July 2018 Issue

CPE Monthly: Soy and Breast Cancer — An In-Depth Review of the Research
By Kylie Buchan, RD, CSO, LD, and Angela Hummel, MS, RDN, CSO, LDN
Today's Dietitian
Vol. 20, No. 7, P. 48

Suggested CDR Learning Codes: 2010, 3020, 4180, 5150
Suggested CDR Performance Indicators: 8.1.5, 8.3.6, 10.4.1, 12.2.1
CPE Level 2

Take this course and earn 2 CEUs on our Continuing Education Learning Library

Nutrition plays a vital role in the prevention and treatment of breast cancer, and research continues to support its role. It's essential for RDs to understand the risk factors, stay up to date with the latest evidence-based research, and communicate this information to patients, caregivers, and members of the health care team.

Soy intake is one of the most controversial topics pertaining to breast cancer, and many patients are confused by the research and recommendations.

This continuing education course explores the research concerning the effects of soy consumption on breast cancer risk and recurrence. It also provides key takeaway messages RDs can use during patient counseling and practical suggestions they can make to clients concerned about soy.

Breast Cancer
Breast cancer is a life-altering and potentially fatal disease that strikes one in eight women and is the second most common cancer in women in the United States.1-3 In 2012, there were nearly 1.7 million diagnosed cases of breast cancer worldwide.2 As a result of improvements in screening and treatment, 89.7% of women survive five years or longer after diagnosis.1

According to the American Cancer Society (ACS), breast cancer occurs when cells in the breast tissue begin to grow out of control into the surrounding tissue or spread to other areas of the body via the lymphatic system. Breast cancer can start in any area of the breast, including the lobules, ducts, or stroma.4

Breast cancer cells are classified by the presence or absence of three different receptors: estrogen, progesterone, and/or human epidermal growth receptors. For example, in estrogen receptor-positive breast cancer, the cancer cells grow in the presence of estrogen; in estrogen receptor-negative breast cancer, cancer cells aren't affected by the hormone.5 Classifying breast cancer cells in this way helps determine which treatment will be most appropriate.

Diagnosis and Treatment
Breast cancer can be discovered in several ways. The common methods are through self-breast examination and mammography, while ultrasound, MRI, and biopsy can provide further information and diagnosis. If the pathology indicates breast cancer cells, additional testing, such as a PET or CT scan, can determine whether the disease is contained in the breast or has metastasized—spread to other parts of the body. The cancer is then staged based on any metastases, and treatment is determined by the disease stage and the patient's condition.6

Depending on the patient's cancer stage, treatment might involve surgery (either lumpectomy or mastectomy), radiation to the tumor, and/or chemotherapy. Most breast cancer treatments also include hormone therapy, such as aromatase inhibitors or selective estrogen receptor modulators (SERMs). Aromatase inhibitors, such as Femara and Arimidex, work by stopping certain hormones from turning into estrogen, while SERMs, such as Tamoxifen, block estrogen from binding to receptor sites.7

Risk Factors
Research has found that certain lifestyle factors, such as weight, activity level, alcohol consumption, the use of estrogen progesterone therapy, and breast-feeding, play a role in the development or prevention of breast cancer. The American Institute for Cancer Research (AICR) estimates that breast cancer rates in the United States could be reduced by one-third if women maintained a healthy weight, engaged in physical activity, and avoided alcohol.8,9 The Women's Health Initiative found that women who took hormone replacement therapy (HRT) had a greater risk of breast cancer than those who didn't, and the risk increased the longer the woman underwent therapy. Other modifiable ways to prevent breast cancer include breast-feeding for at least six months and maintaining adequate serum vitamin D levels.10-12

There also are several breast cancer risk factors that are nonmodifiable. These include increasing age, evidence of a family history of breast cancer, and being a genetic carrier of high-risk genes such as BRCA. People with dense breasts, non-Hispanic whites, and non-Hispanic blacks are all at a higher risk of developing breast cancer, as are women who menstruate before 12 years of age, go through menopause later than 55 years of age, or have children after age 35. The latter three risk factors are due to the longer exposure to estrogen.13-18

Traditional Asian vs Western Lifestyles
The incidence of breast cancer varies from country to country. According to the World Cancer Research Fund, the highest incidence of breast cancer is in North America and Oceania, and the lowest incidence is in Asia and Africa; however, rates in Asia are steadily climbing. According to Youlden and colleagues, the "Westernization" of Asian countries is a significant factor in this increase.19 Migrant studies have shown that Asians who move to the United States and adopt a more Western diet and lifestyle become at risk of developing breast cancer at a level much like that of American women.20,21

The Western lifestyle involves many of the factors that may lead to a higher incidence of breast cancer, including obesity, increased use of HRT, and greater alcohol consumption.22 In addition, a typical Western diet consists of more processed foods, sugar, salt, animal protein, refined grains, and full-fat dairy than does a diet typically consumed by Asian populations. By contrast, traditional Asian diets primarily are plant based, consisting of vegetables, whole grains, and beans and legumes, including soy. On average, Asians consume one to three servings of soy daily, and most consume soy throughout their lifespans.

