespective of meat consumption.30 A statistically significant relationship was not found for breast cancer risk and polymorphisms in NAT1, NAT2, GSTM1, or GSTT1, and levels of meat consumption were not identified in this study.

Women should be advised to decrease their red meat consumption to three or fewer times per week and to avoid processed meats. Well-done and char-broiled meats should be avoided; roasting, stewing, and slow cooker (CrockPot) techniques are the preferred methods of meat preparation.

Vegetarian Diets

A vegetarian diet does not appear to protect against breast cancer. A metaanalysis of five mortality studies comparing vegetarians with health-conscious meat-eaters did not find a statistically significant difference in mortality from breast cancer in the two groups.31 Rates of breast cancer remain high among Adventist populations despite their healthy lifestyle, which includes following a lacto-ovo vegetarian diet.32

Macrobiotic Diets

The macrobiotic diet is a popular complementary approach to the treatment of cancer. The dietary pattern promoted by macrobiotics is vegetarian and emphasizes minimally processed foods. The Great Life pyramid was introduced by Michio Kushi, a proponent of macrobiotics33; it specifies the recommended macrobiotic diet. The diet consists of 40-60% by weight whole cereal grains, including brown rice, barley, millet, oats, wheat, corn, rye, buckwheat, and other whole grains; 20-30% by weight vegetables; 5-10% by weight beans and bean products, including tofu, tempeh, and natto; and daily consumption of sea vegetables. Fish, nuts, seeds, and fruit are recommended to be consumed on a weekly basis. Dairy, eggs, poultry, and red meat are to be consumed no more that once a month, if at all.

There are no direct studies examining the effects of the macrobiotic diet in cancer prevention and survival. This diet does eliminate red meat, which is associated with increased breast cancer risk. Because the macrobiotic diet does not provide adequate vitamin B12, vitamin D, and calcium, these nutrients should be taken in supplement form by any persons following the diet. Women who elect to follow this diet should be educated on how to meet protein and calorie requirements. A macrobiotic diet may be difficult to adhere to during chemotherapy if the patient develops significant appetite and taste changes, or nausea and vomiting.

Vegetables, Fruit, and Fiber

The WCRF has determined that a conclusion cannot be drawn regarding the effect of dietary fiber or consumption of a diet high in vegetables and fruit on breast cancer risk. Epidemiological studies in this area have yielded inconsistent results. However, interest exists in specific bioactive compounds found in vegetables and fruit that may confer protection against cancer. According to the WCRF, there is limited, inconclusive evidence that cruciferous vegetables, flavonoids, green tea, and phytoestrogens may play a role in decreasing breast cancer risk.

Cruciferous Vegetables The cruciferous vegetables of the Brassica genus include broccoli, Brussels sprouts, cabbage, collards, cauliflower, kale, kohlrabi, mustard greens, bok choy, Chinese cabbage, turnips, and rutabagas. Cruciferous vegetables are rich in glucosinolates, a group of sulfur-containing compounds. The hydrolysis of glucosinolates by the plant enzyme myrosinase results in biologically active compounds that include indoles. More than 100 glucosinolates with unique hydrolysis products have been identified in plants. These water-soluble compounds may leach into cooking water; microwaving at high power and steaming and boiling vegetables can also inactivate myrosinase.

Evidence that cruciferous vegetables decrease the risk of breast cancer in population-based studies is limited and inconsistent.34 In addition, genetic polymorphisms may influence the activity of glutathione 5-transferases (GST) and mediate the effects of cruciferous vegetable intake on cancer risk.35

Indole-3-carbinol (I3C) is a constituent of cruciferous vegetables that may offer chemopreventive benefits by shifting the metabolism of 17^-estradiol from 16-a-hydroxyestrone (16aOHEj) to 2-hydroxyestrone (2OHE-,). The 16aOHE: metabolite is thought to be genotoxic and tumorigenic, compared to the 2OHE1 metabolite. In postmenopausal women, increasing the consumption of cruciferous vegetables significantly increases the urinary ratio of 2OHE-! to ^aOHEp36 However, the relationship between urinary 2OHE-! to 16aOHE: and breast cancer risk is unclear. Other proposed anticarcinogenic properties of cruciferous vegetables include their ability to induce apoptosis and inhibit angiogenesis.

The NIH is studying IC3 supplements in preventing breast cancer in nonsmoking women who are at high risk for breast cancer.37 The long-term effects of IC3 supplementation in humans are not known, and women should be advised not to use these supplements until more is known about their potential risks versus their benefits. More generally, women should be encouraged to increase their consumption of cruciferous vegetables.

Flavonoids Flavonoids are a group of more than 5,000 polyphenolic compounds that occur naturally in plant foods. Laboratory studies have shown that flavonoids act as anticarcinogens by inhibiting aromatase activity, tumor cell proliferation, and the formation of reactive oxygen species.

Epidemiological studies suggest that foods high in specific flavonoids are associated with a decreased risk of breast cancer. In a retrospective, population-based, case-controlled study of 1,434 women with breast cancer and 1,440 controls, the consumption of specific flavonoids was associated with a decrease in postmenopausal breast cancer risk.38 Odds ratios (OR) for breast cancer risk were reduced in women with consumption of flavonoids in the highest quintile versus those with consumption in the lowest quintile. The effect was strongest for flavonols (found in onions, cherries, broccoli, tomatoes, tea, red wine, and berries), for which the OR was 0.54; the corresponding ORs were 0.61 for flavones (found in parsley, thyme, and cereal), 0.74 for flavan-3-ols (found in apples, tea, chocolate, red wine, and berries), and

0.69 for lignans (found in flaxseeds, legumes, and whole grains). The data did not support an inverse association between isoflavones (found in soy), anthocyanidins (found in blueberries and raspberries), or flavanones (found in citrus) and breast cancer risk.

The catechins in tea have also been studied for their potential anticarcinogenic properties. Tea is a popular beverage worldwide, and it has been brewed from the Camellia sinensis plant for more than 5,000 years. The method used in its processing results in black, green, oolong, or white tea. Black tea is produced by allowing the picked tea leaves to dry indoors, ferment, and oxidize. Green tea is produced by steaming the tea leaves, which inactivates enzymes and preserves the catechin content. Oolong tea is a partially fermented tea. White tea is the least processed of teas and consequently has even greater antioxidant activity than green tea. White tea is harvested before the leaves are fully opened and when the buds are still covered by fine white hair; the leaves are then picked and air-dried. White tea is widely available in the United States but is more expensive than other types of tea.

Studies of the health properties of tea have generally focused on green tea. Both green and white teas are rich in the flavonols known collectively as catechins. Catechins found in tea include epigallocatechin gallate (EGCG), epi-gallocatechin (EGC), epicatechin gallate (ECG), and epicatechin (EC). Green tea has been proposed to have anticarcinogenic properties as a result of the activity of EGCG. ECCG may protect against cancer by promoting selective apoptosis, suppressing angiogenesis, preventing oxidative damage to DNA, and enhancing the detoxification of carcinogens, including heterocyclic amines.39

Population studies suggest that green tea consumption does not decrease the risk of breast cancer. Most of these studies have been conducted in Asia; to date, few large-scale epidemiological studies or randomized controlled intervention trials have been carried out in Western populations. Ultimately, the protective effect of green tea may depend on the genotype of an individual. In a population-based, case-controlled study of Asian American women in Los Angeles, a significant inverse relationship was found to exist between tea consumption, breast cancer rate, and polymorphisms in the catechol-O-methyltransferase (COMT) gene.40 Women with at least one low-activity COMT allele who drank tea had a significantly reduced risk of breast cancer (adjusted OR = 0.48) compared with non-tea drinkers. This benefit was observed in drinkers of both green and black teas. Breast cancer risk did not differ between tea and non-tea drinkers who were homozygous for the high-activity COMT allele. The COMT gene is involved in the methylation of catechins, and the researchers theorize that tea catechins consumed by women with the low-activity COMT allele were O-methylated and excreted less rapidly, thus conferring a greater cancer-protection benefit.

