The association between breast cancer and modifiable health behaviors is well supported. At least one-half of all cancers are suggested to have a dietary component. It is not surprising therefore that many of the dietary agents and natural health products that have attracted the attentions of scientists and practitioners are now moving into clinical trials. In this report, we review 65 clinical intervention trials evaluating over 30 dietary supplements and natural health products for use in breast cancer. The products being tested in these trials fall broadly into the following categories: (i) vitamins, minerals, cofactors; (ii) herbal extracts; (iii) amino acids; (iv) fatty acids; (v) animal products; (vi) probiotics; (vii) phytochemicals; and (viii) combination formulations. Trial outcome measures include risk modification, efficacy testing (with dietary supplements alone or dietary supplementanticancer drug combinations), toxicity reduction, biomarker identification, symptom management, and quality of life parameters. The wide range of interests in natural product testing at the clinical trial level supports the potential utility of these agents in the breast cancer prevention, treatment, and management regimens of the future.

2. INTRODUCTION

Cancer, overall, is expected to increase in this country by as much as 45% over the next twenty years (1). Breast cancer is a particular concern. The American Cancer Society estimates that there will be well over 200,000 new cases of invasive breast cancer and over 50,000 new cases of in situ breast cancer in this country for the year 2010 alone. According to current statistics, 1500 Americans will die of cancer each day with a significant percentage from breast cancer (2).

Although a wide variety of treatment options are available, breast cancer remains the second leading cause of death in American women. Treatment strategies depend on the characteristics of both the tumor (including stage, grade, and molecular profile(ER, PR, ERBB2, BRCA1/2)), and the patient (age, health, menopausal status, family history). Conventional treatment options for early breast cancers (ductal carcinoma in situ and early invasive breast cancer) include surgery and radiation therapy with or without chemotherapy, endocrine agents, or targeted antibodies (3-5). A partial listing of standard chemotherapeutic drugs is shown in Table 1. Different drugs or therapeutic approaches are often combined in an effort to decrease the severity of side effects while maintaining or improving survival. Nevertheless, toxicity continues to be the most critical limiting factor involved in ensuring patient safety (5-6). Finding an effective treatment protocol with a favorable risk-to-benefit ratio is often the strongest obstacle to successful therapy. Adverse events from systemic therapy with cytotoxic drugs can be severe enough to cause damage to major organ systems; localized radiotherapy can lead to fibrosis, pain, edema, and irreversible changes in mobility (5-8). These problems underscore the need for safer alternatives to conventional cancer therapy (9-10) and promote interest in CAM modalities (10-12).

The use of CAMs, dietary supplements, and natural health products is believed to be high among individuals with chronic health problems. To examine the prevalence of CAM use among women who had been diagnosed with- or were at risk for developing breast cancer we surveyed the literature (13-27). We examined 15 studies conducted in 6 different countries involving over 17,000 women. The average CAM use across all 15 of these studies was approximately 72% with prevalence rates ranging from 40 to 96% (Table 2). Interest in CAMs, dietary supplements, and natural health products by consumers, health care professionals, and patients is burgeoning. It has not only fueled a tremendous expansion in our knowledge, but it is leading the way for a more integrated, multidisciplinary approach to the practice of medicine. When we ask the question of whether the effectiveness of cancer therapy can be increased by natural health products, we will be able to look to clinical trials for answers.

This review describes some of the types of dietary supplements and natural health products that are currently undergoing clinical testing. We identified 65 clinical trials that were either active or open at the time of this writing (through April of 2010). These trials are expected to accrue a cumulative total of over 9,000 women testing more than 30 natural compounds for their abilities to modify breast cancer risk, enhance treatment responses or reduce the toxicities associated with standard chemotherapy. Brief summaries of the available evidence will be provided for a portion of the dietary supplement interventions in the sections that follow. The summaries will also be correlated with the more detailed trial descriptions provided in Table 3.

