Download Obesity, inflammatory markers and endometrial cancer risk: results

WCRF conference: Nutrition, Physical Activity and Cancer Prevention
12-13 September 2010
Obesity, inflammatory markers
and endometrial cancer risk:
results from the EPIC study
Laure Dossus
Division of Cancer Epidemiology
Inflammation and cancer
Coussens and Werb, Nature, 2002
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Laure Dossus
Division of Cancer Epidemiology
Inflammation and cancer
•  Promotion of angiogenesis
•  Cell proliferation
•  Increased production of free radicals leading to
DNA damage
► tumor initiation and development
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Division of Cancer Epidemiology
Prospective studies
One major maker: C-reactive protein
Heikkila et al., 2009
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Division of Cancer Epidemiology
Prospective studies
Other markers: IL-6
Heikkila et al., 2009
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Division of Cancer Epidemiology
Prospective studies
Other markers: TNF-α
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Studies
Cancer
Cases
Markers
RR
Krajcik et al., 2003
Breast
142
TNF- α
+ receptors
N.S.
Il’yasova et al., 2005
Overall
296
TNF-α
N.S.
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Division of Cancer Epidemiology
Inflammation and EC
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Division of Cancer Epidemiology
Inflammation and EC
•  Central role of inflammation in the regulation of
endometrial mucosa growth and shedding during
menstrual cycle
•  Alterations of cytokine production in endometrial cancer
patients
•  Established risk factors for endometrial cancer are
associated with an inflammatory milieu: excess body
weight, type-II diabetes, low physical activity
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Laure Dossus
Division of Cancer Epidemiology
Inflammation and EC in EPIC
Study aims:
  to examine the association between blood
concentrations of inflammatory markers and
endometrial cancer risk
  to estimate the extent to which the association
between obesity and endometrial cancer is
mediated by inflammation
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Laure Dossus
Division of Cancer Epidemiology
The EPIC study
•  521,000 subjects (400,000
with biological samples )
•  Detailed questionnaire data
on diet, lifestyle, illnesses,
medication, reproduction,
anthropometry
•  Follow-up through cancer
registries, health insurance,
pathology registries, active
follow-up
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Division of Cancer Epidemiology
Study population
  Exclusions:
HRT or OC users at blood donation
prevalent cancers (except non melanoma skin cancer)
hysterectomized women
• 
• 
• 
  Case selection:
incident epithelial endometrial cancer
  Control selection:
up to two controls per case, individually matched on:
study center, age, menopausal status, time of the day of blood
collection, fasting status, menstrual cycle phase (pre only)
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Laure Dossus
Division of Cancer Epidemiology
Baseline characteristics
Cases (N=342) Controls (N=644)
Premenopausal
23.4%
22.4%
Postmenopausal
65.8%
66.8%
Perimenopausal / Unknown
10.8%
10.9%
Age at blood collection
56.5
56.6
Age at diagnosis
59.9
-
Lag time (years)
3.5
-
Body mass index (kg/m2)
27.6
26.0
Age at menopause
50.9
49.8
Number of FTP
2.3
2.4
Previous OC use
33.6%
43.5%
Previous HRT use
29.5%
16.7%
Diabetes
4.1%
3.5%
Current smokers
14.9%
17.7%
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Division of Cancer Epidemiology
Laboratory measurements
< LOQ
Intra-batch CVs
Inter-batch CVs
