The Role of Dietary Interventions and Dietary Supplements in Breast Cancer Management

1. The Role of Dietary Interventions and Dietary Supplements in Breast Cancer Management Cynthia Thomson, PhD, RD Associate Professor Nutritional Sciences, Public Health, and Medicine University of Arizona cthomson@u.arizona.edu

3. ESTIMATED # OF PERSONS ALIVE DIAGNOSED W/CANCER: BY SITE

4. “AT RISK”: LIFESTYLE MODULATION OF BREAST CANCER RISK New York Breast Cancer Study Lifetime risk among female BRCA mutation carriers: 82% Delayed onset among probands was demonstrated for: Physically active during adolescence Healthy weight at menstruation onset Healthy weight at age 21 Implies lifestyle can modify risk in “at-risk” subjects

5. WEIGHT AND BREAST CANCER: KEY ISSUES Higher BMI associated with increased risk of breast cancer after menopause Higher BMI in childhood, pre-menopausal associated with decreased risk Weight change over adulthood Weight gain of 21 kg over adult life has been associated with an almost 75% increase in risk for developing breast cancer Inconsistent: weight and risk of recurrent disease

6. WEIGHT GAIN DURING TREATMENT Women who gain weight during treatment have reduced long term survival Less of an issue with current treatment Unique weight gain – significant gain in body fat and loss of lean mass (sarcopenia) Change from baseline may be most significant factor Evidence of reduced REE (metabolism) during treatment Interventions focused on diet and physical activity have proven successful to prevent weight gain: If exercise is included Best with regular RD counseling (face-to-face)