Whole Soyfoods
There are two types of whole soyfoods: fermented and nonfermented. Fermented soy includes natto, miso, tempeh, soy sauce, and fermented tofu. Unfermented soy includes edamame, dry soy nuts, soymilk, soy flour, and tofu. Fermented foods in general are beneficial for gut health due to the probiotics they contain. There are unsupported claims that soy is beneficial only when it's fermented because of its superior absorption in the intestinal tract. Studies, however, show that the fermentation of soy doesn't affect its benefits.23,24

Soybeans are the most significant dietary source of isoflavones, a type of phytoestrogen. The isoflavones found in soy comprise genistein (50%), daidzein (40%), and glycitein (10%).25 Traditional soyfoods contain about 3.5 mg isoflavones per gram of protein. Although isoflavone content in soybeans can vary based on growing conditions, a standard serving size provides approximately 8 g protein and 25 mg isoflavones.24,26 Examples of a standard serving of whole soyfoods include 8 oz soymilk, 1/2 cup cooked soybeans, and 1/2 cup tofu.

Other Sources of Soy
Soy is one of the most widely produced crops in the United States and is among the top allergens. Ingredient lists and food labels can be misleading or confusing since some products that are labeled "product contains soy" or have the word "soy" in the title don't contain any phytoestrogens, such as soy lecithin and soy sauce. Isoflavones, however, are found in many processed foods such as breads, cereals, and protein bars, labeled as soy protein concentrate, soy protein isolate, and soy fiber. These ingredients are added to improve moisture and texture, as well as boost protein and/or fiber content. Isolated soy protein, used as soy protein powder, is added to beverages to increase the protein content; however, 70% of the isoflavone content is lost during processing of the soy.24

Soy and Health
Because soy is considered a complete protein, meaning it contains all of the essential amino acids, it's a highly desirable plant-based protein source, and it's inexpensive. In addition, it contains fiber and alpha-linoleic and alpha-linolenic fatty acids, which can be converted to omega-3 fatty acids in the body.

Isoflavones contain many health benefits, including prevention of heart disease and osteoporosis.24-28 A study published in European Journal of Clinical Nutrition in 2013 found reduced levels of inflammation biomarkers associated with heart disease.29 Akhavan and colleagues found that the isoflavones in soy protein helped reduce the risk of bone fracture and fragility in men by "inhibiting the age-associated rise in hematopoietic parameters."30 In addition, Shenoy and colleagues found that soy protein plus exercise helped boost muscle strength and bone density in postmenopausal women.31

Soy is composed of a variety of compounds with antioxidant and anti-inflammatory properties that work to reduce cancer growth and risk. A study published in The American Journal of Clinical Nutrition found that men with various stages of prostate cancer who consumed at least 30 mg per day of isoflavones from soyfoods for six to 12 months had slower rises in prostate-specific antigen, a marker of prostate cancer, compared with those who didn't consume soy.32 A case-controlled study in Korea investigating more than 900 cases and 2,600 controls found that those who had the highest intake of whole soyfoods had a lower incidence of colorectal cancer.33 In addition, a meta-analysis of epidemiologic studies found that there was a "borderline reduction in risk of lung cancer with daily soy protein intake and a significant inverse association in nonsmokers."34

It's important to know that isoflavone metabolism and absorption vary widely among individuals based on the microbial composition of their intestinal flora. Also, those who have had long-term exposure to antibiotics may absorb fewer isoflavones from soy.35

There are some concerns and questions about soyfoods that affect the general public, such as whether genetically modified (GM) soyfoods cause cancer, and whether soy has a negative effect on the thyroid gland.

