Lise Alschuler, ND, FABNO

1. Altering the Malignant Milieu: Using Dietary and Nutritional Supplements for Prevention and Proactive Survivorship Lise Alschuler, ND, FABNO

2. Questions to answer • Is Cancer inevitable? • Why is cancer more common as we age? • What are the underlying mechanisms of cancer? • Can lifestyle-based strategies impact cancer risk reduction?

3. Let’s start with the stats • In a lifetime 1 in 2 men will develop cancer and 1 in 3 women will develop cancer • Every 60 seconds, someone dies of cancer • According to the World Cancer Research Fund (WCRF) the number of global cancers has increased by a fifth in less than a decade to around 12 million new cases a year. • Cancer diagnoses worldwide are expected to increase by 45% in the next 20 years. • More than 60% of cancer patients will survive more than five years after diagnosis. KellandK, Healthier living could cut 2.8 million cancer cases. Sun, Sep 25, 2011.London (Reuters)

4. Cancer Incidence over age 65 • By the year 2020, it is estimated that between 20% to 25% of the population in the Western world will be aged 65 years or more • According to the National Cancer Institute, >60% of all incident cancers and 70% of all cancer-related deaths occur in patients >65 years of age. Ries L, Kosary C, Hankey B (eds). SEER Cancer Statistics Review, 1975–1995. Bethesda, MA: National Cancer Institute 1998.

5. Cancer Incidence Rates 1993-1997 There is a dramatic increase in cancer risk between the ages of 40 and 80 – primarily due to increases in breast, lung, colon and prostate cancers.

6. The Umbrella of Primary Prevention • Assesses for, and attempts to correct the underlying determinants of carcinogenesis – throughout the cancer continuum Prevention Treatment Carcinogenesis Lifespan No Evidence of Cancer Active Cancer Recurrent Disease No Evidence of Cancer

7. The Determinants: Why does cancer increase as we age? • Aging is characterized by increasing architectural and functional cellular abnormalities that can develop into malignancy • progressively damaged cellular genome • changes in normal gene expression: epimutagenics • genetic instability • loss of differentiation • decreased apoptosis and cell repair • A long history of sub-optimal lifestyle drives malignancy • inflammatory signal transduction • altered stromal integrity • immune dysregulation

8. The deterioration of cell integrity takes decades

9. 9 Cancer: It’s all in the genes… or is it? • True genetic mutations account for only 5% – 10% of all cancers. • So, how does cancer develop? AnandP. Pharmaceutical Research, 2008: 25 (9):2097

10. The origins of cancer Anand P. et al. Pharm Res, 2008; 25(9)

11. Intrinsic carcinogenesis • Our 1014 cells – and their DNA - are continually exposed to genomic injury from: • Spontaneous injury • Oxidative stress as a by-product of cellular metabolism and environmental pollutants • Errors, esp. in rapidly dividing cells • These injuries lead to: • DNA and chromosomal damage • Damaged DNA expression • Damaged mitochondria • Altered apoptosis

12. Cancer Determinant: Chromosomal damage • In the setting of telomere dysfunction and uncapping of chromosome ends, telomeric fusions can occur between sister chromatids. • During anaphase, as sister chromatids are pulled apart, the fused chomosome ends are put under tension and form anaphase bridges. • These pulling forces break chromosomes leading to DNA damage. • Additional uncapped ends causes the cycle to repeat with subsequent cell divisions.

13. Oxidative stress and aneuploidy • Aneuploidy can thus occur from failure of the spindle checkpoint, the safeguard mechanism that halts anaphase onset until mitotic spindle assembly. • Oxidative stress overrides the spindle checkpoint. • It takes approximately 60 cell divisions to form a tumor… • So, depending upon the lifespan of the cell and its doubling time, under on-going oxidative stress, aneuploidy is more likely, however: • If the redox state of the cell is supported with antioxidants, aneuploidy will be reduced, ultimately preserving chromosomal stability and methylation patterns. • Role of lifelong dietary antioxidants: CoQ10, vitamin E (nuts, soy, spinach, seeds), plant flavonoids (green tea, soy, milk thistle, berries, turmeric, etc.) D'AngiolellaV. Cell Cycle. 2007 Mar 1;6(5):576-9.