7. BODY COMPOSITION CHANGE AFTER DIAGNOSIS OF BREAST CANCER Compounding the problem of weight gain, is that of body composition change. This slide depicts body composition changes observed after the diagnosis of breast cancer, with data plotted for patients receiving adjuvant chemotherapy (CT-solid lines) vs. those receiving localized treatment only (surgery+radiation therapy-XRT-dashed lines). The yellow lines feature gains in adipose tissue, and the pink lines depict change in lean mass. Data show that patients who receive CT lose lean body mass as they gain weight. Given that gains in weight are usually comprised of one-fourth to one-third lean mass, this is a unique pattern of weight gain termed “sarcopenic obesity.” This pattern also is observed with prolonged inactivity, Cushing’s disease, and with menopause and aging. The changes in body composition observed among patients with breast cancer who receive CT are comparable to 10-years of normal aging and appear independent of weight gain (thus, data support clinical observations or patient complaints of weight gain (outgrowing clothes), even though changes in weight may be negligible. These findings are corroborated by most studies in this area and also are mirrored by studies in other cancers (prostate, non-small cell lung cancer, and acute lymphoblastic leukemia) and other treatments (hormone therapy and cranial radiation). Theoretically, these decreases in lean mass should result in decreases in metabolic rate; however, findings are mixed and could relate to insensitive technology or the possibility that increases in fat mass offset decreases resulting from losses in lean tissue. References Del Rio G, Zironi S, Valeriani L, et al. Weight gain in women with breast cancer treated with adjuvant cyclophosphomide, methotrexate and 5-fluorouracil. Analysis of resting energy expenditure and body composition. Breast Cancer Res Treat. 2002;73:267-273. Demark-Wahnefried W, Peterson BL, Winer EP, et al. Changes in weight, body composition, and factors influencing energy balance among premenopausal breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol. 2001;19:2381-2389. Freedman RJ, Aziz N, Albanes D, et al. Weight and body composition changes during and after adjuvant chemotherapy in women with breast cancer. J Clin Endocrinol Metab. 2004;89:2248-2253. Harvie MN, Howell A, Thatcher N, et al. Energy balance in patients with advanced NSCLC, metastatic melanoma and metastatic breast cancer receiving chemotherapy — a longitudinal study. Br J Cancer. 2005;92:673-680. Smith MR. Changes in body composition during hormonal therapy for prostate cancer. Clin Prostate Cancer. 2003;2:18-21. Review. Warner JT, Evans WD, Webb DK, et al. Body composition of long-term survivors of acute lymphoblastic leukaemia. Med Pediatr Oncol. 2002;38:165-172.   Compounding the problem of weight gain, is that of body composition change. This slide depicts body composition changes observed after the diagnosis of breast cancer, with data plotted for patients receiving adjuvant chemotherapy (CT-solid lines) vs. those receiving localized treatment only (surgery+radiation therapy-XRT-dashed lines). The yellow lines feature gains in adipose tissue, and the pink lines depict change in lean mass. Data show that patients who receive CT lose lean body mass as they gain weight. Given that gains in weight are usually comprised of one-fourth to one-third lean mass, this is a unique pattern of weight gain termed “sarcopenic obesity.” This pattern also is observed with prolonged inactivity, Cushing’s disease, and with menopause and aging. The changes in body composition observed among patients with breast cancer who receive CT are comparable to 10-years of normal aging and appear independent of weight gain (thus, data support clinical observations or patient complaints of weight gain (outgrowing clothes), even though changes in weight may be negligible. These findings are corroborated by most studies in this area and also are mirrored by studies in other cancers (prostate, non-small cell lung cancer, and acute lymphoblastic leukemia) and other treatments (hormone therapy and cranial radiation). Theoretically, these decreases in lean mass should result in decreases in metabolic rate; however, findings are mixed and could relate to insensitive technology or the possibility that increases in fat mass offset decreases resulting from losses in lean tissue. References Del Rio G, Zironi S, Valeriani L, et al. Weight gain in women with breast cancer treated with adjuvant cyclophosphomide, methotrexate and 5-fluorouracil. Analysis of resting energy expenditure and body composition. Breast Cancer Res Treat. 2002;73:267-273. Demark-Wahnefried W, Peterson BL, Winer EP, et al. Changes in weight, body composition, and factors influencing energy balance among premenopausal breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol. 2001;19:2381-2389. Freedman RJ, Aziz N, Albanes D, et al. Weight and body composition changes during and after adjuvant chemotherapy in women with breast cancer. J Clin Endocrinol Metab. 2004;89:2248-2253. Harvie MN, Howell A, Thatcher N, et al. Energy balance in patients with advanced NSCLC, metastatic melanoma and metastatic breast cancer receiving chemotherapy — a longitudinal study. Br J Cancer. 2005;92:673-680. Smith MR. Changes in body composition during hormonal therapy for prostate cancer. Clin Prostate Cancer. 2003;2:18-21. Review. Warner JT, Evans WD, Webb DK, et al. Body composition of long-term survivors of acute lymphoblastic leukaemia. Med Pediatr Oncol. 2002;38:165-172.  

