Mc tiernan opac2013

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  • Relative risk (RR) of breast cancer by increasing quintiles of hormone concentrations. The position of each square indicates the magnitude of the RR, and the area of the square is proportional to the amount of statistical information available (inverse of the variance of the logarithm of the RR). The length of the horizontal line through the square indicates the 95% confidence interval (CI); the 95% CI that extends beyond the scale of the horizontal axis is indicated by a dotted line. The numbers of case patients and control subjects reported in the figure include only those from informative matched case–control sets. Estimates are from conditional logistic regression on case–control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. DHEA = dehydroepiandrosterone; DHEAS = dehydroepiandrosterone sulfate; SHBG = sex hormone-binding globulin.
  • In this presentation, I will present the result of a year long lifestyle intervention study which examined the individual and combined effects of dietary weight loss and exercise on biomarkers of inflammation.
  • The study sample was a postmenopausal women at age between 50-75 years old. The eligibilities for the trial were
  • The study design was a RCT consisting of 4 intervention arms.
  • No differences in any baseline characteristics.
  • SEM vs SD???
  • For our main analysis, we compared changes in CRP The change in CRP is presented as percent change in CRP from baseline.
  • Unadjusted changes in SHBG and sex hormone levels by randomization assignment, means, and 95% confidence intervals. A, Change in SHBG levels between year 1 and baseline; B, change in DHEA levels between year 1 and baseline; C, change in E2 levels between year 1 and baseline; D, change in T levels between year 1 and baseline. *, P < 0.01 compared with placebo.
  • Mc tiernan opac2013

    1. 1. Appraisal of Evidence for Obesity Effects Anne McTiernan, MD, PhDFred Hutchinson Cancer Research Center Seattle, Washington, USA
    2. 2. Evidence in Humans• Observational studies – Adiposity and cancer risk – Adiposity and prognosis: • All cause • Cancer-specific • Other causes of death • Other outcomes – Associations with potential mechanisms• Randomized controlled trials – Prognosis outcomes (survival, recurrence) – Biomarker outcomes: mechanisms
    3. 3. WCRF/AICR Second Expert Report: Body Fatness
    4. 4. Cancer Risk per 5kg/m2 ↑ in BMI: WomenRenehan et al. Lancet 2008;371:569-78.
    5. 5. Cancer Risk per 5kg/m2 ↑ in BMI: MenRenehan et al. Lancet 2008;371:569-78.
    6. 6. Obesity & Overall Breast Cancer Survival Protani et al. Br Ca Res Treat 2010;123:627- 35
    7. 7. Obesity & Breast Cancer Specific Survival Protani et al. Br Ca Res Treat 2010;123:627- 35
    8. 8. Survival Obese vs. Non-obese Breast Cancer Patients by Hormone Receptor Niraula et al. BCRT 2012;134:769-81
    9. 9. Survival Obese vs. Non-obese Breast Cancer Patients by Menopausal StatusNiraula et al. BCRT 2012;134:769-81
    10. 10. Breast Cancer Specific Survival Obese vs. Non-obese Breast Cancer Patients by Hormone ReceptorNiraula et al. BCRT 2012;134:769-81
    11. 11. Breast Cancer Specific Survival Obese vs. Non-obese Breast Cancer Patients by Menopausal StatusNiraula et al. BCRT 2012;134:769-81
    12. 12. Potential Mechanisms for Adiposity Effect Potential Mechanisms for Adiposity Effect on Cancer Risk & Prognosis on Cancer Risk & Prognosis ↑ inflammation ↑ inflammation ↑ estrogens ↑ estrogens↑ adiposity↑ adiposity ↑ androgens ↑ cancer ↑ cancer ↑ androgens ↓ prognosis ↓ prognosis ↑ insulin ↑ insulin ↑ glucose ↑ glucose altered adipocytokines altered adipocytokines ((↓adiponectin;↑ leptin) ↓adiponectin; ↑ leptin)
    13. 13. Diabetes & Cancer Risk: MenOnitilo et al. Cancer Causes Control 2012;23:967-981,
    14. 14. Diabetes & Cancer Risk: WomenOnitilo et al. Cancer Causes Control 2012;23:967-981
    15. 15. Insulin & Breast Cancer Risk: Meta-analysisAutier P et al. Cancer Causes Control 2013 (e-pub Feb.)