Phytoestrogens Phytoestrogens are plant compounds that can bind to ERs. These substances act as SERMs, as they have both estrogenic and anti-estrogenic effects, depending on the expression of the ER subtype in the target cell and the amount of endogenous estrogen present. In premenopausal women, phytoestrogens appear to exert antiestrogenic effects; in postmenopausal women, they may exert estrogenic effects and minimize menopausal symptoms. These compounds may influence estrogen metabolism through several mechanisms: (1) by promoting C-2 hydroxylation over 16a hydroxylation; (2) by increasing SHBG levels, thereby reducing free estrogens; (3) by inhibiting aromatase activity; and (4) by binding to ERs.

The major types of phytoestrogens are isoflavones and lignans, which are discussed next.

Isoflavones Isoflavones are found in soy, legumes, alfalfa, clover, licorice root, and kudzu root. Two isoflavones, genistein and daidzein, are found in soy, for example. The effects of genistein are well documented. The molecular structure of this compound is similar to that of estradiol-17^. Genistein binds to both ERa and ERp, but it has a weaker transcriptional potency and, consequently, weaker estrogenic properties.

There has been much interest in—and controversy about—the role of soy in breast cancer risk. To date, the data on the beneficial or adverse effects of isoflavones and soy have been contradictory and inconclusive.41 It is theorized that isoflavone intake during childhood and adolescence may decrease breast cancer risk by affecting cellular differentiation. Conversely, isoflavones given to women at the time of menopause may stimulate the proliferation of breast cells and, in theory, increase breast cancer risk.

More research is needed before recommending soy to women with ER-positive breast cancer, and supplementation with isoflavone preparations should be avoided. Preliminary evidence also suggests that genistein and daidzein can interfere with the efficacy of the drug tamoxifen.42 Given this concern, women on tamoxifen should avoid consuming a diet high in soy or isoflavone supplements.

Lignans Lignans are compounds found in fiber-rich foods including flaxseed, whole grains, legumes, and vegetables. Flaxseeds are the richest source of lignans (enterodiol and enterolactone) in the diet.

Lignans have been shown to modify estrogen metabolism, stimulate SHBG production in the liver, inhibit aromatase activity in adipose cells, and decrease cellular proliferation in breast cells. In a small, randomized, double-blind, placebo-controlled study of postmenopausal women, supplementation with 25 g of ground flaxseed/day (in the form of a muffin) resulted in increased excretion of the less biologically active estrogen metabolite 2-OHE1; the excretion of 16a-hydroxyestrone did not increase.43

In another study, 31 women with newly diagnosed breast cancer were randomized to daily intake of a muffin containing 25 g flaxseed or a control (placebo) muffin.44 Their tumor tissue was analyzed for tumor cell proliferation and apoptosis both at the time of diagnosis and at the time of definitive surgery. In the intervention group, significantly reduced cell proliferation and increased apoptosis were observed compared to the control group at the time of definitive surgery.

Although these results are certainly interesting, more research is needed before flaxseed might be recommended to women who have breast cancer. In theory, flaxseed could interfere with the antiestrogenic effects of tamoxifen as a result of its phytoestrogen properties.

Allium Vegetables

The allium family of vegetables, which includes garlic, onions, and shallots, may have anticarcinogenic properties. Allium vegetables have high concentrations of organosulfur compounds, which may selectively inhibit or induce certain P-450 enzymes; they are also high in antioxidant activity due to their flavonoid content. To date, few data on their role in breast cancer risk have been collected. A recent Italian case-controlled study failed to find a protective role for garlic and onion consumption and breast cancer risk.45

Folate

Folate, in the polyglutamate form, occurs naturally in dark-green leafy vegetables, legumes, and fruits. Synthetic folic acid is available in supplements and fortified foods. Several mechanisms have been proposed for the role of folate inadequacy and carcinogenesis. Folate and vitamin B12 are coenzymes needed to regenerate methionine from homocysteine. Methionine in the form of S-adenosylmethione is the principal methyl donor for DNA methylation. Folate inadequacy, in theory, may lead to hypomethylation and, therefore, to gene mutation or altered gene expression. Inadequacy of folate may increase cancer risk by the misincorporation of uracil for thymine during DNA synthesis and by impaired DNA repair. Both of these processes can cause DNA strand breaks and chromosome damage.

Epidemiologic evidence supporting an inverse relationship between folate intake and breast cancer risk is inconclusive. In fact, some studies suggest that high folate intake may increase breast cancer risk. In the prospective, the randomized Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), high folate intake due to supplementation was associated with an increased risk of breast cancer in postmenopausal women.25 Women who consumed more than 400 mcg/day of supplemental folic acid had a 19% greater risk of postmenopausal breast cancer than women who did not take supplemental folic acid. Women in the highest quintile of total folate intake from food and supplements (> 853 mcg/day) had a 32% greater risk than women in the lowest quintile (< 335.5 mcg/day). Folate from food was not associated with increased risk.

As yet, researchers have not identified the mechanisms underlying the reported relationship between increased risk of breast cancer and high folate intake. A very high folate intake might potentially promote the growth of an existing cancer or cause epigenetic changes in gene-regulatory mechanisms, leading to gene silencing and cancer development. Ultimately, both deficiency and excess of folate may contribute to breast cancer carcinogenesis.

The combination of folate deficiency and alcohol use also appears to be positively associated with breast cancer risk. In the PLCO Trial women in the highest quintile in terms of alcohol consumption (> 7.62 g/day or approximately 0.5 serving/day) had a 37% greater risk than women in the lowest quintile of alcohol consumption (< 0.01 g/day).25 The risk associated with alcohol consumption was highest in women with low total folate intake (< 335.5 mcg/day). Women in the lowest quintile of folate intake who consumed 0.5 drink per day had twice the risk of developing postmenopausal breast cancer compared to women in the lowest quintile of folate intake who consumed less than 0.01 g of alcohol per day.

Given this apparent linkage, folate adequacy should be ensured in women who consume alcohol. At the same time, more research is needed to elucidate fully the relationship between folic acid and breast cancer carcinogenesis.

Vitamin D and Calcium

Vitamin D is found in fatty fish such as salmon, sardines, mackerel, and tuna. Wild salmon is higher in vitamin D than farm-raised salmon. Vitamin D is also found in fortified foods such as milk, orange juice, and breakfast cereals. Multivitamins and some calcium supplements also contain vitamin D.

Two forms of supplemental vitamin D are available: vitamin D3 (also known as cholecalciferol) and vitamin D2 (also known as ergocalciferol). Cho-lecalciferol is manufactured through the ultraviolet irradiation of

7-dehydrocholesterol from lanolin; it is the preferred form of supplementation because it has more biological activity. Ergocalciferol is manufactured through the ultraviolet irradiation of ergosterol from yeast, and is less biologically active than cholecalciferol. Humans can produce vitamin D when the skin is exposed to ultraviolet radiation from the sun or from tanning booths.

