Nutrition and Cancer #1

Cancer as a Continuum

Diet may play an important role at multiple points 1. Normal Epithelium Intervention: healthy diet, physical exercise, discontinue tobacco, reduce alcohol 2. Mild Dysplasia Intervention: surgery, nutrients/small molecules to treat IENs, dietary intervention, discontinue tobacco 3. Moderate/Sever Dysplasia Intervention: surgery, nutrients/small molecules to treat IENs, dietary intervention, discontinue tobacco 4. Invasive Cancer Intervention: surgery, chemotherapy/radiation therapy, dietary intervention 5. Metastatic Cancer Intervention: supportive care 6. End of life *Progression can take YEARS depending on cancer type

Implication of Folate Studies

A nutrient may be helpful or harmful A genetic polymorphism is an enzyme involved in nutrient metabolism may be helpful or harmful

Circulation of Bile Acids

Cholesterol is a precursor to bile acids Made in liver, concentrated in gall bladder, secreted into intestine during digestion of fat Secondary bile acids made in colon by bacteria *potential tumor promoters?

Cancer

Collection of related diseases Some of the body's cells divide without stopping and spread to surrounding tissues Cancer cells differ from normal cells in ways that allow them to group out of control Cancer cells evade: *Immune system *Signals that tell cells to stop dividing or begin apoptosis

Total Folate (Diet + Supplements) and Colorectal Cancer

Conclusion: * "folate may have a small protective effect against CRC but confounding by other dietary factors cannot be ruled out"

Strong Evidence for Diet, Nutrition, Physical Activity, and Colorectal Cancer (2017)

Convincing Evidence *Decreases Risk -Physical Activity *Increases Risk -Processed Meat -Alcoholic drinks -Body fatness -Adult attained height Probable Evidence *Decreased Risk -Whole grains -Foods containing dietary fiber -Dairy products -Calcium supplements *Increased Risk -Red meat

Food, nutrition, obesity, physical activity, and cellular processes linked to cancer

DNA repair Proliferation Hormonal regulation Differentiation Inflammation and immunity Apoptosis Cell Cycle Carcinogen Metabolism

Most Common Cancers in USA

Male 1. prostate 2. lung and bronchus 3. urinary bladder Female 1. breast 2. lung and bronchus 3. colon and rectum

Estimating intake of Meat Cooking Mutagens

Meat Cooking Module *Meat type *Frequency *Portion size *Cooking method *Doneness level times (x) Meat Mutagen Database *Mutagen concentration

Meat Sub-types

Red meat (e.g. beef, pork) *red in color when raw *more red than white muscle fibers White meat (e.g. poultry, fish) *Lighter in color when raw Processed meat *red or white meat *preserved by...smoking, curing, salting, addition of chemicals (nitrate, nitrite, many others)

Calcium Supplementation (1200 mg/day) and Colorectal Adenoma Recurrence

0.85 RR (0.74-0.98) for calcium supplementation

Colorectal Cancer Epidemiology: Adenoma to Carcinoma Sequence

1.Normal Epithelium *APC loss 2.Hyper-proliferation 3.Early Adenoma *K-ras mutation 4.Intermediate Adenoma *Chrom 18 loss 5.Late Adenoma *p53 loss 6. Cancer

Global Burden of Cancer - 2018 Estimates

18.1 million cases, 9.6 million deaths Most common globally: lung, breast, prostate, colorectal Most deaths: lung, colorectal, stomach, liver 2006-2016: average annual age-standardized incidence rates for all cancers combined increased in 130 of 195 countries or territories HEAVY burden in USA, Europe, Australia/New Zealand

Diet and Cancer: Early Investigations

Animal Studies *High-dose carcinogens *Uniform genetic strains: often selected for susceptibility *Uniform conditions Unequivocally show diet can influence tumorigenesis *Known for decades

Effect of Baseline Plasma Folate Status on Chemopreventive (stopping cancer from happening) Efficacy

Another RCT on supplemental folic acid (1 mg/day) for recurrent adenoma (3-6.5 years f/u) Hazard ratios for supplemental folic acid (adjusted) *Overall: HR = 0.82 (0.59-1.13) *Low baseline (folate): HR = 0.61 (0.42-0.90) *High baseline (folate): HR = 1.28 (0.82 - 1.99)

Update on Folate and CRC

Another trial of folic acid, vitamins B6 and B12 (WAFACS, JNCI 2012) found no effect on adenoma or advanced adenoma with 9 years follow-up Done in the US population which consumes folate-fortified diet Still unclear whether benefits may be seen in un-fortified populations *Merits further consideration

Folate and Folic Acis

B vitamin found naturally in green leafy veggies, fruit, dried beans, and nuts Folic acid fortification in US in 1998 to prevent neural tube defects

Cancer Prevention Recommendations

Be a healthy weight Be physically active Eat a rich diet in whole grains, vegetables, fruits, and beans Limit consumption of fast foods, and other processed foods high in fat, starches, or sugars Limit consumption of red and processed meat Limit consumption of sugar sweetened drinks Limit alcohol consumption Do not use supplements for cancer prevention For Mothers: breastfeed your baby if you can After a cancer diagnosis: follow our recommendations, if you can

Development of Colorectal Cancer

Duke's A *Cancer Progression: cancer confined to most superficial cell layers of colon or rectum (e.g. the top of the polyp) *90% 5-year survival rate Duke's B *Cancer Progression: Cancer may extend completely through wall of colon or rectum, but there is no lymph node involvement *70% 5-year survival rate 37% of cases diagnosed at Duke's A/B Duke's C *Cancer Progression: Cancer may extend completely through wall of colon or rectum and has spread to lymph nodes *50% 5-year survival rate Duke's D *Cancer Progression: Metastatic disease. The cancer has spread to distant organs, such as the liver. *5% 5-year survival rate 63% of cases diagnosed at Duke's C/D