GM Soy
The World Health Organization (WHO) defines a GMO as an "organism in which the genetic material has been altered in a way that doesn't occur naturally by mating and/or natural recombination." According to the WHO, GMOs could increase the risk of allergens in the foods that contain them and damage the environment. There are regulations in place to make sure GM foods are safe for consumers.36

While soy can be a GMO, there are no available studies addressing whether there's an increased risk of cancer from consuming GM soy. Those concerned about consuming GMOs should choose organic sources of soy or foods that are labeled non-GMO.37

Soy and Thyroid Function
There's been speculation and concern that bioactive components in soy may affect thyroid function and interfere with the absorption of synthetic thyroid hormone. While a literature review found little evidence that whole soyfoods affect thyroid function in men and women with normal thyroid function, evidence appears to show that soy may inhibit absorption of synthetic thyroid hormone, causing a need for a higher dose.38

The Breast Cancer and Soy Connection
The association between soy and breast cancer is a controversial topic in oncology. The safety of soy intake for estrogen receptor-positive breast cancer survivors and those at high risk is debated, stemming from the fact that soy contains phytoestrogens. Therefore, the safety and effect of soy intake is an obvious concern for this vulnerable population.

Phytoestrogens and Cancer
Isoflavones, a specific class of phytoestrogens, are chemically similar in structure to estrogen and thus have the ability to bind to estrogen-binding sites.39 As a result, they can turn gene expression on and off, potentially mimicking the effects of estrogen.40 For this reason, some believe phytoestrogens could cause cancer cells, specifically of hormone-related cancers, to grow. While phytoestrogens resemble estrogen and can bind to estrogen-binding sites, research suggests they may do the opposite of what was originally thought and prevent estrogen from binding to the receptor.41,42

Phytoestrogens also can bind to other types of receptors that can affect anticancer gene expression, including those responsible for antioxidant, antiproliferative, antimutagenic, and antiangiogenic effects of phytoestrogens and their ability to promote human health and longevity.40,43-48

Soy and Breast Cancer Risk
Many studies have investigated soy, isoflavone, and phytoestrogen intake and their effects on breast cancer, dating back to 1991.49 While the research isn't conclusive, overall it suggests a protective effect.

Initial laboratory studies found an increased risk of breast cancer in rodents whose diets were supplemented with the soy isoflavone genistein.50,51 Research has demonstrated that humans metabolize soy isoflavones differently than rodents do; therefore, the results can't be translated into recommendations for humans.52

As data from human studies began to be published, the results offered more favorable conclusions. Soy consumption appears to decrease breast cancer risk, especially in premenopausal women and in those who consumed soy before and during adolescence.53-55 One study found that soy had a protective effect against breast cancer if first consumed between the ages of 5 and 11.56

Similarly, Chinese women in the large Shanghai Women's Health Study who consistently consumed a diet high in soyfoods throughout adolescence and adulthood had a substantially lower risk of premenopausal breast cancer compared with those who didn't.55 Relative risk decreased as soy consumption increased. The lowest quintile consumed 1.73 mg/dL of isoflavones, and the highest consumed approximately 42 mg/dL. According to the AICR, three servings of whole soyfoods averages 75 mg of isoflavones, or 25 mg per serving; therefore, the highest quintile ate approximately two servings of whole soyfoods daily.27

The protective benefit of soy has been studied more in Asian populations than in Western populations.57 Pre- and postmenopausal Asian women consuming more than 20 mg of isoflavones daily, slightly less than one serving of whole soyfoods, had a 29% reduction in breast cancer risk. Reproducing similar observational studies in women consuming Western diets is challenging because soy intake, and therefore isoflavone intake, is typically minuscule. For example, a study conducted in the industrialized West found no association between isoflavone intake and breast cancer risk; however, participants consumed an average of only 0.8 mg of isoflavones per day, less than 5% of one serving.24

Because most studies show that whole soy products offer beneficial or at least neutral effects on the general population, cancer research organizations, such as the AICR, the ACS, and the National Cancer Institute (NCI) recommend that one to two servings of whole soyfoods per day are safe for everyone, including breast cancer survivors and those at high risk of developing breast cancer.58-60

Consumption Before and During Diagnosis
Women who may be at risk of, or who have been diagnosed with, breast cancer may fear that consuming "estrogens" will cause cancer to grow, even though this notion has been discounted. An observational study found that breast cancer survivors who consumed whole soyfoods before diagnosis improved survival compared with women who didn't, and those who consumed the highest amounts appeared to have decreased risk of recurrence and mortality, including those women receiving estrogen therapy.61-66

Similarly, the AICR Continuous Update Project Report on diet, nutrition, physical activity, and breast cancer survivorship concluded that consuming soy after diagnosis, particularly for longer than a year, may lower the risk of all-cause mortality.67 The research, however, isn't conclusive. A follow-up of participants from the Shanghai Breast Cancer Study didn't find any relationship between soy consumption and disease-free survival.68 The DietCompLyf Study, based in the United Kingdom, found no association between prediagnosis phytoestrogen intake and improved breast cancer prognosis. It's important to note that this study included phytoestrogen intake from flaxseed as well as from soy.69

Areas for Further Study
Soy, when consumed as whole food, appears to reduce the risk of breast cancer, especially when consumed early in life, and also seems safe for breast cancer survivors. However, further research is needed to determine whether soy supplementation affects risk and whether soy interacts with estrogen-blocking medications.

