February 2018 Issue

CPE Monthly: Cancer Prevention — Learn the Mechanisms of Cancer Development and How RDs Can Educate Patients on Prevention Strategies
By Leslie Langevin, MS, RD, CD
Today's Dietitian
Vol. 20, No. 2, P. 42

Suggested CDR Learning Codes: 2010, 4040, 5150
Suggested CDR Performance Indicators: 8.1.4, 8.3.1, 8.3.6, 10.4.1
CPE Level 1

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

According to the National Cancer Institute, an estimated 1,688,780 people were diagnosed with cancer in the United States in 2017, and about 35% of these individuals will die from the disease. Obesity, inflammation, diet, and lifestyle, including smoking and inactivity, increasingly are found to influence cancer occurrence. Up to one-third of all cancer deaths in the United States could be avoided through changes to the diet.1

This continuing education course explores the mechanisms of cancer development and discusses the ways RDs can educate patients about current prevention strategies for reducing the risk of various types of cancer.

Role of Obesity and Inflammation
It's well known that obesity increases the risk of chronic diseases such as heart disease, diabetes, and cancer. Overall, 20% of all cancers are related to obesity.2 Furthermore, obesity increases cancer deaths by 20% in women and 14% in men. Part of the reason obesity may increase the risk of cancer is that the positive energy balance in the diet causes increased levels of insulin, insulinlike growth factor-1, sex steroids, and inflammatory biomarkers such as cytokines, all of which are correlated with increased cancer growth. Increased levels of insulin are correlated with increased aggressiveness of colon, pancreatic, liver, breast, and endometrial cancers. Greater levels of insulin also increase growth hormone receptors, while insulin decreases the insulinlike growth factor binding proteins, a situation that reduces the cells' ability to perform apoptosis, or cell death, and increases tumor spread.2

One meta-analysis that included 200,000 breast cancer patients found that there was a 75% increase in mortality in premenopausal women and a 34% increase in mortality in postmenopausal women who were obese at the time of their breast cancer diagnosis.3 This same study shows that obesity is associated with worse prognosis after cancer diagnosis, increased morbidity during cancer treatment, and an increased risk of second malignancies and comorbidities.3 Research has shown that a lower carbohydrate diet will reduce such a high insulin response and may help to stabilize cancer or help with partial remission in advanced cancer.2

Obesity also creates a level of chronic inflammation and high circulating cytokine levels in the body. Increased cyclooxygenase-2 (COX-2) levels result in inflammation in the body and have been associated with increased risk of colorectal cancer.4 Along with increased cytokine levels, obesity results in an overproduction of proinflammatory molecules such as interleukin-6, tumor necrosis factor-a, leptin, and resistin. These are released from adipose tissue.2 The more surplus adipose tissue one has, the more there is an overproduction of these molecules and an increase in systemic inflammation. Increases in leptin have been found to boost cancer progression; in breast cancer, leptin raises estrogen signaling, thereby promoting cancer formation.2

Individuals with excess fat and a BMI >25 kg/m2 may be advised to lose weight to get to a normal range, defined as 18.5 to 24.9 kg/m2. The ideal BMI for cancer reduction is 21 to 23 kg/m2.2 This may not only help prevent cancer but also may reduce the risk of other chronic diseases. Reducing obesity with dietary options, exercise, and creating negative energy balance are important options for reducing cancer risk. Physical activity is an important strategy for regulating body weight, reducing insulin levels, and regulating sex hormone levels and the immune system.2

Obesity also is correlated with low levels of 25-hydroxyvitamin D [25(OH)D], which may be responsible for up to 20% of cancer risk that's linked to an increased BMI.2 Vitamin D reduces cancer risk by inhibiting tumor angiogenesis (creation of new blood vessels), enhancing cell communication, and inhibiting the spread of cancer cells. Research shows a positive correlation between vitamin D deficiency and increased risk of colon, breast, prostate, and ovarian cancers. This increased risk is thought to occur because colon, breast, and prostate cells have vitamin D receptors that are highly sensitive to circulating vitamin D levels. If there isn't adequate vitamin D circulating in the body, there's less control of cancer cell growth, but with adequate vitamin D, these vitamin D receptors can control cancer cell growth and proliferation.2,5 It's estimated that there's a 30% to 50% reduction in the development of colorectal, breast, and prostate cancers if individuals take at least 1,000 IU/day of vitamin D3 or obtain enough sun exposure to raise the levels of the 25(OH)D to more than 30 ng/mL.5

