Diet and Cancer: Can Your Diet Really Reduce Cancer Risk? Tarek Elrafei, D.O. Division Chief, Hematology/Medical Oncology Jacobi Medical Center, Bronx.

Diet and Cancer: Can Your Diet Really Reduce Cancer Risk?

Tarek Elrafei, D.O.Division Chief, Hematology/Medical Oncology

Jacobi Medical Center, Bronx NYAssistant Professor

Albert Einstein college of Medicine

Cancer Prevention

• Diet– Dietary Fat– Red meat– Fruits and Vegetables– Dairy– Fiber– Glycemic load– Omega-3 fatty acids

• Vitamins & Micronutrients• Alcohol• Nutritional support in patients with cancer

Consume a healthy diet, with an emphasis on plant sources. •Choose foods and beverages in amounts that help achieve and maintain a healthy weight.

•Eat five or more servings of a variety of vegetables and fruits each day.

•Choose whole grains in preference to processed (refined) grains.

•Limit consumption of processed and red meats

If you drink alcoholic beverages, limit consumption. •Drink no more than one drink per day for women or two per day for men.

American Cancer Society (ACS) Recommendations for Individual Choices

CA Cancer J Clin 2006; 56:254-281

What’s the evidence?

• Pubmed search for “diet + cancer”– 27,360 scientific publications

• Epidemiological, animal studies, retrospective, prospective observational studies, clinical trials

– 961 Randomized controlled trials– 128 Meta-analysis– 32 practice guidelines

• Pubmed search for “Fava beans and cancer”???

While we have come a long way since this 1940’s Advertisement, we still can not identify who will and will not benefit from dietary intervention strategies

Dietary Fat

• No clear link between total fat intake and colon or breast cancer– Womens Health Initiative Dietary Modification Trial

• 48,835 women followed for 8 years– Behavioral modification program to reduce dietary fat: reduced

% calories consumed as fat 10.7% year 1 and 8 % at year 6– vs.“usual diet” control group– No difference in incidence of colon cancer; a trend towards

decreased breast cancer

• Prostate cancer– Large amounts of alpha linoleic acid and low linoleic

acid increase risk (red meats and dairy)– Mechanism of association may be lower testosterone

levels on men who decrease fat intake

Physicians Health Study

• randomized trial of aspirin and β-carotene (vs. placebo)

• 22,071 U.S. male physicians, ages 40 to 84 in 1982, without a history of cardiovascular disease, cancer, or other major illnesses

• 14,916 U.S. male physicians provided plasma samples, which were frozen at -82 degrees C:

• Blood levels of all the trans-fatty acids examined for the 120 men who developed prostate cancer

Adjusted RR of nonaggressive prostate cancer by control quintiles of total 18:2n-6 trans-fatty acids according to baseline BMI (A) and random aspirin assignment (B).

Chavarro J E et al. Cancer Epidemiol Biomarkers Prev 2008;17:95-101

©2008 by American Association for Cancer Research

Red Meat• Heme content, animal fat, carcinogens when meat is cooked at high

temperatures suggested to increase cancer risk

• High intake of red meat including beef, pork, veal, and lamb, is associated with an elevated risk of colorectal cancer in both men and women in 6 studies…– prospective study 47,949 U.S. male health professionals

• 205 cases of colon cancer after 6 years of follow up• Intakes of total fat, saturated fat, and animal fat were not related to risk of

colon cancer • Men who ate beef, pork, or lamb as a main dish five or more times per week

had a relative risk of 3.57 compared to men eating these foods < once per month

• Other sources of animal fat, including dairy products, poultry, and fish as well as vegetable fat, were slightly inversely related to risk of colon cancer.

• No clear association existed between fiber or vegetable intake and risk of colon cancer.

Red Meat

• prospective study 88,751 women 34 to 59 years

• 150 cases of colon cancer after 6 years of follow up• After adjustment for total energy intake, animal fat was

positively associated with the risk of colon cancer • The relative risk of colon cancer in women who ate beef,

pork, or lamb as a main dish every day was 2.49 as compared with those reporting consumption < once a month

» Processed meats and liver were also significantly associated with increased risk, whereas fish and chicken without skin were related to decreased risk.