14. Plant-based diets: key to prevention • Review of 200 studies examining the link between fruit/vegetable intake and cancers of the lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas and ovary. • Protective effect in 128 out of 156 studies in which results were expressed as relative risk. • Lowest quartile of F/V intake experience 2x the risk of cancer compared with those in the highest quartile of intake. Patterson BG et al. Nutr Cancer. 1992;18(1):1-29.

15. Prudent diet and breast cancer risk • Meta-analysis: • Case-control and cohort studies that identified: • prudent/healthy diet (n= 18) • Western/unhealthy diet (n = 17) and • drinker (n = 4) dietary patterns. • In total, 18 studies met the inclusion criteria and were included in the analysis. • Evidence of a 11% decrease in the risk of breast cancer in the highest compared to the lowest categories of prudent/healthy dietary patterns (OR = 0.89; 95% CI: 0.82, 0.99; P= 0.02) in all studies and in pooled cohort studies alone. • Prudent/healthy diets tended to have high quantities of fruit, vegetables, poultry, fish, low-fat dairy and whole grains. Brennan SF, et al. Am J ClinNutr. 2010 May;91(5):1294-302

16. Diet and Prostate cancer risk • Men (n=30,000) who ate more than a serving of vegetables each week had roughly half the risk of developing advanced-stage prostate cancer compared with their peers who ate these vegetables less than once a month. • Men who ate the most veggies had a 49-percent lower risk of being diagnosed with prostate cancer that had advanced to stage III or IV. • Broccoli and cauliflower appeared to have the biggest impact. Men who ate broccoli more than once a week had a 45% lower risk of advanced prostate cancer than those who ate the vegetable less than once a month, while eating cauliflower this often cut risk by 52%. B. Vastag. J Natl Cancer Inst. 2007;99(18):1364-5

17. Mediterranean diet: the best plant-based diet? • Mediterranean diet: • Large quantity and diversity of plant-derived foods: • Whole grains • Raw and cooked vegetables • Fresh and dried fruits • Legumes • Nuts • Fish • Moderate meat and dairy (preferably goat and sheep) • Olive oil • Moderate wine • Diet of southern Italy and Greece around the 1970’s • Mediterranean diet has been found to reduce all-cause mortality and the risk for chronic disease (especially CVD) in the Seven Countries Study when compared to US and northern European diets. Keys A. et al. Am J Epidemiol. 1986;124:903-15.

18. Mediterranean diet add-on: Soy • Soy consumption can reduce the risk of breast cancer. • Women with a history of ER+ breast cancer have a decreased risk of recurrence and decreased risk of dying from breast cancer if they regularly consume soy foods: • >23mg soy (equivalent to 1 glass soy milk or ½ cup tofu) decreases risk of dying from any cause by 9% and reduces risk for breast cancer recurrence by 15% compared to women who do not eat soy. • Prospective cohort study of women receiving adjuvant endocrine therapy. • median follow-up period for the 524 patients in this study was 5.1 years. • Among premenopausal patients, the overall death rate (30.6%) was not related to intake of soy isoflavones • The risk of recurrence for postmenopausal women in the highest quartile of soy intake was 33% lower (HR = 0.67, 95% CI 0.54–0.85, p for trend = 0.02) than in the lowest quartile of soy isoflavone intake. ShuXO, et al. JAMA, 2009 Kang X, et al. CMAJ, 2010

19. Soy and Breast cancer recurrence • Pooled analysis of three studies: Shanghai Breast Cancer Survival Study (SBCSS), the Life After Cancer Epidemiology (LACE) Study, and the Women’s Healthy Eating & Living (WHEL) Study • 9514 breast cancer survivors, dx’ed btw 1991-2006 • Mean follow-up 7.4 years • Consumption of > 10 mg isoflavones/d associated with: • statistically sig reduced risk recurrence HR: 0.75 • non-stat. sig reduced risk all cause mortality HR: 0.0.87 • non-stat sig reduced risk breast-cancer specific mortality HR: 0.83 • Inverse association in Tamoxifen users • HR: 0.63 for > 10 mg vs < 4 mg/d isoflavones • Inverse association with ER neg. survivors slightly stronger than ER+ • HR: 0.64 for >10 mg vs. < 4 mg/d isoflavones Nechuta SJ, et al. American Journal of Clinical Nutrition. 2012 Jul 1;96(1):123-132

