Download Insulin and Metabolic Pathways in Endometrial Cancer

Insulin and Metabolic Pathways
y
in Endometrial Cancer
Marc J. Gunter, PhD
Reader/Associate Professor
Department of Epidemiology and Biostatistics
Imperial College, London
International Variation in Age-Standardized
Endometrial Cancer Incidence Rates,, 2012
Globocan, 2012
Obesity and Cancer Risk
Renehan et al., 2008
Trends in Overweight and Obesity
80%
Proportion overwe
eight
70%
60%
Canada
50%
England
USA
Spain
40%
Austria
Italy
Australia
30%
France
Korea
20%
1970
1980
1990
Year
2000
2010
2020
WHO, 2010
Obesity and Endometrial Cancer: Mechanisms
Exposures
Mechanisms
Diet
Growth
factors
Insulin
resistance
Adipokines
Inflammation
?
Biomarkers
Endpoint
Physical
activity
Obesity
Steroid
hormones
IGF-1
Insulin
Leptin
Estrogen
IGFBP 3
IGFBP-3
C P tid
C-Peptide
CRP
P
Progesterone
t
Free IGF-I
HbA1c
TNF-α
SHBG
Endometrial Cancer
Insulin and IGF-I Signalling
Experimental
E
i
t l data
d t
support a cancerpromoting effect of
insulin and IGF-I
Are circulating
levels of insulin
and IGF-I
associated
i t d with
ith
future endometrial
cancer risk?
Women’s Health Initiative
•
Case-Cohort Study of Insulin/IGF-I Axis in WHI-OS (93,676
postmenopausal women; 77 months of follow-up):
follow up):
–
–
–
–
Breast Cancer (900 cases) (Gunter et al., JNCI, 101(1):48-60)
C l
Colorectal
t lC
Cancer (500 cases)) (Gunter et al., Cancer Res, 68(1):329-37)
Endometrial Cancer (300 cases) (Gunter et al., CEBP, 17(1):921-9)
Representative Sub-cohort (900 subjects)
– Prospectively assess the association of insulin/IGF-axis
components
p
with these cancers while controlling
g for endogenous
g
estrogen levels.
– Fasting insulin
insulin, glucose
glucose, Total IGF-I
IGF I, Free IGF
IGF-II, IGFBP
IGFBP-3
3,
estradiol
Circulating Insulin, Free IGF-I, Estradiol and
Endometrial
do et a Ca
Cancer
ce Risk
s in tthe
e Women’s
o e s Health
ea t
Initiative
P<0.001
RR
P=0.02
Hazard
Ratio
Oestradiol
Ptrend = 0.01
0 01
IGF-I
Ptrend = 0.10
P=0.01
Quartile of Serologic Factor
Quartile of Serologic Parameter
Metabolic Subtypes in Obesity
Not all obesity is the same-is this relevant for cancer?
Metabolically-defined Obesity Subtypes and
E d
Endometrial
ti lC
Cancer Ri
Risk
k
WHI +EPIC (950 cases, 950 controls)
BMI<25 +
HOMA Q1-2
BMI<25 +
HOMA Q4
BMI>25 +
HOMA Q1-2
BMI>25 +
HOMA Q4
Insulin and IGF-I and Endometrial Cancer
•
Significant positive association between fasting insulin levels and
endometrial cancer risk
– Ri
Risk
k estimates
ti t generally
ll unaffected
ff t d b
by adjustment
dj t
t ffor BMI
BMI, estradiol,
t di l free
f
IGF
suggesting independent pathway
– Generallyy consistent with data from other cohort studies ((EPIC,, NYUWHS))
– Insulin resistance in the absence of obesity may be a significant risk factor for
endometrial cancer
•
Free IGF-I levels inversely related to endometrial cancer risk
– Unexpected but consistent with cross-sectional data
•
What is going on at the tissue level?