3. CLINICAL TRIALS

3.1. Trial activity and enrollment

The purpose of this review was to identify the types of dietary supplements and natural health products that are currently undergoing clinical trial testing for breast cancer. Although not exhaustive, a search conducted between the February and April of 2010, produced 84 trials which met our specifications; all trials were interventional, open at the time of inquiry, and involved interventions with dietary supplements or natural health products for breast cancer. We selected 65 clinical trials from the original 84 for this review. All 65 trials centered on the use of dietary or natural products and most were aimed at measuring treatment efficacy, risk reduction, symptom management or toxicity prevention in breast cancer.

Participant enrollment was highly variable from trial to trial, ranging from 9 (trial 31) to 2,300 (trial 9), as shown in Table 3. The total projected accrual across all trials was over 9,000, with a per trial average of 139. At the time of this writing, 41 trials were actively recruiting participants, 22 trials were active but no longer recruiting while 2 of the trials were open but had not yet begun recruiting their participants. These are identified in Table 3 by green, yellow, or blue coding, respectively.

3.2. Trial Types and Phases

When we reviewed the purpose for each of the 65 trials in Table 3, four different types of trials emerged. These were: Prevention, Treatment, Supportive Care, and Basic Science (summarized in Table 4). We found that 20 trials were focused on breast cancer Prevention, 21 on Treatment, 17 were aimed at Supportive Care and 7 were involved in Basic Science. We also examined the phases designated for each of the trials.

Clinical trial testing traditionally uses the phase designations I- IV to sequentially evaluate new agents or treatments in order to prove safety, activity, and efficacy in human populations. A newer trial phase, designated phase 0, was recently developed in response to the United States Food and Drug Administration's (FDA) exploratory Investigational New Drug (IND) guidelines with the goal of streamlining the clinical evaluation process (28). Phase 0 trials are conducted with small numbers of participants to establish effectiveness and determine pharmacodynamics for further clinical development. Phase I trials test recommended doses and/or schedules needed for progression into phase II testing. Participant numbers in phase I trials are generally small and the doses tested are considered subtherapeutic. This allows accrual to be achieved rapidly while preserving safety (29). Phase I/II clinical trials are designed to obtain data for more definitive phase II level testing. In phase II trials endpoints including toxicity, biologic activity, plasma concentrations, and target interactions are often tested. Efficacy and safety are also evaluated in these trials but they do so with much larger participant numbers over a greater length of time. Phase III trials have the power to explore the effectiveness of a given agent on risk reduction, disease incidence and symptom occurrence. In addition they monitor side effects and evaluate a range of safety and efficacy-related parameters. Phase IV, trials are typically described as post-marketing or safety surveillance trials, aimed at increasing the knowledge surrounding a given agent or treatment and identifying any late effects or long term consequences that may emerge. Many of these designations have become blurred in dietary agent trials or trials investigating drug-dietary agent combinations.

When we examined the phase designations for trials under consideration here, we found that they spanned nearly all phases of investigation (Tables 3-4). If we excluded those trials that were without specified phases, we found that over 70% of the Treatment trials consisted of phase I and phase II activities while 70% of the Supportive Care trials were in phases II and III. By contrast, approximately 55% of the phase-specified trials in the Prevention category were at the phase II level while 50% of those in the Basic Science group were in phase 0. Notably, there were no phase 0 trials in either the Prevention or Treatment groups; only one phase 0 trial was found in the Supportive Care category (Table 4).

4. NATURAL HEALTH PRODUCTS IN CURRENT CLINICAL TRIALS

We found that a variety of CAMs, dietary supplements and natural health products were being evaluated alone or in combination with anticancer agents. There has been an unprecedented increase in the growth in natural product use for health maintenance, disease prevention and cancer control. The acronym CAM has grown to encompass a vast number of treatment modalities - well beyond those reviewed here. In addition, many of the health approaches that had previously been considered complimentary are now being integrated into medical practices considered to be 'conventional'. This progression is reflected in the term 'Integrative Medicine' which is described further elsewhere (30).