20. Don’t forget about Chocolate! • Dark chocolate is a powerful antioxidant. • It shares similar flavonoids compounds to those found in green tea, another potent antioxidant. • Dark chocolate is preferable over milk chocolate, since it has a twice the amount of flavonoids than does milk chocolate • Dark chocolate as a “snack within a balanced diet can improve DNA resistance to oxidative stress in healthy subjects.” • However, the benefit wears off within 22 hours, therefore for long-term and on-going benefit, you must consume dark chocolate daily! Spadafranca A. et al. Br J Nutr. 2010 Apr;103(7):1008-14

21. What about Alcohol? • Women who drink between one and two alcoholic drinks per day increase their relative risk of breast cancer by 10% compared with light drinkers who drink less than one drink a day • 1 drink/d raises a 50y woman’s 5 yr absolute BrCA risk from 3% to 3.45% • Between 3 – 5 drinks/week is associated with reduced all-cause mortality in women • The risk of breast cancer increases by 30% in women who drink more than three drinks a day. • 30% increased risk is the same risk from HRT • 30% increased risk is the same risk from smoking 1 pack cigarettes daily • Red wine = white wine = beer = liquor therefore the risk is attributable to ethyl alcohol • No differences across ethnicities Klatsky, et al., ECCO – The European Cancer Conference 2007, Barcelona, Spain (http://www.fecs.be) Newcomb P. et al. J ClinOncol. 2013;Apr8 (epub ahead of print)

22. Chromosomal Stability: Telomeres Cells with high turnover are the most vulnerable to cancer development – telomeres shorten with each division This is why epithelial cancers are the most common cancers (breast, prostate, lung, colon) This is also one reason why chronic inflammation increases cancer risk – inflamed tissue has higher rate of cell division. Telomerase activity increases with malignant progression as a result of increasing genomic instability

23. Telomeres & Cancer • While telomere elongation is a common molecular feature of advanced malignancies, short telomeres and concurrent chromosomal instability contribute to malignant cell transformation. • Prospective population study of 787 patients without evidence of cancer were followed for 10 years • Baseline telomere length was substantially shorter in participants with incident cancer (mean telomere length, 1.12; 95% CI, 1.01-1.23) than in those who remained free of cancer (mean telomere length, 1.53 [95% CI, 1.47-1.59]; P<001). • Tumors with a high fatality rate tended to exhibit more prominent relationships with telomere length and tumors with a more favorable prognosis showed modest or no associations. Willeit P. et al. JAMA, 2010;304(1):69

24. Cancer and Shortened Telomeres Shortest Shortest Longest Longest

25. Lifestyle factors that shorten telomeres • High perceived stress (with increased urinary output of stress associated Epi. and Norepi.) • Full-time work and longer history of full time work (related to stress) • Sleep deprivation shortens telomeres • Oxidative stress shortens telomeres: • Obesity • Cigarette smoking • Environmental pollution Parks CG, et al. Cancer Epidemiol Biomarkers Prev. 2009 Feb;18(2):551-60. Valdes AM, et al. Lancet. 2005 Aug 20-26;366(9486):662-4.

26. Ornish D, et al.Lancet Oncology, 2013. published online

27. Study Overview • Premise: Prematurely shortened telomere length is associated with chromosomal rearrangements • Follow-up to GEMINAL study which demonstrated that lifestyle changes over 3 mo increased telomerase activity by up to 30%. • Ten men with low-risk prostate cancer under active surveillance + lifestyle change vs. 25 controls (active surveillance only) were evaluated over 5 yrs • PSA <10ug/L, Gleason < 6, stage T1 or T2a tumor and <33% biopsy cores + for disease • Lifestyle change: • Diet high in whole foods, plant-based protein, fruits, vegetables, unrefined grains, legumes, low fat (<10% total calories) • Moderate aerobic exercise (walking 30m/d x 6d/week • Stress management (gentle yoga, breathing, meditation, imagery, progressive relaxation x 60m/day • Increased social support (60 min support-group sessions per week • Peripheral blood mononuclear cells were assessed by PCR for telomere length compared to standard reference DNA and were also assessed for telomerase activity

