Date post: | 13-May-2015 |
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Obesity as a cause of cancer: Epidemiologic and biologic mechanisms
Tim Byers MD MPH
University of Colorado Cancer Center
Colorado School of Public Health
Cause ?
Causes of car crashes
• Vehicle factors– Manufacture, maintenance
• Road factors– Design, maintenance
• Driver factors– Biologic, behavioral
• Weather
• Bad luck
Correlates of obesity• Behavioral
– Diet– Physical activity– Medical care
• Physiologic– Hormonal– Other growth factors– Inflammation– Micronutrients– Microbiome– Epigenome
BMI
Cancer
BMI
Cancer
Intermediaries Micronutrients Hormones Other growth factors Inflammation Immune function
BMI
CancerActivity
Diet
Intermediaries Micronutrients Hormones Other growth factors Inflammation Immune function
Obesity may be the most important of all the nutritional
risk factors for cancer
• Many sites
• Men and women
• Preventable
• Modifiable
WCRF conclusions for ObesityConvincing
• Postmenopausal Breast• Endometrial• Colorectal• Esophagus• Pancreas• Kidney
Probable• Premenopausal breast (reduced risk)• Gallbladder• Ovarian
BMI and cancerCancer BMI
Increment RR of increased body fatness (95% CI) WCRF
Report date
Ovarian 5kg/m2 1.06 (1.02-1.11) 2013Endometrial 5kg/m2 1.50 (1.42-1.59) 2012Pancreatic 5kg/m2 1.10 (1.07-1.14) 2012Colorectal 1kg/m2 1.02 (1.02-1.03) 2011Postmenopausal breast 2kg/m2 1.05 (1.03-1.07) 2010Premenopausal breast 2kg/m2 0.97 (0.95-0.99) 2010Kidney 5kg/m2 1.31 (1.24-1.39) 2007Gallbladder 5kg/m2 1.23 (1.15-1.32) 2007Oesophageal no analysis 2007
WCRF estimates of preventable fraction of specific cancer sites from body fatness
Source: www.wcrf.org/cancer_statistics/preventability_estimates/preventability_estimates_body_fatness
Breast Cancer
BMI and Breast Cancer
Premenopausal Post-menopausal
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
Circulating Sex Hormone Binding Globulin and postmenopausal BMI
BMI
Mechanisms linking obesity and breast cancer
• Estrogens• SHBG• Cytokines • Insulin • IGF / IGFBP3 • Innocent bystander ?
– Probably not
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
Rec
urre
nce-
free
sur
viva
l
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
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
Ovarian Cancer and BMI(CUP 2014)
RR=1.06 ( 1.02-1.11) per 5 kg/m2 I2 =55% n=25
Mechanisms:
Cytokines?
Colorectal Cancer
Colorectal cancer and nutrition
• Many nutritional factors associated with risk
– Obesity
– Physical inactivity
– F&V intake
– Red meats
– Alcohol
– Calcium
– Fiber
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)
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
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)TobaccoAlcohol
Lower 1/3 of esophagus (adenocarcinoma) BMI
Mechanisms linking obesity and
esophageal cancer
• GERD
• Cytokines ?
Pancreatic Cancer and BMI(CUP 2012)
R =1.10 ( 1.07- 1.14) per 5 kg/m2 I2=19% n=23
Mechanisms:
Cytokines
Insulin
Liver Cancer and Excess Body Weight (EBW) and Obesity
Chen et al European J of Cancer 2012
Mechanisms:
Fatty liver
Cytokines
Prostate cancer and obesity
• Not a strong factor overall
• May be associated with more aggressive disease
• Mechanisms not understood
Obesity related diseases
• Heart disease• Stroke• Diabetes• Cancer• Sleep apnea• Arthritis• Reproductive complications• Gall bladder disease• Others
DM, CVD
Cancer
Behavioral factorsDietPhysical activityAdiposity
DM, CVD
Cancer
Metabolic factorsInsulin, IGFCytokines Hormones
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
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
Does intentional weight loss reduce breast cancer risk ?
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)
Breast cancer risk with weight change after menopause
Eliassen et al. JAMA 296:193-201 (2006)
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
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
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%
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
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
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
% C
RP
red
uct
ion
% body weight loss
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
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
Obesity as a cause of cancer: Epidemiologic and biologic mechanisms
Tim Byers MD MPH
University of Colorado Cancer Center
Colorado School of Public Health