Embed Size (px)
Citation preview
Update on Cholangiocarcinoma: What we have learned from the
International Hepatobiliary Neoplasia Biorepository
Roon Chaiteerakij, MDMayo Clinic, Rochester, MN
Outline
• International Hepatobiliary Neoplasia Biorepository (IHNB)
• Studies on cholangiocarcinoma
• How we use liver tissues collected from the IHNB to conduct research
©2013 MFMER | 3299636-3
The IHNB Collects Data and Samples of Patients with Liver, Bile duct and Gallbladder Cancer and Controls
Cancer cases Benign Liver Disease controls Healthy controls
Blood DNA plasma & serum
Urine, Stool & BileTumor & Benign tissue
Questionnaire
Clinical data
©2013 MFMER | 3299636-4
Hepatobiliary cancer
Tumor Tumor BiologyBiology
Novel Novel therapeuticstherapeutics
Early Early diagnosisdiagnosis
Epidemiology Epidemiology studystudy
Personalized Personalized oncologyoncology
Clinical Clinical outcomeoutcome
Our Goal is to Improve Prevention, Diagnosis and Treatment of Liver, Bile Duct and Gallbladder Cancers
©2013 MFMER | 3299636-5
Cholangiocarcinoma
Tumor Tumor BiologyBiology
Novel Novel therapeuticstherapeutics
Early Early diagnosisdiagnosis
EpidemiologyEpidemiologystudystudy
Personalized Personalized oncologyoncology
Clinical Clinical outcomeoutcome
Epidemiology: Understanding the Risk Factors for Hepatobiliary Cancers
©2013 MFMER | 3299636-6
Epidemiology Studies use Clinical Data, Risk Factor Questionnaires, and Blood Samples
Cancer casesHealthy controls
Blood DNA plasma & serum
Urine, Stool & BileTumor & Benign tissue
Questionnaire
Clinical data
Benign Liver Disease controls
Current Epidemiology Studies on Cholangiocarcinoma (CCA)
• Classification of CCA
• Incidence of CCA
• Clinical risk factors for CCA
• Genetic risk factors for CCA
Classification of CCA
CCA is not a single disease but a group of three separate diseases
The three have similarities, but also distinct differences
103 iCCA(intrahepatic)
71 pCCA(perihilar)
22 dCCA (distal)
Image Courtesy of Dr. Gregory Gores
Gallbladder
Cystic duct
Pancreas
Classification of Cholangiocarcinoma (CCA)
The Incidence Rate of Intrahepatic Cholangiocarcinoma
in Olmsted County, MN, US has Increased 7-fold
0.0
0.5
1.0
1.5
2.0
2.5Incidence rates
(Per 100,000 person-year)
1976-1990 1991-2000 2001-2008
2.1
Yang JD, et al. Am J Gastro 2012
P trend = 0.02
Year
0.3
0.8
103 iCCA(intrahepatic)
71 pCCA(perihilar)
22 dCCA (distal)
Image Courtesy of Dr. Gregory Gores
Gallbladder
Cystic duct
Pancreas
Classification of Cholangiocarcinoma (CCA)
0.0
0.5
1.0
1.5
2.0
2.5
1976-1990 1991-2000 2001-2008
2.1 iCCA
Year
1.31.5
2.2
1.9
1.4 dCCA
The Incidence Rate of Distal CCA has Decreased by 35%
0.8
0.3 0.6
pCCA
Incidence rates(Per 100,000 person-year)
Yang JD, et al. Am J Gastro 2012
Demographics of 1267 CCA Patients
Data from IHNB
iCCA
pCCA
dCCA
Distribution of location Proportion of Males(%)
iCCA pCCA dCCA
50%60% 63%
Mean age
(Year)
iCCA pCCA dCCA
61 6267
Factors associated with iCCA developmentRisk (fold)
PSC
Chaiteerakij, et al. Hepatology. 2013
Cirrhosis Diabetes Hepatitis C Smoking
82
8
43
1.5
Primary Sclerosing Cholangitis
Factors associated with iCCA developmentRisk (fold)
PSC Cirrhosis Diabetes DiabetesNo Metformin use
82
8
43
1.5
Metformin use was associated with 60% reduction in risk for iCCA
Chaiteerakij, et al. Hepatology. 2013
DiabetesMetformin use
5
2
Study of Effect of Metformin Treatment on Cholangiocarcinoma in Mice
Control
Metformin
Manuscript, in preparation
Epidemiologic study
• Current classification of CCA
• Clinical risk factors for CCA
• Genetic risk factors for CCA
• Planned GWAS for CCA
• Future directions
Is genetic variation associated with risk of CCA development?
