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  • Breast not sig adamsptre men 0.96 ( o,. 87 – 1.67) simila with post sjorstrom 0.71 ( 0.4 to 1.23) p = 0.24ostlund 0.55 low risk compared to gen population which did not decrease with surgeryIns sensitising effects reduced gherelin and anti incretin also delivery of food direct to jejujunum increases gut hormones peptide yy ad glp-1 which increase incretin and insullun production and sensitivity
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  • Observational evidence for weight change after diagnosis Weight gain increases overall mortality in us and china cohorts not specific bc mortality 15% increase however weight loss was linked to poorer outcome non bc mortality but not bcmortlaityEspecially in women with co morbiditiesCould be real or as weight loss is more commonly seen in women who are overweight or obese ate diagnosis could be residual confounding from thisAlso could be unintentional weight loss due to other conditions exp as linked mainly to non bc deaths and seen in women with co morbidities
  • Typicall 1/3 of obese are metabolically helathy 1/3 normal weight are not and 50% of overweight metabolically helathy and unhealthy is it just metabolically abnormal who are at higher risk ?

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  • 1. Weight loss interventions and cancer risk reduction Michelle Harvie SRD PhD Genesis Prevention Centre & Nightingale Breast Screening Centre, University Hospital of South Manchester WCRF International/IASO joint conference April 16th 2013
  • 2. Weight loss & cancer risk reduction • Weight gain, weight loss & cancer risk: Observational evidence & trials • Optimal weight loss interventions • Weight control after diagnosis: Observational evidence & trials •Who should we target ? •Conclusions & future directions
  • 3. Preventing adult weight gainincreases longevity & health spanMetropolitan Life Insurance Company (N = 4,000,000)“The clients who lived the longest were the ones who maintained their body weight at the level for average 25-year-olds” Louis Dublin statistician at Metropolitan Life Insurance Company 1942Nurses’ Health Study (N = 17,065) Each 1kg adult weight gain reduces odds of healthysurvival at the age of 70 by 5% Sun Q et al BMJ 2009;339:b3796
  • 4. Adult weight gain increases risk of post menopausal breast cancer 2.0 2 1.6Multivariate RR 1.5 1.2 1.0 1 0.5 0 loss or gain gain gain gain 2.0 2.1-10.0 10.1-20.0 >20.0 Weight gain (kg) Huang et al JAMA 287: 1407, 1997
  • 5. Adult weight gain increases risk of post menopausal breast cancer 12 Diabetes 2.0 3 2 Cardiovascular 1.6 disease Multivariate RR 1.5 1.2 1.0 1 0.5 0 loss or gain gain gain gain 2.0 2.1-10.0 10.1-20.0 >20.0 Weight gain (kg)Huang et al JAMA 287: 1407, 1997, Colditz GA et al Arch Int Med 122: 481, 1995 Willett W et al JAMA 273: 461, 1995
  • 6. Modest weight loss (3-15%) reduces post menopausal breast cancer 18 – 50/60 years 30 – 50 years N = 57,923EPIC 2005 >3% IWHS 2005 >5% N=34,000 N = 10,106Miyagi 2010 >3% Framingham N=2873 N = 23,788 2004 >3%PHCPS 2011>10% After menopause N = 99,039 IWHS 2005 >5% N= 34,000NIHAARP 2007 >3% NHS 2006 >15% N=87,000 N=13,055 CPS-II >5% 0 0.5 1 1.5 2 2..5 3 0 0.2 0.4 0.6 0.8 1 1.2
  • 7. Bariatric Surgery30% weight loss65% daily energy restriction Direct effects of surgery Insulin sensitising: gut hormone & vagal effects Changes gut microbiome Low intakes of vit D, C, calcium, folic acid, B vits , zinc , iron, fibre Renehan Lancet Oncology 2009 10:640-1
  • 8. Perspective• Ideal: prevent weight gain during adult life• Risk reduction with weight loss at any age• No randomised trials of weight loss• Multiple health benefits of weight loss• Intervention important despite lack ofRCT data?