Inverse Association Observed in Many Studies of Vitamin D and CRC

EPIC Study: nested case-control study of pre-diagnostic serum 25(OH)D and CRC Results: * <25 nmol/L incidence rate ratio 1.32 (95% CI 0.87-1.32) * 25.0-49.9 1.28 (95% CI 1.05-1.56) *50-75 (referent) 1.0 *75.0-99.9 0.88 (95% CI 0.68 - 1.33) *>=100.0 0.77 (95% CI 0.56 - 1.06) "Strong inverse association between 25(OH)D and colorectal cancer risk"

DNA Methylation

Folate Vitamin B6 Methionine Alcohol

Meat Cooking Mutagens

Formed in meats cooked well done at high temperatures Produce tumors in animal models in various organs Heterocyclic Amines (HCAs) *Reaction of amino acids and creatine (DiMelQx, MelQx, PhIP) Polycyclic Aromatic Hydrocarbons (PAHs) *Incomplete combustion Benzo[a]pyrene (B[a]P) marker of PAHs Mutagenic Activity *Ames Salmonella test (strain T98) *Integrated measure of all mutagens

Iron and Heme Iron

Heme iron *red meat Non-heme iron *dairy products and eggs *fruits and vegetables *grains *nuts *iron-fortified food products

Incidence of Colorectal Cancer by Race/Ethnicity and Sex

More common in men Most common in Black individuals followed by American Indian/Alaska Native

Microbiome

Human body is colonized by a vast number of microbes, collectively referred to as microbiota GI tract contains trillions of microorganisms >1000 species *Some common to all of us *Some highly distinct Gut microbiota play a role in digestion, immune system, etc. Composition a function of many things, especially DIET Health effects under intense investigation Decreased microbiota diversity = increased CRC?

Null Outcome in Studies

If we do not observe the expected result, a randomized trial is very difficult to interpret The diet/nutrient is not associated with cancer risk OR has the study yielded a false negative result?

Fiber

Increases fecal weight Increases frequency of defecation Decreases transit time Dilutes colonic contents Produces butyrate and short chain fatty acids *May inhibit tumorigenesis

Fiber and Colorectal Cancer: EPIC Study -2012

Multi-center prospective cohort design aimed at looking at the association between diet, lifestyle, genetic and environmental factors, with cancer Primary endpoint for the EPIC study was resulting colorectal, colon, proximal colon, distal colon, and rectal cancers Study population for EPIC was recruited from a total of 23 study centers in 10 different European countries FFQs have also traditionally not been great for cross-cultural studies because food across countries are generally not comparable. In the EPIC study, researchers trued to adjust for this using a 24-hour dietary recall for calibration *This adjustment resulted in a strengthened inverse association between dietary fiber and colorectal cancer

Fiber and Colorectal Cancer: Polyp Prevention Trial (PPT)

Multi-center randomized control trial aimed at assessing the effect of a comprehensive dietary intervention on the odds of adenoma reoccurrence in the bowels Primary endpoint for the PPT study recurrence of adenomas in the bowl during the interval from the one to four year colonoscopy *adenomatous polyps are thought to be precursors to a majority of large-bowel cancers. *time between when cells are normal and when they start to develop mild dysplasia but are not yet cancerous is an integral time to intervene Completed a four-day food record as well as an FFQ, the Block Health Habits and History Questionnaire (slightly modified to reflect low-fat and high-fiber goals of study) every year. Additionally, participants in the experimental group did a four-day food record 6 months after they had been randomized. Research staff also utilized unscheduled 24-hour dietary recall each year to a random sample of 10% of the participants Biomarkers *Significant increase in serum carotenoid as well as decrease in weight when compared with control individuals while there was no significant difference between groups in total cholesterol change Possible reasons for negative findings: *Despite biomarkers that confirm not completely falsified self-report measurements, it is still possible that participants in the intervention group underreported intake of fat and overreported intake of dietary fiber. *Another possible reason behind these false negative findings is that the targeted dietary fiber change was inadequate to produce the protective result. A greater increase in dietary fiber may have been necessary to produce a finding of protective association between dietary fiber and colon cancer. *Furthermore, a greater time period of dietary intervention may have been necessary to produce this protective association

Plasma Folate, Related Genetic Variants, and Colorectal Cancer Risk in EPIC

Nested case-control study, 1367 cases and 2325 controls NO overall association between MTHFR genotype and colorectal cancer risk In the presence of limited folate, increased activity (CC) is helpful to maintain constant flux through the system In the presence of excess folate, reduced activity (TT) is helpful to maintain constant flux through the system

American Institute for Cancer Research: Recommendations on Red and Processed Meat

Processed Meat *Avoid Red Meat *Limited red meats (like beef, pork, lamb) *To 3 portions per week (12-18 ounces)

The Causes of Cancer by Doll and Peto - 1982

Proportions of Cancer Deaths Attributed to Various Factors Tobacco - 30% Diet - 35% Infection - 10% Occupation - 4% Pollution - 2% Others minor

RCTs of Vitamin D and CRC

Trivedi: UK Trial of 2686 older adults, gave 100,000 IU every 3 months *RR colorectal cancer incidence = 1.02 (0.60, 1.74) WHI: Replicated strong inverse association between baseline 25-OHD and colon cancer risk *Intervention Ca + 400 IU/d Vit D) ONLY suggested to be beneficial in group with <31 nmol/L *Risk non-significantly INCREASED at higher baseline D status