Cancer casesHealthy controls
A
Single nucleotide polymorphism(SNP)
G
**
Is genetic variation associated with risk of CCA development?
A
Single nucleotide polymorphism(SNP)
TCG
GC
GC
CG
GC
Adenine (A) – Thymine (T)Cytosine (C) – Guanine (G)
Is genetic variation associated with risk of CCA development?
Cancer casesHealthy controls
Blood DNA Blood DNA (N = 370) (N = 740)
A
Single nucleotide polymorphism
G
**
Genetic Variation in COX-2 Gene is Associated with CCA Risk
Manuscript, submitted
% Increases in Risk300%
40%50%
rs2143417 rs689466 both
Epidemiologic study
• Current classification of CCA
• Clinical risk factors for CCA
• Genetic risk factors for CCA
• Planned GWAS for CCA
• Future directions
Genome Wide Association Study (GWAS)
GWAS for CCA
(N = 2000)
Cancer casesHealthy controls
Blood DNA Blood DNA (N = 4000)
* **** *** *** *** *** ***
Accrual for Phase I (n=1974)
MD Anderson Cancer Center (739) Mayo Clinic Rochester (728) Mayo Clinic Arizona (200)Mayo Clinic Florida (12) University of California, San Francisco (18)National Cancer of Institute
Alberta Health Services (44)University Health Network (62)
Imperial College, UK (140)
Biodonostia Research Institute, Spain (31)
Future Directions of Genetic Risk Studies in CCA
2014
GWAS Discovery phase: Complete accrual, Grant applicationValidation phase: Begin accrual
Whole exome sequencing
2015 2016 20182017
Genetic risk study in young-onset CCA
GWASValidation phase: Genotyping
18.4% 17.3% 11.5%Proportion of CCA patients aged < 50
iCCA pCCA dCCA
Summary• Genetic susceptibility for CCA remains
poorly understood
• Findings from GWAS of CCA will improve our understanding of
• genetic predisposition
• pathogenesis
• New information will support efforts at prevention, diagnosis and treatment
©2013 MFMER | 3299636-27
Cholangiocarcinoma
Tumor Tumor BiologyBiology
Novel Novel therapeuticstherapeutics
Early Early diagnosisdiagnosis
Epidemiologic Epidemiologic studystudy
Personalized Personalized oncologyoncology
Clinical staging system
Clinical Outcomes study: Developing a New Clinical Staging System for pCCA
Stage I
Single mass ≤ 3 cm
Stage II
Vascular encasementSingle mass ≤ 3 cm
Stage III
Intrahepatic and/or lymph node metastasisMass > 3 cm
Stage IV
Peritoneal metastasis
©2013 MFMER | 3299636-32
1 2 3 4 50
25
50
75
100
Stage I: 45.7 months (n=57)
Stage II: 13.8 months (n=89)
Stage III: 8.0 months (n=79)
Stage IV: 2.1 months (n=38)
Survival of pCCA Patients Classified by the New Staging System
P<0.0001
Years
Survival(%)
Manuscript, submitted
Cancer casesHealthy controls
Blood DNA plasma & serum
Urine, Stool & BileTumor & Benign tissue
Questionnaire
Clinical data
The International Hepatobiliary Neoplasia Biorepository Collects Liver Tissues
Benign Liver Disease controls
Completeresponse
Partial response
Noresponse
Best candidate drug is used for clinical therapy of the patient
Cancer tissue
Implant into mice
Next Generation Sequencing
Key driver mutations in CCA genome are identified
Candidate targeted drugs are tested in mice
* * *
©2013 MFMER | 3299636-35
Cholangiocarcinoma
Novel gene mutations
Targeted therapies
Clinical & genetic
risk factors
Genetic markers and biomarkers
Patient-derived
xenograft mouse model
Clinical staging system
Summary of Current Projects in the International Hepatobiliary Neoplasia Biorepository
Acknowledgements• Mayo Genome Consortia
• Dr. Manal Hasan, MD Anderson Cancer Center
• Dr. Mitesh J. Borad, Mayo Clinic, Scottdale, ARZ
• Dr. Tushar C. Patel, Mayo Clinic, Jacksonville, FL
• Dr. R. Kate (Katie) Kelley, University of California San Francisco
• Dr. Oliver Bathe, Alberta Health Service, Canada
• Dr. Sean Kelly, University Health Network, Canada
• Dr. Shahid Khan, Imperial College, UK
• Dr. Jesus Banales, Biodonostia Research Institute, Spain
• All CCA patients and family members