    16. 16. Breast Cancer Risk by Sex Hormone Concentrations© Oxford University Press The Endogenous Hormones and Breast Cancer Collaborative Group J Natl Cancer Inst 2002;94:606-616
    17. 17. Risk of Breast Cancer Death by C-peptide (HEAL, 571 stage I-IIIa patients, followed up mean 4.1 years) P trend = 0.03 5 4.5 4 3.5 Hazard Ratio < 1.7 ng/mL 3 1.7-2.5 ng/mL 2.5 > 2.5 ng/mL 2 Diabetics 1.5 1 0.5 0 C-peptideIrwin et al. J Clin Oncol 2011; 29(1):47-53
    18. 18. Risk of Death by C-Reactive Protein (HEAL, 734 stage I-IIIa patients, followed up mean 3.8 years) P trend =0.01 2.5 2 Hazard Ratio 1.5 < 1.2 mg/L 1.3-3.8 mg/L 1 > 3.9 mg/L 0.5 0 Met-hr/wkPierce et al. J Clin Oncol 2009; 27(21):3437-44.
    19. 19. Randomized Clinical Trial Evidence
    20. 20. Effects of Dietary Weight Loss and ExerciseInterventions on Breast Cancer Biomarkers in Overweight/Obese Postmenopausal Women
    21. 21. Study AimsTo examine the individual and combined effectsof 12-month dietary weight loss and exerciseinterventions on: - estrone, estradiol, free estradiol - testosterone, free testosterone - sex hormone binding globulin - insulin resistance markers - inflammation
    22. 22. Methods• Randomized controlled trial• 12-months duration• N = 438• Recruited through mass mailing & media• Postmenopausal women (50-75 years old)• BMI ≥25 kg/m2• < 100 min/week of moderate-vigorous exercise• Healthy• No menopausal hormones• Not smoking• ≤ 2 alcohol drinks/day
    23. 23. Methods Randomized (N=438)Control Dietary Diet + Aerobic (N= 87) weight loss Exercise Exercise (N=118) (N=116) (N=117)Completed Completed Completed Completed (N=80) (N=105) (N=108) (N=106)
    24. 24. Dietary Weight Loss Intervention • Modified from Diabetes Prevention Program/Look Ahead* diet interventions • Individual goal 10% weight loss by 6 months, then maintenance – Calorie deficit plus < 30% calories from fat • 120-174: 1200 kcal • 175-219: 1500 kcal • 220-249: 1800 kcal • ≥ 250: 2000 kcal • 2-4 individual sessions + group sessions – Weekly X 6 months, then monthly X 6 months with interim contacts • Facility weighings at individual + group sessions • > weekly self-weighings at home • Daily food logs • Participants attended a mean 91% of sessions*Knowler et al. NEJM 2002; ;346:393-403; Wadden et al. Obesity 2006; 14:737-52
    25. 25. Exercise Intervention• 45 minutes/day, 5 days/week – 3 d/week facility (FHCRC Prevention Center) – 2 d/week home• Moderate-intensity aerobic activity (walking, elliptical, biking, other sports) – 60-75% VO2max• 8 weeks progression to full program – Start at 15 minutes; 40% VO2max• 80% of target 225 min/week achieved
    26. 26. Baseline Characteristics & Attrition• Age: 58 years• 85% non-Hispanic white• BMI: 31 kg/m2• Weight 83 kg.• 48 % body fat (DEXA)• Aerobic fitness: 23 ml/kg/min (VO2max)• No statistically significant differences by arm• 9% lost-to-follow-up at 12 months
    27. 27. % Weight Change normalized to baseline, 9% missing assumed no change 0 % Weight Loss (from baseline) -5 Diet Diet+Ex Ex -10 Control -15 Baseline 12 MonthsFoster-Schubert et al. Obesity 2012 Aug;20(8):1628-38
