Nutrition and Cancer. Diet and nutrition account for what % of avoidable cancers and cancer deaths? 1. < 5% % % % 5.

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1 Nutrition and Cancer Donald I. Abrams, M.D. Chief, Hematology-Oncology San Francisco General Hospital Integrative Oncology UCSF Osher Center for Integrative Medicine Professor of Clinical Medicine, UCSF Diet and nutrition account for what % of avoidable cancers and cancer deaths? 1. < 5% % % % 5. Nearly 50% :10 Proportion of Cancer Deaths Caused by Different Avoidable Cancers Causes Percent 1981 (US)* Tobacco Diet Medicines <1 Infection: parasites, bacteria, viruses Ionizing and UV light Occupation Pollution: air, water, food < Physical inactivity 1-2 * Doll and Peto, 1981; ** Doll, 1998 Percent 1998 (UK)** 1

2 Proportion of Cancer Deaths Caused by Different Avoidable Cancers Causes Percent 1981 (US)* Tobacco Diet Medicines <1 Infection: parasites, bacteria, viruses Ionizing and UV light Occupation Pollution: air, water, food < Physical inactivity 1-2 Percent 1998 (UK)** 94% * Doll and Peto, 1981; ** Doll, 1998 AICR 2009 Proportion of Cancer Deaths Caused by Different Avoidable Cancers Causes Percent 1981 (US)* Tobacco Diet Medicines <1 Infection: parasites, bacteria, viruses Ionizing and UV light Occupation Pollution: air, water, food < Physical inactivity 1-2 Percent 1998 (UK)** 94% 87% * Doll and Peto, 1981; ** Doll, 1998 AICR 2009 Proportion of Cancer Deaths Caused by Different Avoidable Cancers Causes Percent 1981 (US)* Tobacco Diet Medicines <1 Infection: parasites, bacteria, viruses Ionizing and UV light Occupation Pollution: air, water, food < Physical inactivity 1-2 Percent 1998 (UK)** 94% 51% 87% * Doll and Peto, 1981; ** Doll, 1998 AICR

Proportion of Cancer Deaths Caused by Different Avoidable Cancers Causes Percent 1981 (US)* Tobacco 25-40 29-31 Diet 10-70 20-50 Medicines 0.3-1.

* Doll and Peto, 1981; ** Doll, 1998 AICR 2009 Diet and Cancer Probably involved in 30-35% of all cancers Certainty about diet less firm than tobacco Contradictory study results i.e. fiber Hard to define what the diet actually is Diets are very complex Diets vary over time Is it what we ate in the past?

3 Proportion of Cancer Deaths Caused by Different Avoidable Cancers Causes Percent 1981 (US)* Tobacco Diet Medicines <1 Infection: parasites, bacteria, viruses Ionizing and UV light Occupation Pollution: air, water, food < Physical inactivity 1-2 Percent 1998 (UK)** 94% 51% 87% 46% * Doll and Peto, 1981; ** Doll, 1998 AICR 2009 Diet and Cancer Probably involved in 30-35% of all cancers Certainty about diet less firm than tobacco Contradictory study results i.e. fiber Hard to define what the diet actually is Diets are very complex Diets vary over time Is it what we ate in the past? Or perhaps what our mothers ate? Or theirs? LTR Hypomethylated LTR Hypermethylated Maternal Supplements with zinc, methionine betaine, choline, folate, B 12 Or Genistein Yellow Mouse High risk cancer, diabetes, obesity & reduced lifespan Agouti Mouse Lower risk of cancer, diabetes, obesity and prolonged life Cooney et al. J Nutr 132:2393S (2002); Dolinoy et al. Envir. Health Perspect 114: 567 (2006) 3

ACS and WCRF/AICR Guidelines WEIGHT GUIDELINES Maintain a healthy weight throughout life Balance caloric intake with physical activity Avoid excessive

4 ACS and WCRF/AICR Guidelines WEIGHT GUIDELINES Maintain a healthy weight throughout life Balance caloric intake with physical activity Avoid excessive weight gain throughout the life cycle Achieve & maintain a healthy weight if currently overweight or obese Be as lean as possible without becoming underweight 4

5 The only state with <20% obesity currently 1. Alaska 2. California 3. Colorado 4. Hawaii 5. Louisiana :10 BRFSS, 1985 No Data <10% 10% 14% BRFSS, 1986 No Data <10% 10% 14% 5

6 BRFSS, 1987 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% BRFSS, 1988 No Data <10% 10% 14% BRFSS, 1989 No Data <10% 10% 14% 6

7 BRFSS, 1990 No Data <10% 10% 14% BRFSS, 1991 No Data <10% 10% 14% 15% 19% BRFSS, 1992 No Data <10% 10% 14% 15% 19% 7

8 BRFSS, 1993 No Data <10% 10% 14% 15% 19% BRFSS, 1994 No Data <10% 10% 14% 15% 19% BRFSS, 1995 No Data <10% 10% 14% 15% 19% 8