28. Results For each percentage point increase in adherence score, the average relative telomere length increased by 0·07 T/S units (95% CI 0·02–0·12, p=0·005) after adjustment for age at end of study and length of follow-up. Telomerase did not change – perhaps due to down-regulation after telomeres have stabilized

29. Pessimism and Telomeres Higher pessimism is associated with shorter TL in leukocytes. Pessimism is also associated with higher basal levels of IL-6, an indicator of systemic inflammation (and oxidative stress). Brain Behav Immun. 2009 May; 23(4): 446–449.

30. Other factors affecting telomeres JAMA. 2010;304(1):69-75

31. Cancer Determinant: Epigenetic changes

32. Carcinogenic epigenetic changes Polyphenols, esp. EGCG, inhibit DNA methyltransferaseand decrease SAM (methyl donor) activity ManoharanM. IntBraz J Urol. 2007 Jan-Feb;33(1):11-8.

33. Epigenetic tumorigenesis • Hypomethylation in malignant cells compared with normal cells in the same tissue is one of the first epigenetic alterations in human cancer. • Repetitive DNA sequences are demethylated • This leads to genetic instability and even more hypomethylation as the lesion progresses from benign to invasive cancer. • Hypermethylation of CpG islands in promoter regions of tumor-suppressor genes unique to each tumor type occurs as tumorigenesis progresses. • Decreased: DNA repair, metabolism of carcinogens, cell-to-cell interactions, apoptosis. Cancer Progression Esteller M. NEJM 2008;358(11):1148-59

34. Nutritional influences on epimutagenics Li Y. and T. Tollefsbol. Curr Med Chem. 2010;17(20):2141-2151

35. Epigenetic to genetic alteration Primed Cancer initiated Genetic mutations Epigenetic change Apoptosis Epigenetic change Further DNA mutations and epigenetic changes Normal cells Cancer initiated Apoptosis Genetic mutations Cancer initiated Cancer progression 35

36. Dietary apoptogens • Trans-resveratrol from grapes, peanuts, berries, and red wine activate p53. • Garlic derivative S-allylmercapto-L-cysteine induces p53 activated caspase activity and apoptosis. • Genistein, curcumin and melatonin each activate p53 induced apoptosis. • Curcumin upregulates p53. • Genistein, Vitamin D, Vit. E and resveratrol also stimulate p53 independent apoptosis. M. Alkhalaf, Pharmacology 2007;80:134-143 Y. Lee, Int J Mol Med. 2008 Jun;21(6):765-70 Sanchez-Barcelo EJ, Recent Pat EndocrMetab Immune Drug Discov. 2012;6(2):108. D.Vauzour, et al. Arch BiochemBiophys. 2007;468(2):159-66. A. Goel, et al. BiochemPharmacol. 2008;75(4):787-809

37. Cancer Determinant: Mitochondrial Health • Healthy mitochondria in premalignant and healthy cells restore cellular redox status, eliminate glycolysis, cause apoptosis in the face of overwhelming oxidative stress, and facilitate a differentiated state. • Damaged mitochondriafavor aerobic glycolysis, resulting in reduced glutathione-mediated antioxidation and perpetuation of uncoupling. • Thus, mitochondrial protection with antioxidationis an important component of cancer prevention. Seyfried T and L Shelton. Nutrition & Metabolism, 2010;7:7

38. Mitochondrial uncoupling X Glycolysis 2 Pyruvate Coenzyme A +LDH Uncoupling TCA cycle Lactic acid 2ATP Mitochondrial membrane damage HIF Electron transport chain Oxidative stress 34-36 ATP Cytosol Mitochondria

