Ulrich opac2013

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  • Human physical activity (they run all the time, no strength training)
  • Add gut microbiome
  • stronger intervention effects on CRP in women with higher baseline physical fitness (P(heterogeneity) = 0.040) was found.
  • -8% to -24% change in SAA
  • N=320 randomized, 308/310 at 6 and 12 month time pointTER = treatment effect ratio of exercisers to controls
  • Ulrich opac2013

    1. 1. Physical activity change: what biomarkers tell us about cancer mechanisms and effects Prof. Dr. Cornelia Ulrich Director National Center for Tumor Diseases (NCT) German Cancer Research Center (DKFZ) and Fred Hutchinson Cancer Research Center, Seattle World Cancer Research Fund Obesity, Physical Activity & Cancer April 2013, London
    2. 2. The next 25 minutes • Evidence base for mechanisms linking physical activity to cancer • Mechanisms – results and questions  Inflammation  Immunity  Oxidative stress and DNA repair  Sex hormones, metabolic hormones, adipokines… • Mechanisms in cancer patients • Summary
    3. 3. Evidence base for mechanisms linking physical activity to cancer risk (1) • Animal studies  Direct mechanistic effects in tissue and key biospecimens  Limited generalizability compared to: • Human physical activity • Human biomarkers (e.g., inflammatory processes, PNAS 2013) • Dose-response achievable in humans • Observational epidemiological studies measuring biomarkers concurrently with physical activity levels  Detect long-term associations  E.g., training status and DNA repair capacity  Limitation: confounding factors, such as supplement use, body weight, etc…
    4. 4. Evidence base for mechanisms linking physical activity to cancer risk (2) • Human intervention studies  Experimental design (randomized controlled trial) allows direct measurement of effects and inference of causality  Biomarkers can be “intermediate endpoints” in cancer research CRP  increases colorectal cancer risk (Toriola, Int J Ca 2013)  is associated with cancer survival (Pierce,J Clin Onc 2009)  Limited to: • Shorter time periods (generally up to 1 year) • Certain biospecimens  Dependent on: • Adherence
    5. 5. Physical Activity Caloric Restriction Cancer Risk DNA Repair Capacity Vitamin D Immunity Obesity Inflammation Sex hormones Insulin/Glucose Adipokines Gut microbiome?
    6. 6. Physical activity is highly correlated with vitamin D levels (NHANES) 25 (OH) Vit D Frequency of outdoor activity (times in past month) Scragg & Camargo, Am J Epi 2008 Non-Hispanic White Mexican American Non-Hispanic Black
    7. 7. Exercise Trial – Physical Activity for Total Health Study • Randomized controlled trial examining in overweight, sedentary, postmenopausal women (n=173 PATH Study)  the effects of a one-year exercise intervention (5d/wk 45min)  compared to a one-year stretching program  on cancer biomarkers (0, 3,12 months) • Very good adherence and minimal drop out • Significant improvement in VO2 max McTiernan, Ulrich (IMEX) and colleagues
    8. 8. 0 1 2 3 4 CRP (mg/L) Ctrl-BL Ctrl-12m Ex-BL Ex-12m Waist circ. <88cm Waist circ. >88cm 12m exercise reduces C-reactive protein among obese women P. Campbell, Medicine Sports Science Exerc 2009 n.s. CtrlCtrl ExerExer p<0.001
    9. 9. Alberta Physical Activity and Breast Cancer Prevention Trial – similar effects on CRP • RCT, parallel design, larger sample size (n=160/160), biomarkers at 6 & 12 months  Also excellent adherence and minimal dropout • Differences over 12 months:  Exercisers versus controls Reduced CRP (TER = 0.87, 0.79-0.96, P = 0.005) • But no changes in IL-6 or TNF-alpha.  Decreasing CRP with increasing exercise  Effect mediated by fat loss  No intervention effect if adjusted for dietary fiber  confounding? Friedenreich et al, Cancer Prev Res 2012
    10. 10. Energy balance – is it about exercise or about weight loss?  Better chubby and fit or thin at every price?