» A low intake of fiber from fruits appeared to contribute to the risk of colon cancer, but this relation was not statistically independent of meat intake

Red meat

• European Prospective Investigation into cancer and nutrition (EPIC study)– 478 040 men and women from 10 European countries

between 1992 and 1998. – 1329 incident colorectal cancers were documented

after a mean follow-up of 4.8 years – colorectal cancer risk is positively associated with

high consumption of red and processed meat and support an inverse association with fish intake

Fruits and Vegetable

• A large number of potentially anticarcinogenic agents are found in fruits and vegetables

• Retrospective studies and small prospective studies have suggested a dose-response relationship between fruit and vegetable intake and the prevention of cancers. – Soy decreases prostate cancer in men and breast

cancer in Asian women– Flavonoids (tomatoes, green peppers, berries, and

citrus fruits) may decrease breast cancer– Lycopene (tomatoes) may decrease prostate cancer

Epidemiologic Studies of Lycopene and Cancer Risk

Cancer Type of Study Reference

Breast Cohort Dorgan et al. Can Cau Cont 9: 89-97,

1998

Colon Case-control Franceschi et al. Int J Cancer 72:56-61,

1997

Lung Case-control Agudo et al. Eur J Cancer 33:1256-61,

1997

Prostate Cohort Giovannucci et al. J Natl. Cancer Inst. 87:1767-76,

1995

Soy Intake and Soy Intake and CancerCancer

ConcernsConcernsGrowth enhancement of human mammary tumors transplanted into mice Growth enhancement of human mammary tumors transplanted into mice that were fed soy or isoflavonids that were fed soy or isoflavonids (Hsieh, et al. Cancer Res. 58:3833, 1998).(Hsieh, et al. Cancer Res. 58:3833, 1998).

17 of 26 animal studies reveal soy or 17 of 26 animal studies reveal soy or soybean isoflavones reduce tumor soybean isoflavones reduce tumor tumor developmenttumor development

19 or 21 human epidemiological studies 19 or 21 human epidemiological studies provide evidence of protection against provide evidence of protection against cancer, especially rectal and stomach cancer, especially rectal and stomach cancers (1 study reported increase)cancers (1 study reported increase)

Soymilk Intake & Prostate Cancer Risk

Cancer Causes and Control 9: 553, 1998

0 <1 1 >1confidence interval 0.1-1.0

Daily Intake (servings)

Re

lativ

e R

isk

1.00.9

0.8

0.3*

Fruits and Vegetables• Large prospective studies have not found such a benefit:

– 71,910 women from the Nurses' Health Study and 37,725 men in the Health Professionals' Follow-up Study found no association between fruit and vegetable intake and risk of cancer (for an increment of five servings daily, relative risk [RR] 1.00, 95% CI 0.95 to 1.05)

– The European Prospective Investigation into Cancer and Nutrition (EPIC) study examined the association between fruit and vegetable intake and risk of breast cancer in 285,526 women ages 25 to 70.

• Comparing highest and lowest quintiles, there was no association with intake of fruits (RR 1.09, 95% CI 0.94-1.25) or vegetables (RR 0.98, CI 0.84-1.14).

• Conclusions and Interpretations– there is a long lag time between exposures and the development of cancer,

during which time individuals may change their diets, limiting the power of studies to detect effects

– Additionally, exposures in childhood may be more important in the development of cancer than exposures later in life

– It is possible that intake of specific fruits and vegetables may have effects on specific cancers.