9 BRFSS, 1996 No Data <10% 10% 14% 15% 19% BRFSS, 1997 No Data <10% 10% 14% 15% 19% 20% BRFSS, 1998 No Data <10% 10% 14% 15% 19% 20% 9

10 BRFSS, 1999 No Data <10% 10% 14% 15% 19% 20% BRFSS, 2000 No Data <10% 10% 14% 15% 19% 20% BRFSS, 2001 No Data <10% 10% 14% 15% 19% 20% 24% 25% 10

11 BRFSS, 2002 No Data <10% 10% 14% 15% 19% 20% 24% 25% BRFSS, 2003 No Data <10% 10% 14% 15% 19% 20% 24% 25% BRFSS, 2004 No Data <10% 10% 14% 15% 19% 20% 24% 25% Source: Behavioral Risk Factor Surveillance System, CDC. 11

12 BRFSS, 2005 No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% Source: Behavioral Risk Factor Surveillance System, CDC. BRFSS, 2006 No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% Source: Behavioral Risk Factor Surveillance System, CDC. BRFSS, 2007 No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% Source: Behavioral Risk Factor Surveillance System, CDC. 12

13 BRFSS, 2008 No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% Source: Behavioral Risk Factor Surveillance System, CDC. BRFSS, 1990, 1999, 2008 (*BMI 30, or about 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% 13

Obesity-Associated Malignancies Breast (postmenopausal) Endometrium Prostate Kidney Colon Esophagus Pancreas Gallbladder AICR report estimates that obesity-related excesses of these 7 cancers account

14 Obesity-Associated Malignancies Breast (postmenopausal) Endometrium Prostate Kidney Colon Esophagus Pancreas Gallbladder AICR report estimates that obesity-related excesses of these 7 cancers account for approx 105,000 preventable deaths a year in the US Body Fat Increases CA Risk Body fat secretes cytokines that promote inflammation Too much body fit triggers insulin resistance, raising levels of insulin and growth factors that promote cancer Fat increases estrogen production Increase in body fat may impair immunity ENERGY DENSE FOODS GUIDELINES Choose foods and beverages in amounts that help achieve & maintain a healthy weight Avoid sugary drinks Limit consumption of energy dense foods Particularly processed foods high in added sugar, low in fiber or high in fat 14

15 Source: US Department of Agriculture How can anyone consume that much sugar??? 15

16 OUT! Glycemic Load and Colon CA Study of 131,000 people to determine effect of dietary glycemic load, GI, CHO, fructose and sucrose on colon CA In Nurse s Health Study cohort no association found In Health Professional s Follow-Up Study men, 27-37% increased CA risk with increasing intake of CHO, GL, sugars Michaud CA Epi Bio Prev

17 Mortality in CA with Diabetes Systematic review and meta-analysis comparing overall survival in cancer pts with and without preexisting diabetes 8-18% newly dx ed CA pts with DM (7% US) Equivocal data on impact of DM on CA death This analysis evaluates long-term, all-cause mortality 23 articles of 7858 titles met all criteria Barone et al, JAMA, 2008 Meta-analysis and Pooled Hazard Ratio of Long-term, All-Cause Mortality in 23 Studies Comparing Cancer Patients With and Without Preexisting Diabetes Mellitus Barone, B. B. et al. JAMA 2008;300: Endometrial (HR 1.76), breast (1.61) and colorectal (1.32) Mortality in CA with Diabetes Explanations for observed association Increased proliferation and metastases with hyperinsulinemia, hyperglycemia and ROS Less aggressive CA treatment offered DM pts DM pts may have poorer response to CA Rx Pts with DM may present with later stage dz b/o suboptimal screening Dx and Rx of CA may distract from glycemia mx Excess mortality may be independent of CA & Rx Barone et al, JAMA,

18 Insulin Like Growth Factor-I Substantial evidence implicates IGF-I signaling in the development and progression of many cancers, including breast High IGF-I levels predict increased risk Antiestrogens reduce IGF-I levels IGF-IR hyperactive and overexpressed in many breast cancers IGF-IR being targeted in therapy IGF-I caused gene expression changes in breast CA cells associated with cell proliferation, metabolism and DNA repair Creighton et al JCO 2008 Is this a healthy supplement for cancer patients WATER, CORN MALTODEXTRIN, SUGAR (SUCROSE), CORN SYRUP, MILK PROTEIN CONCENTRATE, COCOA POWDER (PROCESSED WITH ALKALI), SOY OIL, SHORT-CHAIN FRUCTOOLIGOSACCHARIDES, SOY PROTEIN ISOLATE, CANOLA OIL Is this a healthy supplement for cancer patients 1. Yes 2. No :10 18

