Physical activity change: what biomarkerstell us about cancer mechanisms and effectsProf. Dr. Cornelia UlrichDirectorNational Center for Tumor Diseases (NCT)German Cancer Research Center (DKFZ)andFred Hutchinson Cancer Research Center,SeattleWorld Cancer Research FundObesity, Physical Activity &CancerApril 2013, London
The next 25 minutes• Evidence base for mechanisms linkingphysical activity to cancer• Mechanisms – results and questions Inflammation Immunity Oxidative stress and DNA repair Sex hormones, metabolic hormones,adipokines…• Mechanisms in cancer patients• Summary
Evidence base for mechanisms linkingphysical 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 measuringbiomarkers 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…
Evidence base for mechanisms linkingphysical activity to cancer risk (2)• Human intervention studies Experimental design (randomized controlled trial)allows direct measurement of effects and inference ofcausality Biomarkers can be “intermediate endpoints” in cancerresearchCRP 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
Physical activity is highly correlatedwith vitamin D levels (NHANES)25 (OH)Vit DFrequency of outdoor activity (times in past month)Scragg & Camargo, Am J Epi 2008Non-Hispanic White Mexican American Non-Hispanic Black
Exercise Trial – PhysicalActivity for Total Health Study• Randomized controlled trial examining in overweight,sedentary, postmenopausal women (n=173 PATH Study) the effects of a one-yearexercise intervention (5d/wk 45min) compared to a one-yearstretching program on cancer biomarkers(0, 3,12 months)• Very good adherence and minimaldrop out• Significant improvement in VO2 maxMcTiernan, Ulrich (IMEX) and colleagues
Alberta Physical Activity andBreast 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 controlsReduced 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 dietaryfiber confounding?Friedenreich et al, Cancer Prev Res 2012
Energy balance – is it aboutexercise or aboutweight loss? Better chubby and fitor thin at every price?
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-intensityexercise program, weight reduction diet,or both exercise + diet in postmenopausalwomen on body weight and composition,and cancer biomarkers
CRP concentrations % change as a result of12-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= .091.1%
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 ExerciseImaya, Ulrich, McTiernan et al. Cancer Res 2012
Percent leukocytes % change as a result of12-month diet or exercise intervention*-2.0%-9.2%P< .001-7.1%P< .001-2.5%p=.78Imaya, Ulrich, McTiernan et al. Cancer Res 2012
00.10.20.30.40.50.6Incidence ofcolds1st Qtr 2nd Qtr 3rd Qtr 4th Qtr12-month study periodExerciseControlP=0.02Chubak et al Am J Med 2006
No effects of exercise intervention on broadspectrum of biomarkers of immune function• No effects on Lymphocyte proliferationfrom cryopreserved cells Natural killer cellcytotoxicity Cell counts andphenotypes Immunoglobulins• Despite excellentretention, adherence andintervention efficacy• Value of snapshotimmune markers?Campbell P et al, J Appl Physiol 2008
Oxidative stress and DNA repair-- why do we expect effects?Exercise or general metabolism inducesoxidative DNA damage• Training of the DNA repair system throughexercise?• Reduced levels of oxidative damage?Supporting preliminary data from animalexperiments, cross-sectional studies(frequently athletes) and smallinterventions
-15-10-505%ChangeOverall By % gain in V02maxPhysical Activity for Total Health Study:Exercise reduces urinaryF2-isoprostane levels among those with greatesttraining efficacy (n=173)Campbell P et al. Med Sci Sports Exerc 2010CtrlExn.s.P-trend=0.005Ctrl***<55-15 >15No effects on DNA repair capacity overall, as measured by Comet AssayOther assays needed?(Habermann, Ulrich et al, in prep.)
NEW: Diet & Exercise interventions decrease serumleptin levels among postmenopausal women (n=439)051015202530Diet+Exercise Diet Exercise ControlLeptinµg/mLBaseline12 monthsAbbenhardt J Int Med 2013P<0.0001 P<0.0001 P<0.005
NEW: Diet, but not exercise interventionsincrease serum adiponectin levels amongpostmenopausal women(n=439)Abbenhardt C et al. J Int Med 20131010.51111.51212.51313.51414.515Diet+Exercise Diet Exercise ControlAdiponectinµg/mLBaseline12 monthsP=0.001 P=0.001N.S.