Tomato VarietiesTomato Varieties

Types of Bioactive CompoundsCompounds May Vary with New Varieties

Dairy

• A meta-analysis of 21 studies evaluating the relationship of dairy food intake and ovarian cancer found no evidence of association in case control studies (RR 0.96) but…

• Of 4 prospective cohort studies, 3 did demonstrate increased risk of ovarian cancer with high intake of dairy foods

• Netherlands Cohort Study on Diet and Cancer. – 62 573 postmenopausal women participating in the

Netherlands Cohort Study. – After 11.3 years of follow-up, data of 252 incident

epithelial ovarian cancer cases with no association

Dairy Intake and Breast Cancer

• Nurses Health Study– 88,000 women– Breast cancer risk inversely associated with Low-fat

dairy, calcium (from dairy) and vitamin D (non-dairy intake) in premenopausal women but not postmenopausal

• Pooled analysis of 8 prospective studies confirm no association between dairy and breast cancer in postmenopausal women– 351,041 women, 7379 of whom were diagnosed with

invasive breast cancer during up to 15 years of follow-up

Int J Epidemiol. 2002 Feb;31(1):78-85

Dairy

• Dairy Food, Calcium, and Risk of Cancer in the NIH-AARP Diet and Health Study – Calcium intake, as determined by a food frequency

questionnaire, was associated with decreased total cancer risk over seven years in women, but not in men, in a large US cohort of 567,000 participants aged 50 to 71

– A decrease in cancers of the digestive tract (particularly colon cancer) with higher dairy food and calcium intake was noted in both men and women

Fiber and Cancer• The relationship between fiber intake and colorectal cancer risk is unsettled.

– No relationship was noted in the large observational Nurses' Health Study (N Engl J Med 1999 Jan 21;340(3):169-76 ).

– In contrast, some large observational studies have found a reduced risk of colorectal adenomas and cancer with increased fiber intake.

• A systematic review of five studies involving a total of 4349 patients concluded that there was no definitive evidence that increased dietary fiber reduces the incidence or recurrence of adenomatous polyps within a two- to four-year period

• Similarly, a pooled analysis of 13 prospective cohort studies (involving 725,628 men and women followed for 6 to 20 years) found that dietary fiber intake was inversely associated with the risk of colorectal cancer but the association was no longer apparent after accounting for other dietary risk factors

– One possible explanation is that the sources of dietary fiber differed across the various study populations.

– Other possible explanations are that the fiber intake in the Nurses' Health Study was relatively low even in the participants in the highest quintile of intake, or that dietary fiber is a marker for the intake of fruits, vegetables, and grains but is not actually protective in and of itself

– Diet-Gene interactions

Diet-Gene Interactions in Colon Cancer

*(high fat and phosphate, low calcium and vitamin D)

Yang et al, Cancer Res. 61, 565, 2001

0 4 8 12 16 20 24 28 32 360

10

20

30

40

50

60

70

80

90

100

Weeks

Per

cen

t su

rviv

alp21+/+ AIN-76A Diet

p21+/- AIN-76A Diet

p21-/- AIN-76A Diet

p21+/+ *Western Diet

p21+/- Western Diet

p21-/- *Western Diet

Glycemic Load

• Glycemic load is a function of glycemic index, carbohydrate content per serving, and frequency of intake– Glycemic Index = how rapidly and to what extent

blood glucose levels rise

• Insulin and Insulin like growth factors promote cell proliferation and possibly certain cancers

• 15 studies (2.5 million patients) estimate 30% higher risk of colon cancer among diabetics

Glycemic Load• NIH-AARP Diet and Health Study

– 7 years of follow up– found no association in 15,000 cancers in women and 33,000 cancers

cases in men• Women’s Health Study

– 174 colon cancers in 38,451 women with a calculated 2.85 increased risk

• Canadian trial– 49 124 women participating in a randomized, controlled trial of

screening for breast cancer in Canada – 16.5 years of follow-up, 616 incident cases of colorectal cancer and no

association of increased risk with higher glycemic index• Nurse’s Health Study & Health Professionals Follow up Studies

– 20 years of follow-up. 1,809 incident colorectal cancers – found no association for women but an increased risk for men of colon

cancer

Omega-3 Fatty Acids

• Individual studies have found increased and decreased risk of cancer with no consistent pattern

• Systematic Review of all prospective trials revealed no association between Omega-3 FA and cancer– 20 cohorts from 7 countries for 11 different

cancer types – 700,000 patients

Vitamins and Micronutrients

• National Institutes of Health (NIH) consensus conference panel concluded that… – "present evidence is insufficient to

recommend either for or against the use of multivitamin supplements by the American public to prevent chronic disease"

Prostate Cancer Prevention Selenium and Vitamin E

Cancer Prevention Trail (SELECT) ($175M)35,000 men, age >55 (> 50 for Black Men)

Selenium 200 ug/dVitamin E 400 mg/d

Vitamin E Placebo

Selenium

7 + Years TreatmentEndpoint Prostate Cancer Incidence

SELECT Trial• SELECT stands for the Selenium and Vitamin E Cancer Prevention

Trial, a prevention clinical trial to see if one or both of these dietary supplements prevent prostate cancer.

