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Rock opac2013

  1. 1. Energy Balance, Adiposity, Physical Activity and Breast Cancer Cheryl L. Rock, PhD, RD Dept. of Family and Preventive Medicine Cancer Prevention and Control Program
  2. 2. Obesity and Risk and Progression of Breast CancerBreast cancer is the most common cancer worldwide in women, accounting for 23% of the total number of new cancers diagnosedDeath rates from breast cancer have been steadily declining, and there are now an estimated 2.9 million women in the US alone with a history of breast cancerThe relationship with BMI and incident breast cancer is complex: Positively related in postmenopausal women, but inversely related in premenopausal women
  3. 3. Relative Risk of Breast Cancer Across Quintiles of BMI in Premenopausal and in PostmenopausalWomen Who Did Not (or Did) Use Hormone Therapy Pischon et al. Proc Nutr Soc 2008;67:128–145
  4. 4. Multivariate Adjusted RR of Breast Cancer by BMI andCurrent Hormone Use Among Postmenopausal Women (N=103,344), EPIC Study Lahmann et al. Int J Cancer 2004;111:762–771
  5. 5. Physical Activity and Breast Cancer RiskThe majority of epidemiological studies have found a significant risk reduction among the most (vs. least) physically active women, with an average risk reduction of 25-30%, and a dose- response effectEvident in both pre- and postmenopausal women, but greater in magnitude for postmenopausal women and also in leaner (vs. obese) womenStronger risk reduction for recreational, lifetime or later life and vigorous activity, in non-white women and women without a family history Friedenreich et al. Br J Sports Med 2008;42:636–647
  6. 6. Case-Control Studies of Physical Activity and Breast Cancer Risk Friedenreich et al. Br J Sports Med. 2008;42:636–647
  7. 7. Cohort Studies of Physical Activity and Breast Cancer Risk Friedenreich et al. Br J Sports Med. 2008;42:636–647
  8. 8. Obesity and Cancer Progression and/or SurvivalConsistent evidence suggests that obesity is a negative prognostic factor in breast cancerExcess adiposity is a major risk factor for breast cancer recurrence and mortality in both pre- and postmenopausal womenHigher BMI is a significant independent predictor of mortality regardless of tumor characteristicsIn women who have been diagnosed with breast cancer, obesity is associated with a 30% increased risk of breast cancer outcomes (recurrence, all-cause and breast cancer-specific mortality)
  9. 9. Adiposity and Breast Cancer Outcome Patterson et al., Maturitas 2010;66:5–15
  10. 10. Disease-free Survival of 557 Patients with Breast Cancer and Negative Nodes According to Obesity at Diagnosis Non-obeseDisease-free Survival (%) Obese Disease-free Months The number of patients at risk at time 0, at 5 years, and at 10 years is shown for each set of survival curves. Hazard ratio, 1.93 (95% CI, 1.29 to 2.88: P= 0.001). (Senie et al. Ann Int Med 1992;116:26-32)
  11. 11. Meta-Analysis and Pooled Hazard Ratio of the Effect of Obesity on Breast Cancer-Specific Survival in Breast Cancer Patients Protani et al. Breast Cancer Res Treat 2010;123:627–635
  12. 12. Meta-Analysis and Pooled Hazard Ratio of the Effect ofObesity on Overall Survival in Breast Cancer Patients Protani et al. Breast Cancer Res Treat 2010;123:627–635
  13. 13. Physical Activity and Breast Cancer Prognosis Consistent evidence from epidemiological studies suggests that physical activity before or after breast cancer diagnosis is associated with reduced all-cause and breast cancer-specific mortality, and with a dose response effect Some evidence for effect modification by BMI, but not consistent, and no differences for pre- and postmenopausal women or race or ethnicity Higher level of physical activity appears to be associated with a 30% decreased risk of mortality