An estimated 1 billion people worldwide are vitamin D insufficient or deficient. Obese individuals are particularly at risk for vitamin D deficiency. Because vitamin D from the diet or from sunlight is efficiently deposited in the body fat stores, it is not bioavailable. This process leads to low serum levels in obese persons.

The active form of vitamin D, 1,25-dihydroxyvitamin D, directly or indirectly controls more than 200 genes, including genes involved in the regulation of cellular proliferation, differentiation, apoptosis, and angiogenesis. Breast tissue expresses 25-hydroxyvitamin D-1a hydroxylase and produces 1,25-dihydroxyvitamin D locally to control genes that prevent cancer by regulating cellular proliferation and differentiation. It has been theorized that if a cell becomes malignant, 1,25-dihydroxyvitamin D can induce apoptosis and prevent angiogenesis, thereby decreasing the ability of the malignant cell to survive.

Prospective and retrospective studies suggest that serum levels of 25-hydoxyvitamin D less than 20 ng/mL are associated with a 30-50% increased risk of breast, colon, and prostate cancer and a greater risk of mortality.46 The few intervention studies that have focused on calcium and/or vitamin D have shown a reduction in breast cancer in women who take these supplements. In a four-year, population-based, double-blind, randomized,

placebo-controlled trial involving 1,179 women, risk of all cancers—including breast cancer—was reduced in the intervention group receiving 1,400-1,500 mg of calcium and 1,100 IU of vitamin D3 per day and in the group receiving 1,400-1,500 mg of supplemental calcium per day.47

The optimal intake of vitamin D for cancer protection purposes is not known. The recommended daily intake of vitamin D developed by the Institute of Medicine is thought by most experts to be inadequate.46 Most experts agree that without adequate sun exposure, children and adults require approximately 800-1,000 IU of vitamin D per day. Supplementation should be in the form of cholecalciferol. Assessment of vitamin D status using serum 25(OH) levels can be helpful in determining individual needs. Optimal vitamin D levels have not been established. Holick has defined vitamin D deficiency measured by 25(OH) vitamin D as less than 20 ng/mL, insufficiency as 21-29 ng/mL, sufficiency as more than 30 ng/mL, and toxicity as more than 150 ng/mL.46 Other sources have proposed an optimal range of 40-65 ng/mL.48

Environmental Pollutants

A total of 216 chemicals have been identified in at least one animal study as increasing the incidence of mammary tumors.49 These substances include industrial chemicals, chlorinated solvents, products of combustion, pesticides, dyes, radiation, drinking water disinfectant by-products, pharmaceuticals and hormones, natural products, and research chemicals. Of these chemicals, 73 are present in consumer products or as contaminants in food, 35 are air pollutants, 25 are associated with occupational exposure, and 29 are produced in the United States in large amounts. Laboratory research indicates that many environmental toxins cause mammary gland tumors in animals by mimicking estrogen or by increasing the susceptibility of the mammary gland to carcinogenesis.

The epidemiologic evidence that environmental pollutants play a role in human breast cancer risk is limited, although support for the relationship is building.50 Meaningful evidence indicates that polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) increase the risk of breast cancer in women with certain genetic polymorphisms including GSTM1. PAHs include products of combustion from air pollution, tobacco smoke, and cooked food and are prevalent in our environment. PCBs were used in the production of electrical equipment in the past, but were banned in the 1970s. The primary source of PCB exposure is through consumption of fish from rivers contaminated with the industrial pollutant. PCBs are found in high concentrations in breast milk, and they accumulate in fat. Although breast milk contains PCBs, the American Academy of Pediatrics remains a staunch advocate of breastfeeding infants because of the health, nutritional, immunological, developmental, psychological, social, economic, and environmental benefits associated with this practice.51

Additional epidemiologic research is needed on breast cancer risk and other chemicals that act as endocrine disruptors, including chlorinated solvents, diesel exhaust, dibutyl phthalate, ethylene oxide, perfluorooctanoic acid, and bisphenol A.

Nutrition Care During and After Cancer Treatment

Nutrition Assessment

Evaluation of nutritional status is important during and following treatment. Traditional nutrition assessment includes medical history, diet and weight history, laboratory data, and anthropometric measurements. The Mini Nutritional Assessment (MNA) and the Scored Patient-Generated Subjective Global Assessment (PG-SGA) are two tools that have been studied in the cancer population. Of these tools, the PG-SGA has been validated for use in cancer patients but is time-consuming and must be administered by a trained individual.52 The MNA is a simple tool that can be managed by a nontrained person but is validated only for use in the elderly population.

In a study comparing the two tools in cancer patients, the MNA was found to have high sensitivity but low specificity: It adequately identified patients in need of nutrition intervention but also categorized patients as requiring nutrition intervention when it was not needed.53 The PG-SGA appears to be more applicable in cancer patients than the MNA, but if staffing and resources are limited, its use may not be realistic. A modification of the MNA could be developed to increase its specificity in the cancer setting.

In clinical practice, many individuals with breast cancer who are treated on an outpatient basis may not require the use of any of these tools. Metastatic breast cancer is more likely to trigger the need for nutrition intervention. Lifestyle and nutrition issues related to survivorship, such as weight gain, exercise, vegetable and fruit intake, and prevention and treatment of the metabolic syndrome—all of which may influence the risk of recurrence—are common nutritional concerns in this population. For this reason, a system for identifying patients and providing education is important. Patients should be asked about the use of CAM, as there is potential for drug-supplement interactions. In one study, two-thirds of women who received traditional treatment for breast cancer also used one or more CAM therapies that they believed could prevent cancer recurrence and/or improve their quality of life.54

Nutritional Implications of Chemotherapy

Chemotherapy side effects affecting nutritional status include nausea and vomiting (N/V), mucositis, altered taste, xerostomia, dysphagia, myelosup-pression, fatigue, and diarrhea. Symptoms can be decreased with pharmacologic interventions such as antiemetic, antidiarrheal, and hematopoietic agents, although many patients who are treated with “dose-intensive” regimens experience significant side effects. In premenopausal women treated with CT, infertility and early menopause causing hot flashes and night sweats may occur. These women are also at risk for osteoporosis due to early menopause. Chemotherapeutic agents commonly used to treat breast cancer (summarized in Table 8.1) include cyclophosphamide (Cytoxan), docetaxel (Taxotere), doxorubicin (Adriamycin), epirubicin (Ellence), 5-fluorouracil (5-FU), methotrexate, and paclitaxel (Taxol).

Table 8.1 Medications Commonly Used to Treat Breast Cancer

Drug (Route of Administration)

Mode of Action

Potential Side Effects/ Nutrition Implications

Chemotherapeutic Agents

Cyclophosphamide (Cytoxan) (intravenous or oral)

Alkylating agent

Interferes with RNA transcription, causing growth imbalance and cell death

I uric acid; X platelets, hemoglobin, red blood cells, white blood cells; anorexia, nausea and vomiting, stomatitis, mucositis, abdominal pain, cardiotoxicity in high doses

Docetaxel (Taxotere) (intravenous)

Inhibits mitosis and leads to cell death

I alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and bilirubin; X hemoglobin, platelets, white blood cells; stomatitis, nausea and vomiting, diarrhea, myalgia, arthralgia, nail pigmentation

Doxorubicin

(Andriamycin)

(intravenous)

Interferes with DNA-dependent RNA synthesis

I uric acid; X platelets and white blood cells; esophagitis common in patients who have also received radiation; nausea and vomiting, diarrhea, stomatitis, anorexia, cardiotoxicity

Epirubicin (Ellence) (intravenous)