• SELECT is continuing to evaluate the effects of the supplements but participants are no longer taking study supplements. The independent Data and Safety Monitoring Committee for the trial found that selenium and vitamin E, taken alone or together for an average of five and one-half years, did not prevent prostate cancer.

• The SELECT data showed two concerning, but not statistically significant, trends: there were slightly more cases of prostate cancer in men taking only vitamin E and slightly more cases of diabetes in men taking only selenium. Neither of these findings proves an increased risk from the supplements and may be due to chance.

http://www.cancer.gov/newscenter/qa/2008/selectqa

Vitamins and Micronutrients

• Vitamin D may reduce colon cancer risk by improving calcium absorption

• Prostate and Breast Cancer: Vit. D + calcium showed no effect on breast cancer in 3 trials

• One randomized prospective trial of calcium + vit D in 1179 women over 4 years has shown decrease in all cancer types

Am J Clin Nutr. 2008 Mar;87(3):794

Alcohol

Obesity and EBC Outcomes

• Obesity (BMI > 30) associated with poorer DFS and OS in operable breast cancer

• Evaluation of women with EBC in adjuvant trials of doxorubicin, cyclophosphamide plus other agents to determine relationship between obesity and

– Clinical characteristics

– Clinical outcomes

– Clinical outcomes and breast cancer subtype• ER/PgR-positive, HER2-negative disease

• HER2-positive disease

• Triple-negative disease

ECOG Trials Included in Analysis

E1199 E5188 E3189Population • Node positive

• High-risk node negative

• ER positive• Node positive• Premenopausal

• ER negative• PgR negative• Node positive

Chemotherapy Cyclophosphamide, doxorubicin, taxane

Cyclophosphamide, doxorubicin, fluorouracil

Cyclophosphamide, doxorubicin,

fluorouracil vs 16-wk regimen

Endocrine therapy

Tamoxifen ±aromatase inhibitor

None vs goserelin vs goserelin +

tamoxifen

None

Patients with BMI data, n

3484 1502 613

Obesity and Outcomes in Subgroup Analysis of E1199

E1199 Subgroup

DFS OS

HR (95% CI)

P Value

HR (95% CI)

P Value

ER and/or PgR positive, HER2 negative

1.23 (1.02-1.49) .035 1.46 (1.15-1.85) .002

ER, PgR, HER2 negative (n = 708)

1.01 (0.77-1.33) .93 1.05 (0.77-1.43) .75

HER2 positive (n = 661)

1.07 (0.77-1.47) .70 0.89 (0.60-1.31) .55

Sparano J, et al. SABCS 2010. Abstract S2-1.

Validation by Analysis of Trial Data From E5188 and E3189

Trial DFS OS

HR (95% CI)

P Value

HR (95% CI)

P Value

E5188 (ER/PgR positive, HER2 negative)

1.41 (1.19-1.67) < .0001 1.51 (1.24-1.83) < .0001

E3189 (ER negative) 0.90 (0.70-1.16) .41 0.83 (0.63-1.09) .18

Sparano J, et al. SABCS 2010. Abstract S2-1.

Nutritional support in patients with cancer

• Ginger

• Vitamin E effects on chemotherapy

Supportive care for those with cancer

• Ginger for chemotherapy-related nausea in cancer patients: A URCC CCOP randomized, double-blind, placebo-controlled clinical trial of 644 cancer patients. J Clin Oncol 27:15s, 2009 (suppl; abstr 9511)

• Patients were randomized into four arms: – 1) placebo,

– 2) 0.5g ginger,

– 3) 1.0g ginger, or

– 4) 1.5g ginger • All doses of ginger significantly reduced nausea (p=0.003)

compared to placebo.