Individuals' genetic differences also can predict disease outcomes. The genetic potential relating to vitamin D levels is another strong area of research. There are two different genotypes that will affect a person's ability to create, process, and use vitamin D. The recessive bb genotype, carried by about 35% of the US population, is associated with a lower circulating concentration of vitamin D.6 Men with this genotype were found to have twice the incidence of colon and prostate cancer than were those with the BB genotype (the dominant genotype associated with higher vitamin D levels). Women with the bb genotype had twice the risk of breast cancer and were four times more likely to develop metastases than were women with the BB genotype. Finally, 40% of colon and prostate cancers may be related to the bb genotype and low vitamin D levels.6

With all that clinicians know about the importance of vitamin D, it's crucial that RDs recommend proper supplementation and that patients get their 25(OH)D levels checked. Overall research shows that individuals who have higher circulating levels of vitamin D have reduced mortality and occurrence overall from cancer.6

Encouraging patients to ask their primary care providers for the 25(OH)D lab test is one of the first steps. If the patient's levels are below 30 ng/mL, it's important to replenish vitamin D levels to reduce the risk of breast, colon, and prostate cancer. The upper limit of 25(OH)D is 150 ng/mL. It's estimated that daily sun exposure of 15 minutes in summer and 20 minutes in early fall or late spring between 11 AM and 2 PM, will maintain a serum 25(OH)D level of 30 ng/mL. Supplementation doses are recommended at about 1,000 IU/day for adults, but depending on the individual's current level, higher doses may be required.6 RDs can ensure their patients use supplementation correctly for their particular genotypes as nutrigenetics becomes more mainstream.

Phytochemical-Rich Foods and Cancer Prevention
Phytochemicals, the active plant compounds in various fruits and vegetables that work to suppress oxidative damage to cellular DNA, and their role in cancer prevention have been a significant focus of research. There's strong evidence that several phytochemicals may contribute to cancer prevention.4 Phytochemicals influence cancer through many mechanisms. They help detoxify carcinogens from the body, repair mutated DNA, regulate gene expression including tumor suppressor genes, regulate the growth and proliferation of cells, induce apoptosis, and decrease inflammation, which can reduce oxidative damage.7 Many patients may be unaware of the importance of phytochemicals, and RDs can help educate them and explain which ones may most effectively reduce disease risk.

"Eat the rainbow for fruits and vegetables" is a common recommendation for increasing phytonutrient intake in the general population. Incorporating more phytochemicals into the diet is a reasonable and attainable cancer prevention strategy because these foods can be found at most grocery stores.4 The cancer-preventing phytochemicals that will be explored further in this course are found in green tea, berries, turmeric, red and orange vegetables, cruciferous vegetables, cocoa, and soy.

Green Tea Catechins and EGCG
Green tea, which contains flavonols called catechins, has been found to help suppress the development and growth of cancer by inhibiting COX-2 and nuclear factor κB (NF-κB) as well as activator protein-1 (AP-1). By reducing the overexpression of these inflammatory molecules, green tea improves the immune system and induces apoptosis in cancer cells.7 Epigallocatechin 3-gallate (EGCG), which is one of the catechins, shows promise in preventing brain, prostate, cervical, and bladder cancers. It works by inhibiting the antiapoptotic action of cancerous cells so the cells can undergo apoptosis more readily. The catechins and EGCG in green tea also may inhibit cancer cell proliferation.8 As more research has been done on the microbiome, green tea ingestion has been found to increase the abundance of beneficial Bifidobacterium spp. in the gut.7 RDs can advise their patients to drink green tea daily. The only contraindication to drinking green tea is for patients taking blood thinners, as green tea interacts with the efficacy of these medications.