Inhibits DNA, RNA,

and protein synthesis

X hemoglobin, neutrophils, platelets, white blood cells; nausea and vomiting, diarrhea, anorexia, mucositis

Drug (Route of Administration)

Mode of Action

Potential Side Effects/ Nutrition Implications

Chemotherapeutic Agents

5-Fluorouracil (5-FU)

Inhibits DNA and

I alkaline phosphatase, alanine

(intravenous)

RNA synthesis

aminotransferase, aspartate aminotransferase, lactate dehydrogenase, bilirubin; X hemoglobin, platelets, red blood cells, white blood cells, albumin; anorexia, nausea and vomiting, gastrointestinal ulceration; contraindicated in poor nutritional status or following major surgery within previous month

Methotrexate

Antimetabolite

I uric acid; X platelets, red

(intravenous)

Reversibly binds to

blood cells, white blood cells;

dihydrofolate

gingivitis, stomatitis, diarrhea,

reductase, blocking the

abdominal distress, anorexia,

reduction of folic acid

gastrointestinal ulceration and

to tetrahydrofolate, a

bleeding, enteritis, nausea and

cofactor necessary for

vomiting.

purine, protein, and

May alter results of laboratory

DNA synthesis

assay for folate status. Folic acid derivatives antagonize methotrexate effects and should be avoided.

Alcohol may increase heptotoxicity.

Paclitaxel (Taxol)

Inhibits normal

I alkaline phosphatase, aspartate

(intravenous)

reorganization of

aminotransferase, triglycerides; X

microtubule network

neutrophils, white blood cells,

needed for mitosis and

hemoglobin, platelets; nausea

other vital cellular

and vomiting, diarrhea, mucositis

functions

peripheral neuropathy, myalgia, arthralgia

Targeted Biologic Therapy

Bevacizumab (Avastin)

Recombinant

X white blood cells; I

(intravenous)

humanized monoclonal

proteinuria; diarrhea, nausea and

IgGx antibody

vomiting, anorexia, stomatitis,

Binds and inhibits the

abdominal pain, wound healing

biological activity of

complications, gastrointestinal

vascular endothelial

perforations, congestive heart

growth factor (VEGF) Inhibits angiogenesis

failure, hypertension

Drug (Route of Administration)

Mode of Action

Potential Side Effects/ Nutrition Implications

Targeted Biologic Therapy

Trastuzumb (Herceptin)

Recombinant DNA-

^ hemoglobin, white blood cells;

(intravenous)

derived monoclonal antibody that selectively binds to HER-2 Inhibits proliferation of cells that overexpress HER-2

anorexia, abdominal pain, diarrhea, nausea and vomiting

Hormonal Therapy

Anastrozole (Arimidex)

Aromatase inhibitor;

T liver enzymes, hot flashes,

(oral)

aromatase is an enzyme that converts testosterone to estrogen in the peripheral tissue

Significantly decreases estrogen levels

For use in postmenopausal women with ER/PR-positive tumors

bone pain; T risk of osteoporosis Ensure adequate calcium and vitamin D for bone health and encourage weight-bearing exercise.

Exemextane (Aromasin)

Aromatase inhibitor

T bilirubin, alkaline phosphatase,

(oral)

Mechanism and indication the same as for Arimidex

creatinine, hot flashes;

T risk of osteoporosis Ensure adequate calcium and vitamin D for bone health and encourage weight-bearing exercise.

Letrozole (Femara)

Aromatase inhibitor

T cholesterol, hot flashes; Trisk

(oral)

Mechanism and indication the same as for Arimidex

for osteoporosis

Ensure adequate calcium and vitamin D for bone health and encourage weight-bearing exercise.

St. John’s wort may decrease effectiveness of the medication.

Tamoxifen (Nolvadex)

Selective estrogen-

T BUN, calcium, T4, liver

(oral)

receptor modulator

(SERM)

For use in premenopausal women or women with DCIS or LCIS

enzymes; T white blood cells and platelets; T risk of pulmonary embolism, thromboembolism, endometrial cancer, hot flashes Ensure adequate calcium and vitamin D for bone health and encourage weight-bearing exercise.

Source: Nursing 2007 Drug Handbook. 27th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2007.

Weight Gain Associated with Chemotherapy and Hormonal Therapy

Patients who experience anorexia or N/V often lose weight and should be referred to a registered dietitian (RD). In contrast, weight gain during CT is common; the typical increase ranges from 2.5 to 6.2 kg, though greater gains are not uncommon. Weight gain also occurs in the first 6 months after completion of CT.

Harvie et al. studied the causes of weight gain in women receiving CT.55 Women in the study gained significant amounts of weight (5 kg ± 3.8 kg) and body fat (7.1 kg ± 4.5 kg) over the year. Waist circumference increased by 5.1 cm ± 4.5 cm; abdominal skin-fold increased by 16.2 mm ± 10 mm; and fat-free mass decreased by 1.7 kg ± 2.5 kg. Resting energy expenditure (REE) declined by 3% during CT and remained depressed for at least 3 months after treatment. There was no significant change in dietary intake or physical activity over the year, and weight gain was attributed to a decline in REE combined with a failure to decrease caloric intake or increase physical activity.

In another study, sarcopenic obesity (weight gain with lean tissue loss or the absence of lean tissue gain) and decreased physical activity, but not overeating, were determined to be the causes of weight gain in premenopausal women receiving CT.56 Resistance training, especially that focusing on the lower body, should be encouraged in women undergoing CT to prevent loss of lean body mass, which leads to a decrease in REE and subsequent weight gain. In the Women’s Healthy Eating and Living (WHEL) study, all regimens of CT were associated with weight gain and only 10% of study participants returned to their initial weight.57

Although women commonly complain of weight gain when they are treated with tamoxifen, use of this hormonal therapy was not associated with weight gain in the WHEL study.57 Previous studies have reported conflicting results about tamoxifen’s role in weight gain. Studies reporting significant weight gains with tamoxifen were limited by short follow-up, small sample size, and lack of a control group.

Menopausal Vasomotor Symptoms

The most common complaints in women with ER-positive tumors are the result of early menopause due to CT-induced ovarian failure, surgical ovarian oblation, or treatment with antiestrogenic drugs including SERMs and AIs.58 Most women experience hot flashes associated with these kinds of treatments. Although hot flashes can affect the quality of life in survivors, they may also be a strong predictor of breast cancer recurrence in women who are treated with tamoxifen.59 Data from the WHEL study showed that women who reported hot flashes at baseline were less likely after 7.3 years to develop breast cancer recurrence than those who did not report hot flashes at baseline. Hot flashes were a stronger predictor of recurrence than age, hormone receptor status, or the stage of cancer at diagnosis (stage I versus stage II). Additional research is needed to clarify the relationship between hot flashes and recurrence.

Few studies have addressed the management of menopausal symptoms in breast cancer survivors.60 HRT is contraindicated in breast cancer survivors, especially those with ER-positive tumors. The use of selective serotonin reuptake inhibitors (SSRIs), the selective serotonin and norepinephrine reuptake inhibitor (SSNRI) venlafaxine, and the anticonvulsant gabapentin has been shown to reduce hot flashes, but the long-term safety of these agents is unknown.61

Many women are interested in CAM approaches for the alleviation of their menopausal symptoms. The safety of phytoestrogens from soy, lignans, and supplements of red clover, licorice root, kudzu root, and soy isoflavones has not been established in breast cancer survivors, and it is prudent to advise women to avoid these supplements. Black cohosh (Cimicifuga racemosa) has been approved by the German E Commission for the nonprescription treatment of menopausal symptoms. Black cohosh has a relatively good safety profile but research supporting its use for the treatment of hot flashes in women with breast cancer is inconclusive.62 This herb is not a phytoestrogen, and its mechanism of action is not clear.