  14. 14. Physical Activity and Cancer Outcome Patterson et al. Maturitas 2010;66:5–15
  15. 15. Forest Plot of Risk Estimates from Observational Studies of Physical Activity and Mortality Outcomes in Breast Cancer Survivors Indicate hazard ratios (HRs) 95% Confidence intervals (CIs) Indicates point of unity Ballard-Barbash et al. J Natl Cancer Inst 2012;104:815-840
  16. 16. Obesity: Possible MechanismsSeveral mechanisms have been proposed to explainthe adverse effect of excess adiposity (and physicalactivity) on the risk and progression of breast cancerCirculating reproductive steroid hormonesInsulin and interactions with growth factorsInflammatory cytokines
  17. 17. Reproductive Steroid Hormones Adipose tissue is an important extragonadal source of estrogens from precursor adrenal androgens Endogenous circulating estrogens are 50-100% higher in postmenopausal obese (vs. normal weight) women Obesity is associated with decreased sex-hormone binding globulin (SHBG) High circulating estrogen levels are a risk factor for breast cancer recurrence (Rock et al. CEBP 2008;17:614-620)
  18. 18. Adipose Tissue Production of Estrone andEstradiol from Androstenedione and the Bioavailability of Estradiol in Postmenopausal Women Rose & Davis. Maturitas 2010;66:33-38
  19. 19. Insulin, Growth Factors, and Inflammation Insulin exhibits mitogenic effects that influence both premalignant and cancerous stages of cell growth, and insulin and insulin like growth factor (IGF) – I stimulate mammary cell proliferation in vitro Insulin also stimulates the synthesis of sex hormone steroids and inhibits the synthesis of SHBG Obesity is characterized by chronic mild inflammation, and weight loss reduces inflammatory factors Inflammation plays a central role in the insulin resistance associated with obesity: Cytokines decrease insulin action by affecting insulin receptor activity
  20. 20. 120 r=.54 100Insulin ųIU/ml 80 60 40 20 0 15 20 25 30 35 40 45 50 55 60 Body Mass Index (kg/m2)
  21. 21. Potential Effect of Weight Loss on Proposed Hormonal and Biological Factors Linking Obesity to Breast Cancer
  22. 22. Primary PreventionIn the general population, even a modest degree of intentional weight loss favorably affects many breast cancer-relevant risk factors and potential mediators (Byers & Sedjo. Diabetes Obesity Metab 2011;1312:1063-1072) Reduced levels of estrogens (30% reduction expected with 10% weight loss) and increased SHBG CRP levels decline with similar magnitude after weight loss Reductions in TNF-α and IL-6 also observed but of smaller magnitude
  23. 23. Issues Specific to Cancer SurvivorsBody image issues related to cancer and cancer treatmentsEnduring psychosocial symptoms, such as depression and fatigue, affect efforts to make changes in behaviorsChanges in family dynamics and social supportIncreased physical activity is particularly important, due to effects of treatments on body composition, and the relationship between lean body mass and resting energy expenditure
  24. 24. Reach Out to ENhancE Wellness in Older Survivors (RENEW)• Test the impact of a diet-exercise mailed material/telephone counseling program on weight loss and physical functioning in prostate, colorectal and breast cancer survivors (N=641)• Study participants: >65 years of age and overweight, within 5 years of diagnosis, 45% maleMorey et al. JAMA 2009;301:1883-1891