    11. 11. PI: Anne McTiernan, Seattle TREC (Ulrich Project Leader) • Randomized, controlled, 12 month, 4-arm clinical trial of diet and/or exercise • 439 postmenopausal overweight-to- obese women • Average Age: 58 years • Average BMI: 30.8 kg/m2 Body fat: 48% AIMS: Assess effects of a moderate-intensity exercise program, weight reduction diet, or both exercise + diet in postmenopausal women on body weight and composition, and cancer biomarkers
    12. 12. CRP concentrations % change as a result of 12-month diet or exercise intervention * p<0.0001 * Imaya, Ulrich, McTiernan et al. Cancer Res 2012 * -46.9% P= <.001 - 37.7% P= <.001 -46.9% P= <.001 -11.4% P= .09 1.1%
    13. 13. Changes in CRP by weight loss * -51.2% P< .001† -52.0% P< .001† -27.8% P= .001† 0.9% 0.9% 0.9% -3.7% -13.0% -7.3% Diet Diet + Exercise Exercise Imaya, Ulrich, McTiernan et al. Cancer Res 2012
    14. 14. Percent leukocytes % change as a result of 12-month diet or exercise intervention * -2.0% -9.2% P< .001 -7.1% P< .001 -2.5% p=.78 Imaya, Ulrich, McTiernan et al. Cancer Res 2012
    15. 15. 0 0.1 0.2 0.3 0.4 0.5 0.6 Incidence of colds 1st Qtr 2nd Qtr 3rd Qtr 4th Qtr 12-month study period Exercise Control P=0.02 Chubak et al Am J Med 2006
    16. 16. No effects of exercise intervention on broad spectrum of biomarkers of immune function • No effects on  Lymphocyte proliferation from cryopreserved cells  Natural killer cell cytotoxicity  Cell counts and phenotypes  Immunoglobulins • Despite excellent retention, adherence and intervention efficacy • Value of snapshot immune markers? Campbell P et al, J Appl Physiol 2008
    17. 17. Oxidative stress and DNA repair -- why do we expect effects? Exercise or general metabolism induces oxidative DNA damage • Training of the DNA repair system through exercise? • Reduced levels of oxidative damage? Supporting preliminary data from animal experiments, cross-sectional studies (frequently athletes) and small interventions
    18. 18. -15 -10 -5 0 5 %Change Overall By % gain in V02max Physical Activity for Total Health Study: Exercise reduces urinary F2-isoprostane levels among those with greatest training efficacy (n=173) Campbell P et al. Med Sci Sports Exerc 2010 Ctrl Ex n.s. P-trend=0.005 Ctrl *** <5 5-15 >15 No effects on DNA repair capacity overall, as measured by Comet Assay Other assays needed? (Habermann, Ulrich et al, in prep.)
    19. 19. NEW: Diet & Exercise interventions decrease serum leptin levels among postmenopausal women (n=439) 0 5 10 15 20 25 30 Diet+Exercise Diet Exercise Control Leptinµg/mL Baseline 12 months Abbenhardt J Int Med 2013 P<0.0001 P<0.0001 P<0.005
    20. 20. NEW: Diet, but not exercise interventions increase serum adiponectin levels among postmenopausal women(n=439) Abbenhardt C et al. J Int Med 2013 10 10.5 11 11.5 12 12.5 13 13.5 14 14.5 15 Diet+Exercise Diet Exercise Control Adiponectinµg/mL Baseline 12 months P=0.001 P=0.001 N.S.
    21. 21. Alberta Physical Activity and Breast Cancer Prevention Trial (Friedenreich et al) • Across the study period comparing exercise group to controls (treatment effect ratio: statistically significant reduction in leptin (TER=0.82, 0.78-0.87) increase in the adiponectin/leptin ratio (TER=1.21, 1.13-1.28) Friedenreich et al. Endocr.-related Ca 2011
    22. 22. Half-time summary • Intervention trials of exercise have shown significant and reproducible effects on biomarkers of cancer risk  Inflammation, adipokines, sex hormones, insulin/IGF, oxidative stress • Unclear effects on immunity, DNA repair & Vit D • Effects strongest in diet and exercise group • Fat-loss important mediator for many, but not all mechanisms
    23. 23. Inflammation - What’s fat got to do with it?