The dietary supplements and natural products identified in the 65 clinical trials shown in Table 3 include vitamins, minerals, trace elements and cofactors (vitamins: B6, B12, D, and E; calcium; germanium and coenzyme Q10); herbal extracts (mistletoe, grapeseed, broccoli sprout, green tea, coriolus vesicolor and herba scutellaria barbata); amino acids and amino acid derivatives (l-carnitine-l-tartrate, l-acetyl-l-carnitine and glutamine), fatty acids (omega-3-fatty acids and conjugated linoleic acid); animal products (glucosamine chondroitin); probiotics (lactobacillus); phytochemicals (flaxseed, soy, garlic, d-limonene, diindolylmethane and ginseng); and proprietarial combinations (FemMED^®, THL-P and Chinese Herbals). We will provide a brief summary for some of the dietary and natural health products and describe how they are being evaluated in clinical trials at this time. For each of the following correlations, the reader is referred to Table 3.

4.1. Vitamins, minerals, and cofactors in breast cancer trials4.1.1. Vitamin D

Vitamin D has been shown to inhibit the proliferation of mammary tissue and promote its differentiation (31-33). Moreover, there is evidence that the vitamin D signaling pathway plays a role in breast tissue remodeling and homeostasis (34). Whether vitamin D signaling becomes dysregulated in mammary cancer is not known. Results from the National Health and Nutrition Examination Survey (NHANES) and from the Nurses' Health Study (35-36) provide support for the role of vitamin D in reducing the risk of developing breast cancer. Alternatively, the Women's Health Initiative (WHI) failed to demonstrate an association between breast cancer risk and vitamin D intake (37). Despite the mixed results in the literature, most experts agree that vitamin D adequacy is a key factor in the quality of life for women with breast cancer (38-41). The active form of vitamin D₃ is calcitriol or 1,25 dihydroxyvitamin D₃ (40). Other forms such as cholecalciferol and calcidiol are also referred to as 'vitamin D'. Cholecalciferol is an inactive precursor of calcidiol (25-hydroxyvitamin D). Calcidiol itself is a prehormone which must undergo hydroxylation for conversion to the biologically active form of vitamin D: calcitriol (1,25-dihydroxyvitamin D₃). The enzyme required for this conversion is 1-alpha-hydroxylase. The kidneys produce this rate-limiting enzyme and are thus responsible for putting the active form of vitamin D into the circulation (42). Although optimum vitamin D levels are not clearly defined for breast cancer patients, the current evidence suggests that maintaining adequate vitamin D levels before, during and after therapy may result in better symptom management, improved bone health, lower treatment toxicity and reduced rates of recurrence (38-45). Members of the vitamin D family are being examined in several of the trials in this report. Most focus on dosing, prevention, potential treatment efficacy (given prior to surgery), and bone health (see trials 22-25, Table 3). Vitamin D and calcium are also being examined together (trials 55-58) in order to assess risk reduction or to test efficacy in delaying bone metastasis, reducing bone loss or improving musculoskeletal symptoms associated with aromatase inhibitor (endocrine) therapy.

4.1.2. vitamin B6 (pyroxidine)

Vitamin B6 or pyroxidine is being evaluated in combination with the chemotherapeutic drugs doxorubicin (trials 17 and 20) and capecitabine (trials 18-19) for efficacy in preventing palmar-plantar erythrodysthesia and to determine maximum tolerated doses, MTDs (Table 3). Palmar-plantar erythrodysthesia, also referred to as hand-foot syndrome, is a side effect of capecitabine and other drugs used in chemotherapy.

4.1.3. Vitamin B12 (cobalamin)

The efficacy of vitamin B12 and folate in combination with pralatrexate is described in trial 21 (Table 3) which is enrolling patients with advanced metastatic breast cancer. Pralatrexate is an antifolate anticancer drug which has shown greater clinical activity than methotrexate (46).