IL-6
0%
6.3%
8.2%
CRP
2%
6.8%
9.3%
IL-1Ra
50%
15.0%
27.7%
TNF-α
21%
16.7%
27.0%
sTNF-RI
sTNF-RII
0%
0%
5%
5%
6%
7%
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Division of Cancer Epidemiology
Correlation with BMI
adjusted for age at blood donation and laboratory batch
CRP IL-6
0.36
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0.33
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IL-1Ra
0.20
TNF-α sTNF-RI sTNF-RII
0.07
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0.14
0.18
Inflammatory markers & risk of EC
Crude
Cases/
CRP (ng/mL) Controls
< 581
68/152
581-1127
67/152
1128-285
89/152
> 2285
102/152
1.00
1.03
1.40
1.66
IL-6 (pg/mL)
< 0.85
0.85-1.20
1.21-1.78
> 1.78
71/150
66/151
75/152
115/150
1.00
0.94
1.10
1.76
IL-1Ra (pg/mL)
≤ 16.0
159/325
16.1-58.0
36/100
58.1-135.4
58/98
> 135.4
82/104
1.00
0.79
1.34
1.83
OR
Ptrend
OR
Ptrend
0.004
1.00
0.92
1.20
1.12
0.36
0.002
1.00
0.84
0.91
1.30
0.17
0.002
1.00
0.69
1.12
1.47
0.07
0.5
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Adj for BMI
1
2
Division of Cancer Epidemiology
0.5
1
2
Inflammatory markers & risk of EC
Cases/
Controls
TNF-α (pg/mL)
< 0.59
57/128
0.60-0.95
59/127
0.96-1.33
54/127
> 1.33
97/127
1.00
1.10
1.04
1.82
sTNFR1 (pg/mL)
< 856.4
54/128
856.5-987.7
60/129
987.8-1124.4
62/127
> 1124.5
92/127
1.00
1.13
1.26
1.96
sTNFR2 (pg/mL)
< 1583.4
56/128
1583.5-1815.9 50/128
1816.0-2147.8 78/128
> 2147.9
84/127
1.00
0.90
1.45
1.67
OR
Ptrend
OR
Ptrend
0.005
1.00
0.98
1.02
1.73
0.01
0.005
1.00
1.21
1.21
1.68
0.07
0.01
1.00
0.86
1.42
1.53
0.03
0.5
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Crude
1
2
Division of Cancer Epidemiology
Adjusted
0.5
1
2
Inflammation and EC in EPIC
Study aims:
  to examine the association between blood
concentrations of inflammatory markers and
endometrial cancer risk
  to estimate the extent to which the association
between obesity and endometrial cancer is
mediated by inflammation
9/17/10 |
Laure Dossus
Division of Cancer Epidemiology
Obesity, Inflammation and EC
OBESITY
Inflammation
cytokines↑
Peripheral
aromatization ↑
Insulin ↑
IGFBP-1 ↓
IGFBP-2 ↓
SHBG↓
Bio-active IGF-I ↑
OVARY
Androgens↑
Progesterone↓
ENDOMETRIAL CARCINOGENESIS
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Laure Dossus
Division of Cancer Epidemiology
Estrogens ↑
(post only)
Obesity, Inflammation and EC
For 258 cases & 452 controls, data were available on:
• C-peptide (a marker of pancreatic insulin secretion)
• Estrone
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Laure Dossus
Division of Cancer Epidemiology
Obesity, Inflammation & EC in EPIC
Obese vs. normal weight women
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Laure Dossus
Division of Cancer Epidemiology
Summary
•  Elevated inflammatory markers are associated with
endometrial cancer risk
•  Possible mediators of the association between
obesity and endometrial cancer
•  Also direct role in endometrial cancer development,
independently of BMI (TNF-α)
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Laure Dossus
Division of Cancer Epidemiology
Possible mechanisms
•  Indirect obesity-related effects:
o  Modulation of the aromatase activity by cytokines within the
adipose tissue
o  Development of insulin resistance
•  Direct effect on endometrial carcinogenesis (NF-kB
pathway)
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Laure Dossus
Division of Cancer Epidemiology
Acknowledgments
Rudolf Kaaks
Annie Lukanova
Susen Becker
Sigrid Henke
Britta Lederer
Sabina Rinaldi
David Achaintre
Thomas Cler
Bertrand Hemon
EPIC colleagues & participants
The study was funded by the WCRF grant 2007/13
9/17/10 |
Laure Dossus
Division of Cancer Epidemiology