This document discusses the relationship between excess body weight, metabolic risk factors, and pancreatic cancer. It summarizes several meta-analyses and prospective cohort studies that found increased risks of pancreatic cancer associated with higher BMI, diabetes, and blood glucose levels. Specifically, a BMI over 30 was associated with a 6-12 times increased risk of pancreatic cancer. Diabetes was also found to double the risk of pancreatic cancer. Multiple biomarkers related to inflammation and glucose metabolism were also found to correlate with higher risks of pancreatic cancer. However, the document notes that the exact mechanisms linking metabolic factors and pancreatic cancer require further study.

1. Excess body weight, metabolic risk
factors and pancreatic cancer
Rudolf Kaaks
Dept. of Cancer Epidemiology

2. Page 2 Rudolf Kaaks Obesity, Metabolism and Pancreatic Cancer
Incidence rates of pancreas cancer (men, all ages)

3. Page 3 Rudolf Kaaks Obesity, Metabolism and Pancreatic Cancer
Risk factors of pancreatic cancer
• Smoking
• Chronic pancreatitis
• Excess body weight
• Diabetes mellitus
• Allergies

4. Page 4 Rudolf Kaaks Obesity, Metabolism and Pancreatic Cancer
BMI and pancreas cancer risk –
meta-analysis of prospective cohort studies
Aune et al., Ann Oncol 2012 Overall summary RR = 1.10, for 5 kg/m2

5. Page 5 Rudolf Kaaks Obesity, Metabolism and Pancreatic Cancer
Aune et al., Ann Oncol 2012
BMI and pancreas cancer risk –
meta-analysis of prospective cohort studies

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Diabetes mellitus and pancreas cancer risk – meta-analysis of
prospective cohort studies
Ben et al., Eur J Cancer, 2011
Overall Summary RR ≈ 2.0
Duration
(yrs)
# studies RR
<1 3 5.38
1-4 5 1.95
5-9 4 1.49
≥10 4 1.47
>1 14 1.96
>5 11 1.83

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Associations (odds ratios) between BMI, type-2 diabetes
and pancreas cancer risk (EPIC, nested case-control study)
Pancreatic Cancer
Excess Body Weight Type 2 Diabetes Mellitus
BMI 25-30 : 2.40 ♂ / 3.92 ♀
BMI ≥ 30 : 6.74 ♂ / 12.41 ♀
1.82
BMI 25-30: 1.09 ♂ / 1.29 ♀
BMI ≥ 30: 1.50 ♂ / 1.46 ♀
(among non smokers)

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Relative risks of cancer, by quintiles/quartiles of fasting serum
glucose -- large prospective cohort studies
Korea; Jee et al. JAMA 2005 P-trend
Pancreas (M) 1.0 1.08 1.34 1.37 2.09 0.03
Pancreas (F) 1.0 1.27 1.39 1.99 1.67 0.04
Liver (M) 1.0 1.01 1.16 1.45 1.72 0.01
Kidney(M) 1.0 1.08 1.07 1.24 1.26 0.02
Austria; Rapp et al. Diabetologia 2006 P-trend
Liver (M) 1.59 1.00 2.63 3.50 4.58 0.001
Biliary tract (M+F) 0.92 1.00 1.90 3.74 3.35 0.0002
Endometrium (F) 0.78 1.00 1.63 0.84 1.62 0.05
Sweden; Stattin et al., Diabetes Care, 2007 P-trend
Pancreas (M+F) 1.0 1.19 1.11 2.49 0.006
Kidney (M+F) 1.0 1.35 1.49 2.08 0.09
Melanoma (M+F) 1.0 1.41 2.14 2.16 0.013
Endometrium (F) 1.0 1.32 1.16 1.86 0.02

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Relative risk of pancreas cancer, by levels of fasting glucose, insulin,
and insulin resistance – Stratified by follow-up time
Stolzenberg-Solomon et al., JAMA 2005

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Risk of pancreatic cancer by categories of HbA1c
(EPIC cohort)
Level
ptrend
1 2 3 4
HbA1c Cut-offs (%) 4.8-5.4 5.5-5.7 5.8-6.0 6.0-11.0
Crude 1.0 1.26 1.77 1.83
Adj. BMI,
smoking
1.0 1.28 1.78 1.67
Grote et al., Diabetologia 2011

