This document summarizes the epidemiologic and biologic mechanisms linking obesity to increased cancer risk. Obesity is associated with increased risks of cancers of the breast, endometrium, colon, kidney, pancreas, and esophagus. Potential mechanisms include increased production of estrogens, insulin, inflammatory cytokines, and other growth factors induced by excess body fat. While weight loss is associated with reduced cancer risk and changes in metabolic factors in observational studies, large randomized trials are still needed to confirm causal relationships. Understanding the biologic pathways involved could help identify prevention and treatment targets.

1. Obesity as a cause of cancer:
Epidemiologic and biologic mechanisms
Tim Byers MD MPH
University of Colorado Cancer Center
Colorado School of Public Health
Tim.Byers@ucdenver.edu

2. Cause ?

3. Causes of car crashes
• Vehicle factors
– Manufacture, maintenance
• Road factors
– Design, maintenance
• Driver factors
– Biologic, behavioral
• Weather
• Bad luck

4. Correlates of obesity
• Behavioral
– Diet
– Physical activity
– Medical care
• Physiologic
– Hormonal
– Other growth factors
– Inflammation
– Micronutrients
– Microbiome
– Epigenome

5. BMI
Cancer

6. BMI
Cancer
Intermediaries
Micronutrients
Hormones
Other growth factors
Inflammation
Immune function

7. BMI
Cancer
Activity
Diet
Intermediaries
Micronutrients
Hormones
Other growth factors
Inflammation
Immune function

9. Obesity may be the most
important of all the nutritional
risk factors for cancer
• Many sites
• Men and women
• Preventable
• Modifiable

10. WCRF conclusions for Obesity
Convincing
• Postmenopausal Breast
• Endometrial
• Colorectal
• Esophagus
• Pancreas
• Kidney
Probable
• Premenopausal breast (reduced risk)
• Gallbladder
• Ovarian

11. BMI and cancer
Cancer BMI
Increment
RR of increased body fatness (95% CI) WCRF
Report date
Ovarian 5kg/m2
1.06 (1.02-1.11) 2013
Endometrial 5kg/m2
1.50 (1.42-1.59) 2012
Pancreatic 5kg/m2
1.10 (1.07-1.14) 2012
Colorectal 1kg/m2
1.02 (1.02-1.03) 2011
Postmenopausal breast 2kg/m2
1.05 (1.03-1.07) 2010
Premenopausal breast 2kg/m2
0.97 (0.95-0.99) 2010
Kidney 5kg/m2 1.31 (1.24-1.39) 2007
Gallbladder 5kg/m2
1.23 (1.15-1.32) 2007
Oesophageal no analysis 2007

12. WCRF estimates of preventable fraction of specific cancer
sites from body fatness
Source: www.wcrf.org/cancer_statistics/preventability_estimates/preventability_estimates_body_fatness

13. Breast Cancer

14. BMI and Breast Cancer
Premenopausal Post-menopausal

15. Postmenopausal breast cancer
risk and circulating estradiol
Quartile 1 Quartile 2 Quartile 3 Quartile 4
RR
Hankinson et al. JNCI 1998;90:1292-9 BMI

16. Circulating Sex Hormone Binding
Globulin and postmenopausal BMI
BMI

17. Mechanisms linking obesity
and breast cancer
• Estrogens
• SHBG
• Cytokines
• Insulin
• IGF / IGFBP3
• Innocent bystander ?
– Probably not

18. Obesity and risk of breast
cancer recurrence
• Recurrence risk increased among obese
(BMI > 30) vs normal weight (BMI<25)
• Obesity risk seen in various subgroups
– Postmenopausal
– Premenopausal
– ER positive
– ER negative
– Even with Tamoxifen
Obese
Not obese
Months
Recurrence-freesurvival

19. Obesity and mortality after
breast cancer diagnosis
• Protani et al. BC Res Treat 123:627-35 (2010)
• Metanalysis of 43 studies
• HR = 1.33 (1.21 to 1.47)
• Pre-men HR = 1.47; Post-men HR = 1.22

20. Endometrial Cancer and BMI
(CUP 2013)
RR=1.50 ( 1.42-1.59) per 5 kg/m2
I2
= 86% n=25
Mechanisms:
Estrogens
Estrogens
Estrogens
Estrogens
Cytokines

21. Ovarian Cancer and BMI
(CUP 2014)
RR=1.06 ( 1.02-1.11) per 5 kg/m2
I2
=55% n=25
Mechanisms:
Cytokines?

22. Colorectal Cancer

23. Colorectal cancer and nutrition
• Many nutritional factors associated with risk
– Obesity
– Physical inactivity
– F&V intake
– Red meats
– Alcohol
– Calcium
– Fiber