19 PLANT-BASED GUIDELINES Consume a healthy diet, with an emphasis on plant sources Eat 5 or more servings of a variety of fruits and vegetables each day; every meal and snacks Choose whole grains in preference to refined Eat more of a variety of vegetables, fruits, whole grains and legumes U.S. Diets Fall Short on F&Vs CDC reports only 14% of adults eat recommended number of servings/day 33% eat 2 or more servings of fruit a day 27% eat 3 or more servings of vegetables DC 20.1%, VT, ME, HI, MA top 5 WV, SD, AL, OK/SC, MS 8.8% rank last Only 9.5% of high school students meet recommendations (32% fruit, 13% veg) Healthy People 2010 objective was to have 75% meet fruit and 50% vegetable Centers for Disease Control 2009 Antioxidant Rich Foods Fruits Vegetables Nuts Grains Some meat, fish and poultry 19

20 I generally try to purchase organic produce 1. Always 2. Mostly 3. Sometimes 4. Never :10 Nutritional Prevention Strategies Eat More: Phytoestrogens Soy foods Flaxseed (Omega 3 s) Cruciferous vegetables Garlic and onions Turmeric and ginger Green tea F&V and Colorectal Cancer 85,903 men and 105,108 women yo in Hawaii and California followed 7 years Detailed questionnaires on dietary habits 2110 participants developed CRC (1138 men) For men, high levels of F&V associated with lower risk across 5 ethnic groups studied (RR [0.59,0.93]) For women, no risk reduction seen for F&V Risk reduction colon CA > rectal CA in men Intake of grains had no effect in either sex Nomura et al Am J Clin Nutr

21 Understanding the WHEL Results Women s Healthy Eating and Living (WHEL) enrolled 3088 women from 7 centers Stage I-IIIa invasive breast CA treated with lumpectomy and XRT or mastectomy Intervention group: 5 vegetables plus 16 oz vegetable juice, 3 fruits, 30 gm fiber and <15-20% calories from fat Control group: 5-A-Day print guidelines Pierce et al JAMA 2007 Understanding the WHEL Results Intervention group had 65% in vegetables, 25% fruit, 30% fiber and 13% fat Patterns differed significantly during the 7.3 years of the study At 1 yr, intervention group consumed 12 F&V servings/day vs 7.3 in control group No difference in disease-free or overall survival between the groups More good does not change rates Pierce et al JAMA 2007 Fig 1. Kaplan-Meier survival after Women's Healthy Eating and Living (WHEL) Study enrollment by four diet and physical activity categories Pierce, J. P. et al. J Clin Oncol; 25:

22 Soy and Breast Cancer Numerous nutritional benefits Isoflavones Daidzein (40%), genistein (50%) and glycetin (10%) Essential amino acids Fibers Poly-unsaturated fatty acids Vitamins and minerals Isoflavones acts as selective estrogen receptor modifiers? Safety of soy products in ER+ women LACE Study Life After Cancer Epidemiology Study followed 1954 breast CA survivors dx for 6.3 yrs 282 breast CA recurrences ascertained Isoflavone intake assessed Soy intake at levels comparable to those consumed in Asian population May reduce the risk of recurrence in women who have been treated with tamoxifen In postmenopausal women (HR 0.48, , p=0.008) Does not appear to negate the effects of tamoxifen Further confirmation required before recs issued Guha et al, Breast CA Res and Treat, 2009 Green Tea: Human Studies Animal studies: Green tea has a protective effect against tumors of the colon, prostate, esophagus, liver, stomach, lung, breast, pancreas and skin Iowa Women s Health Study- catechin intake from tea was associated with a lower incidence of digestive tract cancers. Chinese tea drinking men have half the risk of developing stomach or esophageal cancer, and have significantly lower risk of prostate cancer. 22

23 Mushrooms and Green Tea Case control study in SE China women with confirmed breast CA and 1009 age-matched controls Compared with non-consumers OR (95% CI 0.25, 0.51) for daily intake >10g fresh mushrooms OR (95% CI 0.38, 0.73) for daily intake > 4 g dried mushrooms ORs 0.11 and 0.18 for fresh and dried in combo with >1.05 g dried green tea leaf beverages/day Effects seen in pre and post-menopausal women Zhang et al, Int J CA, 2009 RED MEAT GUIDELINES Limit consumption of processed and red meats Limit consumption of red meats (beef, pork and lamb) and avoid processed meats Meat Intake and Colon Cancer Armstrong and Doll, 1975 in Willett,

24 Omega 3 vs Omega 6 Fatty Acids 24

fold increased risk with regular consumption of well-done and fried meats High iron content may also be a factor Exogenous hormones in cattle may promote tumor growth Red meat