– Lack of data on expression of insulin/IGF pathways in different endometrial
tissues (normal, malignant)
– Serum versus local levels? Circulating IGF-I is regulated by GH and mainly
hepatic in origin; Uterine IGF-I regulated by estrogen
Molecular Pathologic Study of Insulin/IGF
Signaling
•
Normal Endometrium (hysterectomy samples)
•
•
Premenopausal women (n=80)
Postmenopausal women (n=56)
•
Hyperplasias (n=67)
•
(
,
)
Endometrioid Adenocarcinomas (n=1,230)
•
•
•
•
Stage I (n=78)
Stage II (n=408)
Stage III (n=598)
Stage IV (n=146)
•
FFPE, fresh frozen tissue, serum, risk factor data
•
BRTE (NCI); Albert Einstein College of Medicine (New York); Hammersmith,
Charing Cross Hospitals, (London); GOG-0210
Insulin and IGF-I Signalling
1. Comparison of
expression
across
endometrial
tissues
2. Impact of EC
Risk factors
3. Understand
circulating
versus local
levels
IR-IGF-P Receptor
Secretory
Proliferative
Insulin Receptor
Secretory
Proliferative
Insulin Receptor Expression in
Endometrial Tissues
P <0.001
40
35
Tra
anscripts
TranscriptsX
-6 -6
1010
X
30
25
20
15
10
5
0
Tiss e TType
Tissue
pe
Secretory Proliferative
*Normalized to 18s rRNA
CAH
Type I-II EC Type III-IV EC
Role of Sex Hormone and Insulin/IGF Axes in
Endometrial Cancer Prognosis
• Nested cohort study of 900 stage II-IV EA patients recruited to GOG0210
•Serum (obtained prior to surgery)
•Insulin, IGF-I, IGF-II, IGFBP-1, -3
•Estrogens, Progesterone, SHBG
• Fresh Frozen Tissue
•Gene expression (mRNA)-IGF-I, IGF-II, IGFBP-1, IGFBP-3, IR,
IGF-IR,, ER,, PR,, Akt,, PTEN
•Tumor Microarrays
•Immunohistochemical expression of IGF-IR, IR, Phospho-IGF-IR,
Phospho-Akt, PTEN, ER, PR
Insulin, IGF-I, IGFBP-3 and
Progression
og ess o Free
ee Su
Survival
a in GOG
GOG-0210
0 0
(287 recurrences to date)
RR
Hazard
Ratio
Oestradiol
Ptrend = 0.01
0 01
P<0.001
Quartile of Serologic Factor
Quartile of Serologic Parameter
IGF-I
Ptrend = 0.10
Multivariate model
includes age, stage,
grade, BMI
Metabolite Profiling and Endometrial Cancer
•Hyperinsulinemia is associated with increased risk of endometrial
cancer suggesting this pathway is important for endometrial
tumorigenesis but:
• Complex relationship with IGF-I for both risk and prognosis
• Predictive value of hyperinsulinemia is likely not high (common)
•
Are there biochemical pathways specific for endometrial cancer
development that increase a woman’s risk?
•
Example: Panel of 4 amino acids (Leu, Val, Phe, Ile) shown to
be predictive of DM-II risk beyond traditional risk factors and
insulin resistance (Wang et al., Nat Med. 2011; 17(4):448–453)
•
Case-control ((n=250)) study
y of metabolomic p
profiling
g and
endometrial cancer reported significant association with stearic
acid and acylcarnitines (Gaudet et al., J Clin Endocrinol Metab. 2012
97(9):3216-23)
Metabolomic Profiling and Endometrial Cancer Risk
•To investigate the association of metabolomic proflies with
endometrial cancer
• Profile 1
1,500
500 incident cases and 1
1,500
500 matched controls (2
(2-stage
stage design)
• E2C2: NHS, EPIC, CPS-II, NYUWHS, MEC
• Metabolomic platform at Broad Institute (>600 characterised metabolites;
unannotated peak data)
• Proportion of cases/controls with existing hormonal data (insulin, IGF-I,
steroid hormones)
•To
T assess the
th association
i ti off endometrial
d
t i l cancer risk
i k ffactors
t
with
ith
metabolite profiles
•
•
•
•
Anthropometric parameters
Genetic loci
Hormone profiles
Ethnicity
•To explore the extent to which metabolites explain the association
of endometrial cancer with its risk factors (mediation analyses)
INTERCEPT
Weight
loss
Serum
markers
• Insulin/IGF
• Inflammation
• Metabolomics
Tissue
markers
k
• Cancer
associated
molecular or
morphological
changes in
tissue
Collaboration with Professor Jane Wardle (UCL); CR-UK Funded
INTERCEPT
~300 obese subjects enrolled
Blood, urine, stool, colon
biopsies banked
Endometrial Tissue?
Intensive Weight
Loss (VLCD)
General Dietary
Advice
(10-20%)
(1-2%)
9-12 months
Blood, urine, stool,
colon biopsies banked
(i) Insulin/IGF/mTOR
(ii) Metabolomic Profiling
Acknowledgements/Collaborators
Imperial College
Others:
Elio Riboli
Hector Keun
Melissa Merritt
Maria Kyrgiou
Hani Gabra
Herbert Yu ((University
y of Hawaii))
JoAnn Manson (Harvard)
Garnet Anderson (Fred Hutchinson Cancer
Research Center)
M k Sherman
Mark
Sh
(NCI)
Louise Brinton (NCI)
Hannah Yang (NCI)
Mia Gaudet (ACS)
Jane Wardle (UCL)
Immaculata DeVivo (Harvard)
Sara Olson (MSKCC)
Anne Zelenuich-Jacquotte (NYU)
Albert Einstein College of
Medicine
Howard Strickler
Gloria Huang
Tom Rohan
Xiaonan Xue
Gloria Ho
Mark Einstein
Funding Sources Grants R01-CA93881 (H.
Strickler); R01-CA133010 (M. Gunter); CRUK; OCA(M. Gunter)