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 gain
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 gain increases
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 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 = 57,923
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% weight loss
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: 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 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 & low carb 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 energy restriction 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 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 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 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% <0.04
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% 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 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
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 of weight 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 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 ?
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 :
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 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
Notas del editor
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
Change order
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 ?