4.1.4. Vitamin E

Vitamin E, an antioxidant, is being studied in two of the trials reviewed here (trials 14 and 15, Table 3) with pentoxifylline, for the efficacy of this combination to lessen the symptoms of radiotherapy, particularly radiation-induced fibrosis. Pentoxifylline is derived from a hemorrheologic methylxanthine. This drug is of interest in radiation oncology because it has shown the potential to enhance tumor oxygenation and promote radiosensitivity. Radiation-induced fibrosis is a late and generally irreversible consequence of radiotherapy (47) which is believed to respond to pentoxifylline-vitamin E cotreatment than to treatment with pentoxifylline alone. Previously published findings support the efficacy of this combination in attenuating the symptoms associated with fibrosis induced by radiation (47-48).

4.1.5. Coenzyme Q10

Coenzyme Q10 is a ubiquinone which is structurally similar to vitamin K. It is a natural component of living cells and can be synthesized in the body (49). Coenzyme Q10 functions as a cofactor in the mitochondrial electron transport chain and is essential to the ATP production. Coenzyme Q10 has antioxidant, neuroprotective and cardioprotective activities - qualities which are being exploited to reduce toxicities associated with anthracycline chemotherapy (50). Coenzyme Q10 is being given to participants enrolled in trials 16 and 17 with chemotherapeutic drugs like doxorubicin to determine the MTD or to evaluate the efficacy of this combination plus vitamin E (Coenzyme Q10-doxorubicin-vitamin E) in relieving treatment-related fatigue (Table 3).

4.2. Herbal extracts in breast cancer trials

Extracts of mistletoe, grapeseed, broccoli sprouts, green tea (polyphenon E), coriolus vesicolor (yunzhi) and herba scutellaria barbata are currently being examined in the breast cancer trials reviewed here.

4.2.1. Mistletoe extract (viscum album pini; iscador P)

Mistletoe (viscum album) is one of the most widely studied CAM therapies for solid cancers in Europe. Mistletoe extract contains lectins, viscotoxins, oligo- and polysaccharides. The lectins in mistletoe extract have demonstrated immune-modulating properties. Iscador P^® is an extract of mistletoe that has been prescribed to cancer patients in Germany for years (51). The FDA in this country has approved mistletoe extract for cancer treatment studies. This review includes two interventional trials that are examining mistletoe extract, trials 12 and 13. In trial 12, it is given in combination with gemcitabine (a chemotherapeutic drug) in order to identify the MTD, tumor response and toxicity during metastatic breast cancer treatment. In trial 13, the study participants are given mistletoe extract (Iscador P) during chemo- or hormonal therapy to identify surrogate parameters of efficacy. For greater detail, see Table 3.

4.2.2 grape seed extract (IHS636)

Grape seed extract contains a number of procyanidins which have been attributed with antioxidant, anti-inflammatory, cytoprotective, and antitumor properties. In preclinical studies, grapeseed extract has been shown to protect cell membranes from oxidative damage and from the protein and lipid oxidation caused by cytotoxic drugs or radiation. Clinical trials testing the efficacy of IHS636 grape seed extract in reducing or reversing induration caused by high dose radiation therapy in breast cancer patients have produced mixed results (52). Nevertheless, it is currently being tested (trial 42) as a potential strategy against fibrotic tissue changes associated with prior radiation therapy. Grape seed extract interventions enrolling healthy, high and low risk participants, are also being conducted for risk reduction, dose finding and serum marker evaluation, in trials 40, 41, and 43 (Table 3).