Berries
Berries, well known as superfoods, are rich in ellagic acid and other flavonoids that have been shown to slow the replication and spread of cancer cells. The flavonoid anthocyanidin offers significant protection against many cancers, especially those of the skin, bladder, lung, esophagus, and breast.8 Anthocyanidin flavonoids reduce oxidative species and stimulate phase II detoxification enzymes in the liver; this can decrease inflammatory enzymes such as NF-κB and COX-2.8 To help clients gain these benefits, RDs can advise patients to eat fresh blueberries and add berries to smoothies, breads, and other baked goods.

Turmeric
Curcumin is a polyphenol present in the root turmeric. Its most powerful action for reducing the risk of cancer derives from its anti-inflammatory properties. Curcumin can reduce NF-κB and AP-1 binding power, a situation that can reduce cancer risk in breast, ovary, prostate, colon, and pancreas cells.4 Curcumin also induces apoptosis in cancer cells without killing healthy cells. One study found that oral doses up to 12 g/day have anti-inflammatory antioxidant and anticancer properties.8

Anyone who takes blood-thinning agents should use curcumin with caution, as it can increase blood thinning. Research shows that curcumin is better absorbed when consumed with black pepper. RDs can advise clients to make turmeric milk (similar to chai) by blending cloves, cinnamon, turmeric, and almond milk with a little maple syrup for an anti-inflammatory boost; they also can add turmeric to rice, soups, or salad dressings.

Carotenoids
Carotenoids are the most abundant pigments in fruits and vegetables. They're commonly found in orange vegetables and fruits as beta-carotene, and in red fruits and vegetables in the form of lycopene. Carotenoids help reduce cancer risk, because they act as antioxidants and help inactivate reactive oxygen species. Reducing oxidative stress on the body is imperative to decreasing cancer risk. Dietary carotenoids from food sources have shown promise in lowering the risk of skin, breast, and prostate cancers.9

Consuming carotenoids from food sources is important, as supplementation with beta-carotene either has no effect or an adverse effect. Beta-carotene supplements were shown to increase lung cancer risk among individuals who smoked.9,10 This reinforces that foods rich in carotenoids have more promise for reducing cancer than do supplements.11 Common vegetables such as carrots, orange and yellow peppers, and sweet potatoes are excellent sources of carotenes. RDs can advise their clients to consume more of these vegetables each day.

Cruciferous Vegetables
Cruciferous vegetables contain many powerful cancer-fighting phytochemicals. Diindolylmethane, a derivative of indole-3-carbinol (I3C), is found in high concentrations in cruciferous vegetables such as broccoli, cauliflower, kale, and cabbage. I3C has shown promise in preventing hormone-responsive cancers such as breast, prostate, and ovarian. I3C also has been shown to increase phase 2 detoxification enzymes and reduce inflammatory responses.8 Cruciferous vegetables also contain kaempferol, which has been shown to have antiangiogenic, anticancer, and antioxidant effects and can induce apoptosis of cancer cells, especially those in the ovary.8

Another compound in cruciferous vegetables, phenethyl isothiocyanate (PEITC), has been shown to induce apoptosis in cancer cells. PEITC has shown strong promise against melanoma and breast, cervical, and prostate cancers. The last powerful compound, sulforaphane, derives from glucoraphanin in broccoli and cauliflower. Once consumed and digested, sulforaphane induces detoxification enzymes and enhances tumor suppression proteins. Sulforaphane decreases the inflammatory compound COX-2 and inhibits cancer cell growth by inducing apoptosis.8

RDs can recommend clients boost their intake of cruciferous vegetables by making broccoli or cabbage slaws as a salad base instead of lettuce, adding shredded cabbage as a topping on tacos or burritos, or preparing broccoli and cabbage soup.

Cocoa
Cocoa powder contains high amounts of flavonoids and proanthocyanidins. Cocoa powder has been shown to have antioxidant and anti-inflammatory properties, as it suppresses activity of NF-κB and proinflammatory enzyme COX-2 in the colon. Cocoa powder also exerts strong influence on the microbiome.