  • 9. Dietary breast cancer prevention - RCTs Women’s Health Initiative Canadian Diet & Breast 1993-2005 Cancer Prevention Study 1988 - 2005N 48, 835 4690Participants General population Breast density>50% Age 50 – 79 Age 30 – 65 BMI = 30 BMI = 23Dietary Intervention 6 years 10 Years Sustained fat reduction Sustained fat reduction 25% vs. 35% energy 30% vs. 20% energy 5 vs. 4 fruit and veg 5 vs. 4 wholegrainWeight change- kg -2.4 vs + -0.4 +1.2 vs +2HR breast cancer 0.91 (0.83 – 1.01) 1.19 (0.9 – 1.55)
  • 10. Mediterranean & low carb dietsbetter than low fat for weight loss Shai I et al. N Engl J Med 2008;359
  • 11. Calorie restriction is difficult to achieve and maintain in humans!• 25-30% adherence to low cal diets at 12 months• 20%- 40 achieve > 5% weight loss at 1 year• Only 20% of our women at high risk of breastcancer maintain > 5% weight loss at 5 years Dansinger et al . JAMA 2005;293:43-53.
  • 12. Could intermittent energy restriction be a better approach ? 5 days 0% Animal data Intermittent ER -25% equivalent orEnergy restriction superior to daily restriction for reducing -75% 2 days 2 days spontaneous: Breast, prostate, 0 pancreatic tumours sarcoma & lymphoma 25% DER 25% ER 7 days / week energy restriction IER 75% ER 2 days/ week Harvie & Howell Proc Nutr Soc. 2012 Mar 14:1-13.
  • 13. RCT Intermittent low carbohydrate vs. daily ER Mediterranean diet High risk overweight women randomised to three groups N = 115 25% ER 25% daily 2 day 3 months 2 day low energy ad lib weight loss carbohydrate restriction low low energy Med diet carbohydrate 5 days Med 5 days Med diet diet 1 month 1 day Maintenance 1 dayweight loss low Med diet ad libmaintenance carbohydrate low low energy carbohydrateDrop Out N=4 N = 13 N = 10
  • 14. Change in weight & body fatincluding drop outs (N = 115) 0 Weight Baseline Mean IECR Change from -2 ICR DER -4 -6 -8 P<0.05 0 1 2 Months 3 4 0 Body Fat -1 IECRBaseline Mean Change from -2 ICR DER -3 -4 -5 -6 P<0.01 0 1 2 3 4 Months
  • 15. Results: reductions at 3 months n = 115 Restricted Ad lib Mediterranean 2 DAY 2 DAY Continuous P-value (n=37) (n= 38) (n=40)Losing > 5% 65% 60% 37% <0.04weightWaist -5.2 -4.7 -3.7 0.04reduction (cm) (-7.1 to -3.9) (-6.0 to -3.4) (-4.7 to -1.9)Insulin -22 -14 -4 0.02% change on (-35 to -11)% (-27 to -5%) (-16 to 9)%non restricteddays *Mean (95% confidence interval)
  • 16. Additional 25% reduction in insulin on restricted days (n =14) Diet Group 2 day low carb energy restricted 14 2 day Ad lib low carb 12 Daily restricted MediterraneanInsulin m/UL 10 N=5 8 N=3 N=6 6 4 Baseline 3 months After 3 days after 2 day restriction Restriction Immediate
  • 17. Intermittent diet study- Summary• IER superior to daily restriction for reducing bodyfat and insulin.• 2 day ad lib low carb is equivalent to 2 days energyrestricted diet• 1 day of restriction / week maintains weight loss
  • 18. Weight control and energy restriction after diagnosis
  • 19. Obesity at diagnosis & BC survival Overall survival Breast cancer survival Niraula S et al Breast Cancer Res Treat. 2012 134:769-81
  • 20. Weight loss & gain after diagnosis &outcome: Pooling project (N = 12,915) Caan BJ et al Cancer Epidemiol Biomarkers Prev. 2012 21:1260-71