24. Colorectal Cancer and BMI
(CUP 2011)
RR=1.02 (1.02-1. 03) per 1 kg/m2
I2
=60% n=23
Mechanisms:
Cytokines ?
Insulin ?
IGF ?
Innocent
bystander ?
(maybe so)

25. CRC recurrence and BMI
• Meyerhardt et al. J Clin Oncol 26:4109-15 (2008)
• CALGB CRC adjuvant trials
• Neither BMI nor weight change were related to
recurrence or survival

26. Obesity and esophageal cancer
Very different histology and risk factor profiles
for cancers of the upper vs lower esophagus
Upper 2/3 of esophagus (squamous cell)
Tobacco
Alcohol
Lower 1/3 of esophagus (adenocarcinoma)
BMI

27. Mechanisms linking
obesity and
esophageal cancer
• GERD
• Cytokines ?

28. Pancreatic Cancer and BMI
(CUP 2012)
R =1.10 ( 1.07- 1.14) per 5 kg/m2
I2
=19% n=23
Mechanisms:
Cytokines
Insulin

29. Liver Cancer and
Excess Body Weight (EBW) and Obesity
Chen et al European J of Cancer 2012
Mechanisms:
Fatty liver
Cytokines

30. Prostate cancer and obesity
• Not a strong factor overall
• May be associated with
more aggressive disease
• Mechanisms not understood

31. Obesity related diseases
• Heart disease
• Stroke
• Diabetes
• Cancer
• Sleep apnea
• Arthritis
• Reproductive complications
• Gall bladder disease
• Others

32. DM,
CVD
Cancer

33. Behavioral factors
Diet
Physical activity
Adiposity
DM,
CVD
Cancer
Metabolic factors
Insulin, IGF
Cytokines
Hormones

34. How can we determine
causal pathways?
• Measure effect modification
– Works only for strong associations
• Conduct interventions
– Modulate weight and measure effects on cancer
– Modulate weight and measure effects on mediators
– Modulate mediators and measure effects on cancer

35. How can we determine
causal pathways?
• Measure effect modification
– Works only for strong associations
• Conduct interventions
– Modulate weight and measure effects on cancer
– Modulate weight and measure effects on mediators
– Modulate mediators and measure effects on cancer
• Draw pictures
– Combining imagination, hope, and PowerPoint is
intellectually hazardous

36. Does intentional weight loss
reduce breast cancer risk ?

37. How can we know that weight
loss will reverse cancer risk?
• Observational epidemiology
• Randomized controlled trials
– (large trials with cancer endpoints)
• Understanding of intermediary factors
– (proof of their modulation in small trials)

38. Breast cancer risk with weight
change after menopause
Eliassen et al. JAMA 296:193-201 (2006)

39. Weight change and
endometrial cancer risk
• Trentham-Dietz et al. Int J Epid 35:151-8 (2006)
• Case-control study (740:2342)
• OR = 0.7 for weight loss

40. Cancer risk
after bariatric surgery
• Sjostrom et al. Lancet Oncol 10:653-62 (2009)
• 14% to 27% wt losses followed for 15 years
• Women: HR = 0.58
• Men: HR = 0.97

41. Breast cancer risk reduction
compared to weight loss in 3 RCTs
Wt loss BC reduction
WHEL 0 pounds 0%
WHI 2 pounds 9%
WINS 6 pounds 20%

42. ENERGY Trial
• Collaboration between 4 US cancer centers
– Colorado (Tim Byers)
– Alabama (Wendy Demark)
– Saint Louis (Graham Colditz)
– San Diego (Cheryl Rock)
• 700 women 0.5 to 5 years after stage 1-2 BC treatment
• Randomized to group weight loss program vs control aimed
at 7% weight loss differential
• Vanguard for a 2400 patient trial with recurrence endpoint

43. RCT’s of intentional weight loss and
changes in cancer-relevant mediators
• Estradiol is reduced
• SHBG is increased
• Several cytokines are reduced
– CRP, IL6, TGF-alpha, leptin, others

44. CRP reduction with weight loss
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25 30 35 40
%CRPreduction
% body weight loss

45. Why do we need to understand
obesity-cancer intermediaries?
• Complete our understanding of cancer biology
• Create surrogates for cancer in trials
• Identify targets for prevention

46. Recommendations for research
• Find better ways to reduce obesity
• Invest in large-scale weight loss trials with
cancer endpoints
• Better understand the several mechanisms and
test their change in focused weight loss trials
• Thereby find ways to pharmacologically unlink
obesity and cancer

47. Obesity as a cause of cancer:
Epidemiologic and biologic mechanisms
Tim Byers MD MPH
University of Colorado Cancer Center
Colorado School of Public Health
Tim.Byers@ucdenver.edu