    24. 24. Targeting tissue – effects of energy balance on adipose tissue biology • Adipose tissue is active in metabolism and synthesis of IL-6, TNFalpha, sex steroid metabolism…  Goal: To learn about molecular mechanisms in target tissue • N=49 women randomized to exercise and or weight- loss intervention • Subcutaneous adipose tissue sampling at baseline and 6 months
    25. 25. Adipose tissue biopsies and biomarkers Collagenase digestion Adipocytes Stromavascular cells (SVC) for flow cytometry (Kratz) Snap-frozen whole tissue for RNA extraction and gene expression Biopsy: subcutaneous abdominal fat local anaesthetic (incision, 14-gauge needle) yield ~ 500 mg Campbell, Ulrich et al. Cancer Prev Res 2013 Analysis: • candidate genes • candidate pathways • unsupervised clustering • By intervention • By weight-loss
    26. 26. Weight loss affects adipose tissue gene expression • Analysis by weight loss: % change P trend adj. P value Sex Steroid-Related: HSD17B1 -0.35 0.0002 0.01 ESR1 0.24 0.0037 0.08 STS -0.26 0.0198 0.20 HSD17B10 -0.05 0.045 0.37 Inflammation-Related: CRP 0.23 0.0081 0.13 ICAM4 -0.09 0.0110 0.13 SAA1 -0.38 0.0110 0.13 VCAM1 0.34 0.044 0.37 Other Genes of Interest: LEP -0.44 0.0000 0.00 IGFBP3 0.37 0.0032 0.08 Campbell, Ulrich et al. Cancer Prev Res 2013
    27. 27. –omics results • Unsupervised clustering of >37,000 transcripts by weight loss • Reveals 78 transcripts with statistically significant adjusted p-values  Multiple hits in histone clusters  Leptin is #33  suggests strong effects of weight loss on other pathways in adipose tissue • However: unsupervised approach results also misses significant hits in candidate pathways (=false negatives) • Combination of hypothesis-driven and empirical approach is complementary!! Campbell, Ulrich et al. Cancer Prev Res 2013
    28. 28. 6m 12m 24m 36m Treatment information • Blood draws • Urine • Feces • Questionnaires on symptoms, QoL & current health habits, Food frequency (FFQs) • Accelerometer 3m • Questionnaires on symptoms, QoL & current health habits Surgery • Pre-surgery blood • Urine • Feces • Tumor & normal tissue • Visceral & subcutaneous adipose tissue • Fascia • Questionnaires Outcomes •Surgical outcomes •Treatment toxicity • Recurrence • Survival • Symptoms, QoL Baseline Diagnosis ColoCare – Study Design Multicenter colorectal cancer patient cohort
    29. 29. Exercise in the adjuvant therapy of cancer patients There is substantial potential for exercise in aiding in the recovery of cancer patients  unknowns regarding type, timing, intensity and duration of intervention Clinical trial: n=170 hematopoietic stem-cell transplantation patients  exercise prior to and during the transplant process  cancer-related fatigue, distress and  physical functioning/fitness PFS (months) Wiskemann, Blood 2011 Greatest benefit on physical fitness in the initially unfit!
    30. 30. Biomarkers in cancer patients undergoing energy balance interventions • Little research during time periods during and right after therapy  Impact of therapy?  Impact on therapy success?  E.g., Biomarkers of inflammation related to fatigue  differential effects of energy balance on inflammation than in healthy individuals? Multiple exercise trials underway in Heidelberg Breast, HSCT, lung, soon pancreas With Karen Steindorf and Joachim Wiskemann
    31. 31. Summary and outlook • There are many possible mechanisms by which exercise/energy balance can affect cancer  These are likely to act in combination • Exercise/diet trials among overweight/obese show:  ↓ Inflammation in plasma and tissue • Substantial effect, but weight loss required  ↓ Oxidative stress  Effects on estrogens, adipokines, adipose gene expression  Immunity? DNA repair? • Studies in cancer patients are needed to understand mechanisms and substantiate recommendations for patients  Different setting for biomarkers, e.g., biomarkers of inflammation under therapy • Interdisciplinary studies are needed that address multiple dimensions of energy balance  Physical activity, biomarkers, adipose tissue, etc…
    32. 32. FHCRC: Anne McTiernan Kristin Campbell Mario Kratz Karen Foster-Schubert Clare Abbenhardt Marc Horton Kristin Campbell Peter Campbell Brandon Pierce Alanna Boynton Liz Poole Jessica Chubak Laura Hooper Julie Meyers NCT/DKFZ: Karen Steindorf Joachim Wiskemann Dirk Jäger Martina Schmidt Ursula Bollow Dominik van den Bergh + many others… Support : NIH Grants (TREC) Manfred Lautenschläger Stiftung Stiftung Leben mit Krebs Milon Colleagues and staff from the Heidelberg ISZB NIH TREC Initiative HEAL Study

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