Insulin and Metabolic Pathways in Endometrial Cancer · Insulin and Metabolic Pathways in...
Transcript of Insulin and Metabolic Pathways in Endometrial Cancer · Insulin and Metabolic Pathways in...
Insulin and Metabolic Pathways yin Endometrial Cancer
Marc J. Gunter, PhDReader/Associate ProfessorDepartment of Epidemiology and BiostatisticsDepartment of Epidemiology and BiostatisticsImperial 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
70%
80%
60%
eigh
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50%
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USAEngland
Canada
40%
P Spain
Austria
Australia
Italy
30% France
Australia
Korea
20%1970 1980 1990 2000 2010 2020
Year
WHO, 2010
Obesity and Endometrial Cancer: Mechanisms
Exposures ObesityDiet Physicalactivity
Mechanisms Growth factors
Adipokines Inflammation
Steroid hormones
Insulin resistance
?Biomarkers
Insulin
C P tid
Estrogen
P t
Leptin
CRPIGF-1
IGFBP 3
?C-Peptide
HbA1c
Progesterone
SHBG
CRP
TNF-αIGFBP-3
Free IGF-I
Endometrial CancerEndpoint
Insulin and IGF-I Signalling
E i t l d tExperimental data support a cancer-promoting effect of insulin and IGF-I
Are circulating levels of insulin and IGF-I
i t d ithassociated with 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):postmenopausal women; 77 months of follow up):
– Breast Cancer (900 cases) C l t l C (500 )
(Gunter et al., JNCI, 101(1):48-60)
– Colorectal Cancer (500 cases)– Endometrial Cancer (300 cases) – Representative Sub-cohort (900 subjects)
(Gunter et al., Cancer Res, 68(1):329-37)
(Gunter et al., CEBP, 17(1):921-9)
– Prospectively assess the association of insulin/IGF-axis components with these cancers while controlling for endogenous p g gestrogen levels.
– Fasting insulin glucose Total IGF-I Free IGF-I IGFBP-3Fasting insulin, glucose, Total IGF I, Free IGF I, IGFBP 3, estradiol
Circulating Insulin, Free IGF-I, Estradiol and Endometrial Cancer Risk in the Women’s Health do et a Ca ce s t e o e s ea t
Initiative
RR P<0.001
OestradiolP 0 01
Hazard Ratio
P=0.02
Ptrend = 0.01
IGF-IPtrend = 0.10trend =
P=0.01
Quartile of Serologic ParameterQuartile of Serologic Factor
Metabolic Subtypes in Obesity
Not all obesity is the same-is this relevant for cancer?
Metabolically-defined Obesity Subtypes and E d t i l C Ri kEndometrial Cancer Risk
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 riskRi k ti t ll ff t d b dj t t f BMI t di l f IGF– Risk estimates generally unaffected by adjustment for BMI, estradiol, free IGF suggesting independent pathway
– Generally consistent with data from other cohort studies (EPIC, NYUWHS)y ( , )
– 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 SignalingSignaling
• Normal Endometrium (hysterectomy samples)• Premenopausal women (n=80)• 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 acrossacross endometrial tissues
2. Impact of EC2. Impact of EC Risk factors
3. Understand circulatingcirculating versus local levels
IR-IGF-P Receptor Insulin Receptor
Secretory Secretory
Proliferative Proliferative
Insulin Receptor Expression in Endometrial Tissues
40
Endometrial TissuesP <0.001
30
35
20
25
Tran
scrip
ts
X 1
0-6
ansc
ripts
X
10-6
10
15
Tra
0
5
Tiss e T peTissue Type
Secretory Proliferative CAH Type I-II EC Type III-IV EC
*Normalized to 18s rRNA
Role of Sex Hormone and Insulin/IGF Axes in Endometrial Cancer Prognosis
• Nested cohort study of 900 stage II-IV EA patients recruited to GOG-0210
•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 Free Survival in GOG-0210og ess o ee Su a GOG 0 0
(287 recurrences to date)
RR
OestradiolP 0 01
Hazard Ratio
Ptrend = 0.01
IGF-IPtrend = 0.10
P<0.001
trend =
Quartile of Serologic ParameterQuartile of Serologic Factor
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 of metabolomic profiling and ( ) y p gendometrial 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 1 500 incident cases and 1 500 matched controls (2 stage design)• Profile 1,500 incident cases and 1,500 matched controls (2-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)
T th i ti f d t i l i k f t ith•To assess the association of endometrial cancer risk factors with metabolite profiles
• Anthropometric parameters• Genetic loci• 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
WeightWeight loss
Serum markers
• Insulin/IGF• Inflammation• Metabolomics
Tissue k
• Cancer associated molecular or morphologicalmarkers 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 AdviceLoss (VLCD)
(10-20%)Advice
(1-2%)
9-12 months
Blood, urine, stool, colon biopsies banked
(i) Insulin/IGF/mTOR (ii) Metabolomic Profiling
Acknowledgements/CollaboratorsImperial College
Elio Riboli
Others:
Herbert Yu (University of Hawaii)Hector KeunMelissa MerrittMaria Kyrgiou
( y )JoAnn Manson (Harvard)Garnet Anderson (Fred Hutchinson Cancer Research Center)M k Sh (NCI)Hani Gabra
Albert Einstein College of Medicine
Mark Sherman (NCI)Louise Brinton (NCI)Hannah Yang (NCI)Mia Gaudet (ACS)Medicine
Howard StricklerGloria Huang
Mia Gaudet (ACS)Jane Wardle (UCL)Immaculata DeVivo (Harvard)Sara Olson (MSKCC)Gloria Huang
Tom RohanXiaonan XueGloria Ho
Sara Olson (MSKCC)Anne Zelenuich-Jacquotte (NYU)
Mark Einstein Funding Sources Grants R01-CA93881 (H. Strickler); R01-CA133010 (M. Gunter); CR-UK; OCA(M. Gunter)