8. PROPOSED MODEL TO EXPLAIN WEIGHT GAIN IN BREAST CANCER This slide depicts a proposed model to explain the weight gain that occurs with adjuvant chemotherapy for breast cancer. The model includes the contribution of decreased physical activity (as observed in several studies) and also factors in decreased energy needs. Because recent studies have failed to observe changes in caloric intake, this model includes a stable (uncompensated) energy intake with the net result being weight gain. To illustrate this model, let’s use the example of a 42-year-old woman who has just been diagnosed with stage II breast cancer and is being treated with adjuvant chemotherapy. As a result, ovarian function is diminished and, in turn, lean body or muscle mass is reduced (concomitant increases fat mass), which then affects metabolic rate. Another likely event is a decrease in the level of physical activity, which also negatively affects muscle mass (and metabolic rate), and directly reduces energy needs. Therefore, to avoid weight gain, patients either have to reduce their normal calorie intake or, because losses of muscle mass and reduced physical activity are truly the root causes of this problem, increase exercise — especially exercises that preserve muscle mass (resistance training). With the exclusion of ovarian function, this model can be modified to explain the effects of other forms of treatment on other cancers.   References Demark-Wahnefried W, Hars V, Conaway M, et al. Reduced rates of metabolism and decreased physical activity in breast cancer patients receiving adjuvant chemotherapy. Am J Clin Nutr. 1997;65:1495-1501. Demark-Wahnefried W, Rimer BK, Winer EP. Weight gain in women diagnosed with breast cancer. J Am Diet Assoc. 1997;97:519-526. Review. Harvie MN, Campbell IT, Baildam A, et al. Energy balance in early breast cancer patients receiving adjuvant chemotherapy. Breast Cancer Res Treat. 2004;83:201-210.This slide depicts a proposed model to explain the weight gain that occurs with adjuvant chemotherapy for breast cancer. The model includes the contribution of decreased physical activity (as observed in several studies) and also factors in decreased energy needs. Because recent studies have failed to observe changes in caloric intake, this model includes a stable (uncompensated) energy intake with the net result being weight gain. To illustrate this model, let’s use the example of a 42-year-old woman who has just been diagnosed with stage II breast cancer and is being treated with adjuvant chemotherapy. As a result, ovarian function is diminished and, in turn, lean body or muscle mass is reduced (concomitant increases fat mass), which then affects metabolic rate. Another likely event is a decrease in the level of physical activity, which also negatively affects muscle mass (and metabolic rate), and directly reduces energy needs. Therefore, to avoid weight gain, patients either have to reduce their normal calorie intake or, because losses of muscle mass and reduced physical activity are truly the root causes of this problem, increase exercise — especially exercises that preserve muscle mass (resistance training). With the exclusion of ovarian function, this model can be modified to explain the effects of other forms of treatment on other cancers.   References Demark-Wahnefried W, Hars V, Conaway M, et al. Reduced rates of metabolism and decreased physical activity in breast cancer patients receiving adjuvant chemotherapy. Am J Clin Nutr. 1997;65:1495-1501. Demark-Wahnefried W, Rimer BK, Winer EP. Weight gain in women diagnosed with breast cancer. J Am Diet Assoc. 1997;97:519-526. Review. Harvie MN, Campbell IT, Baildam A, et al. Energy balance in early breast cancer patients receiving adjuvant chemotherapy. Breast Cancer Res Treat. 2004;83:201-210.

9. TOTAL PHYSICAL ACTIVITY BEFORE AND AFTER BREAST CANCER DIAGNOSIS

10. Total Physical Activity Before and After Breast Cancer Diagnosis by Treatment

11. Why weight control and physical activity? Reduced levels of circulating hormones Reduced levels of insulin and insulin-like growth factors Reduced levels of pro-inflammatory cytokines (immune cells) May improve bioavailability of drugs to treat disease (Tamoxifen, AIs, Chemo, etc) Improved psychosocial well being / QOL

13. METABOLIC SYNDROME IN BREAST CANCER SURVIVORS Study Mean (SD) (n=42) Fasting glucose (mg/dl) 98.7 (12.9)OGTT at 2hrs (N=23) 119.0 (32.4)Insulin (uU/ml) 16.1 (13.2)Glycosylated hemoglobin (HbA1c, %) 6.0 (0.53) Triglycerides (TG, mg/dl) 129.4 (55.72)Total cholesterol (mg/dl) 199.9 (33.69)HDL cholesterol (mg/dl) 57.7 (17.46)LDL cholesterol (mg/dl) 116.4 (28.60) C-reactive protein (hsCRP, mg/L) 5.12 (5.31)Systolic blood pressure (mmHg) 129.9 (18.13)Diastolic blood pressure (mmHg) 79.1 (11.45)  Metabolic SyndromeNCEP ATP III revised criteria 23 (53.5%)TG/HDL 12 (27.9%)