The North American Menopause Society (NAMS), in its position paper on the management of hot flashes, suggests lifestyle-related strategies for dealing with mild menopausal symptoms, including keeping the core body temperature cool, using paced respiration, and exercising regularly.63 NAMS found no benefit with the use of dong quai, evening primrose oil, ginseng, a Chinese herbal mixture, acupuncture, or magnet therapy. Hot flash “triggers” such as alcohol, hot drinks, or spicy foods are a problem for some, but not all, women.

Osteoporosis

Breast cancer survivors are at risk for osteoporosis and fractures because of low estrogen levels caused by early menopause as a result of CT or oophorectomy in premenopausal women or the use of AIs in postmenopausal women.64 Tamoxifen has been shown to preserve bone mineral density (BMD) in the spine and hip in postmenopausal women, although the extent of the protection is not clear—few studies have directly investigated the net BMD increase.65 Likewise, few studies have focused on the purported link between tamoxifen and a decreased risk of bone fractures.

Recommendations for preventing and treating bone loss in breast cancer survivors are similar to those for women without breast cancer. Women are advised to undergo an initial dual-energy x-ray absorptiometry (DEXA) bone scan and then an annual or biennial DEXA to assess BMD.

Recommendations have also been made regarding the use of calcium, vitamin D, and exercise to ward off bone loss. In 2006, for example, NAMS issued a position paper supporting the role of calcium and vitamin D in reducing fractures. It recommends 1,200 mg of calcium per day from food and supplements and adequate vitamin D, defined as a serum level of 25 (OH)D of 30 ng/mL (or higher).66 In clinical practice, supplementation with 800-1,000 IU of vitamin D3 is typically needed to obtain a level of 30 ng/mL (or more) of 25(OH)D, but some women may need even larger amounts. Women should be advised to engage in regular weight-bearing and musclestrengthening exercise to prevent and bone loss and to prevent falls. The use of bisphosphonates in combination with AIs may minimize bone loss.67

Cardiovascular Disease

The risk of cardiovascular disease (CVD) depends on the type of adjuvant systemic therapy received. Radiation to the left chest wall is associated with an increase in the long-term risk of cardiovascular events. Early menopause also increases the long-term risk of CVD because it results in the loss of the protective effects of estrogen. Some concerns have been raised that the reduction of estrogen associated with use of AIs may also increase CVD risk, but studies to date have been inconclusive. For all these reasons, women should follow the standard guidelines for reducing CVD risk, such as maintaining a healthy weight, avoiding smoking, exercising regularly, and controlling blood pressure, blood sugar, and lipids.

Congestive heart failure can result from CT consisting of anthracyclines or tratuzumab. Tamoxifen increases the risk of deep venous thrombosis and cerebrovascular disease.

Preventing Recurrence

In the United States, the number of breast cancer survivors is estimated to exceed 2 million. Many of these survivors are interested in nutrition and lifestyle interventions beyond conventional treatment to improve their prognosis. Although hundreds of studies have focused on the potential links between diet and etiology of breast cancer, only a few studies to date have addressed diet and survival.68 The Women’s Intervention Nutrition Study (WINS) and the WHEL study are two randomized trials that focused on lifestyle intervention, including diet and exercise (Table 8.2).69 70 Both WINS

Name of Study/ Year Published/ Country

Size of Cohort/ Years of Follow-up

Findings

Women’s Healthy

1,490 women with

A combination of consuming five or

Eating and Living

early-stage breast

more servings of vegetables/fruit and

(WHEL), 2007,

cancer

accumulating the equivalent of

United States71

Mean 6.7 years of follow-up

walking 30 minutes 6 days per week was associated with a significant survival advantage (HR = 56). Benefits were observed in both obese and non-obese women.

Women’s Intervention

2,437 women with

Reducing dietary fat to 15-20% of

Nutrition Study (WINS),

early-stage breast

calories was associated with a longer

2006, United States72

cancer 5 years

relapse-free survival in women with ER-negative/PR-negative cancers. No benefit was seen in ER-positive/PR positive cancers.

and WHEL enrolled women who had completed primary conventional cancer treatment. In addition to these two studies, at least five ongoing prospective cohort studies are addressing diet and breast cancer survival in women who have undergone conventional therapy and are in remission.

Weight and Risk of Recurrence and Mortality

Weight and elevated body mass index (BMI) have been associated with a poorer prognosis, but more recent data on this subject are mixed. In the Nurses’ Health Study, 5,204 participants who were diagnosed with invasive, nonmetastatic breast cancer between 1976 and 2000 were followed for a median of 9 years.73 High body weight prior to diagnosis was associated with poorer survival. Participants who gained 6 pounds after diagnosis had a RR of death from breast cancer of 1.35; those who gained 17 pounds had a RR of 1.64. Similar findings were seen for breast cancer recurrence and mortality from all causes.

Abrahamson et al., in a large population-based follow-up study, found that breast cancer survival is reduced among younger women aged 20-54 with general or abdominal obesity.74 Young women who had a BMI of 30 or more or a waist-to-hip ratio (WHR) of 0.80 or more near the time of their diagnosis of breast cancer also had increased mortality. In contrast to these findings, more recent data from the WHEL study revealed that combined healthy lifestyle behaviors, consisting of live servings of vegetables and fruit per day and the equivalent of walking 30 minutes at a moderate pace 6 days per week, was associated with a 50% reduction in mortality rates in both obese and non-obese women with early-stage breast cancer.70

The means by which overweight influences survival include increased endogenous production of estrogen by adipose tissue, decreased levels of SHBG, diagnosis at a later stage, larger tumor size at diagnosis, increased insulin and insulin-like growth factors, and poorer response to treatment. Obesity is also associated with reduced immune function, which could indirectly promote recurrence. Elevated WHR is associated with hyperinsuline-mia and insulin resistance independent of BMI and may be a contributing factor in mortality. A higher BMI may also be related to increased mortality as a result of incorrect dosing of CT, incomplete removal of the primary tumor, or difficulty in detecting recurrences in large women.

Low-Fat, High-Fiber, High-Vegetable and -Fruit Diet A low-fat, high-fiber, high-vegetable and -fruit diet does not appear to reduce mortality or recurrence in breast cancer survivors. In the WHEL trial, a diet including 5 vegetable servings plus 16 ounces of vegetable juice, 3 fruit servings, 30 grams of fiber, and 15-20% of calories from fat did not reduce mortality from breast cancer, mortality from any cause, or the combined outcome of invasive breast cancer recurrence or new primary breast cancer during the 7.3-year follow-up period in women with early-stage breast cancer (stage I, stage II, or stage IIIa).69 Women in the control group consumed 5 servings of vegetables and fruit per day, so it is possible that eating more than 5 servings of vegetables and fruit per day does not confer additional benefit. These results were surprising, as a high-fiber, low-fat diet intervention has been demonstrated to decrease serum bioavailable estradiol levels in women with a history of breast cancer.70

Dietary Fat and ER-Negative/PR-Negative Breast Cancer Recurrence Dietary fat intake may influence the recurrence or the diagnosis of a new breast cancer in women with early-stage breast cancer, according to interim analyses from the Women’s Intervention Nutrition Study (WINS).72 WINS, a randomized, prospective, multicenter trial involving more 2,400 participants, showed that a reduction in dietary fat to 15-20% of total calories was marginally associated with longer relapse-free survival. The benefit was mainly seen in women with ER-negative/PR-negative cancers. Reduced body weight in the intervention group might be responsible for the improvement in relapse-free survival. Although additional research is needed to confirm the relationship between dietary fat and relapse, women with ER-negative/PR-negative breast cancers should be advised to reduce their dietary fat intake to 20% of calories. The expertise of a registered dietitian should be utilized to help women achieve this goal.

