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Nutrition and Cancer Prevention Jackilen Shannon, PhD, RD.

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1 Nutrition and Cancer Prevention Jackilen Shannon, PhD, RD

2 Overview Historical perspective ◦ Population data to molecular mechanisms Diet and Breast Cancer ◦ What is the evidence? ◦ Overview of findings from Shanghai ◦ Future research directions Challenges and future directions in Nutrition and Cancer Prevention Research

3 Yong-He Yan Poor nutrition a cause for esophageal cancer AD Wiseman - cancer may arise from “ an errour in Diet, a great acrimony in the meats and drinks meeting with a fault in the first Concoction (digestion)” – advised abstention from ‘salt, sharp and gross meats’ John Snow tracks source of Cholera outbreak Roger Williams ‘probably no single factor is more potent in determining the outbreak of cancer in the predisposed, then excessive feeding’ citing specifically, ‘deficient eating and probably lack of sufficient vegetable food’. (The Natural History of Cancer) World War I Frederick Hoffman (founder of ACS) - concluded from a systematic literature review ‘excessive nutrition if not the chief cause is at least a contributory factor of the first importance’ 1937 Great Depression World War II 1492 Columbus “discovers” America Watson & Crick publish the structure of DNA 1953

4 Population studies: Correlational results Armstrong B, Doll R. Int J Cancer 1975; 15: – correlational study of incidence of 27 cancers in 23 countries and dietary intake.

5 Further Evidence: Case-Control and Cohort Studies Doll and Peto (1981) 35% of cancer deaths may be attributed to dietary factors Doll R, Peto R. The causes of cancer. JNCI 1981; 66: World Cancer Research Fund (1997) Cancer incidence can be reduced by 30%-40% with diet, physical activity and appropriate body size. World Cancer Research Fund,. Food, Nutrition and the Prevention of Cancer: a Global Perspective. Washington DC (USA): American Institute for Cancer Research; 1997:

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7 EXCRETION Bioactive dietary constituents B-vitamins, glutathione, flavonoids Alcohol Smoking Genes Phase I metabolizing enzymes P450’s etc. Bioactive dietary constituents Isothiocyanate, selenium, other phytochemicals Phase II metabolizing enzymes  glutahione, glutathione transferase, N-acetyl transferases Genes Dietary Carcinogens Aflotoxin, heterocyclic amines N-nitroso compounds Procarcinogen Ultimate carciongen Smoking, chewing tobacco, betel Workplace Role of Diet in the Cancer Process - Metabolism & Excretion of Carcinogens Block metabolic activation Increase metabolic detoxification

8 NORMAL DNA Physical Activity Energy Intake DNA Repair Genes Somatic alteration of oncogenes, Tumour-suppressor genes and DNA repair genes DNA adducts Folate Deficiency Inadequate Methyl groups Hypomethylation of P53 Role of Diet in the Cancer Process – Initiation PhiP Heterocyclic Amines

9 REDIFFERENTIATION APOPTOSIS Fibre Volatile fatty acids Colonic Bacteria  Physical Activity  Energy  Fat Obesity Dietary factors  Protein  Methionine  Cholesterol Hormones Growth factors Specific nutrients e.g. carotenoids, retinol Abnormal DNA & cell replication Precancerous lesions & dysplasia Genes  -3 fatty acids Phytoestrogens Role of Diet in the Cancer Process – Promotion

10 DNA Repair Genes DNA Damage Immune System Growth factors Hormones Dietary factors DNA Damage Smoking & other exposures DNA Repair Genes Precancerous lesions & dysplasia Cancer Metastasis Less work in this area Some of the same factors that function in initiation Role of Diet in the Cancer Process – Progression

11 Diet in the Cancer Process Procarcinogen Ultimate carcinogen Precancerous lesions & dysplasia Cancer Metastasis Dietary Carcinogens, heterocyclic amines, amines, PAHs Somatic alteration of oncogenes,Tumour- suppressor genes and DNA repair genes DNA adducts Abnormal DNA & cell replication Isothiocyanate, selenium, other phytochemicals B-vitamins, glutathione, flavonoids Folate Deficiency Hypomethylation of P53 Obesity  Protein  Methionine  Cholesterol Specific nutrients e.g. carotenoids, retinol  -3 fatty acids Phase I metabolizing enzymes Phase II metabolizing enzymes Hormones & Growth Factors Redifferentiation Apoptosis Physical Activity