Soy Isoflavone Supplementation
There's limited research investigating the link between breast cancer and soy isoflavone supplementation as compared with whole food consumption. Concerns over isoflavone supplementation arose because there's limited evidence about the safety of high isoflavone intake and breast cancer risk. In 2008, a meta-analysis by Velentzis and colleagues investigated the effect of soy supplementation on breast cell proliferation. Overall, it found that soy supplementation either increased cell proliferation or had no effect on it. Most of the studies examined were small, had short durations, and had great variation in the interventions used and type of participants included. Therefore, study results were too variable to determine a conclusion.70

Other experimental studies suggest that soy supplementation may promote breast cancer cell growth. For example, one study reported that soy protein supplementation given to women with invasive breast cancer increased expression of genes that drive cell cycle and proliferation pathways. This study was short in duration, not lasting long enough to determine whether these changes in gene expression would lead to tumor growth.71 Another study found that soy isoflavone supplementation in premenopausal women at high risk of breast cancer stimulated breast cancer cell growth over the course of six months. This result, however, wasn't found in high-risk postmenopausal women.72

The evidence for the impact of soy isoflavone supplements on breast cancer risk and recurrence is too variable and inconclusive to recommend use in high-risk populations.

Soy and SERMs
SERMs, such as tamoxifen or raloxifene, are used for breast cancer treatment in women with estrogen receptor-positive breast cancer. The drugs bind to the estrogen receptor, thus displacing estrogen. Isoflavones also are considered SERMs. Therefore, there's reason for concern that isoflavones from soy may negate the antiproliferation effect of the prescribed medications.73

Preliminary research conducted in humans indicates that isoflavones may work synergistically with tamoxifen.74 In the study, women who consumed the highest amount of soy products (about 1.5 servings of whole soyfoods daily) had reduced risk of recurrence compared with those who ate the least amount.

More research is needed to ensure that phytoestrogens don't affect tamoxifen efficacy.75 Furthermore, it's critical that research examine dose response to determine what level of phytoestrogen intake is safe to consume by those taking SERMs.76

Current Recommendations
Recent research concluding that soy isoflavone intake from whole soyfoods is safe for the general population and for breast cancer survivors has influenced recommendations of many oncology research organizations, including the AICR and the ACS. The AICR considers consumption of one to two servings of whole soyfoods per day safe for the general public and breast cancer survivors but doesn't recommend the use of soy protein isolate supplements.58

The ACS considers moderate intake of soy and soy-derived foods safe for the general population and for cancer survivors because of the possible protective effect against hormone-dependent cancers. The ACS recommends incorporating whole soyfoods into a healthful diet because they're excellent plant sources of protein, antioxidants, and phytochemicals.77 The NCI concludes that soy is safe to consume in moderate amounts and as part of a healthful diet.59 It doesn't suggest, however, that breast cancer survivors should begin to consume soy specifically to prevent recurrence or enhance survival.

Additional Considerations
It's possible that the beneficial effects of soy arise from the whole plant rather than individual components such as isoflavones. For example, soy contains a good amount of fiber, which also is known to be preventive against cancer. Another thing to consider is that people who consume soy usually also lead a healthful lifestyle.78 For instance, research has shown that Asians tend to make lifestyle choices conducive to cancer prevention. The Shanghai Women's Health Study found that the study participants who consumed more soy also engaged in more exercise, ate less red meat, and ate more vegetables, fruit, and fish.55 Research has shown that Asians who consume few soyfoods also have a reduced risk of breast cancer, showing that overall lifestyle may play a significant role.79

Aside from soy and the impact that isoflavones play on estrogen receptors, lifestyle factors can influence cancer risk. Physical activity, alcohol intake, body weight, and fiber intake all appear to influence cancer risk. An adequately planned plant-based or vegetarian diet can help with weight maintenance and provide cancer-preventing antioxidants. Therefore, since soy is a plant food choice that's high in fiber and low in calories and provides healthful fats, it would be an appropriate addition to a cancer-preventive diet.

