1. Appraisal of Evidence for
Obesity Effects
Anne McTiernan, MD, PhD
Fred Hutchinson Cancer Research Center
Seattle, Washington, USA

2. Evidence in Humans
• Observational studies
– Adiposity and cancer risk
– Adiposity and prognosis:
• All cause
• Cancer-specific
• Other causes of death
• Other outcomes
– Associations with potential mechanisms
• Randomized controlled trials
– Prognosis outcomes (survival, recurrence)
– Biomarker outcomes: mechanisms

3. WCRF/AICR Second Expert Report: Body Fatness

4. Cancer Risk per 5kg/m2 ↑ in BMI: Women
Renehan et al. Lancet 2008;371:569-78.

5. Cancer Risk per 5kg/m2 ↑ in BMI: Men
Renehan et al. Lancet 2008;371:569-78.

6. Obesity & Overall Breast Cancer Survival
Protani et al.
Br Ca Res
Treat
2010;123:627-
35

7. Obesity & Breast Cancer Specific Survival
Protani et al. Br
Ca Res Treat
2010;123:627-
35

8. Survival Obese vs. Non-obese Breast Cancer Patients by Hormone
Receptor
Niraula et al. BCRT
2012;134:769-81

9. Survival Obese vs. Non-obese Breast Cancer Patients
by Menopausal Status
Niraula et al. BCRT 2012;134:769-81

10. Breast Cancer Specific Survival Obese vs. Non-obese Breast
Cancer Patients by Hormone Receptor
Niraula et al. BCRT 2012;134:769-81

11. Breast Cancer Specific Survival Obese vs. Non-obese Breast
Cancer Patients by Menopausal Status
Niraula et al. BCRT 2012;134:769-81

12. Potential Mechanisms for Adiposity Effect
Potential Mechanisms for Adiposity Effect
on Cancer Risk & Prognosis
on Cancer Risk & Prognosis
↑ inflammation
↑ inflammation
↑ estrogens
↑ estrogens
↑ adiposity
↑ adiposity ↑ androgens ↑ cancer
↑ cancer
↑ androgens
↓ prognosis
↓ prognosis
↑ insulin
↑ insulin
↑ glucose
↑ glucose
altered adipocytokines
altered adipocytokines
((↓adiponectin;↑ leptin)
↓adiponectin; ↑ leptin)

13. Diabetes & Cancer Risk: Men
Onitilo et al. Cancer Causes Control 2012;23:967-981,

14. Diabetes & Cancer Risk: Women
Onitilo et al. Cancer Causes Control 2012;23:967-981

15. Insulin & Breast Cancer Risk: Meta-analysis
Autier P et al. Cancer Causes Control 2013 (e-pub Feb.)

16. Breast Cancer Risk by Sex Hormone Concentrations
© Oxford University Press
The Endogenous Hormones and Breast Cancer Collaborative Group J
Natl Cancer Inst 2002;94:606-616

17. Risk of Breast Cancer Death by C-peptide
(HEAL, 571 stage I-IIIa patients,
followed up mean 4.1 years)
P trend = 0.03
5
4.5
4
3.5
Hazard Ratio
< 1.7 ng/mL
3
1.7-2.5 ng/mL
2.5
> 2.5 ng/mL
2
Diabetics
1.5
1
0.5
0
C-peptide
Irwin et al. J Clin Oncol 2011; 29(1):47-53

18. Risk of Death by C-Reactive Protein (HEAL, 734
stage I-IIIa patients, followed up mean 3.8 years)
P trend =0.01
2.5
2
Hazard Ratio
1.5 < 1.2 mg/L
1.3-3.8 mg/L
1 > 3.9 mg/L
0.5
0
Met-hr/wk
Pierce et al. J Clin Oncol 2009; 27(21):3437-44.

19. Randomized Clinical Trial Evidence

20. Effects of Dietary Weight Loss and Exercise
Interventions on Breast Cancer Biomarkers in
Overweight/Obese Postmenopausal Women

21. Study Aims
To examine the individual and combined effects
of 12-month dietary weight loss and exercise
interventions on:
- estrone, estradiol, free estradiol
- testosterone, free testosterone
- sex hormone binding globulin
- insulin resistance markers
- inflammation

22. Methods
• Randomized controlled trial
• 12-months duration
• N = 438
• Recruited through mass mailing & media
• Postmenopausal women (50-75 years old)
• BMI ≥25 kg/m2
• < 100 min/week of moderate-vigorous exercise
• Healthy
• No menopausal hormones
• Not smoking
• ≤ 2 alcohol drinks/day

23. Methods
Randomized
(N=438)
Control Dietary Diet + Aerobic
(N= 87) weight loss Exercise Exercise
(N=118) (N=116) (N=117)
Completed Completed Completed Completed
(N=80) (N=105) (N=108) (N=106)