39. Sources of mitochondrial damage • Oxidative stress • Mitochondria are loaded with glutathione to handle the superoxides and H2O2 generated from oxidative phosphorylation. • However, too much ROS will outpace glutathione. Causes: • Macronutrient overload (overconsumption): eating a lot of food, but lack of energy = mitochondrial dysfunction • Hyperglycemia • Excess fructose • Saturated fat • Advanced GlycationEndproducts (protein exposed to high heat and/or sugar) • Inflammation • Hypoxia • Environmental toxins (especially bisphenol-A) • Toxic metals • Ionizing radiation • Medications (statins inhibit mitochondrial biogenesis leading to increased ROS)

40. Building Healthy Mitochondria • Exercise and Movement: restores mitochondrial dynamics and builds mitochondria • Exercise is cancer preventative • Meta-analysis (27 observational studies published between 1950 and 2011): Consistent evidence that physical activity is associated with reduced risk (41% - 61%) of all-cause, breast and colon cancer specific mortality. • Physical activity improves quality of life of people diagnosed with cancer. • Exercise reduces obesity, now characterized as an independent risk factor for cancer Ballard-Barbash R, et al. J Natl Cancer Inst 2012;104:815-840

41. Exercise and Breast Cancer • Meta-analysis of prospective studies examining the relationship between exercise and breast cancer risk. • Overall, 31 studies with 63,786 cases were included • The overall association between physical activity and breast cancer risk was RR= 0.88 (CI=0.85–0.91). • Stronger inverse associations were found for subjects with BMI<25 kg/m2 [0.72 (0.65–0.81)], premenopausal women [0.77 (0.72–0.84)], and estrogen and progesterone receptor-negative breast cancer [0.80 (0.73–0.87)]. • Vigorous exercise reduced BrCA risk more than moderate activity [RR = 0.86 (0.82-0.89) vs. RR = 0.97 (0.94-0.99)] • The risk of breast cancer, in relationship to exercise intensity, decreased by: • 2% (P < 0.00) for every increment of 10h light household activity (= 25 metabolic equivalent (MET)-h) per week in non-occupational physical activity • 3% (P < 0.00) for every 4 h/week of walking at 2 miles/h or 1 h/week of running at 6 miles/h (= 10 MET-h/week) increment in recreational activity • 5% (P < 0.00) for every 2 h/week increment in vigorous recreational activity Wu Y. et al. Breast Cancer Res Treat. 2012; Feb;137(3):869-82.

42. Exercise and Breast CA Mortality risk • Data over a median of 23 months post-diagnosis (interquartile range 18–32 months) were pooled in the After Breast Cancer Pooling Project (n = 13,302). • 2.5 h (10 MET-hours/week) of moderate intensity physical activity per week was associated with: • 27% reduction in all cause mortality (n = 1,468 events, Hazard Ratio (HR) = 0.73, 95% CI, 0.66–0.82) • 25% reduction in breast cancer mortality (n = 971 events, HR = 0.75, 95% CI 0.65–0.85) • compared with women who did not meet the physical activity Guidelines (<10 MET-hours/week). Beasley JM, et al. Breast Cancer Res Treat. 2012 Jan;131(2):637-43

43. Exercise and Breast cancer • Women who engaged in the equivalent of at least two to three hours of brisk walking each week in the year before they were diagnosed with breast cancer were 31% less likely to die of the disease than women who were sedentary before their diagnosis. [multivariable hazard ratios (HR) = 0.69 (95% CI, 0.45 to 1.06; P = .045)] • Women who increased physical activity after diagnosis had a 45% lower risk of death (HR = 0.55; 95% CI, 0.22 to 1.38) when compared with women who were inactive both before and after diagnosis • Women who decreased physical activity after diagnosis had a four-fold greater risk of death (HR = 3.95; 95% CI, 1.45 to 10.50). Irwin et al. J ClinOncol. 2008 Aug 20;26(24):3958-64.