25 Industrialization of agriculture has yielded an increased omega 6:omega 3 ratio in 1. Dairy products 2. Pork 3. Beef 4. Eggs 5. All of the above :10 Red Meat and Breast Cancer Heterocyclic amines created during hightemperature cooking of meat are estrogenic Iowa Women s Health Study analysis revealed 4- fold increased risk with regular consumption of well-done and fried meats High iron content may also be a factor Exogenous hormones in cattle may promote tumor growth Red meat consumption viewed as possible risk for hormone-sensitive breast cancer Linos and Willett, JNCCN, 2007 Transformation of food chain Omg-6 / Omg-3 x6 x10 x15 x20 Ailhaud et al., Prog. Lip. Res., 2006 Simopoulos & Salem. NEJM,

26 Dietary Patterns in Colon CA Prospective observational study of 1009 pts with Stage III colon cancer enrolled in CALGB between 4/99-5/01 Pts reported on dietary intake using a ffq during and 6 months after the trial Two major dietary patterns recognized Two major dietary patterns identified Western pattern characterized by high intakes of meat, fat, refined grains, and dessert Prudent pattern characterized by high intakes of fruits and vegetables, poultry and fish Every patient scored along the spectrum of both Patients were followed up for cancer recurrence or death Meyerhardt et al JAMA 2007 CALGB Prospective Observational Study: Western Dietary Pattern and Cancer Outcomes F/U 5.3 years, 324 patients recurred, 223 died with recurrence and 28 died without CA Dietary Patterns in Colon CA Highest quintile in Western diet had daily median 1 serving of red meat 5 servings of refined grains 2 sugar desserts Lowest quintile in Western diet had daily median 0.3 serving red meat (2 per week) 2 servings refined grain 0.5 sugar desserts (3 per week) So the recommendation is more of an avoidance than an increase in diet components Meyerhardt Personal Communication 26

Dietary Fat and Pancreatic CA NIH/AARP study, 6.3 yrs f/u 525K 1337 cases Pancreatic cancer risk directly related to the intake of: Saturated fat 51.

05) Strongest associations for saturated fat from animal sources 52 vs 32.2 cases/100k py HR= 1.43 (1.20,1.70; P trend <.

27 Dietary Fat and Pancreatic CA NIH/AARP study, 6.3 yrs f/u 525K 1337 cases Pancreatic cancer risk directly related to the intake of: Saturated fat 51.5 vs 33.1 cases/100k py HR= 1.36 (1.14,1.62; P trend <.001) Monounsaturated fat 46.2 vs 32.9 cases/100k py HR= 1.22 (1.02,1.46; P trend =.05) Strongest associations for saturated fat from animal sources 52 vs 32.2 cases/100k py HR= 1.43 (1.20,1.70; P trend <.001) Specifically, intakes from red meat (HR=1.27) and dairy products (HR=1.19) were both associated with increased risk Thiebaut et al, JNCI 2009 Omega-3 Fatty Acids Vitamin D in Fish 27

28 Vitamin D3 (Cholecalciferol) A vitamin with hormone-like action Controls phosphorus, calcium and bone metabolism and neuromuscular function The only vitamin the body can manufacture from sunlight Increasing percentage of population now deficient b/o indoor living, heliophobia and sunscreen use Vitamin D3 (Cholecalciferol) Estimate that 1 billion people worldwide may be Vitamin D deficient Dark skin, obesity, heredity may hinder production Seniors need to ingest more because of decreased skin and renal synthesis 25(OH)-Vitamin D is good blood test < 30 ng/ml insufficient ~ 45 ng/ml adequate >80 ng/ml optimal Vitamin D3 (Cholecalciferol) Long recognized as involved in bone health, but now felt to be linked to: Depression/Schizophrenia Back pain (osteomalacia) Cancer (Breast, prostate, colon, pancreas) Insulin resistance Impaired immunity/autoimmunity Infections (URI/TB) Macular degeneration Pre-eclampsia 28

My Standard Recommendations Increase plant based foods Whole grains Fruits (deep pigment) and vegetables (cruciferous) Decrease animal fats Eliminate dairy and red meat Poultry preferably organic

29 My Standard Recommendations Increase plant based foods Whole grains Fruits (deep pigment) and vegetables (cruciferous) Decrease animal fats Eliminate dairy and red meat Poultry preferably organic Increase marine omega-3 s Decrease refined carbohydrates Sugar, white flour, white rice Season with garlic, ginger, onions, turmeric Drink green tea and red wine Let your food be your medicine And your medicine be your food Hippocrates 29

Leveraging Prospective Cohort Studies to Advance Colorectal Cancer Prevention, Treatment and Biology

Leveraging Prospective Cohort Studies to Advance Colorectal Cancer Prevention, Treatment and Biology Charles S. Fuchs, MD, MPH Director, Yale Cancer Center Physician-in-Chief, Smilow Cancer Hospital New