12 Specific Dietary Factors Associated with Breast Cancer Risk Fruits and Vegetables. Total Fat Red Meat Phytoestrogens.

13 Fruits and Vegetables and Breast Cancer Risk Biologic Mechanism – ◦ Unclear – but thought to be primarily due to antioxidants (phytoestrogens (lignans), other biochemical substance) ◦ Phytochemicals have been shown to induce detoxifying (Phase II) enzymes. ◦ May also function later in cancer process – redifferentiation (promotion) Epidemiologic Evidence: ◦ Strong correlational evidence ◦ Case-control studies – Probable ◦ Cohort studies – inconsistent Procarcinogen Ultimate carcinogen Precancerous lesions & dysplasia Cancer Metastasis Somatic alteration DNA adducts Abnormal DNA & cell replication Folate Deficiency Hypomethylation of P53 B-vitamins, glutathione, flavonoids Phase I metabolizing enzymes Isothiocyanate, selenium, other phytochemicals Phase II metabolizing enzymes Specific nutrients e.g. carotenoids, retinol Redifferentiation

14 Epidemiologic Evidence Recent cohort studies have cast doubt- ◦ Pooling project  8 cohort studies  No evidence of a protective effect ◦ EPIC (8 European countries)  285,526 women, 5.4 years follow- up  Vegetables, OR = 0.98 (95% CI, )  Fruit, OR=1.09 (95% CI, ) Meta-analysis of 15 Case-control and 10 Cohort studies. Change in Breast Cancer risk with each additional 100g intake. OR (95% CI) Riboli E, Norat T. Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk. Am J Clin Nutr 2003;78(suppl):559S–69S. Smith-Warner SA, Spiegelman D, Yaun SS, et al. Intake of fruits and vegetables and risk of breast cancer: a pooled analysis of cohort studies. JAMA. 2001; 285: Van Gils C, Peeters PHM et al. Consumption of Vegetables and Fruits and Risk of Breast Cancer. JAMA. 2005;293:

15 Evidence for the Role of Fat in Breast Carcinogenesis Animal evidence: 1940’s Tannenbaum: ◦ Kcal restricted = ↓ mammary tumors ◦ ↑ fat diet = ↑ mammary tumors. ◦ Indirectly impacts breast cancer risk through altering hormonal pathways 1997 Fay & Freedman – Meta- analyses of animal studies. ◦ Similar findings, still unclear if effect is due to fat, calories, type of fat etc… ◦ Indirect impacts of fat on –  Calories  Protein  Meat  F&V  Body size Procarcinogen Ultimate carcinogen Precancerous lesions & dysplasia Cancer Metastasis Dietary Carcinogens, heterocyclic amines, amines, PAHs Somatic alteration DNA adducts Abnormal DNA & cell replication Obesity  Protein  Methionine  Cholesterol Hormones & Growth Factors  -3 fatty acids Apoptosis High Fat – High Meat High Fat  -6 fatty acids Lipid peroxidation

16 Dietary Fat and Breast Cancer Risk Epidemiologic Evidence: Since 1996 nearly 500 articles have been published on fat intake and breast cancer risk in humans. ◦ Strongest evidence of an association from correlational studies ◦ Inconsistent evidence from case-control studies ◦ No association found in cohort studies

17 Red Meat and Breast Cancer Biologic Mechanism: ◦ Directly- May contribute procarcinogens –  heterocyclic amines- through overcooking  N-nitroso compounds (proteins) ◦ Indirectly – Associated with high fat and energy intake. Epidemiologic Evidence: ◦ Strong correlational evidence ◦ Case-control studies – inconsistent ◦ Cohort studies – inconsistent –  pooling project found no association

18 Soy and Breast Cancer Risk Soy products are high in phytoestrogens ◦ Competitive binding of the estrogen receptor ◦ Increase production of SHBG and thus reduce free estrogen ◦ Decrease cell proliferation and induce apoptosis Majority of evidence comes for ecologic and in vitro studies. Epidemiologic studies- ◦ Inconsistent findings, but few large long-term studies. ◦ Two recent case-control studies suggest assoc. with intake in adolescence ◦ Little evidence of an increased risk

19 What is the important time of intake? ◦ BC and height (growth) What is the correct nutrient/ food to measure? ◦ Oils? Monounsaturated vs. Poly ◦ -3 vs.  -6 ◦ All phytoestrogens v. Isoflavones v. Lignan Foods vs. Nutrients ◦ Fruits and Vegetables v. Carotenoids Why the conflicting findings?

