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Harvie opac2013
- 1. Weight loss interventionsand 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 weightgain increases longevity & health span Metropolitan 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 1942 Nurses’ Health Study (N = 17,065) Each 1kg adult weight gain reduces odds of healthy survival at the age of 70 by 5% Sun Q et al BMJ 2009;339:b3796
- 4. Adult weight gainincreases risk of post menopausal breast cancer 2.0 2 1.6 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
- 5. Adult weight gainincreases 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 = 57,923 EPIC 2005 >3% IWHS 2005 >5% N=34,000 N = 10,106 Miyagi 2010 >3% Framingham N=2873 N = 23,788 2004 >3% PHCPS 2011>10% After menopause N = 99,039 IWHS 2005 >5% N= 34,000 NIHAARP 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 Surgery 30% weightloss 65% 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: preventweight 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 of RCT data?
- 9. Dietary breast cancer prevention - RCTs Women’s Health Initiative Canadian Diet & Breast 1993-2005 Cancer Prevention Study 1988 - 2005 N 48, 835 4690 Participants General population Breast density>50% Age 50 – 79 Age 30 – 65 BMI = 30 BMI = 23 Dietary 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 wholegrain Weight change- kg -2.4 vs + -0.4 +1.2 vs +2 HR breast cancer 0.91 (0.83 – 1.01) 1.19 (0.9 – 1.55)
- 10. Mediterranean & lowcarb diets better 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 breast cancer maintain > 5% weight loss at 5 years Dansinger et al . JAMA 2005;293:43-53.
- 12. Could intermittent energyrestriction be a better approach ? 5 days 0% Animal data Intermittent ER -25% equivalent or Energy 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 lowcarbohydrate 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 day weight loss low Med diet ad lib maintenance carbohydrate low low energy carbohydrate Drop Out N=4 N = 13 N = 10
- 14. Change in weight& body fat including 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 IECR Baseline Mean Change from -2 ICR DER -3 -4 -5 -6 P<0.01 0 1 2 3 4 Months
- 15. Results: reductions at3 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% <0.04 weight Waist -5.2 -4.7 -3.7 0.04 reduction (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 restricted days *Mean (95% confidence interval)
- 16. Additional 25% reductionin insulin on restricted days (n =14) Diet Group 2 day low carb energy restricted 14 2 day Ad lib low carb 12 Daily restricted Mediterranean Insulin 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 body fat and insulin. • 2 day ad lib low carb is equivalent to 2 days energy restricted diet • 1 day of restriction / week maintains weight loss
- 18. Weight control andenergy 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 - 2006 N 2437 3088 Age 48 – 79 18 - 70 Time post diagnosis Up to 1 year Up to 4 years Intervention 5 years 6 years Sustained fat reduction Transient fat reduction 20% vs 29% 20% vs 29% 12 vs 6 fruit & veg / day Weight change- kg -2.7 vs + 0.7 +0.5 vs +0.4 Disease free 0.76 (0.6 – 0.98) 0.96 (0.8 – 1.14) survival
- 22. Ongoing RCT ofweight loss after diagnosis in early breast cancer Trial Trialists Intervention Population N Results expected SUCCESS-C Hauner 24 months Overweight 3547 2014 Germany Diet and exercise after adjuvant 5-10% weight loss chemotherapy DIANA-5 Berrino WCRF Any weight 1208 2015 Italy recommendations Within 5 years 5 year FUP diagnosis ENERGY Rock 24 months Overweight 693 Vanguard USA Diet and exercise 5- Within 5 years for larger 10% weight loss diagnosis outcome 5 year FUP RCT NCKMA32 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 chemotherapy Outcomes 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 Tyrosine Kinase 3 ligand markers) • CVD risk parameters: lipids, blood pressure • Fitness, Quality of life, Dietary intake, Physical activity
- 24. Perspective • Need toprevent weight gain after diagnosis • Weight loss unlikely to be harmful but await results for randomised trials of weight loss
- 25. Who should wetarget for weight loss interventions ?
- 26. The metabolically healthyobese 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 mortality Nonobese IS HR P Obese IS 0.99 (0.46–2.11) 0.97 Nonobese IR 1.11 (0.90–1.36) 0.35 Obese IR 1.40 (1.08–1.81) 0.01 Cancer mortality Nonobese IS HR P Obese IS 1.04 (0.32–3.30) 0.95 Nonobese IR 1.09 (0.78–1.52) 0.64 Obese IR 1.52 (1.02–2.26) 0.04 Calori G et al Diabetes Care. 2011;34:210-5.
- 28. After diagnosis : AleaIacta 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 & futuredirections Need effective intervention to prevent weight gain for prevention and after diagnosis Weight loss- prevention Animal & observational data support weight loss/ energy restriction for prevention Randomised weight loss cancer prevention trials not feasible- 55,000 for breast cancer Need biomarker studies ; we need a cholesterol Choice of intervention (IER?) Weight loss- After diagnosis Await RCT data of weight loss after diagnosis Who will benefit from ER & what are the best interventions?
- 30. Acknowledgements FAMILY HISTORY LIFESTYLE COLLABORATORS CLINIC/PROCAS Tony Howell Mary Pegington Rob Clarke – Patterson Institute Gareth Evans Debbie McMullen Kath Spence – Patterson Institute Paula Stavrinos Kath Sellers Andy Sims – Breakthrough Edinburgh Louise Donnelly Ellen Mitchell Roy Goodacre - UOM R Greenhalgh Clare Wright Mark Mattson – NIH Baltimore Jenny Affen Pam Coates Jayne Beesley Genesis Volunteers FUNDING Genesis Breast Cancer Prevention National Institute of Health Research Breast Cancer Campaign WCRF Breast Cancer Research Trust
Editor's Notes
- #8 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
- #14 Change order
- #21 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
- #27 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 ?