Combined Healthy Lifestyle Behaviors

Healthy lifestyle behaviors, when combined, have been demonstrated to have a beneficial effect on mortality in breast cancer survivors. Combined healthy lifestyle behaviors, consisting of 5 servings of vegetables and fruit per day, and the equivalent of walking 30 minutes at a moderate pace 6 days per week, were associated with a 50% reduction in mortality rates in a prospective study of 1,490 women diagnosed with early-stage breast cancer. The women in this study had completed primary therapy, although the majority of them were still taking tamoxifen.71 Women who were physically active and consumed 5 servings of vegetables and fruit per day had an estimated 10-year mortality rate of 7%, or approximately half of the rate in women with lower levels of physical activity and lower vegetable and fruit consumption. The effect was seen in both obese and non-obese women; it was stronger in women with ER-positive or PR-positive cancers.

Green Tea Epidemiologic research in Japan suggests that Asian women who have been treated for stage I or stage II breast cancer and who drink 3-5 cups of green tea per day reduce their risk of recurrence compared to women who drink 0-2 cups of green tea per day (HR stage I = 0.37; HR stage II = 0.80).75 No benefit was found for stage III and IV breast cancer. This study suggests regular green tea consumption may protect against recurrence of breast cancer when patients are diagnosed with and treated for early-stage cancer, though the results need to be confirmed with randomized trials. Nevertheless, women with early-stage breast cancer may want to consider drinking 3-5 cups of green tea per day, as there are no known harmful effects and some potential benefit.

Vitamin D Low vitamin D levels at the time of diagnosis may be associated with a poor prognosis. In a prospective study involving 512 women with newly diagnosed breast cancer, vitamin D deficiency at the time of breast cancer diagnosis was associated with an increased risk of distant recurrence and death.76

Vitamin D levels were deficient (< 50 nmol/L or <20 ng/mL) in 37.5% of these patients, insufficient (50—72 nmol/L or 20—28.8 ng/mL) in 38.5%, and adequate (> 72 nmol/L or 28.8 ng/mL) in 24%. Low vitamin D levels were associated with premenopausal status, high BMI, high insulin levels, high tumor grade, and low dietary intake of retinol, vitamin E, grains, and alcohol. Distant disease-free survival (DDFS) was significantly worse in women with deficient (versus adequate) vitamin D levels (HR = 1.94), as was overall survival (HR = 1.73). There was no survival difference between women with insufficient versus adequate vitamin D levels. Associations with DDFS were independent of age, BMI, insulin, tumor stage and nodal status (T and N in the TNM system), ER status (positive or negative), and tumor grade. The data suggested a small but not statistically significant increased risk of metastasis with high levels of vitamin D.

Epidemiological studies suggest that the season in which diagnosis is made may also affect survival. Diagnosis of breast cancer in the summer is associated with greater survival than diagnosis in the winter. Women of all ages in Norway who were diagnosed in the summer had 25% better survival after standard treatment compared with women who were diagnosed in the winter.77 Women younger than age 50 had 40% better survival if they were diagnosed in the summer versus the winter. Although no conclusions about the biological mechanism could be made based on this epidemiological study, the authors theorized that women diagnosed in the summer had higher circulating vitamin D levels, which may have modulated cell signaling, induced apoptosis, regulated cell-cycle progression, and reduced angiogenic activity and invasiveness. Similar findings have been reported in the United Kingdom.78

Women with a history of breast cancer should have their serum 25(OH) levels measured. Additional research identifying the optimal serum level to prevent recurrence is needed, but the study results suggest that women should take enough vitamin D to maintain an adequate serum level.

Cruciferous Vegetables A clinical trial seeking to determine whether cruciferous vegetables are protective against breast cancer recurrence is now under way.79 In the meantime, it is reasonable to encourage women to increase consumption of cruciferous vegetables because of these foods’ proposed anticarcinogenic properties and ability to modulate estrogen metabolites. Currently, there is no evidence to support the use of supplements of I3C, the component of cruciferous vegetables thought to modulate estrogen levels.

Table 8.3 provides a summary of the recommendations for prevention of recurrence for breast cancer survivors.

1. Engage in the equivalent of brisk walking 6 days per week for !/2 hour per session. Eat 5 servings of vegetables and fruits per day. Select colorful vegetables that are yellow, orange, and deep green. Increase consumption of broccoli, cabbage, cauliflower, and other cruciferous vegetables, which should be either uncooked or lightly steamed to ensure maximum benefit.

2. Maintain a healthy weight. Avoid sweetened beverages such as soda, lemonade, and sports drinks. Consume energy-dense foods sparingly. Avoid fast foods.

3. Limit red meat to 3 servings per week or less, and avoid processed meats. If processed meat (including turkey breast) is consumed, select brands that are nitrate- and preservative-free. These foods can be found in many health food supermarkets.

4. Avoid charbroiled and overcooked foods (burnt or charred), including beef, chicken, lamb, pork, or fish. Cook these foods at a temperature below 325° F—the surface temperature at which heterocyclic amines (HCAs) form—whether grilling, pan-frying, or oven-roasting the foods. When grilling, marinating the meat prior to cooking can reduce the formation of HCAs. Avoid cooking over a direct flame, as fat or marinade drippings can cause flare-ups that deposit HCAs and other carcinogens on the surface of food. Flip food once a minute. Microwaving the meat for 1—2 minutes at a medium setting prior to grilling can inhibit HCAs formation. Use other methods of food preparation such as stewing, poaching, or slow-cooking in a Crock-Pot.

5. Aim for 1,400—1,500 mg of calcium per day and 1,100 IU of vitamin D3 as cholecalciferol. Measure serum 25(OH) vitamin D levels to determine vitamin D sufficiency. Low levels of vitamin D are associated with increased risk of recurrence and death. Increase vitamin D supplementation as necessary to achieve a sufficient serum level of vitamin D, currently thought to be 30 ng/mL or more. Optimal serum ranges of vitamin D for the prevention of breast cancer recurrence are not known.

6. Drink 3—5 cups of green tea per day.

7. Avoid alcoholic drinks. Even small amounts of alcohol increase breast cancer risk, regardless of the type of alcohol. Women who drink alcohol should take a multivitamin supplement with the RDA for folic acid.

8. For ER-negative/PR-negative breast cancer, dietary fat should be decreased to 15—20% of total daily calories. Recommend consultation with a registered dietitian to achieve this goal.

9. Breast cancer survivors should receive nutritional care from a registered dietitian for diet and supplement advice. A registered dietitian can help with weight management and the prevention and treatment of the metabolic syndrome. In general, a multivitamin supplement should not provide more than the RDA for nutrients, with the exception of vitamin D. Calcium supplementation is often necessary to meet the recommendations for this nutrient. Nutrients and phytochemicals should come from food, not from supplements. Excess amounts of some nutrients, such as folic acid, may increase breast cancer risk in some individuals.