  25. 25. Changes in Lifestyle Behaviors Weekly Minutes of Exercise120 101.1 107.5100 100.9 80 69 60 40 37.5 Healthy Eating Index 33.3 20 68 66.4 0 Baseline 1-yr 2-yr 66 66.2 65.2 64 62 Immediate RENEW Intervention 61.1 60 59.6 Delayed Intervention 59.3 58 Baseline 1-yr 2-yr
  26. 26. Change in BMI Body Mass Index (kg/m2)29.429.2 29.1 29 29.128.8 28.828.628.4 28.328.2 28.2 28.2 28 Baseline 1-yr 2-yr Immediate RENEW Intervention Delayed Intervention
  27. 27. Change in Physical Function (SF36)80 76.1 74.475 70.5 70.670 69.465 6560 Baseline Baseline 1-yr 1-yr 2-yr 2-yr Immediate RENEW Intervention Delayed Intervention
  28. 28. Combining Weight Loss Counseling With Weight Watchers• Obese breast cancer survivors (N=48) assigned to individualized weight loss counseling, referral to the Weight Watchers program, a combination of both, or control• Weight change after 12 months of intervention was 0.85 + 6.0 kg (<1% of initial weight) in controls, -2.6 + 5.5 kg (2.7% of initial weight) in the Weight Watchers only group, -8.0 + 5.5 kg (8.4% of initial weight) in the individualized counseling only group, and -9.4 + 8.6 kg (9.8% of initial weight) in the combined groupDjuric et al. Obesity Res 2002;10:657-665
  29. 29. Weight Loss with Time in Each Study Arm:Mean and SD of Change in Body Weight
  30. 30. Reducing Breast Cancer Recurrence with Weight Loss: A Vanguard Trial Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial (Rock et al. Contemp Clin Trials 2013;34:282-295) Randomized controlled study with the primary endpoint of clinically significant weight loss in 693 overweight or obese breast cancer survivors, with demonstration of improvements in quality of life and co-morbidities Prospective collection of blood and DNA samples to examine effects on hormones and other factors to explain the mechanism and probable differential response across subgroups Serves as vanguard for a larger cancer outcome study with sufficient statistical power to assess effects of weight loss on cancer outcomes in overweight or obese breast cancer survivors
  31. 31. Preliminary StudiesHealthy Weight Management Study, N=85, group-basedcognitive-behavioral weight loss program plus telephone contacts(Mefferd et al. Breast Cancer Res Treat 2007;1042:145-152) • Intervention group mean 83.9 kg at baseline, 78.2 kg at 16 wks (7% of initial weight), and 77.3 kg (8% of initial weight) at 12 mos; reported 7.4 hrs/wk mod + vig activity at 12 months • Favorable changes in % body fat, waist circumference, SHBG, bioavailable estradiol, and total and LDL cholesterolBreast Cancer Survivors Health and Physical Exercise (SHAPE)Study N=259, group-based behavioral weight loss program (Rocket al. Clin Breast Cancer 2013) • Intervention participants lost -4.6 kg (5.5% of initial body weight) at 6 months and -3.8 kg (4.5% of initial body weight) at 18 months • Weight loss of >5% associated with favorable changes in depression, self-esteem, insulin, leptin, and estrogens (in postmenopausal women)
  32. 32. SHAPE Study: Biological Factors by Follow-up Weight Loss Category* 6-Month Follow-up 18-Month Follow-up ≥5% Weight <5% Weight ≥5% Weight <5% Weight Loss Loss Loss Loss (n = 74) (n = 139) P Value (n = 63) (n = 140) P ValueInsulin, µIU/mL Baseline 16.9 (9.0) 16.3 (8.1) .64 16.9 (7.1) 17.1 (8.3) .08 Follow-up 13.2 (6.1) 19.8 (17.4) <.0001 15.8 (7.3) 23.0 (13.0) <.0001Leptin, ng/mL Base 36.4 (18.6) 39.5 (22.4) .32 34.5 (20.3) 40.3 (22.1) .08 Follow-up 20.3 (11.4) 34.5 (18.2) <.0001 20.1 (15.7) 29.8 (14.9) .0001Sex hormone binding globulin, nmol/L Baseline 58.9 (35.2) 58.4 (32.6) .92 64.9 (37.9) 55.5 (31.0) .06 Follow-up 71.7 (37.6) 56.3 (33.2) .004 63.9 (29.6) 45.1 (26.6) <.0001* Values shown are mean (SD). P values represent results of t-tests between weight loss groups.