    28. 28. Categories of % Weight Loss by Study Arm Ex + Diet Diet Only Exercise Only Control (N=87) (N=117) (N=118) (N=117)Gained(>0%) 3.4 7.6 24.8 46.00-5% loss 18.8 28.0 49.6 39.1Moderate weightloss 18.0 22.9 22.2 10.3(5-9.9%)Major weight loss(≥ 10%) 59.8 41.5 3.4 4.6 Foster-Schubert et al. Obesity 2012 Aug;20(8):1628-38
    29. 29. Estrone: % Change 10 5 0 Control -5 Diet Alone Exercise Alone -10 Diet + Exercise * + * -15 -20 *P<0.001 vs. CO % Change Baseline to 12 Months + P<0.01 vs. COCampbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
    30. 30. Estradiol: % Change 5 0 -5 Control -10 Diet Alone -15 Exercise Alone -20 Diet + Exercise * * -25 -30 *P<0.001 vs. CO % Change Baseline to 12 MonthsCampbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
    31. 31. Testosterone: % Change 2 0 -2 Control -4 Diet Alone Exercise Alone -6 Diet + Exercise -8 * -10 *P=0.02 vs. CO % Change Baseline to 12 MonthsCampbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
    32. 32. Sex Hormone Binding Globulin: % Change 30 25 20 15 10 Control 5 Diet Alone 0 Exercise Alone -5 * * Diet + Exercise -10 -15 -20 *P<0.001 vs. CO % Change Baseline to 12 MonthsCampbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
    33. 33. Free Estradiol: % Change 10 5 0 -5 Control -10 Diet Alone -15 Exercise Alone -20 Diet + Exercise -25 * + * -30 -35 *P<0.001 vs. CO % Change Baseline to 12 Months P=0.08 vs. COCampbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
    34. 34. Free Testosterone: % Change 5 0 -5 Control Diet Alone -10 Exercise Alone Diet + Exercise -15 + * -20 *P<0.0001 vs. CO % Change Baseline to 12 Months +P<0.001 vs. COCampbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
    35. 35. Estrone: % Change by Weight Change 10 5 0 Control -5 Gain/lost < 5% -10 Lost >=5% * * -15 + -20 *Ptrend<0.001 vs. CO Diet Only Exercise Only Diet + Exercise + Ptrend<0.01 vs. COCampbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
    36. 36. Estradiol: % Change by Weight Change 10 5 0 -5 Control -10 Gain/lost < 5% -15 Lost >=5% -20 * + * -25 -30 *Ptrend<0.0001 vs. CO Diet Only Exercise Only Diet + Exercise + Ptrend<0.01 vs. COCampbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
    37. 37. Free Estradiol: % Change by Weight Change 10 5 0 -5 -10 Control -15 Gain/lost < 5% -20 Lost >=5% -25 * + -30 * -35 *Ptrend<0.0001 vs. CO Diet Only Exercise Only Diet + Exercise + Ptrend<0.001 vs. COCampbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
    38. 38. Insulin: % Change 0 -5 -10 Control -15 Diet Alone -20 Exercise Alone -25 Diet + Exercise * * -30 -35 *P<0.001 vs. CO % Change Baseline to 12 MonthsMason et al. Am J Prev Med. 2011 Oct;41(4):366-75.
    39. 39. Similar Reductions with Weight Loss• C-peptide• HOMA (marker of insulin resistance calculated from insulin & glucose)
    40. 40. Adiponectin: % Change * * P<0.0001Abbenhardt et al. J of Internal Medicine 2013 Feb 25.
    41. 41. Leptin: % Change All p<0.005 vs. controlsAbbenhardt et al. J of Internal Medicine 2013 Feb 25.