Vitamin E Inhibits Cisplatin-InducedApoptosis in MCF-7 Breast Cancer Cells.

Salganik, et al. Carcinogenesis 21: 909, 2000.

Control E CP CP+E

6 -

4 -

2 -

0 -

% A

pop

tosi

s +

*

**

Antioxidant reduces

efficacy of cisplatin

American Cancer Society (ACS) Recommendations for Individual Choices

http://caonline.amcancersoc.org/cgi/content/full/56/5/310

Maintain a healthy weight throughout life. •Balance caloric intake with physical activity.

•Avoid excessive weight gain throughout the life cycle.

•Achieve and maintain a healthy weight if currently overweight or obese.

Adopt a physically active lifestyle. •Adults: engage in at least 30 minutes of moderate to vigorous physical activity, above usual activities, on 5 or more days of the week. Forty-five to 60 minutes of intentional physical activity are preferable.

•Children and adolescents: engage in at least 60 minutes per day of moderate to vigorous physical activity at least 5 days per week.

CA Cancer J Clin 2006; 56:254-281

Consume a healthy diet, with an emphasis on plant sources. •Choose foods and beverages in amounts that help achieve and maintain a healthy weight.

•Eat five or more servings of a variety of vegetables and fruits each day.

•Choose whole grains in preference to processed (refined) grains.

•Limit consumption of processed and red meats

If you drink alcoholic beverages, limit consumption. •Drink no more than one drink per day for women or two per day for men.

American Cancer Society (ACS) Recommendations for Individual Choices

CA Cancer J Clin 2006; 56:254-281

Fruits• 1 medium apple, banana, orange

• 1/2 cup of chopped, cooked, orcanned fruit

• 1/2 cup of 100% fruit juice

Vegetables• 1 cup of raw leafy vegetables

• 1/2 cup of other cooked or raw vegetables, chopped

• 1/2 cup of 100% vegetable juice

Grains• 1 slice bread

• 1 ounce ready-to-eat cereal

• 1/2 cup of cooked cereal, rice, pasta

What Counts as a Serving?

What Counts as a Serving?

Beans and nuts• 1/2 cup cooked dry beans

• 2 tablespoons peanut butter

• 1/3 cup nuts

Dairy foods and eggs• 1 cup milk or yogurt

• 1 1/2 ounces of natural cheese

• 2 ounces processed cheese

• 1 egg

Meats 2–3 ounces of cooked lean meat, poultry, fish

Conclusions

• Inconsistencies in results of nutritional studies– Observational studies

• Imprecise diet recall• Confounding cancer risk factors

– Randomized studies• Poor adherence to dietary intervention• Insufficient follow up time• Wrong dose or form of nutrient• Study population may be replete with in nutrient studied

• One consistent finding is that excess calories from any source leads to weight gain and increased risk of multiple cancers

Conclusions by tumor type:Breast Cancer

• Decreased risk– Low fat diet may decrease risk– Low fat dairy, calcium, Vit D (in premenopausal)– Folic acid may decrease risk

• No difference– Red meat– Dietary fat– Fruits and Vegetables– Vitamin D and Calcium (in postmenopausal)

• Increased Risk– Alcohol (2 or more drinks)

Conclusions by Tumor Type: Prostate Cancer

• Increased risk– large amounts of alpha-linoleic acid and low amounts

of linoleic acid increase risk of nonaggresive cancers– Calcium?

• No difference– Selenium – Vitamin E

• Decreased risk– Soy milk?

Conclusions by tumor type:Colon cancer

• Decreased Risk– Fish (men and women)– Chicken without skin (women)– Calcium and Dairy (men and women)Red meat

increases risk in men and women• No difference

– Fiber• Increased Risk

– Red meat (men and women)– Processed meat– Liver– High glycemic load (men and women)

Conclusions by tumor type:

• Ovarian cancer– Dairy may increase risk??

• “All cancers”– Calcium + vit D

Just when I knew all of life’s answers,They changed all the questions!!