Conclusion
The relationship of soy consumption and isoflavones to breast cancer is complex. Most studies investigating soy consumption and breast cancer are observational, which can't prove that soy or isoflavones reduce breast cancer risk. The body of research is vast, yet many unanswered questions remain.

Whole soyfoods appear to have a protective effect against breast cancer, particularly when consumption begins early in life. Whole soyfood consumption appears to improve breast cancer prognosis and may decrease recurrence. While observational studies can't prove that soy consumption is protective against breast cancer, they have demonstrated that soy doesn't increase breast cancer risk. Future studies are needed to evaluate the safety of soy supplements in breast cancer survivors and women with a high risk of developing breast cancer. In addition, the impact of soy isoflavone supplementation on SERMs and aromatase inhibitors needs in-depth investigation.

Putting It Into Practice
Little is known about the impact of concentrated soy isoflavones and supplements on breast cancer risk, especially in women with a previous history of breast cancer. In addition, it's unknown how these supplements interact with breast cancer treatments, such as tamoxifen or aromatase inhibitors. When working with women with estrogen receptor-positive breast cancer, breast cancer survivors, and those taking tamoxifen or aromatase inhibitors, RDs should emphasize caution regarding the use of soy supplements and concentrated sources of soy.

RDs should advise their clients or patients who are interested in adding soyfoods to their diets to choose whole soyfoods as an overall goal for cancer prevention. A primarily plant-based diet has shown to be protective against cancer, and whole soyfoods are a good source of protein, fiber, and cancer-fighting antioxidants. Several studies have concluded that the intake of whole soyfoods and/or isoflavones reduced the risk of certain types of cancer, including lung cancer, colorectal cancer, and prostate cancer.

It's important for RDs to understand patients' concerns regarding soy and correct the common misconceptions that may affect nutrition status or cancer risk.

— Kylie Buchan, RD, CSO, LD, and Angela Hummel, MS, RDN, CSO, LDN, are consulting dietitians for Savor Health, a comprehensive oncology nutrition service for people with cancer and their caregivers.

Learning Objectives
After completing this continuing education course, nutrition professionals should be better able to:
1. Distinguish the difference in soy consumption and breast cancer risk in Western and Asian cultures.
2. Assess the safety of soy consumption for people at risk of developing estrogen-positive breast cancer and for those who have survived it.           
3. Provide specific recommendations for whole soyfood intake for breast cancer survivors.

CPE Monthly Examination

1. Which of the following is a risk factor for breast cancer?
a. Consuming alcohol
b. Low fruit and vegetable intake
c. Breast implants
d. Red meat intake

2. Which is a benefit of consuming soy?
a. Reduced risk of heart disease
b. Reduced risk of diabetes
c. Reduced risk of endometrial cancer
d. Prevention of gout

3. Which is not an isoflavone found in soy?
a. Daidzein
b. Genistein
c. Glycitein
d. Lignans

4. A standard serving of soy provides approximately which dose of isoflavones?
a. 3.5 mg isoflavones per 8 g protein
b. 3.5 mg isoflavones per 7 g protein
c. 25 mg isoflavones per 1 g protein
d. 25 mg isoflavones per 8 g protein

5. The American Institute for Cancer Research recommends how many daily servings of whole soyfoods for the general public as well as breast cancer survivors?
a. Zero servings
b. One to two servings
c. Three to four servings
d. Five to six servings

6. Which of the following statements about fermented soy is correct?
a. It doesn't contain isoflavones.
b. It has a higher concentration of isoflavones than does unfermented soy.
c. It contains a concentration of isoflavones equal to unfermented soy.
d. It has a lower concentration of isoflavones than does unfermented soy.

7. Consumption of soy before a breast cancer diagnosis appears to do which of the following?
a. Decreases breast cancer risk with higher intakes
b. Increases breast cancer risk with higher intakes
c. Increases breast cancer risk at all levels of intake
d. Results in no effect on breast cancer risk

8. Beginning soy consumption significantly decreases breast cancer risk when it occurs at which of the following times?
a. During breast cancer treatment
b. During preadolescence and adolescence
c. After breast cancer treatment
d. During menopause

9. Besides breast cancer, research has shown soy to be protective against what other type of cancer?
a. Pancreatic
b. Colorectal
c. Endometrial
d. Melanoma

10. What is a SERM?
a. Selective estrogen receptor motivator
b. Soy estrogen response method
c. Selective estrogen receptor modulator
d. Soy estrogen recovery medication

References
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46. Lim U, Song MA. Dietary and lifestyle factors of DNA methylation. Methods Mol Biol. 2012;863:359-376.

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