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

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

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% 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

Tim.Byers@ucdenver.edu