(continues)

Continued

10. Women with ER-positive/PR-positive breast cancers who experience hot flashes due to endocrine therapy or early menopause should avoid taking supplements containing phytoestrogens from soy or lignans, or supplements of red clover, licorice root, kudzu root, or soy isoflavones. The safety of these supplements has not been established for the management of hot flashes in breast cancer survivors. Diets high in soy from food should also be avoided. Black cohosh, which is not a phytoestrogen, has a relatively good safety profile, but research supporting its use for the treatment hot flashes in women with breast cancer is inconclusive. No benefit has been found for dong quai, evening primrose oil, or ginseng. Lifestyle strategies such as keeping the core body temperature cool, using paced respiration, and exercising regularly may help for managing mild hot flashes. Spicy foods, hot drinks, or alcohol may be hot flash triggers in some women.

Future Directions for Research

Nutrition’s part in the etiology, treatment, prevention, and recurrence of breast cancer continues to unfold. Although strong evidence is lacking about the relationship between diet and breast cancer, women should continue to embrace healthy eating and lifestyle behaviors for their potential overall health benefits. Additional research is needed about the role of diet during fetal development, infancy, childhood, and adolescence as part of the etiology of breast cancer. Diet during these periods of development may be an important predictor of breast cancer risk, but as yet data are lacking in this area. Areas for additional exploration include how diet influences subgroups of women characterized by certain tumor subtypes and genetic, epigenic, or hormonal status. Similarly, research is needed on breast cancer risk and chemicals that act as endocrine disruptors. Additionally, studies addressing survivorship and diet are essential, especially those geared toward finding the optimal levels of vitamin D to prevent recurrence.

REFERENCES

1. American Cancer Society. Cancer Facts and Figures 2008. Atlanta, GA: American Cancer Society; 2008.

2. Nguyen PL, Taghian AG, Katz MS, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol. 2008;26:2373-2378.

3. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354:270-282.

4. Armstrong K, Eisen A, Weber B. Assessing the risk of breast cancer. N Engl J Med. 2000; 342:564-571.

5. Estimating breast cancer risk: Questions and answers. National Cancer Institute website. http://www.cancer.gov/cancertopics/factsheet/estimating-breast-cancerrisk. Accessed November 11, 2007.

6. Barlow WE, White E, Ballard-Barbash R, et al. Prospective breast cancer risk prediction model for women undergoing screening mammography. J Natl Cancer Inst. 2006;98:1204-1214.

7. Modan B, Chetrit A, Alfandary E, Katz L. Increased risk of breast cancer after low-dose radiation. Lancet. 1989;333:629-631.

8. Smith RA, Saslow D, Sawyer KA, et al. American Cancer Society guidelines for breast cancer screening: Update 2003. CA Cancer J Clin. 2003;54:141-169.

9. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007; 57:75-89.

10. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: Breast cancer. V.2. 2007. http://www.nccn.org/professionals/physician_gls/PDF/ breast.pdf. Accessed December 5, 2007.

11. Brenton JD, Carey LA, Ahmed AA, Caldas C. Molecular classification and molecular forecasting of breast cancer: Ready for clinical application? J Clin Oncol. 2005;23:7350-7360.

12. Harris EE, Correa C, Hwang WT, et al. Late cardiac mortality and morbidity in early stage breast cancer patients after breast-conservation treatment. J Clin Oncol. 2006;24:4100-4106.

13. Smedira H. Practical issues in counseling healthy women about their breast cancer risk and use of tamoxifen citrate. Arch Intern Med. 2000;160:3034-3042.

14. FDA approves new uses for Evista. US Food and Drug Administration website. http:// fda.gov/bbs/topics/NEWS/2007/NEW01698.html. Accessed December 5, 2007.

15. Bundred NJ. The effects of aromatase inhibitors on lipids and thrombosis. Br J Cancer. 2005;93:S23-S27.

16. Mouridsen H, Keshaviah A, Coates AS, et al. Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: Safety analysis of BIG 1-98 trial. J Clin Oncol. 2007;25:5715-5722.

17. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington DC: AICR; 2007.

18. Michels KB, Mohllajee AP, Roset-Bahmanyar E, et al. Diet and breast cancer: A review of the prospective observational studies. Cancer. 2007;109(12)(suppl): 2712S-2749S.

19. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: Collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet. 2002;360:187-195.

20. Hilakivi-Clarke L, Cho E, deAssis S, et al. Maternal and prepubertal diet, mammary development and breast cancer risk. J Nutr. 2001;131:154S-157S.

21. Eliassen AH, Colditz GA, Rosner B, Willett WC, Hankinson SE. Adult weight change and risk of postmenopausal breast cancer. JAMA. 2006;296:193-201.

22. Smith-Warner SA, Spiegelman D, Yaun SS, et al. Alcohol and breast cancer in women: A pooled analysis of cohort studies. JAMA. 1998;279:535-540.

23. Hamajima N, Hirose K, Tajima K, et al. Alcohol, tobacco and breast cancer— collaborative reanalysis of individual data from 53 epidemiological studies including

58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer. 2002;87:1234-1245.

24. Suzuki R, Ye W, Rylander-Rudqvist T, et al. Alcohol and postmenopausal breast cancer risk defined by estrogen and progesterone receptor status: A prospective cohort study. J Natl Cancer Inst. 2005;97:1601-1608.

25. Stolzenberg-Solomon R, Chang SC, Leitzmann M, et al. Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening. Am J Clin Nutr. 2006;83:895-904.

26. Thiebaut AC, Kipnis V, Chang SC, et al. Dietary fat and postmenopausal invasive breast cancer in the National Institutes of Health-AARP Diet and Health Study cohort. J Natl Cancer Inst. 2007;99:451-462.

27. Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and the risk of invasive breast cancer: The Women’s Health Initiative randomized controlled dietary modification trial. JAMA. 2006;295:629-642.

28. Cho E, Chen WY, Hunter DJ, et al. Red meat intake and risk of breast cancer among premenopausal women. Arch Intern Med. 2006;166:2253-2259.

29. Taylor E, Burley V, Greenwood D. Meat consumption and risk of breast cancer in the UK Women’s Cohort Study. Br J Cancer. 2007;96:1139-1146.

30. van der Hel OL, Peeters PH, Hein DW, et al. GSTM1 null genotype, red meat consumption and breast cancer risk. Cancer Causes Control. 2004;3:295-303.

31. Key T, Fraser G, Thorogood P, et al. Mortality in vegetarians and nonvegetarians: Detailed findings from a collaborative analysis of 5 prospective studies. Am J Clin Nutr. 1999;70(suppl):516S-524S.

32. Willet W. Lessons from dietary studies in Adventists and questions for the future. Am J Clin Nutr. 2003;78(suppl):539S-543S.

33. Kushi, P. What is macrobiotics? Kushi Institute website. http://www.kushi institute.org/html/what_is_macro.html. Accessed December 10, 2007.

34. Higdon JV, Delage B, Williams DE, et al. Cruciferous vegetables and human cancer risk: Epidemiologic evidence and mechanistic basis. Pharmacol Res. 2007;55: 224-236.

35. Lampe J, Peterson S. Brassica biotransformation and cancer risk: Genetic polymorphisms alter the preventive effects of cruciferous vegetables. J Nutr. 2002;132: 2991-2994.

36. Fowke JH, Longcope C, Herbert JR. Brassica vegetable consumption shifts estrogen metabolism in healthy postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2000;9:773-779.

37. Indole-3-carbinol in preventing breast cancer in nonsmoking women who are at high risk for breast cancer. National Institutes of Health website. http://www.clinical trials.gov/ct2/show/record/NCT00033345. Accessed December 16, 2007.