4.2.3. Green tea extract (polyphenon E extract)

Green tea, rich in bioactive compounds, has been referred as both drug and beverage, (53). The bioactive compounds of interest are the catechins: EGCG, EGC, ECG, and EC ((-) epigallocatechin-3-gallate, (-) epigallocatechin, (-) epicatechin-3-gallate, and (-) epicatechin, respectively). The literature has consistently shown an association between these bioactive agents and chemoprevention (54). Findings from a prospective cohort study conducted in Japan have shown that 10 or more cups of green tea per day (the equivalent of 2.5 grams of green tea extract) can significantly decrease the relative risk of cancer incidence and delay onset (55-57). The results of a recent review point to an inverse relationship between green tea consumption and breast cancer recurrence (58). Polyphenon E is a Japanese product which consists of decaffeinated catechins (200 mg EGCG, 37 mg EGC, 31 mg EC) and other polyphenols (59). Current clinical testing is being conducted using polyphenon E (trials 35, 36 and 39) or green tea extract (trials 37 and 38) in order to assess a variety of factors, including markers of breast cancer progression, MTDs, and risk reduction (Table 3).

4.2.4. Coriolus vesicolor extract (yunzhi extract)

Coriolus vesicolor is a fungus derived from the Asian mushroom yunzhi. Yunzhi has been shown to act as both a radio- and immunoprotectant; it has been used as a restorative or safeguard to reverse or limit tissue damage caused by radiation treatment for cancer (60). It is currently being evaluated for efficacy as an adjuvant during chemotherapy for breast cancer, protection against treatment-induced toxicity, and MTD determinations in trials 53 and 54 (Table 3).

4.2.5. Herba scutellaria barbata (chinese herbal extract, BZL101)

Herba scutellaria barbata or Bezielle (BZL101™) is an oral botanical designed to target cancer cells. It has been tested in preclinical studies (61) and is currently undergoing phase I/II efficacy and safety testing in women with histologically confirmed, metastatic breast cancer (trials 47-48). Various pharmacokinetic parameters including toxicity and MTDs and tumor responses are being evaluated (Table 3).

4.3. Amino acids and derivatives in breast cancer trials

4.3.1. Carnitine (acetyl-l-carnitine)

Acetyl-l-carnitine has been shown to be both neurotrophic and neuroprotective (62-63). Current evidence suggests that that acetyl-l-carnitine promotes the regeneration of injured nerve fibers, decreases oxidative stress, regulates acetyl CoA levels, modulates the acetylation of critical cellular proteins, enhances mitochondrial DNA synthesis, and increases intraneuronal levels of nerve growth factor, NGF (62-63). Moreover, acetyl-l-carnitine has demonstrated efficacy and tolerability in patients with chemotherapy-induced peripheral neuropathies; overall it is thought to play a protective role in patients suffering with treatment-induced neuropathy associated with paclitaxel or cisplatin chemotherapy (64-65). A current intervention trial (trial 45) is being conducted to examine the efficacy of oral acetyl-l-carnitine with taxane chemotherapy for the prevention or reduction of treatment-induced fatigue and peripheral neuropathy in breast cancer; similar studies are also being conducted with l-carnitine-l-tartrate in trial 46 (Table 3).

4.3.2. Glutamine

Glutamine is a nonessential amino acid which serves as an energy source for rapidly dividing cells; it can become depleted during stress, advanced cancer or during anticancer treatment regimens. Studies support the role of glutamine as a neuroprotectant. Glutamine is currently undergoing phase IV testing (trials 26 and 27). It is administered to breast cancer patients orally or intravenously to determine efficacy in reducing chemotherapy-induced peripheral neuropathy associated with taxane treatment (Table 3).

4.4. Fatty acids

4.4.1. Omega-3-fatty acids

Omega-3 polyunsaturated fatty acids (n-3) are essential fatty acids necessary for human health and well being. Moreover, n-3 fatty acids have demonstrated antitumor activities in preclinical studies and epidemiologic studies suggest that high n-3 levels may lower cancer risk (66). We have identified five clinical trials that are actively testing omega-3-fatty acids, trials 7-11 (Table 3). These trials are using omega-3-fatty acid supplements to reduce breast cancer risk in high risk women, evaluate mammographic breast density and biomarker expression during endocrine therapy with raloxifene, identify markers of breast cancer progression, reduce the musculoskeletal and neuropathic symptoms of taxane-induced toxicity during chemotherapy.