20 The Nutrition Study ( ) Primary Aim: To determine if increased risk of breast cancer is associated with high consumption of fat and red meat, and low consumption of soy, and fruits and vegetables. Randomized Trial of Breast Self Examination (BSE) Cell Proliferation Study (CPS) Reproductive Health Study

21 What can be learned from the Shanghai analysis? Potential for greater variation in total fat and soy intake. Proposed dose response association between dietary exposures and cancer risk. McMichael A, Potter J. JNCI 1985 Soy exposure in Western studies Soy exposure in proposed study Soy Foods Exposure low high Cancer Incidenc e Rate

22 What can be learned from the Shanghai analysis? Variation in meat consumption (heme iron) with greater intake of organ meats. Higher consumption of particular types of vegetables (e.g leguminosae, cruciferea) than seen in Western populations.

23 The Shanghai Nutrition Study ◦ Primary Aim:  To determine if increased risk of breast cancer is associated with high consumption of fat and red meat, and low consumption of soy, and fruits and vegetables in a population of women in Shanghai, China.

24 Nutrition Study Design Biopsy Women Recruited into the Breast Self-Examination Study ( ) (n= 266,064) Recruit and Interview Women with Breast Biopsies into The Cell Proliferation Study ( ) Complete FFQ & blood draw (n=703/ 862) Malignant (n=378/ 436) Complete FFQ & blood draw Select Controls from unaffected cohort Complete FFQ & blood draw (n=367) Fibrocysitic (n=551/ 622) Fibroadenoma (n=327) Recruit and Interview Women for The Diet Study ( ) Select Controls from unaffected cohort Benign (n=949+)

25 Food Frequency Questionnaire Modified from a validated NCI questionnaire used previously in Shanghai. 24- hour recall portion was added. Reviewed by colleagues in Shanghai Portion size section was dropped Added items regarding dietary change, supplement and herbal remedy use.

26 The Food Frequency Questionnaire

27 Dietary Assessment Interviewers were trained by J. Shannon Pilot dietary data were collected from 100 retrospective cases. Reviewed for face validity

28 Blood specimens Pre-biopsy blood specimens were collected. Processed for assessment of antioxidants, fatty acids & DNA Stored in Shanghai

29 Analyses Daily intake was determined using the reported frequency and average portion sizes reported on the Chinese Health and Nutrition Survey (1993). Individual food intake converted to intake per month. Groupings created based on traditional food groups and botanical groups.

30 Analyses cont. Food group intake converted from continuous variable to categories of intake- based on control group consumption. Why group foods and create categorical variables for intake??

31 Analyses cont. Association between food groupings and breast cancer risk modeled using conditional logistic regression stratified by year of interview. ◦ ODDS RATIOS (OR) and 95% Confidence Interval All foods models adjusted for age and total energy, botanical models adjusted for age and total fruits and vegetables. Covariates considered for inclusion (maintained in model if change OR >10%) Only duration of breast feeding maintained. Trend OR determined entering category score as a continuous variable and using Wald test of significance.

32 Blood analyses Isoflavones (Daidzein/ Genestein) -- liquid chromatography-coularray method (LC-coularray) and liquid chromatography-mass spectrometry (LC-MS) RBC fatty acids analyzed by FHCRC. Membrane Percent of individual Fatty Acids was determined. Levels of fatty acid groups (e.g. total omega-3) were calculated. Ratio groups were calculated – ◦ Omega-3:omega-6, Saturation index (Palmitic: Palmitoleic and Stearic:Oleic)

33 Associations with Reported Dietary Intake Trend OR and 95% CI for Each quartile Vs. next lowest quartiles of food groups Conditional Logistic regression adjusted for age, total energy and breastfeeding Milk Total Meat Eggs Seafood Soyfood Vegetables Rice Cured foods Fruits Fried foods Desserts Trend OR (95%CI) Shannon J, Ray RM, Wu C, Nelson ZC, Gao DL, Li GD, Wei HY, Lampe JW, Horner N, Abouta JS, Patterson R, Fitzgibbons ED, Thomas DB. Food and botanical groupings and risk of breast cancer: Cancer Epidemiol Biomarker & Prev 2005;14:81-90.

34 Summary of Questionnaire Findings A diet high in fruits and vegetables may be protective against breast cancer. ◦ The association does not appear to be due entirely to any single botanical group assessed. Egg intake may be protective against breast cancer but difficult to determine what we are actually measuring. We found no association between soy food intake and breast cancer risk in this population of high soy consumers.