  33. 33. ENERGY TrialFour sites; UCSD is the Coordinating CenterSubjects: Women aged > 21 years; diagnosed with breast cancer (Stages I [≥1 cm], II, or III) between 6 months and 5 years earlier; BMI between 25 and 45 kg/m2Intervention: Cognitive-behavioral closed group sessions, tailored newsletters, individual participant contacts (by email and/or telephone)Control: Two individual counseling sessions, health seminars, monthly contacts
  34. 34. ENERGY Trial: Comparability of Study Groups Control Intervention (n = 348) (n = 345) Age, years (mean [SD]) 56.5 (9,5) 56.1 (9.5) Education, years (mean [SD]) 15.5 (2.4) 15.6 (2.5) Hispanic (%) 5.8 7.6 Race (%) White 84.5 83.1 African-American 10.6 10.5 Asian-American 2.0 1.5 American Indian 0.3 0.6 Hawaiian/Pacific Islander 0 0.3 Mixed/Other 2.0 3.8 Missing or refused 0.6 0.3 Postmenopausal at study entry (%) 85.0 85.7 Weight, kg (mean[SD]) 84.7 (13.8) 85.0 (14.3) Body mass index, kg/m2 (mean [SD]) 31.4 (4.6) 31.6 (4.7) Years between diagnosis and study entry (mean) 2.83 2.72 Breast cancer stage (%) I 31.9 32.0 II 51.7 48.6 III 16.4 19.5
  35. 35. Measurements and Outcomes Measurements • Blood pressure • Questionnaires: Quality of life, physical activity • Weight, waist circumference, step test • Blood sample collection Outcomes • Weight loss and weight loss maintenance over a two-year period (goal is 7% of initial weight) • Quality of life • Co-morbidities • Cancer outcomes in preparation for a larger trial • Biological samples
  36. 36. Transdisciplinary Research in Energetics and Cancer (TREC) Cooperative agreement initiative (U54) that explores the relationship between obesity and cancer, funded by the National Cancer Institute (Patterson et al. Cancer Causes Control 2013) Integrates the study of diet, weight, and physical activity and their effects on energy balance and cancer Projects: Biologic and physiologic mechanisms of energy balance; behavioral, sociocultural, and environmental influences on diet, physical activity and weight in cancer survivors and other populations Across the four centers, two (at UCSD and Univ. of Penn.) are focused on energy balance and weight loss interventions in breast cancer prevention and control
  37. 37. ConsiderationsLimitations of observational studies  Confounding: Difficult if not impossible to control for other influencing factors, clustering of behaviors  Obesity is inextricably linked to behavioral determinants  Measurements are crude: Few if any physical activity studies used objective measures, and few include full assessment of all types and dosesObesity and breast cancer risk and progression  Potential modulators, such as obesity-related comorbidities  Energy restriction versus reduced adiposity  Manage metabolic changes associated with obesity rather than focus on weight loss?
  38. 38. Weight Loss Interventions for Breast Cancer SurvivorsThis target population is motivated and able to make modifications in diet and physical activity to promote weight lossIndividualized counseling (in person or telephone), group sessions, and mailed material can promote weight lossMore intensive interventions produce greater weight lossEvidence suggests that proposed biological mediators are favorably affected
  39. 39. ENERGY Research Team ENERGY Trial investigators (in alphabetical order): Tim Byers, MD, MPH, Graham Colditz, MD, DrPH (Data Management and Analysis), Wendy Demark- Wahnefried, PhD, RD, Patricia Ganz, MD, Bilgé Pakiz, EdD, Barbara Parker, MD, Cheryl Rock, PhD, RD (PI of Parent Grant and Coordinating Center), Rebecca Sedjo, PhD, Kathleen Wolin, ScD, Holly Wyatt, MD NCI: Catherine Alfano, PhD (program officer) and Julia Rowland, PhD, Office of Cancer Survivorship; also Robert Croyle, PhD, Division of Cancer Control and Population Sciences