44. Dynamic Duo: Exercise and Diet • A combination of 5-6 servings of vegetables/d and exercise equivalent to walking 30m 6 days/week (540 MET) reduced the risk of death from breast cancer by 44% among early stage breast cancer patients (hazard ratio, 0.56; 95% CI, 0.31 to 0.98). Pierce, et al. Journal of Clinical Oncology. 2007;25 (17):2345-41

45. Exercise and Colon cancer • From a cohort of adults without colorectal cancer at baseline in 1992-1993, 2,293 participants were diagnosed with invasive, nonmetastatic colorectal cancer up to mid-2007. • Mean follow-up time from diagnosis to death or end-of-study was 6.8y • Participants completed detailed questionnaires that included information concerning recreational physical activity and leisure time spent sitting at baseline, before their cancer diagnosis, and again after their cancer diagnosis. Campbell P. et al. J ClinOncol. 2013; Mar 1;31(7):876-85

46. Results • The highest prediagnosis recreational physical activity category (8.75 or more MET hours per week = >150min/week) compared with the lowest category (3.5 MET hours per week) was associated with a 28% lower risk of all-cause mortality. • The same comparison for postdiagnosis recreational physical activity resulted in an RR of 0.58. • In cause-specific mortality analyses, only the results for CVD mortality were statistically significant (prediagnosis RR, 0.60; postdiagnosis RR, 0.36). • Leisure time spent sitting of 6 or more hours per day on the prediagnosis survey was associated with a statistically significant 36% higher risk of all-cause mortality. • Postdiagnosis sitting time was associated with a statistically significant 62% higher risk of colorectal cancer–specific mortality and a nonstatistically significant higher risk of CVD mortality. • This study supports recommendations for recreational physical activity and the avoidance of sedentary time among colorectal cancer survivors.

47. Exercise and Prostate cancer • Health Professionals Follow-up Study, a prospective cohort study of 47,620 US male health professionals, followed up from February 1, 1986, to January 31, 2000. • In men 65 years or older, a lower risk in the highest category of vigorous activity was observed for advanced (RR=0.33; 95% CI, 0.17-0.62) and for fatal (RR=0.26; 95% CI, 0.11-0.66) prostate cancer. • No associations were observed in younger men. • Regular vigorous activity may slow the progression of and reduce mortality from prostate cancer. • Giovannucci EL, et al. Arch Intern Med 2005 May;165(9):1005-1010

48. Building Healthy Mitochondria • Caloric restriction: upregulates PCG-1alpha which activates PPARγ to increase glucose metabolism and decreases Insulin to reduce glucose influx and IGF-1 to reduce proliferation stress • Cruciferous vegetables: (Glucoraphanin, precursor to Sulforaphane) increase fatty acid B-oxidation and Ox Phos • Acetyl-L-carnitine: Increases β- oxidation of fatty acids and also regulates key enzymes involved in glycolysis. • Berberine: PPAR agonist

49. Building health mitochondria • CoQ10 (as ubiquinol): integral component of the electron transport chain; modulates mitochondrial permeability • Riboflavin: key factor in electron transport protein function and co-factor in fatty acid oxidation and krebs cycle • Alpha lipoic acid: Studies performed in rats have also shown that supplementation with alpha-lipoic-acid and acetyl-L-carnitine reduce oxidative stress and improve mitochondrial function. • N-acetyl cysteine: functions as a powerful antioxidant and prevents the induction of MCT4 (marker of oxidative stress and glycolysis) expression in stromal fibroblasts that were co-cultured with MCF7 cells Parikh, S. et al. Curr Treat Options Neurology. 2009;11:414-430.

50. Mitochondrial antioxidation: Glutathione • The risk of oral cancer is reduced by more than 50 percent in individuals with the highest blood levels (>5.9mmol/g Hb) of glutathione compared to those with the lowest levels (<4.9mmol/g Hb). • Men and women who consumed the greatest daily amount of glutathione in their diet (50 to 242 mg) had a more than 50 percent reduction in their risk of developing pharyngeal cancer compared to those with the lowest intake (5mg-33mg). • Low levels of glutathione have also been linked to the development of cancers of the colon, prostate, breast, and bladder. • Note: Glutathione is CONTRAINDICATED DURING ACTIVE RADIATION THERAPY AND MOST CHEMOTHERAPY TREATMENTS Flagg EW, et al. American Journal of Epidemiology 139(5):453-65, Mar 1994. Schwartz, JL, Shklar, G. Nutr Cancer 26:229-36, 1996.