14. Change in Weight with Change in Diet

15. Prevention of Frailty in Breast Cancer Survivors Goal: Determine if muscle health & physical function can be improved w/weight bearing exercise Intervention Group based flexibility, balance, and muscle strength training 2 days per week at UMC Health and Wellness Center Home based aerobic training 3-5 days per week Who Is Eligible? Overweight breast cancer survivors with early stage disease Post-menopausal Currently inactive or minimally active Those not currently on weight loss diet Willing to perform moderate exercise most days of the week for 8 weeks Willing to come to UMC Health and Wellness Center 2 days per week Contact: Jennifer W. Bea, PhD at 520-626-0912 or jwright@azcc.arizona.edu

16. Women’s Intervention Nutrition Study (WINS) HYPOTHESIS: Dietary fat reduction will reduce the incidence of recurrence and increase survival for women treated for early stage breast cancer. Now on to ADHERENCE ISSUES (not compliance) We are all aware each participant is an individual – They may all be survivors of breast cancer, but they are an individual. In order to facilitate behavior change we need to recognize it is Dynamic, Individualized, and requires continued attention. Dynamic: dietary behavior change is a process with relapse and recycling fairly common occurrences. Individualized: some women may require more time and assistance than others in adopting a dietary behavior change. Requires Continued Attention: All participants benefit from an assessment at each follow-up visit to promote adherence and prevent relapse. Now on to ADHERENCE ISSUES (not compliance) We are all aware each participant is an individual – They may all be survivors of breast cancer, but they are an individual. In order to facilitate behavior change we need to recognize it is Dynamic, Individualized, and requires continued attention. Dynamic: dietary behavior change is a process with relapse and recycling fairly common occurrences. Individualized: some women may require more time and assistance than others in adopting a dietary behavior change. Requires Continued Attention: All participants benefit from an assessment at each follow-up visit to promote adherence and prevent relapse.

17. WINS TRIAL DESIGN Women 48-79 yrs Early breast cancer Primary surgery +/- R Systemic therapy* Dietary fat intake > 20% of calories

18. WINS: Inclusion Criteria Women 48 to 79 years of age Histologically confirmed, resected, unilateral invasive breast cancer Lymph nodes examined Acceptable adjuvant systemic therapy Dietary fat intake > 20% of calories Able to accept either randomization Provide informed consent

19. WINS: Fat Gram Intake by Treatment Group

23.   The majority of BAFC in the human diet are found in plant foods and are widely dispersed therein. Individual plants provide anywhere from a few to over 100 BCFA, with variable bioactivity. Generally, each BAFC is plant species specific; however, BAFC from various species can have similar mechanisms of biological activity. For example, both green tea polyphenols and curcumin from turmeric have been shown to inhibit cycloxygenase 2 enzyme activity resulting in inhibition of the inflammatory response.The majority of BAFC in the human diet are found in plant foods and are widely dispersed therein. Individual plants provide anywhere from a few to over 100 BCFA, with variable bioactivity. Generally, each BAFC is plant species specific; however, BAFC from various species can have similar mechanisms of biological activity. For example, both green tea polyphenols and curcumin from turmeric have been shown to inhibit cycloxygenase 2 enzyme activity resulting in inhibition of the inflammatory response.

27. DEMOGRAPHIC CHARACTERISTICS OF THE WHEL COHORT

28. CLINICAL CHARACTERISTICS OF THE WHEL COHORT

30. DISEASE FREE SURVIVAL BY INTERVENTION ARM & STAGE AT DIAGNOSIS

31. OVERALL SURVIVAL BY INTERVENTION ARM & STAGE AT DIAGNOSIS

32. CAROTENOIDS AND RECURRENCE-FREE SURVIVAL: COHORT STUDY Subjects assigned to the control group in the Women’s Healthy Eating and Living (WHEL) Study; women in that group did not change their diets in response to study participation 1,551 women followed for a median of 7 years Early-stage (Stage I, II or IIIA) breast cancer, who were within four years post-diagnosis at randomization (between 3/1995 and 11/2000), and had completed initial treatments 205 women had a breast cancer recurrence or a new primary breast cancer before July 31, 2004 that was medically confirmed by mid-November 2004