24. Dietary Weight Loss Intervention
• Modified from Diabetes Prevention Program/Look Ahead* diet
interventions
• Individual goal 10% weight loss by 6 months, then maintenance
– Calorie deficit plus < 30% calories from fat
• 120-174: 1200 kcal
• 175-219: 1500 kcal
• 220-249: 1800 kcal
• ≥ 250: 2000 kcal
• 2-4 individual sessions + group sessions
– Weekly X 6 months, then monthly X 6 months with interim contacts
• Facility weighings at individual + group sessions
• > weekly self-weighings at home
• Daily food logs
• Participants attended a mean 91% of sessions
*Knowler et al. NEJM 2002; ;346:393-403; Wadden et al. Obesity 2006; 14:737-52

25. Exercise Intervention
• 45 minutes/day, 5 days/week
– 3 d/week facility (FHCRC Prevention Center)
– 2 d/week home
• Moderate-intensity aerobic activity (walking,
elliptical, biking, other sports)
– 60-75% VO2max
• 8 weeks progression to full program
– Start at 15 minutes; 40% VO2max
• 80% of target 225 min/week achieved

26. Baseline Characteristics & Attrition
• Age: 58 years
• 85% non-Hispanic white
• BMI: 31 kg/m2
• Weight 83 kg.
• 48 % body fat (DEXA)
• Aerobic fitness: 23 ml/kg/min (VO2max)
• No statistically significant differences by arm
• 9% lost-to-follow-up at 12 months

27. % Weight Change
normalized to baseline, 9% missing assumed no change
0
% Weight Loss
(from baseline)
-5 Diet
Diet+Ex
Ex
-10 Control
-15
Baseline 12 Months
Foster-Schubert et al. Obesity 2012 Aug;20(8):1628-38

28. Categories of % Weight Loss by Study Arm
Ex + Diet Diet Only Exercise Only Control (N=87)
(N=117) (N=118) (N=117)
Gained
(>0%)
3.4 7.6 24.8 46.0
0-5% loss 18.8 28.0 49.6 39.1
Moderate weight
loss 18.0 22.9 22.2 10.3
(5-9.9%)
Major weight loss
(≥ 10%)
59.8 41.5 3.4 4.6
Foster-Schubert et al. Obesity 2012 Aug;20(8):1628-38

29. Estrone: % Change
10
5
0
Control
-5 Diet Alone
Exercise Alone
-10 Diet + Exercise
* + *
-15
-20 *P<0.001 vs. CO
% Change Baseline to 12 Months
+ P<0.01 vs. CO
Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26

30. Estradiol: % Change
5
0
-5
Control
-10
Diet Alone
-15 Exercise Alone
-20 Diet + Exercise
* *
-25
-30 *P<0.001 vs. CO
% Change Baseline to 12 Months
Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26

31. Testosterone: % Change
2
0
-2
Control
-4 Diet Alone
Exercise Alone
-6 Diet + Exercise
-8 *
-10 *P=0.02 vs. CO
% Change Baseline to 12 Months
Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26

32. Sex Hormone Binding Globulin: % Change
30
25
20
15
10 Control
5 Diet Alone
0 Exercise Alone
-5 * * Diet + Exercise
-10
-15
-20 *P<0.001 vs. CO
% Change Baseline to 12 Months
Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26

33. Free Estradiol: % Change
10
5
0
-5
Control
-10
Diet Alone
-15 Exercise Alone
-20 Diet + Exercise
-25 * + *
-30
-35 *P<0.001 vs. CO
% Change Baseline to 12 Months
P=0.08 vs. CO
Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26

34. Free Testosterone: % Change
5
0
-5 Control
Diet Alone
-10 Exercise Alone
Diet + Exercise
-15
+ *
-20 *P<0.0001 vs. CO
% Change Baseline to 12 Months
+P<0.001 vs. CO
Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26

35. Estrone: % Change by Weight Change
10
5
0
Control
-5
Gain/lost < 5%
-10 Lost >=5%
* *
-15 +
-20 *Ptrend<0.001 vs. CO
Diet Only Exercise Only Diet + Exercise
+ Ptrend<0.01 vs. CO
Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26

36. Estradiol: % Change by Weight Change
10
5
0
-5
Control
-10
Gain/lost < 5%
-15 Lost >=5%
-20 * + *
-25
-30 *Ptrend<0.0001 vs. CO
Diet Only Exercise Only Diet + Exercise
+ Ptrend<0.01 vs. CO
Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26

37. Free Estradiol: % Change by Weight Change
10
5
0
-5
-10 Control
-15 Gain/lost < 5%
-20 Lost >=5%
-25 * +
-30
*
-35 *Ptrend<0.0001 vs. CO
Diet Only Exercise Only Diet + Exercise
+ Ptrend<0.001 vs. CO
Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26

38. Insulin: % Change
0
-5
-10
Control
-15
Diet Alone
-20 Exercise Alone
-25 Diet + Exercise
* *
-30
-35 *P<0.001 vs. CO
% Change Baseline to 12 Months
Mason et al. Am J Prev Med. 2011 Oct;41(4):366-75.