In a study of individuals who drank a cocoa beverage with high polyphenol content for four weeks, there was a significant increase in Bifidobacterium spp., Lactobacillus spp., and Enterococcus spp., and a decrease in the abundance of Clostridium histolyticum.7 Cocoa powder is a lower-calorie substitute for chocolate and can be added to smoothies, milk, or oatmeal as a powerful cancer-fighting food.

Soy Isoflavones
There's strong evidence that consumption of soy-based foods lowers the risk of many cancers, including those of the ovary, bladder, colon, liver, pancreas, lung, head, and neck, as well as lymphoma and leukemia.7 Soy consumption also is linked with a decrease in inflammation and a reduction in heart disease.

Breast cancer and soy consumption has been a controversial topic. Many studies show that daily moderate consumption can reduce the risk of breast cancer, especially if it occurred at a young age.12,13

There's some concern that soy isoflavone consumption is linked with an increased risk of endometrial cancer, but more research must be done.

Soy contains the lignans genistein and daidzein, which have been shown to be estrogen receptor modulators. They lower cancer risk by changing the activity of DNA methyltransferase, thereby increasing expression of the tumor suppressor genes and decreasing cancer promotion.7

Another mechanism by which soy works to decrease cancer occurs in the gastrointestinal (GI) tract.7 In the gut, soy isoflavones are converted to a compound called equol. This conversion has been shown to decrease prostate and breast cancers, especially in Asians, who can generate equol more efficiently than can those in Westernized countries.6

Supplements and Cancer Prevention
Supplement use has been a highly contested topic in health care, particularly with respect to cancer prevention. Commonly recommended supplements for general health include vitamin C, vitamin A, selenium, and vitamin E. In the SELECT (Selenium and Vitamin E Cancer Prevention Trial), vitamin E supplementation was significantly correlated with increased risk of prostate cancer.10 Another meta-analysis of randomized controlled trials reviewed the supplements vitamins A, C, and E; beta-carotene; and selenium and their role in cancer prevention and found that they had no overall association.11

Another study looked at folic acid supplementation, which has been shown to slightly increase cancer risk, especially prostate cancer. This study also found that smokers had a further increased cancer risk compared with nonsmokers following folic acid supplementation.14 Moreover, smokers who took beta-carotene supplements had an increased lung cancer risk.14 Long-term folic acid supplementation also has been associated with a greater colorectal cancer risk.15 It would seem that obtaining phytochemicals and nutrients from whole foods is preferable to consuming nutrients from supplements. The exceptions to this are vitamin D and probiotics, as discussed in this article.

The efficacy and safety of multivitamin use in cancer prevention also is unclear. An interesting study that investigated the Physicians Health Study II followed middle-aged men who took a daily multivitamin/mineral for 11 years. Men taking multivitamins experienced a significant 8% reduction in cancer incidence, and those with a cancer history saw an even greater benefit; their cancer incidence was decreased by 27% more than those in the placebo group.16 Many studies, however, have shown no benefit or an adverse effect on health relating to multivitamin use. Consequently, RDs must be conservative in their recommendations since more research is needed. It also must be noted that multivitamin users often have a more healthful diet than do nonusers, and this potentially confounds the results.

However, it's been found that micronutrient deficiencies still exist in the United States. The most common deficiencies found are vitamins D, E, A, and C; calcium; and magnesium. These deficiencies are present because the typical American diet can be energy rich but nutrient poor. Low levels of vitamin D have been shown to increase cancer risk, while vitamin C is a potent antioxidant. A meta-analysis of studies involving multivitamin use has shown that research is more promising in cancer reduction for men, but some studies found no significant correlation, especially in women.17

In the Cancer Prevention Study II, regular use of multivitamins (>15 times/month) was associated with increased risk of death from prostate cancer vs nonusers, although in the Physician's Health Study II there was no association found between multivitamin use and increased prostate cancer mortality. Overall, multivitamins are highly contested products, and although one large randomized controlled trial found increased benefit, there are many studies that have found no effect or adverse effects with multivitamin supplementation.17