Alberta Physical Activity andBreast Cancer Prevention Trial(Friedenreich et al)• Across the study period comparingexercise group to controls (treatmenteffect ratio:statistically significant reduction inleptin (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
Half-time summary• Intervention trials of exercise have shownsignificant and reproducible effects onbiomarkers 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, butnot all mechanisms
Inflammation -What’s fat got to do with it?
Targeting tissue – effects ofenergy balance on adiposetissue biology• Adipose tissue is active in metabolism and synthesisof 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 baselineand 6 months
Adipose tissue biopsies andbiomarkersCollagenasedigestion AdipocytesStromavascular cells (SVC)for flow cytometry (Kratz)Snap-frozenwhole tissue forRNA extractionand geneexpressionBiopsy:subcutaneous abdominal fatlocal anaesthetic (incision, 14-gauge needle)yield ~ 500 mgCampbell, Ulrich et al. Cancer Prev Res 2013Analysis:• candidate genes• candidate pathways• unsupervised clustering• By intervention• By weight-loss
Weight loss affects adiposetissue gene expression• Analysis by weight loss:% change P trendadj. PvalueSex Steroid-Related:HSD17B1 -0.35 0.0002 0.01ESR1 0.24 0.0037 0.08STS -0.26 0.0198 0.20HSD17B10 -0.05 0.045 0.37Inflammation-Related:CRP 0.23 0.0081 0.13ICAM4 -0.09 0.0110 0.13SAA1 -0.38 0.0110 0.13VCAM1 0.34 0.044 0.37Other Genes of Interest:LEP -0.44 0.0000 0.00IGFBP3 0.37 0.0032 0.08Campbell, Ulrich et al. Cancer Prev Res 2013
–omics results• Unsupervised clustering of >37,000 transcriptsby weight loss• Reveals 78 transcripts with statisticallysignificant adjusted p-values Multiple hits in histone clusters Leptin is #33 suggests strong effects ofweight loss on other pathways in adiposetissue• However: unsupervised approach results alsomisses significant hits in candidate pathways(=false negatives)• Combination of hypothesis-driven andempirical approach is complementary!!Campbell, Ulrich et al. Cancer Prev Res 2013
6m 12m 24m 36mTreatmentinformation• Blood draws• Urine• Feces• Questionnaires onsymptoms, QoL ¤t health habits,Food frequency (FFQs)• Accelerometer3m• Questionnaireson symptoms,QoL & currenthealth habitsSurgery• Pre-surgery blood• Urine• Feces• Tumor & normal tissue• Visceral & subcutaneousadipose tissue• Fascia• QuestionnairesOutcomes•Surgical outcomes•Treatment toxicity• Recurrence• Survival• Symptoms, QoLBaselineDiagnosisColoCare – Study DesignMulticenter colorectal cancer patient cohort
Exercise in the adjuvant therapy ofcancer patientsThere is substantial potential for exercise in aiding in the recovery ofcancer patients unknowns regarding type, timing, intensity and duration of interventionClinical trial: n=170 hematopoietic stem-cell transplantation patients exercise prior to and during the transplant process cancer-related fatigue, distress and physical functioning/fitnessPFS (months)Wiskemann, Blood 2011Greatest benefiton physical fitnessin the initiallyunfit!
Biomarkers in cancer patients undergoingenergy balance interventions• Little research during time periods during andright after therapy Impact of therapy? Impact on therapy success? E.g., Biomarkers of inflammation related tofatigue differential effects of energy balanceon inflammation than in healthy individuals?Multiple exercise trials underway inHeidelbergBreast, HSCT, lung, soon pancreasWith Karen Steindorf and Joachim Wiskemann
Summary and outlook• There are many possible mechanisms by whichexercise/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 understandmechanisms and substantiate recommendations forpatients Different setting for biomarkers, e.g., biomarkers ofinflammation under therapy• Interdisciplinary studies are needed that address multipledimensions of energy balance Physical activity, biomarkers, adipose tissue, etc…
FHCRC:Anne McTiernanKristin CampbellMario KratzKaren Foster-SchubertClare AbbenhardtMarc HortonKristin CampbellPeter CampbellBrandon PierceAlanna BoyntonLiz PooleJessica ChubakLaura HooperJulie MeyersNCT/DKFZ:Karen SteindorfJoachim WiskemannDirk JägerMartina SchmidtUrsula BollowDominik van den Bergh+ many others…Support : NIH Grants (TREC)Manfred Lautenschläger StiftungStiftung Leben mit KrebsMilonColleagues and staff from theHeidelberg ISZBNIH TREC InitiativeHEAL Study