39. Similar Reductions with Weight Loss
• C-peptide
• HOMA (marker of insulin resistance
calculated from insulin & glucose)

40. Adiponectin: % Change
*
*
P<0.0001
Abbenhardt et al. J of Internal Medicine 2013 Feb 25.

41. Leptin: % Change
All p<0.005 vs. controls
Abbenhardt et al. J of Internal Medicine 2013 Feb 25.

42. C-Reactive Protein: % Change
%
1.1%
-11.4%
P= .09
- 37.7%
P= <.001
-46.9%
P= <.001
Imayama et al. Cancer Research 2012; 72(9); 2314–26

43. Interleukin-6: % Change
%
0.7%
-2.0%
P= .48
-21.9%
P< .001 -24.3%
P< .001
Imayama et al. Cancer Research 2012; 72(9); 2314–26

44. Cancer-related Biomarker Changes in the
Diabetes Prevention Program Weight Loss Diet
• Sex hormones
• Inflammation
• Insulin

45. Endogenous Sex Hormone Changes in
Postmenopausal Women in the Diabetes
Prevention Program
Kim C, Kong S, Laughlin GA, Golden SH, Mather KJ,
Nan B, Edelstein SL, Randolph JF Jr, Labrie F,
Buschur E, Barrett-Connor E.

46. Study Design
• 3-group randomized clinical trial
• 27 clinical sites
• Standardized across clinics:
– Common protocol and procedures manual
– Staff training
– Data quality control program

47. Eligibility Criteria
• Age > 25 years
• Plasma glucose
– 2 hour glucose 140-199 mg/dl (7.8- <11.1 mmol/L)
and
– Fasting glucose 95-125 mg/dl (5.3- <7.0 mmol/L)
• Body mass index > 24 kg/m2
• All ethnic groups
goal of up to 50% from high risk populations

48. Study Interventions
Eligible participants
Randomized
Standard lifestyle recommendations
Intensive Metformin Placebo
Lifestyle
(n = 1079) (n = 1073) (n = 1082)

49. Methods
• Secondary analysis to DPP trial
• N=382
• Eligibility:
– Postmenopausal
– Not using hormone therapy
– Available blood baseline & 1-year

50. Methods: Analytes
• Sex hormone binding globulin (SHBG)
• Follicle stimulating hormone (FSH)
• Total estradiol (E2) (20% undetectable)
• Total testosterone (T) (30% undetectable)
• Dehydroepiandrosterone (DHEA)

51. Lifestyle Intervention
An intensive program with the following
specific goals:
• > 7% loss of body weight and maintenance of
weight loss
– Dietary fat goal -- <25% of calories from fat
– Calorie intake goal -- 1200-1800 kcal/day
• > 150 minutes per week of physical activity

52. Interventions:
Medications
Metformin- 850 mg per day escalating after
4 weeks to 850 mg twice per day
parallel with active drugs

53. DPP: Unadjusted Changes in SHBG and Sex Hormones
levels
Kim C et al. JCEM 2012;97:2853-2861
©2012 by Endocrine Society

54. One-Year Weight Loss Effects on
C-Reactive Protein in Participants With
Impaired Glucose Tolerance: Median Changes
• Men:
– Lifestyle: -33%
– Placebo: +5%
– P<0.001
• Women:
– Lifestyle: -29%
– Placebo: 0%
– P<0.001
The Diabetes Prevention Program Research Group. Diabetes 2005; 54:
1566–1572

55. DPP Effects on Insulin Resistance
Diabetes Prevention Program Research Group. Lancet
2009;274:1677-1686.

56. Biomarker Issues
• Some are not well measured in humans
• High variability of measures
• Tissue difficult to obtain
• Mixed tissues for most sampling (for
example, breast biopsies might include
epithelium, stroma, inflammatory cells,
blood)
• Effects of adjuncts to biopsies (skin or other
preps, analgesics, anesthetics)
• Power issues if multiple markers (e.g. gene
expression)

57. Conclusions re: Biomarkers
• Still unanswered questions on obesity and
cancer biomarkers:
– Effects in specific populations (various
geographic areas, racial groups, high risk
persons)
– Different weight loss methods (surgery,
medications, types of diet)
– Direct tissue effects

58. Conclusions
• Obesity related to risk for many cancers
• Randomized controlled clinical trials in
humans support biological effects of weight
loss relevant to cancer
• > 5% weight loss produces greatest change
in metabolic and sex hormone levels

59. Problems/Issues with Research on Obesity & Cancer
• Biomarker studies may not reflect cancer effect
• Rodents are not humans and vice versa
• Survivorship studies at high risk of confounding
by disseminated disease and treatment effects
• Exposures poorly measured
• Adverse effects of exercise & weight loss largely
ignored
• Head-to-head comparisons of weight loss,
exercise, diet are rare
• Publication bias

60. Funding Sources
• U.S. National Cancer Institute
• U.S. National Institutes of Health
• Susan G. Komen for the Cure

61. Fred Hutchinson Cancer Research Center, Seattle, WA, USA