1. Diet & exercise & breast cancer Mary Pegington Research Dietitian Genesis Prevention Centre & Nightingale Breast Screening Centre, University Hospital of South Manchester

2. Breast cancer rates are increasing 1-2% per year 2011 : 50,285 cases / year

3. Breast cancer incidence trends Bray et al Breast Cancer Research 6: 229, 2004 Europe 120 100 80 70 60 50 40 30 20 10 1960 197019801990 2000 Year Age standardised rate (world) Americas 120 100 80 70 60 50 40 30 20 10 1960 197019801990 2000 Year Age standardised rate (world) Asia/Oceania 120 100 80 70 60 50 40 30 20 10 1960 197019801990 2000 Year Age standardised rate (world) UK FINLAND SPAIN SLOVAKIA USA CANADA PUERTO RICO COLUMBIA AUSTRALIA JAPAN INDIA

4. Western lifestyle & breast cancer risk

5. loss or gain 2.0 gain 2.1-10.0 gain 10.1-20.0 gain >20.0 Weight gain (kg) Multivariate RR Adult weight gain increases risk of post menopausal breast cancer 1.0 1.2 1.6 2.0 0 0.5 1 1.5 2 Huang et al JAMA 287: 1407, 1997, Colditz GA et al Arch Int Med 122: 481, 1995

6. loss or gain 2.0 gain 2.1-10.0 gain 10.1-20.0 gain >20.0 Weight gain (kg) Multivariate RR Adult weight gain increases risk of post menopausal breast cancer 1.0 1.2 1.6 2.0 0 0.5 1 1.5 2 12 Diabetes 3 Cardiovascular disease 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 Aleksandrova K et al Eur J Cancer. 2013 49:3526-36. 1.5 Colorectal cancer

7. Weight loss reduces breast cancer incidence Cohort studiesPopulationWeight lossRR Harvie et al 2005 34,000 postmenopausal women >5% ~3.5 kg 0.61 (0.46 – 0.80) Eliassen et al 2006 87,000 postmenopausal women >10kg ~ 15% 0.43 (0.25 – 0.86) Prentice et al 2006 48,835 postmenopausal women 2 kg ~3% 0.91 (0.83 – 1.01) Teras et al 2011 Bariatric surgery 13,055 overweight & obese postmenopausal women >5 kg ~7% 0.78 (0.55 – 1.10)

8. Obesity and Cancer Hursting SD & Hursting MJ Arterioscle Thomb Vasc Biol 32: 1766, 2012

9. Premenopausal weight is important Excess weight increases risk age >35yrs - General population (Peacock et al Am J Epidemiol. 1999) - Family History (Cecchini et al Cancer Prev Res 2012) Pre menopausal weight gain increases postmenopausal risk UK data shows 10/12 kg of adult weight gain occurs by age of 50 (Health Survey England 2012)

10. Exercise & breast cancer Each hour of exercise/ week reduces risk of breast cancer by 6% Aim for 3 hours of exercise / week Friedenreich Recent Results Cancer Res. 2011;188:125-39

11. -27% -24% -18% <1% <22 22-24.9 25-29.9 >30 Friedenreich Recent Results Cancer Res. 2011;188:125-39. BC risk reduction BMI “Fit and Fat” does not protect against breast cancer

12. Alcohol 10 units / week vs. no drinking increases BC risk by 10% BUT No alcohol increases risk of heart disease by 40% No alcohol increases risk of dying from any cause by 13% Lowest risk for dying from any cause with 3–15 g/day Higher risk for dying from any cause with >60 g/day Ronksley P E et al. BMJ 2011;342:bmj.d671

13. Recommended Mediterranean diet

14. Weight control and energy restriction after diagnosis

15. Niraula S et al Breast Cancer Res Treat. 2012 134:769-81 Obesity & overall survival Obesity & breast cancer survival 20% more likely to die from any cause 26% more likely to die from breast cancer

16. Weight gain after diagnosis 60 - 75% of patients gain weight after diagnosis Most weight gained during first year Weight gain persists - long term problem Greatest weight gain in: premenopausal, adjuvant chemotherapy, thinner women, chemotherapy induced menopause

17. Dietary interventions - RCT WINS – 1994-2004 WHEL 1995 - 2006 N2437 3088 Age 48 – 7918 - 70 Time post diagnosisUp to 1 yearUp to 4 years Intervention 5 years Sustained fat reduction 20% vs 29% 6 years Transient fat reduction 20% vs 29% 12 vs 6 fruit & veg / day Weight change- kg-2.7 vs + 0.7+0.5 vs +0.4 Disease free survival 0.76 (0.6 – 0.98)0.96 (0.8 – 1.14)

18. Kwan ML et al CEBP 2013 22(1): 32–41. Trend for increased alcohol & reduced overall mortality & cardiovascular mortality Alcohol after diagnosis

19. 2.5 hours of moderate activity /week & outcome (n = 13,302) RecurrenceBreast cancer mortality All cause mortality Normal weight 0.93 (0.81 – 1.07) 0.72 (0.61 – 0.86) 0.72 (0.63 – 0.83) Overweight 0.98 (0.85 – 1.14) 0.78 (0.65 – 0.94) 0.69 (0.59 – 0.81) Obese 0.96 (0.77 – 1.19) 0.72 (0.61 – 0.86) 0.86 (0.7 – 1.06) Beasley et al Breast Cancer Res Treat 2012 ; 131 : 637 - 643

20. 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.

21. Our first intermittent study RCT of IER vs. daily restriction 2006-2009 1. Is intermittent energy restriction acceptable & easier to follow than daily restriction? 2. Does IER have better effects on risk markers for breast cancer, diabetes, CVD compared to daily restriction?

22. Change in weight & body fat including drop outs (N = 115) P<0.05 P<0.01

23. Intermittent diet study 2 - Summary IER superior to daily restriction for reducing body fat and insulin. IER superior to daily restriction for reducing body fat and insulin. 1 day of restriction / week maintains weight loss 1 day of restriction / week maintains weight loss

24. Intermittent diets may reduce chemotherapy toxicity Animal studies and case studies suggest IER may reduce chemotherapy toxicity May reduce oxidative stress & upregulate stress response mechanisms. B-AHEAD 2 will look at the effects on chemotherapy toxicity: self report data and two novel blood biomarkers Safdie et al Aging (Albany NY) 2009 1:988-1007 Lee et al Sci Transl Med 2012 7;4 (124)

25. B-AHEAD 2 Study 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 n = 170 Scheduled to receive adjuvant or neoadjuvant chemotherapy 2 day / week IER (& exercise) Individual advice and telephone support Group 1: n = 85 Group 2: n = 85 Daily energy restricted diet (& exercise) Individual advice and telephone support 4 ½ to 6 months of chemotherapy

26. Acknowledgements FAMILY HISTORY CLINIC/PROCAS Tony Howell Gareth Evans Paula Stavrinos Louise Donnelly R Greenhalgh Jenny Affen Jayne Beesley LIFESTYLE Michelle Harvie Mary Pegington Debbie McMullen Kath Sellers Ellen Mitchell Pam Coates Lesley Coates Cheryl Barlow Nina Brogden Genesis Volunteers FUNDING FUNDING Genesis Breast Cancer Prevention National Institute of Health Research Breast Cancer Campaign WCRF Breast Cancer Research Trust Rob Clarke – Patterson Institute Kath Spence – Patterson Institute Andy Sims – Breakthrough Edinburgh Roy Goodacre - UOM Mark Mattson – NIH Baltimore COLLABORATORS The Patients

27. Any questions?