The Microbiome
Much is being learned about the gut microbiome and its relationship to many chronic diseases and physical and mental health. Its role in cancer also is being explored. The body houses trillions of microbial cells. A healthy microbiome is protective against cancer development, just as certain bacteria and viruses can cause certain cancers throughout the body. There's a measurable change in the types of microbiota present in different cancers; this is thought to be related to the increase in inflammation. Obesity increases inflammation, and the microbiome can change when there's increased inflammation in the body. This can lead to an unhealthy microbiome and may promote cancer.18

The microbiome regulates the immune system and influences inflammation as well as tumor progression. It's known that genetics, diet, antibiotic use, and certain medications can influence the type of microbes that live in the body. One study found that up to 20% of all cancers are preceded by chronic inflammation at the cancer site.18

Some conditions, such as inflammatory bowel disease, Helicobacter pylori-induced gastritis, and esophageal or gastric cancer, are associated with increased colon cancer risk.17 The increase in inflammatory cytokines and inflammatory proteins is a common mechanism of greater cancer risk in these diseases.

Another reason for increased inflammation and increased tumor formation is thought to be a disruption of the healthy mucosal layer in the GI tract.7 Certain bacteria have been found to be pathogenic, especially in colorectal cancer. These particular strains—E coli, Streptococcus bovis, H pylori, Bacteroides fragilis, and Enterococcus spp.—can attach to epithelial cells and lead to hyperplasia, which can produce toxins that damage cells and cause inflammation and a breakdown of the healthy mucosal layer.18

There are ways to reduce inflammation in the microbiome, especially in the GI tract. Consuming prebiotics and probiotics and a higher-fiber diet can help keep the mucosal layers healthy and decrease inflammation. Low-fiber diets were found to be associated with higher levels of bacteria that produce hydrogen, a situation associated with the presence of colon adenomas. High-fiber diets can reduce negative hydrogen-producing bacteria and increase a beneficial bacteria, Faecalibacterium prausnitzii, which is thought to have anti-inflammatory properties.18 Some of the most common probiotics in supplements are lactobacillus and bifidobacterium, both of which have been shown to increase the detoxification of toxins and carcinogens in the colon, stimulate immunity, and inhibit tumor growth.18

Phytonutrients recently have been studied for their ability to alter the gut microbiome. Flavonoid-rich foods such as black tea, green tea, coffee, cocoa, cruciferous vegetables, and blueberries reduce inflammation and promote recovery from injury to the mucosal wall. Five percent to 10% of ingested polyphenols are absorbed in the small intestine, leaving the remainder to be metabolized in the colon by the gut microbiome. Interestingly, specific phytonutrients also have been found to modulate the gut microbiota.7 Encouraging patients to eat probiotic-rich foods such as yogurt, kimchi, and kombucha, along with increasing their intake of fiber and prebiotic foods such as garlic, bananas, and whole grains, can help them feed a healthy microbiome.

Foods to Limit
There's increased evidence that many commonly consumed foods raise cancer risk, especially colon cancer. These include red meat, processed meat, and heterocyclic amines from charred meats.19,20 These foods are fermented by colonic bacteria and can cause DNA damage and contribute to colon cancer.

Red meat, processed meats, and other high-protein foods are thought to contribute to DNA disruption as well because when they're metabolized they yield hydrogen sulfide.19 Other studies found that red meat and processed meat didn't increase the risk of prostate or pancreatic cancer.21,22 White meats haven't been associated with any increase in colorectal cancer. One portion of red meat (100 g) is associated with a 12% to 17% increase in colorectal cancer, and one slice of processed meat (25 g) per day increases the risk of colorectal cancer by 49%.23 Red meat and processed meats have been found to have a strong correlation with increased colorectal cancer risk, and processed meats have been found to increase stomach cancer risk; evidence for the associations with other types of cancer is weak, and more research is necessary.