    42. 42. C-Reactive Protein: % Change % 1.1% -11.4% P= .09 - 37.7% P= <.001 -46.9% P= <.001Imayama et al. Cancer Research 2012; 72(9); 2314–26
    43. 43. Interleukin-6: % Change % 0.7% -2.0% P= .48 -21.9% P< .001 -24.3% P< .001Imayama et al. Cancer Research 2012; 72(9); 2314–26
    44. 44. Cancer-related Biomarker Changes in theDiabetes Prevention Program Weight Loss Diet • Sex hormones • Inflammation • Insulin
    45. 45. Endogenous Sex Hormone Changes inPostmenopausal Women in the Diabetes Prevention ProgramKim C, Kong S, Laughlin GA, Golden SH, Mather KJ, Nan B, Edelstein SL, Randolph JF Jr, Labrie F, Buschur E, Barrett-Connor E.
    46. 46. Study Design• 3-group randomized clinical trial• 27 clinical sites• Standardized across clinics: – Common protocol and procedures manual – Staff training – Data quality control program
    47. 47. Eligibility Criteria• Age > 25 years• Plasma glucose – 2 hour glucose 140-199 mg/dl (7.8- <11.1 mmol/L) and – Fasting glucose 95-125 mg/dl (5.3- <7.0 mmol/L)• Body mass index > 24 kg/m2• All ethnic groups goal of up to 50% from high risk populations
    48. 48. Study Interventions Eligible participants Randomized Standard lifestyle recommendationsIntensive Metformin PlaceboLifestyle(n = 1079) (n = 1073) (n = 1082)
    49. 49. Methods• Secondary analysis to DPP trial• N=382• Eligibility: – Postmenopausal – Not using hormone therapy – Available blood baseline & 1-year
    50. 50. Methods: Analytes• Sex hormone binding globulin (SHBG)• Follicle stimulating hormone (FSH)• Total estradiol (E2) (20% undetectable)• Total testosterone (T) (30% undetectable)• Dehydroepiandrosterone (DHEA)
    51. 51. Lifestyle Intervention An intensive program with the following specific goals:• > 7% loss of body weight and maintenance of weight loss – Dietary fat goal -- <25% of calories from fat – Calorie intake goal -- 1200-1800 kcal/day• > 150 minutes per week of physical activity
    52. 52. Interventions: MedicationsMetformin- 850 mg per day escalating after 4 weeks to 850 mg twice per day parallel with active drugs
    53. 53. DPP: Unadjusted Changes in SHBG and Sex Hormones levels Kim C et al. JCEM 2012;97:2853-2861©2012 by Endocrine Society
    54. 54. One-Year Weight Loss Effects on C-Reactive Protein in Participants With Impaired Glucose Tolerance: Median Changes• Men: – Lifestyle: -33% – Placebo: +5% – P<0.001• Women: – Lifestyle: -29% – Placebo: 0% – P<0.001The Diabetes Prevention Program Research Group. Diabetes 2005; 54:1566–1572
    55. 55. DPP Effects on Insulin ResistanceDiabetes Prevention Program Research Group. Lancet2009;274:1677-1686.
    56. 56. Biomarker Issues• Some are not well measured in humans• High variability of measures• Tissue difficult to obtain• Mixed tissues for most sampling (for example, breast biopsies might include epithelium, stroma, inflammatory cells, blood)• Effects of adjuncts to biopsies (skin or other preps, analgesics, anesthetics)• Power issues if multiple markers (e.g. gene expression)
    57. 57. Conclusions re: Biomarkers• Still unanswered questions on obesity and cancer biomarkers: – Effects in specific populations (various geographic areas, racial groups, high risk persons) – Different weight loss methods (surgery, medications, types of diet) – Direct tissue effects
    58. 58. Conclusions• Obesity related to risk for many cancers• Randomized controlled clinical trials in humans support biological effects of weight loss relevant to cancer• > 5% weight loss produces greatest change in metabolic and sex hormone levels
    59. 59. Problems/Issues with Research on Obesity & Cancer• Biomarker studies may not reflect cancer effect• Rodents are not humans and vice versa• Survivorship studies at high risk of confounding by disseminated disease and treatment effects• Exposures poorly measured• Adverse effects of exercise & weight loss largely ignored• Head-to-head comparisons of weight loss, exercise, diet are rare• Publication bias
    60. 60. Funding Sources• U.S. National Cancer Institute• U.S. National Institutes of Health• Susan G. Komen for the Cure
    61. 61. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

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