  • 21. Dietary interventions - RCT WINS – 1994-2004 WHEL 1995 - 2006N 2437 3088Age 48 – 79 18 - 70Time post diagnosis Up to 1 year Up to 4 yearsIntervention 5 years 6 years Sustained fat reduction Transient fat reduction 20% vs 29% 20% vs 29% 12 vs 6 fruit & veg / dayWeight change- kg -2.7 vs + 0.7 +0.5 vs +0.4Disease free 0.76 (0.6 – 0.98) 0.96 (0.8 – 1.14)survival
  • 22. Ongoing RCT of weight loss after diagnosis in early breast cancerTrial Trialists Intervention Population N Results expectedSUCCESS-C Hauner 24 months Overweight 3547 2014 Germany Diet and exercise after adjuvant 5-10% weight loss chemotherapyDIANA-5 Berrino WCRF Any weight 1208 2015 Italy recommendations Within 5 years 5 year FUP diagnosisENERGY Rock 24 months Overweight 693 Vanguard USA Diet and exercise 5- Within 5 years for larger 10% weight loss diagnosis outcome 5 year FUP RCTNCKMA32 Goodwin 5 years Metformin Any weight 3582 2016 International 850mg bd after adjuvant chemotherapy
  • 23. B-AHEAD 2 Study n = 170 Scheduled to receive adjuvant or neoadjuvant chemotherapy Group 1: n = 85 Group 2: n = 85 2 day / week IER (& exercise) Daily energy restricted diet (& exercise) Individual advice and telephone support Individual advice and telephone support 4 ½ to 6 months of chemotherapyOutcomes 3 weeks post final chemotherapy• Weight, body fat (DXA), waist, hips• Breast cancer prognosis marker – insulin• Oxidative stress markers• Chemotherapy toxicity (self report & Cytokeratin 18 & FMS Like TyrosineKinase 3 ligand markers)• CVD risk parameters: lipids, blood pressure• Fitness, Quality of life, Dietary intake, Physical activity
  • 24. Perspective• Need to prevent weight gain after diagnosis• Weight loss unlikely to be harmful but await results for randomised trials of weight loss
  • 25. Who should we target for weight loss interventions ?
  • 26. The metabolically healthy obese Men Women v Wildman et al Arch Intern Med. 2008 168 :1617-24
  • 27. The metabolically healthy obese & cancer Cremona cohort 2011 men and women aged 40-65 15 year all cause mortality All-cause mortalityNonobese IS HR PObese IS 0.99 (0.46–2.11) 0.97Nonobese IR 1.11 (0.90–1.36) 0.35Obese IR 1.40 (1.08–1.81) 0.01 Cancer mortalityNonobese IS HR PObese IS 1.04 (0.32–3.30) 0.95Nonobese IR 1.09 (0.78–1.52) 0.64Obese IR 1.52 (1.02–2.26) 0.04 Calori G et al Diabetes Care. 2011;34:210-5.
  • 28. After diagnosis :Alea Iacta Est? or "Is the Die Cast?" Sparano et al Oncology 2011 25 1002 Creighton CJ, Breast Cancer Res Treat. 2012 132:993-1000
  • 29. Conclusions & future directions Need effective intervention to prevent weight gain for prevention and after diagnosisWeight loss- preventionAnimal & observational data support weight loss/ energy restriction for preventionRandomised weight loss cancer prevention trials not feasible- 55,000 for breast cancerNeed biomarker studies ; we need a cholesterolChoice of intervention (IER?)Weight loss- After diagnosisAwait RCT data of weight loss after diagnosisWho will benefit from ER & what are the best interventions?
  • 30. AcknowledgementsFAMILY HISTORY LIFESTYLE COLLABORATORSCLINIC/PROCASTony Howell Mary Pegington Rob Clarke – Patterson InstituteGareth Evans Debbie McMullen Kath Spence – Patterson InstitutePaula Stavrinos Kath Sellers Andy Sims – Breakthrough EdinburghLouise Donnelly Ellen Mitchell Roy Goodacre - UOMR Greenhalgh Clare Wright Mark Mattson – NIH BaltimoreJenny Affen Pam CoatesJayne Beesley Genesis Volunteers FUNDING Genesis Breast Cancer Prevention National Institute of Health Research Breast Cancer Campaign WCRF Breast Cancer Research Trust