The American Institute for Cancer Research (AICR) recommends individuals consume no more than 18 oz per week of red meat and avoid processed meat since even small portions daily will increase cancer risk.20 Along with eating a primarily plant-based diet, marinating meats, not overcooking them, and cooking them at a lower temperature are ways to reduce heterocyclic amine formation.23

Putting It Into Practice
Creating a healthy microbiome is a recent aspect of cancer prevention, but consuming large amounts of phytochemicals and plant foods daily has been shown to be beneficial in many areas of health, especially in cancer prevention. Working with clients to help them decrease foods that act as carcinogens and increase those that have been shown to reduce cancer risk can be an effective strategy for cancer prevention, as can helping them lose weight and decrease inflammation.

Additional recommendations RDs should communicate to clients include consuming prebiotic and probiotic foods, especially those containing bifidobacterium,18 and eating a variety of anti-inflammatory foods with high amounts of the following phytochemicals: ellagic acid, flavonoids, lignans, polyphenols, and sulforaphane compounds.

Foods such as cruciferous vegetables, berries, herbs, spices (especially turmeric), orange vegetables (eg, carrots and sweet potatoes), and dark-colored fruit or vegetables—as almost every one has some phytochemical benefit—can be helpful in preventing cancer. Increasing these foods in the diet also will help increase fiber to a level that will promote a healthy microbiome. The recommended amount of fiber consumption for women is at least 25 g daily; for men it's 38 g daily.

Another important way to help clients reduce cancer risk is to help them lose weight until they reach an ideal BMI range of 21 to 23 kg/m2.2 Exercising daily can help with weight loss. To lower cancer risk, the AICR recommends limiting alcohol intake to one drink per day for women and two per day for men.20 The AICR advises against using supplements to try to prevent cancer.20 However, for patients with low vitamin D levels, there's evidence that replenishing their levels with a supplement may decrease cancer risk.6 In addition, for clients who don't consume probiotic foods in their diets, supplemental probiotics may be helpful.

— Leslie Langevin, MS, RD, CD, co-owns the private practice Whole Health Nutrition, LLC, provides individual counseling, and teaches weight management classes.

Learning Objectives
After completing this continuing education course, nutrition professionals should be better able to:
1. Discuss how obesity increases cancer risk.
2. Evaluate how the microbiome affects cancer risk and what can be done about it.
3. Identify three phytonutrients that may help decrease cancer risk and recommend food sources for each when counseling clients and patients.

CPE Monthly Examination

1. In what way does obesity increase cancer risk?
a. It increases insulin and inflammatory proteins.
b. It increases apoptosis.
c. It creates a negative energy balance.
d. It decreases insulin and inflammatory proteins.

2. How do probiotics such as lactobacillus and bifidobacterium reduce cancer risk?
a. They decrease detoxification in the colon.
b. They disrupt mucosal layers.
c. They stimulate detoxification of toxins and carcinogens.
d. They disrupt enzymatic processes.

3. Helicobacter pylori increases the risk of which type(s) of cancer?
a. Breast
b. Esophageal, gastric, and colon
c. Bladder
d. Prostate

4. What's the recommended BMI to reduce cancer risk?
a. 18 to 20 kg/m2
b. 21 to 23 kg/m2
c. 25 to 28 kg/m2
d. 29 to 32 kg/m2

5. What percentage of cancers is related to obesity?
a. 10%
b. 20%
c. 30%
d. 40%

6. What level of vitamin D in the blood reduces cancer risk?
a. 15 ng/mL
b. 20 ng/mL
c. 30 ng/mL
d. >150 ng/mL

7. How do phytochemicals in cruciferous vegetables reduce cancer risk?
a. They increase detoxification enzymes.
b. They reduce carcinogen absorption through the gastrointestinal tract.
c. They act as inflammatory agents.
d. They inhibit tumor suppression proteins.

8. What food should be limited in the diet to reduce cancer risk?
a. Processed meat
b. Dairy
c. Wheat
d. Cheese

9. How does an unhealthy microbiome increase cancer risk?
a. It increases inflammation.
b. It decreases the amount of hydrogen-producing bacteria.
c. It increases the number of microvilli.
d. It decreases inflammation.