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OR for pancreatic cancer by categories of C-peptide (EPIC)
overall, excluding diabetic subjects, and by fasting status
1 2 3 4 ptrend
Cases/Controls
All crude 1.0 1.42 1.38 1.42
adj. smoking, BMI 1.0 1.27 1.16 1.15
without T2D ** crude 1.0 1.25 1.06 1.15
adj. smoking, BMI
1.0 1.23 1.00 1.09
Non-fasting crude 1.0 1.44 1.21 1.44
adj. smoking, BMI
1.0 1.45 1.16 1.29
Fasting crude 1.0 1.39 1.38 2.20
(117/111) adj. smoking, BMI 1.0 1.22 1.22 1.90
** at blood donation Grote et al., Diabetologia 2011

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Relative risk for pancreatic cancer by quartiles of plasma C-peptide;
HPFS, NHS, PHS and WHI cohorts
All cases /
controls
46 / 144
1.00
40 / 141
0.82
36 / 143
0.78
75 / 143
1.52 (0.87 – 2.64)
Ptrend = 0.005
> 4 years
follow-up
29 / 103
1.00
30 / 91
1.10
27 / 107
0.99
51 / 98
1.90 (0.97 – 3.73)
Ptrend = 0.01
Fasting
Non-fasting
1.00
1.00
0.79
1.21
0.81
0.86
1.21 (0.66 – 2.24)
4.24 (1.30 – 13.8)
Ptrend = 0.19
Ptrend < 0.001
Michaud et al., CEBP 2007

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breast pancreas
colorectal prostate
Currie et al., Diabetologia, 2009
Metformin only
Metformin +
sulfonylurea
Sulfonylurea only
Insulin-based
Metformin only
Metformin + sulfonylurea
Insulin-based
Sulfonylurea only
Progression to solid tumor cancers in diabetics receiving
different glucose-lowering therapies.
UK General Practices study

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Adiponectin and pancreas cancer risk (prospective studies)
study cases / controls 1 2 3 4 5 ptrend
ATBC 311/510 1.00 0.76 1.12 1.08 1.00 0.78
adj. smoking 0.96 0.69 0.80 0.65 0.04
EPIC 452/452 1.00 0.94 1.07 0.67 0.045
Adj. BMI 1.00 1.20 0.77 0.20
adj. smoking 0.96 1.11 0.72 0.11
Never smokers 1.02 0.92 0.44 0.005
5 US
cohorts
468/1080
adj. smoking
(matched)
1.00 0.60 0.57 0.55 0.60 0.004
Stolzenberg-Solomon et al., Am J Epidemiol, 2008;
Grote et al., Int J Cancer, 2012;
Bao et al., JNCI, 2013

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Inflammation markers and pancreas cancer risk –
EPIC cohort
No associations for:
• CRP
• IL-6
• sTNF-R1
Grote et al., Br J Cancer 2012
sTNF-R2

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Serum CML (Nε-carboxymethyl-lysine) and pancreas cancer risk – EPIC
Grote et al., Cancer Epidemiol Biomarkers Prev, 2012

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Serum esRAGE and pancreas cancer risk – EPIC
Grote et al., Cancer Epidemiol Biomarkers Prev, 2012

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Serum CML (Nε-carboxymethyl-lysine), sRAGE and pancreas
cancer risk – ATBC cohort
study cases / controls 1 2 3 4 5 ptrend
CML 255/485 1.00 0.49 0.48 0.60 0.46 0.003
adj. smoking, BMI 0.49 0.47 0.58 0.45 0.003
sRAGE 255/485 1.00 0.75 0.69 0.35 0.39 0.0001
adj. smoking, BMI 0.72 0.69 0.36 0.40 0.0002
CML / sRAGE
ratio
255/485 1.00 1.45 1.30 1.38 2.02 0.01
adj. smoking, BMI 1.46 1.30 1.39 2.02 0.02
Jiao et al., Cancer Res, 2011

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Conclusions – Interpretation (i)
• BMI significantly, but not strongly associated with pancreas cancer risk,
and only among non-smokers.
• Pancreas cancer is associated with pre-existing, increased glycemia and
diabetes (mostly adult-onset); associations with serum insulin still unclear
• BMI correlates strongly with fasting insulin/insulin resistance, but only
weakly with blood glucose.
 Insulin resistance may not generally be the major cause of deteriorated
glucose metabolism
 interaction between insulin resistance and other (“host”) factors in
development of pancreatic beta-cell insufficiency.

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Relationships between insulin sensitivity and pancreatic β-cell
function, in normal and impaired glucose tolerance

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Conclusions – Interpretation (ii)
• Diabetes as cause, effect, or epi-phenomenon of pancreas cancer ?
• Is pancreas cancer associated with “pancreatogenic” (“type 3c”) diabetes?
• Role of inflammatory processes in (diabetes preceding) pancreas cancer?
• Causes for the large international differences in pancreas cancer
incidence are not well-understood.

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Thank you for your attention