35 Odds ratios (OR) and 95% confidence intervals (CI) of fibrocystic breast conditions and breast cancer in relation to quartiles of plasma daidzein and genistein concentrations. *missing data were excluded in the analysis†adjusted for age and isoflavone analysis method and stratified by year of blood draw‡ futher adjusted for the status of proliferative changes Lampe JW, Nishino Y, Ray RM, Wu C, Li W, Lin MG, Gao DL, Hu Y, Shannon J, Stalsberg H, Porter PL, Frankenfeld CL, Wähälä K, Thomas DB.Plasma isoflavones and fibrocystic breast conditions and breast cancer among women in Shanghai, China. Cancer Epidemiol Biomarkers Prev Dec;16(12):

36 OR and 95% CI for Highest Vs. Lowest Quartiles of RBC Fatty Acid. Conditional logistic regression, adjusting for age, stratified by year of interview. Shannon J, King IB, Lampe JW, Gao DL, Ray RM, Lin M-G, Stalsberg H, Thomas DB. Erythrocyte fatty acids and risk of proliferative and non-proliferative fibrocystic disease in women in Shanghai, China. Am J Clin Nutr. 12/2008; e-pub, ahead of print.

37 Summary of RBC Fatty Acid Findings Normal Fibroadenoma Non-Proliferative FCD Invasive Cancer Proliferative FCD with & without Atypia ↓ risk with total n-3 PUFA, specifically EPA 2. No association with n-3 or n ↓ risk with ↑ total n-3 PUFA, specifically EPA 4. ↓ risk with total n-3 PUFA, specifically EPA, DHA, n3:n6 ratio DCIS

38 OHSU Cancer Institute – pilot funding OCTRI / CTRC Resources EPIC Imaging Collaborators Amy Thurmond Judith Richmond Maureen Filipek OHSU Co- Investigators John Vetto Philippe Thuillier Shannon McWeeney Rosalie Sears OHSU Comprehensive Breast Cancer Clinic

39 Aim 1: Determine the effect of purified fish oil supplementation (75% EPA / DHA) on markers of cancer progression in women newly diagnosed with DCIS. Aim2a: Determine the effect of n-3 fatty acids on the targets identified in Aim 1 in breast cancer cells. Aim 2b: Establish the effect of n-3 fatty acids on the targets identified in Aim 1 in primary cultures from benign and malignant human mammary tissue.

40 Treatment/ Intervention: ◦ ~2 week supplementation with 2.0 gram EPA/ DHA (ROPUFA 75) or placebo. Analyses for Primary Endpoints: ◦ Pre- post changes in erythrocyte and NAF fatty acid levels ◦ Pre- post changes in gene expression using genome wide array ◦ Pre- post changes in c-myc phosphorylation and stem cell markers.

41 Table 3.0. Schedule of Events (w-3 FA and DCIS/ADH) STUDY VISITS Test/ Procedure Pre- Trial Baseline/ Registration Visit Week 1 Week 2 Week 3 Week 4 Weeks 5-8 Surgery 1 or Post- Intervention Appt Study Follow- up Initial Biopsy (request tissue sample) X Screening X Eligibility (Incl./ Excl. Criteria) XX Informed Consent X Randomization X Height, weight, blood pressure XX Research Specimens: Plasma, Serum, Urine, Nipple Aspirate XX Confirm eligibility: Urine HcG test X Diet & Family History Questionnaire X Questionnaire: Adverse Events XXXXXXXX Questionnaire: Changes to Diet and Medications XXXXXXX Questionnaire: Placebo/Supplement X Study Supplement Dispensed XX* * Supplements to be provided only if surgery is delayed due to non-study related concerns 1 Request tissue sample if surgery is completed

42 Inclusion criteria: Biopsy confirmed diagnosis of any of the following: ◦ DCIS or ADH or both ◦ DCIS with a component of invasive carcinoma ◦ ADH with a component of invasive carcinoma ◦ DCIS and ADH with a component of invasive carcinoma Age over 21 years (no upper age limit) English or Spanish speaking Female patients Exclusion criteria: Using therapeutic anticoagulation Pure invasive breast cancer on biopsy without a component of DCIS or ADH Pregnancy (as determined by urine hCG test) Male patients Patient reported allergy to fish oil or olive oil Patient reported current use of fish oil greater than 1 gram per day Any condition which, in the opinion of the study clinician, would make participation in the study harmful to the subject

43 Recruit and randomize 40 women

44 Challenges in Diet and Cancer Prevention Research The role of genetic variation. Incomplete knowledge of compounds in foods. Difficulty in capturing “true” dietary intake. A constantly changing food supply.

45 Bridging the disciplines Case-control Cohort Correlational Population Studies In Vitro Animal Studies Laboratory Studies Human Trials Randomized Clinical Trials Intervention Studies

46 What Next? Green Tea Nutrient Supplements Soy


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