Lifestyle changes

Caloric Restriction in Yeast causes silencing of genes and extended life span (Guarente and Kenyon Nature 2000; 408:255

Colon Cancer and Exercise

More is Not Always Better: Energy Intakes and Expenditures Are Linked to Health!

Caffeine

Tea (Camellia sinensis)

Green Tea Black Tea

30-40% Catechins 3-6% Caffeine~310 mg polyphenols per 6 ounces

3-10% Catechins 2-6% Theaflavins> 20% Thearubigens 3-6%  Caffeine~340 mg polyphenolsper 6 ounces

Dried

Tea Leaves

Crushed tea leaves

Polyphenol oxidase

Oxidation,Polymerization

O

OR 2

HO

OH

OH

R1

HO

Yang CS. Personal Communication

Tea and Cancer Prevention

Camellia Sinensis

Yang CS. Personal Communication

SkinLiver

Colon

Oral

Esophagus

LungStomach

ProstateMammary

< 300 mg Caffeine > 300 mg

6

-12

0

-6

Vitamin D Receptor Genotype

TT Tt tt TT Tt tt

S

pine

Bon

e M

ass

Den

sity

(%

)Influence of Caffeine on Bone Mass May Depend on Genes

Rapuri et al. Am J Clin Nutr 2001 Nov;74(5):694-700

Recent meta-analysis of Data from 11 trials concluded The random-effects relative risk (RR) estimate for raw and cooked garlic and colorectal cancer was 0.69 and for stomach was 0.53. Fleischauer, et al. Amer JClin Nutr 72, 1047, 2000.

Prospective cohort study with 41,837 women age 55 to 69, examined 127 food items. “The strongest association in the present study was that for garlic consumption, with an approximate 50% lesser risk associated with high consumption.” Steinmetz et al. Amer. J. Epidemiology Steinmetz et al. Amer. J. Epidemiology 139:1, 1994139:1, 1994

Linking diet, religion and cancerJournal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No.

18S (June 20 Supplement), 2007: 21172

• This study was done to see cancer incidence in children of Jain religion as compared to other religions at a single centre. – Jain religion does not consume garlic and onion due to religious belief.

• retrospective analysis of consecutive children less than 16 years of age diagnosed with cancer at Sir Ganga Ram Hospital from January 2005 to January 2007.

• Incidence of cancer in children of different religions is similar to that of proportions of population of different religions in Delhi except for Jain religion where incidence of cancer is 6 times higher despite lesser number children in 0-6 year in this population as compared to other religions . – Major difference is the diet lacking in onion and garlic . – Other reason could be increased literacy levels in Jain community . – “This link between diet ,religion and cancer in Jain population needs to

be studied in a larger muticenteric setting as it has implications for the whole world.”

Selenium Placebo RR 97% CISkin Cancer

Squamous cell 218 190 1.14 0.93-1.39Basal cell 377 350 1.10 0.95-1.28

Cancer (- Skin)Lung 17 31 0.54 0.30-0.98Prostate 13 35 0.37 0.18-0.71Colorectal 8 19 0.42 0.18-0.95Breast 9 3 2.88 0.72-16.5

All Sites (- Skin) 77 119 0.63 0.47-0.85

Selenium & Skin Cancer Prevention Trial

Clark et al. JAMA 276: 1957, 1996.

Phase III trial with 1,312 skin cancer subjects

Se (200 g) as Brewers Yeast vs. Placebo, follow-up 6.4 yrs

Effects of Microwave Heating of Garlic on Total DMBA-Induced DNA Adducts

a

b b

0

250

500

750

1000

D

NA

Ad

du

cts

(nm

ol A

dd

uct

s/m

ol D

NA

)

Control Peel/Crushed

30 seconds

60 seconds

Microwave/ Peel/Crushed

a

Song and Milner J Nutr 1999;129:657-61

150 mg

3 grams

150 grams

MARKET STAGE BROCCOLI

3-DAY SPROUTS

FREEZE-DRIEDSPROUT EXTRACT

All preparations contain the same quantity of detoxification enzyme inducer activity, (Glutathione S-transferase and Quinone Reductase)

How Should We Consume Bioactive Food Components?