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Rock opac2013 Rock opac2013 Presentation Transcript

  • Energy Balance, Adiposity, Physical Activity and Breast Cancer Cheryl L. Rock, PhD, RD Dept. of Family and Preventive Medicine Cancer Prevention and Control Program
  • 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
  • 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
  • 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
  • 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
  • Case-Control Studies of Physical Activity and Breast Cancer Risk Friedenreich et al. Br J Sports Med. 2008;42:636–647
  • Cohort Studies of Physical Activity and Breast Cancer Risk Friedenreich et al. Br J Sports Med. 2008;42:636–647
  • 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)
  • Adiposity and Breast Cancer Outcome Patterson et al., Maturitas 2010;66:5–15
  • 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)
  • 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
  • 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
  • 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
  • Physical Activity and Cancer Outcome Patterson et al. Maturitas 2010;66:5–15
  • 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
  • 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
  • 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)
  • Adipose Tissue Production of Estrone andEstradiol from Androstenedione and the Bioavailability of Estradiol in Postmenopausal Women Rose & Davis. Maturitas 2010;66:33-38
  • 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
  • 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)
  • Potential Effect of Weight Loss on Proposed Hormonal and Biological Factors Linking Obesity to Breast Cancer
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Weight Loss with Time in Each Study Arm:Mean and SD of Change in Body Weight
  • 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
  • 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)
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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?
  • 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
  • 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