38. Fink B, Steck S, Wolff M, et al. Dietary flavonoid intake and breast cancer risk among women on Long Island. Am J Epidemiol. 2006;165:514-523.

39. Carlson JR, Bauer B, Vincent A, et al. Reading the tea leaves: Anticarcinogenic properties of (-)-epigallocatechin-3-gallate. Mayo Clin Proc. 2007;82:725-732.

40. Wu A, Tseng CC, van den Berg D, et al. Tea intake, COMT genotype, and breast cancer in Asian-American women. Cancer Res. 2003;63:7526-7529.

41. Wuttke W, Hubertus J, Seidlova-Wuttke D. Isoflavones: Safe food additives or dangerous drugs? Ageing Res Rev. 2007;6:150-188.

42. Messina M, Loprinzi C. Soy for breast cancer survivors: A critical review of the literature. J Nutr. 2001;131:3095S-3108S.

43. Brooks J, Ward W, Lewis J, et al. Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy. Am J Clin Nutr. 2004;79:318-325.

44. Thompson L, Chen J, Li T, et al. Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer. Clin Cancer Res. 2005;11:3828-3835.

45. Galeone C, Pelucchi C, Levi F, et al. Onion and garlic use and human cancer. Am J Clin Nutr. 2006;84:1027-1032.

46. Holick M. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.

47. Lappe J, Travers-Gustafson, Davies K, et al. Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial. Am J Clin Nutr. 2007;85: 1586-1591.

48. Vasquez A, Manso G, Cannell J. The clinical importance of vitamin D (cholecalcif-erol): A paradigm shift with implications for all healthcare providers. Altern Ther. 2004;10:28-36.

49. Rudel R, Attfield K, Schifano J, et al. Chemicals causing mammary gland tumors in animals signal new directions for epidemiology, chemicals testing, and risk assessment for breast cancer prevention. Cancer. 2007;109(12)(suppl):2635S-2666S.

50. Brody J, Moysich K, Humblet O, et al. Environmental pollutants and breast cancer: Epidemiologic studies. Cancer. 2007;109(12)(suppl):2667S-2711S.

51. Gartner LM, Morton J, Lawrence RA, et al. Breast feeding and the use of human milk. Pediatrics. 2005;115:496-506.

52. Bauer J, Capra S, Ferguson M. Use of the scored Patient-Generated Subjective Global Assessment (PG-SGA) as a nutrition assessment tool in patients with cancer. Eur J Clin Nutr. 2002;56:779-785.

53. Read JA, Crockett N, Volker DH, et al. Nutritional assessment in cancer: Comparing the Mini-Nutritional Assessment (MNA) with the Scored Patient-Generated Subjective Global Assessment (PGSGA). Nutrition and Cancer. 2005;53:51-56.

54. Henderson J, Donatelle R. Complementary and alternative medicine use by women after completion of allopathic treatment for breast cancer. Altern Ther Health Med. 2004;10:52-57.

55. Harvie M, Campbell I, Baildam A, et al. Energy balance in early breast cancer patients receiving adjuvant chemotherapy. Breast Cancer Res Treat. 2004;83: 201-210.

56. Denmark-Wahnefried W, Peterson B, Winer E, et al. Changes in weight, body composition, and factors influencing energy balance among premenopausal breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol. 2001;19:2381-2389.

57. Saquib N, Flatt S, Natarajan L, et al. Weight gain and recovery of pre-cancer weight after breast cancer treatments: Evidence from the Women’s Healthy Eating and Living (WHEL) study. Breast Cancer Res Treat. 2007;105:177-186.

58. Hayes, D. Follow-up of patients with early breast cancer. N Engl J Med. 2007;356: 2505-2513.

59. Mortimer J, Flatt S, Parker BA, et al. Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res Treat. 2008;108:421-426.

60. Antoine C, Liebens B, Carly B, et al. Safety of alternative treatments for menopausal symptoms after breast cancer: A qualitative systematic review. Climacteric. 2007; 10:23-26.

61. Management of menopausal symptoms in patients with breast cancer: An evidence-based approach. Lancet. 2005;6:687-695. http://www.oncology.thelancet.com. Accessed December 23, 2007.

62. Walji R, Boon H, Guns E, et al. Black cohosh (Cimicifuga racemosa [L.]Nutt.): Safety and efficacy for cancer patients. Support Cancer Care. 2007;15(8):913—921.

63. Treatment of menopause-associated vasomotor symptoms: Position statement of the North American Menopause Society. Menopause. 2004;11:11-33.

64. Winer E, Hudis C, Burstein HG, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors for early breast cancer for postmenopausal women with hormone receptor-positive breast cancer: Status report. J Clin Oncol. 2005;23:619-629.

65. Ding H, Field T. Bone health in postmenopausal women with early breast cancer: How protective is tamoxifen? Cancer Treat Rev. 2007;33:506-513.

66. North American Menopause Society. The role of calcium in peri- and postmenopausal women: Position statement of the North American Menopause Society. Menopause. 2006;13:859-861.

67. Berry, J. Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer. Clin Ther. 2005;27:1671-1684.

68. Kushi L, Kwan M, Lee M, et al. Lifestyle factors and survival in women with breast cancer. J Nutr. 2007;137:236S-242S.

69. Pierce J, Natarajan L, Caan B, et al. Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer. The Women’s Healthy Eating and Living (WHEL) randomized trial. JAMA. 2007; 298:289-298.

70. Rock CL, Flatt SW, Thomson CA, et al. Effects of a high-fiber, low-fat diet intervention on serum concentrations of reproductive steroid hormones in women with a history of breast cancer. J Clin Oncol. 2004;22:2379-2387.

71. Pierce J, Stefanick M, Flatt S, et al. Greater survival after breast cancer in physically active women with high vegetable-fruit intake regardless of obesity. J Clin Oncol. 2007;25:2345-2351.

72. Chlebowski R, Blackburn G, Thomson C, et al. Dietary fat reduction and breast cancer outcome: Interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst. 2006;98:1767-1776.

73. Kroenke C, Chen W, Rosner B, et al. Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol. 2005;23:1370-1378.

74. Abrahamson P, Gammon M, Lund M, et al. General and abdominal obesity and survival among young women with breast cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:1871-1877.

75. Inoue M, Tajima K, Mitzutani M, et al. Regular consumption of green tea and the risk of breast cancer recurrence: Follow-up study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. Cancer Letters. 2001;167:175-182.

76. Goodwin PJ, Ennis M, Pritchard I, et al. Frequency of vitamin D deficiency at breast cancer diagnosis and association with risk of distant recurrence and death in a prospective cohort study of T1-3, NO-0, MO BC. J Clin Oncol. 2008;26(May 20 suppl; abstr 511).

77. Porojnicu A, Lagunova Z, Robsahm T, et al. Changes in risk of death from breast cancer with season and latitude. Breast Cancer Res Treat. 2007;102:323-328.

78. Lim, HS, Roychoudhuri R, Peto J, et al. Cancer survival is dependent on season of diagnosis and sunlight exposure. Int J Cancer. 2006;119:1530-1506.

79. Thomson CA, Rock CL, Caan BJ, et al. Increase in cruciferous vegetables intake in women previously treated for breast cancer participating in a dietary intervention trial. Nutr Cancer. 2007;57:11-19.

Рекомендуем к просомтру

www.kievoncology.com благодарны автору и издательству, которые способствует образованию медицинских работников. При нарушении авторских прав, сообщите нам и мы незамедлительно удалим материалы.