10. Indole-3-carbinol is a phytochemical found in what food?
a. Red grapes
b. Tomatoes
c. Broccoli
d. Parsnips

References
1. Liu RH. Potential synergy of phytochemicals in cancer prevention: mechanism of action. J Nutr. 2004;134:(12 Suppl):3479S-3485S.

2. De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes. 2013;2013:291546.

3. Ligibel JA, Alfano CM, Courneya KS, et al. American Society of Clinical Oncology position statement on obesity and cancer. J Clin Oncol. 2014;32(31):3568-3574.

4. Shirakami Y, Sakai H, Kubota M, Kochi T, Shimizu M. Dietary phytochemicals as cancer preventive agents: efficacy and mechanisms. J Bioanal Biomed. 2015;7:40-49.

5. Holick MF. Vitamin D and sunlight: strategies for cancer prevention and other health benefits. Clin J Am Soc Nephrol. 2008;3(5):1548-1554.

6. Garland CF, Garland FC, Gorham ED, et al. The role of vitamin D in cancer prevention. Am J Public Health. 2006;96(2):252-261.

7. Benninghoff AD, Lefevre M, Hintze KJ, Ward WE, Broadbent JR. Fighting cancer with functional foods: new approaches to investigate the interactions of dietary bioactive chemicals and the gut microbiome. J Dev Sustainable Agric. 2015;10:34-54.

8. Wang H, Khor TO, Shu L, et al. Plants vs. cancer: a review on natural phytochemicals in preventing and treating cancers and their druggability. Anticancer Agents Med Chem. 2012;12(10):1281-1305.

9. How carotenoids help protect against cancer. Physicians Committee for Responsible Medicine website. https://www.pcrm.org/health/cancer-resources/diet-cancer/nutrition/how-carotenoids-help-protect-against-cancer

10. Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549-1556.

11. Myung SK, Kim Y, Ju W, Choi HJ, Bae WK. Effects of antioxidant supplements on cancer prevention: meta-analysis of randomized controlled trials. Ann Oncol. 2010;21(1):166-179.

12. Hilakivi-Clarke L, Andrade JE, Helferich W. Is soy consumption good or bad for the breast? J Nutr. 2010;140(12):2326S-2334S.

13. Jaceldo-Siegl K, Gatto N, Beeson L, Fraser G. Intake of soy isoflavones reduces breast cancer incidence among women in North America. FASEB J. 2015;29(1):406.5.

14. Martínez ME, Jacobs ET, Baron JA, Marshall JR, Byers T. Dietary supplements and cancer prevention: balancing potential benefits against proven harms. J Natl Cancer Inst. 2012;104(10):732-739.

15. Wien TN, Pike E, Wisløff T, Staff A, Smeland S, Klemp M. Cancer risk with folic acid supplements: a systematic review and meta-analysis. BMJ Open. 2012;2(1):e000653.

16. Hardy ML, Duvall K. Multivitamin/multimineral supplements for cancer prevention: implications for primary care practice. Postgrad Med. 2015;127(1):107-116.

17. Angelo G, Drake VJ, Frei B. Efficacy of multivitamin/mineral supplementation to reduce chronic disease risk: a critical review of the evidence from observational studies and randomized controlled trials. Crit Rev Food Sci Nutr. 2015;55(14):1968-1991.

18. Francescone R, Hou V, Grivennikov SI. Microbiome, inflammation, and cancer. Cancer J. 2014;20(3):181-189.

19. Bultman SJ. Emerging roles of the microbiome in cancer. Carcinogenesis. 2014;35(2):249-255.

20. Recommendations for cancer prevention. American Institute for Cancer Research website. http://www.aicr.org/reduce-your-cancer-risk/recommendations-for-cancer-prevention/

21. Bylsma LC, Alexander DD. A review and meta-analysis of prospective studies of red and processed meat, meat cooking methods, heme iron, heterocyclic amines and prostate cancer. Nutr J. 2015;14:125.

22. Miller PE, Alexander D. A review and meta-analysis of prospective studies of red and processed meat and pancreatic cancer. FASEB J. 2016;30(1):902.9.

23. Aykan NF. Red meat and colorectal cancer. Oncol Rev. 2015;9(1):288.