4.5. Phytochemicals

4.5.1. Garlic

Studies to determine the therapeutic potential of garlic (allium sativum) and its chemical constituents (diallyl disulfide, S-allylcysteine and ajoene) in patients with breast and other cancers are relatively new despite a vast amount of knowledge regarding its medicinal properties which dates back for centuries (67-68). Early evidence for the anti-cancer effects of garlic from population-based case-control studies provided the impetus for laboratory testing. Garlic constituents were shown to have bioactivity against chemically induced cancers and favorable effects on carcinogen metabolism in animal models and to cause growth inhibition, apoptosis, and cell cycle arrest in tumor cells (69-72). Currently, as shown in trial 31, garlic tablets are being given to patients with incurable or metastatic breast cancer during chemotherapy with docetaxel. The main objective is to assess changes in the pharmacokinetics and toxicity profile of docetaxel in the presence of garlic (Table 3) in order to achieve a more favorable outcome.

4.5.2. d-Limonene

d-Limonene, a constituent of many citrus oils, is a monocyclic monoterpene and solvent of cholesterol (73). Therapeutically, it has been used to dissolve gallstones, relieve gastric acidity, and treat gastroesophageal reflux disease, GERD (73-74). d-Limonene has also demonstrated chemopreventive activity in a number of cancers (75). Early clinical trials of breast and colorectal cancer showed modest responses to d-limonene (76). Trial 32 is recruiting women with breast cancer who will take d-limonene orally for 2 to 6 weeks prior to surgery during which time biomarkers of activity and the tissue distribution will be determined (Table 3).

4.6. Other natural health products currently undergoing clinical trial testing

Other dietary supplements and natural health products that are also undergoing current clinical trial testing, but which are not discussed here, include the following: organic germanium; broccoli sprout extract (sulforafane); conjugated linoleic acid; soy isoflavones, soy protein; diindolylmethane (DIM); flaxseed; freeze-dried table grape powder; American ginseng; THL-P Extract; Chinese herbal therapy; a natural supplement combination consisting of indole-3-carbinol, perillyl alcohol, glucuronic acid, and flavonoids; lactobacillus; and the FemMED™ Breast Health Formula. These are shown in Tables 3-4.

5. COMPLEMENTARY AND CONVENTIONAL THERAPY COMBINATIONS

In several of the clinical trials reviewed here, dietary agents and natural health products are being evaluated in combination with chemotherapeutic drugs, endocrine agents, or radiation.

5.1. Natural health products and chemotherapeutic drugs

The following dietary/natural product - chemotherapeutic drug combinations are currently being tested in cotreatment trials: (i) omega-3-fatty acids, garlic, l-acetyl-l-carnitine or various phytochemicals with taxanes such as paclitaxel and docetaxel (trials 11, 31, 45, 61); (ii) coenzyme Q10, vitamin B6 or Chinese herbals with doxorubicin (trials 17, 20, 59); (iii) mistletoe extract with gemcitabine (trial 12); and (iv) vitamin B6 with capecitabine (trials 18-19). In a number of other trials the use of mistletoe extract, vitamin B12, glutamine, lactobacillus, l-carnitine-l-tartrate or yunzhi extract (coriolus vesicolor) is being explored in the context of more than one chemotherapeutic drug given concurrently or using chemotherapeutic drugs that were not specified (trials 13, 21, 26-27, 33, 46, 54). All trials are described further in Table 3.

5.2. Natural health products and endocrine agents

The dietary agents and natural health products that are being given in combination with endocrine therapies including antiestrogens (tamoxifen, raloxifene) and aromatase inhibitors (letrozole, anastrozole) include: (i) soy protein isolate with tamoxifen (trial 5); (ii) omega-3-fatty acids with raloxifene (trial 10); (iii) omega-3-fatty acids, glucosamine-chondroitin sulfate or flaxseed with the aromatase inhibitor anastrazole (trials 8, 30, 51, 52), as shown in Table 3.