33. Cox Proportional Hazards Model: Breast Cancer Endpoint*

34. Does the WHEL diet Modulate Biomarkers of Oxidative Stress? Sub-study of 204 WHEL study participants 24 urine analyzed for *8-Epi-prostaglandin-F-2a*8-hydroxy-2’-deoyguanosine Results *Low baseline oxidative stress*Trend toward reduction by treatment group (non-significant)*8 EPG & 8 OHdG inversely associated w/ vitamin E intake*8-EPG positively associated with BMI & polyunsaturated fat*Increased 8OHdG w/ increase arachidonic acid intake & higher BMI

35. BREAST CANCER: DIETARY BIOMARKERS AS PREDICTORS OF DISEASE RECURRENCE 317 cases median of 8 years post-diagnosis: Increased risk of recurrence associated with highest (vs. lowest) tertile of plasma lipoperoxide (RR 2.1, 95% CI 1.1, 4.0) and alpha-tocopherol (RR 1.7, 95% CI 1.0, 3.0) concentrations (Saintot et al. Int J Cancer 2002;97:574)

36. BASELINE ESTROGENS (IN POSTMENOPAUSAL WOMEN) AND RECURRENCE: NESTED CASE CONTROL ANALYSIS Estradiol pg/ml HR - 1.51 Free E2 HR pg/ml HR - 1.36 Bioavailable E2 pg/ml HR - 1.41 Significant reduction associated with increase in dietary fiber intake Reductions in estrogen also shown with dietary fat reduction when habitual diet is high in fat (> 40% total energy)

38. Indole-3-carbinol: chemoprotective actions Anti-estrogenic effect Inhibit growth of ER+ human breast cancer cells Enhanced effect of Tamoxifen® (Cover et al, 1999) Stimulate apoptosis of ER- human breast cancer cells Reduced adduct formation Induction of apoptosis and cell cycle arrest Anti-proliferation Up-regulation of tumor suppressor gene PTEN and adhesion molecule E-cadherin Anti-angiogenesis Enhanced effect of tamoxifen but they appear to function by different mechanisms – appears to modulate cytochrome p450 isoenzymes Enhanced effect of tamoxifen but they appear to function by different mechanisms – appears to modulate cytochrome p450 isoenzymes

39. CRUCIFEROUS VEGETABLES, TAM AND BREAST CANCER RECURRENCE

40. DIETARY SUPPLEMENT USE AMONG BREAST CANCER SURVIVORS Norm not exception (> 80% of patients) Used to treat symptoms and to reduce perceived risk of recurrence Use greatest among physically active, nl BMI, non-smokers, low fat diet, higher education Polysupplementation more common in those with metastatic disease, fatigue, cancer-related pain 50% of patients on chemotherapy Report higher QOL Bardia et al. J Supportive Oncol, 2007; Politi et al. Supportive Care Ca, 2006; Velicer C and Ulirch, J Clin Oncol, 2008

41. Evidence? Or lack thereof? Limited well-designed studies; no conclusive evidence to date Symptoms: Ginger – nausea Melatonin – sleep Black cohosh, soy – hot flashes Alpha-lipoic acid – neurotoxicity Coenzyme Q-10 - cardiotoxicity Secondary prevention Antioxidants Fish oil Turmeric

42. VITAMIN D SUPPLEMENTATION AND RESPONSE TO AI: REASON FOR CONCERN? Aromatase inhibitors widely used to treat ER+ disease AI inhibits estrogen biosynthesis via inhibition of P450 aromatase, encoded by CYP19 gene AIs lead to bone loss Many breast cancer survivors advised to take vitamin D for bone health Vitamin D stimulates CYP19 transcription and aromatase activity

43. Folate vs Folic Acid Dietary intake – food fortification Fortification increased folic acid intake by approx. 200 µg/day Dietary sources: folate Multivitamin use and fortified cereals primary sources of “exposure” Alcohol use – effect modification Risk promoting of etoh can be reduced if diet is sufficient in folate Gene-diet interactions DHFR 19-bp deletion polymorphism – high folic acid may increase risk

45. Questions?