5.3. Natural health products and radiation therapy

Currently, organic germanium, grape seed extract, and coriolus vesicolor are being examined during or after radiation therapy (trials 29, 42, 53).

6. CLINICAL TRIALS TESTING NATURAL HEALTH PRODUCTS IN HEALTHY WOMEN

Twenty-three percent of all the trials reviewed here are enrolling healthy women with no prior diagnosis of cancer. About half of these include trials investigating the efficacy of various dietary and natural compounds for risk reduction in women with higher than normal risk for developing breast cancer. These include women with mutated BRCA1/2 genes, those having more than one family member with these gene mutations, or other positive family history factors. . Trials 9, 22-23, 28, 40, 43, and 50 are currently evaluating the effects of omega-3-fatty acids, cholecalciferol, DIM, grapeseed extract or freeze-dried powder, and THL-P (an extract of several natural herbs) on risk reduction in women who are at higher than normal risk for developing breast cancer. Trials that are enrolling healthy women without risk factors were also included for comparison; these are trials 1, 3, 6, 38, 41, 56, and 60. Most of these trials are designed to assess changes in surrogate markers relevant to breast cancer such as changes in serum, tissue, and molecular markers; hormone and hormone metabolite levels; and mammographic breast density. Trial interventions included: soy isoflavones, soy protein, green tea extract, grape seed extract, calcium with or without vitamin D, and the FemMED™ Breast Health Formula (a proprietarial combination of vitamin D, milk thistle, schizandra, stinging nettle, calcium and hydroxymatairesinol). For greater detail, see Table 3.

7. SUMMARY AND PERSPECTIVES

There is a critical need to identify natural compounds with low toxicity and high utility in breast cancer (77). This report describes 65 open clinical intervention trials testing a range of dietary supplements and natural health products. Vitamins and minerals, herbal extracts, amino- and fatty acids, probiotics and phytochemicals were among the compounds being tested. Outcome measures included markers of risk (in high risk women), MTDs, efficacy (alone and in combination with standard anticancer drugs), toxicity and symptom management (in breast cancer patients). In addition, breast cancer markers (molecular, tissue, and serum), mammographic breast density were also incorporated into the design of many of the trials. Although definitive analyses will have await trial completion, data from these trials can be anticipated to improve treatment strategies in the future, and to produce toxicity profiles and tumor responses that are compatible with long term survival.

8. ACKNOWLEDGEMENTS

We gratefully acknowledge Wendi Rodgers Wilson, MLIS, for her technical assistance during the writing of this manuscript.

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Abbreviations: CAMs: complementary and alternative medicines; NHANES: national health and nutrition examination survey; WHI: women's health initiative; MTDs: maximum tolerated doses; ER: estrogen receptor; PR: progesterone receptor; FDA: food and drug administration; IND: investigational new drug; EGCG: (-)epigallocatechin-3-gallate; EGC: (-)epigallocatechin; ECG:(-)epicatechin-3-gallate; EC: epicatechin; NGF: nerve growth factor; GERD: gastrointestinal reflux disease; DCIS: ductal carcinoma in situ; LCIS: lobular carcinoma in situ; ADH: atypical ductal hyperplasia; y.o.: year old; IL: interleukin; IGF: insulin-like growth factor; IGFBP: insulin-like growth factor binding protein 3; gm: grams; mg: milligram; HCL: hydrochloride; FU: follow up; s.c.: subcutaneous; IV: intravenous; IM: intramuscular; VEGF: vascular endothelial growth factor.

Key Words: Dietary supplements, antioxidants, phytochemicals, CAMs, natural health products, clinical trials, breast cancer, chemoprevention, vitamins and minerals, vitamin D, mistletoe extract, Iscador P, grapeseed extract, coriolus vesicolor, scutellaria barbata, natural health product-chemotherapy combinations, endocrine therapy, complementary-conventional therapy combinations, green tea polyphenols,