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Update on Cholangiocarcinoma:
What we have learned from the
International Hepatobiliary Neoplasia Biorepository
Roon Chaiteerakij, MD
Mayo Clinic, Rochester, MN
[email protected]
Outline
• International Hepatobiliary Neoplasia
Biorepository (IHNB)
• Studies on cholangiocarcinoma
• How we use liver tissues collected
from the IHNB to conduct research
The IHNB Collects Data and Samples of Patients with
Liver, Bile duct and Gallbladder Cancer and Controls
Questionnaire
Clinical data
Tumor & Benign tissue
Blood DNA
plasma & serum
Urine, Stool & Bile
©2013 MFMER | 3299636-3
Our Goal is to Improve Prevention, Diagnosis and
Treatment of Liver, Bile Duct and Gallbladder Cancers
Tumor
Biology
Clinical
outcome
Epidemiology
study
Hepatobiliary
cancer
Early
diagnosis
Personalized
oncology
Novel
therapeutics
©2013 MFMER | 3299636-4
Epidemiology: Understanding
the Risk Factors for Hepatobiliary Cancers
Tumor
Biology
Clinical
outcome
Epidemiology
study
Cholangio
carcinoma
Early
diagnosis
Personalized
oncology
Novel
therapeutics
©2013 MFMER | 3299636-5
Epidemiology Studies use Clinical Data,
Risk Factor Questionnaires, and Blood Samples
Questionnaire
Clinical data
Tumor & Benign tissue
Blood DNA
plasma & serum
Urine, Stool & Bile
©2013 MFMER | 3299636-6
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
Classification of Cholangiocarcinoma (CCA)
103 iCCA
(intrahepatic)
71 pCCA
(perihilar)
Gallbladder
Cystic duct
Pancreas
Image Courtesy of Dr. Gregory Gores
22 dCCA
(distal)
The Incidence Rate of Intrahepatic Cholangiocarcinoma
in Olmsted County, MN, US has Increased 7-fold
Incidence rates
(Per 100,000 2.5
person-year)
P trend = 0.02
2.1
2.0
1.5
1.0
0.5
0.8
0.3
0.0
1976-1990
Yang JD, et al. Am J Gastro 2012
1991-2000
Year
2001-2008
Classification of Cholangiocarcinoma (CCA)
103 iCCA
(intrahepatic)
71 pCCA
(perihilar)
Gallbladder
Cystic duct
Pancreas
Image Courtesy of Dr. Gregory Gores
22 dCCA
(distal)
The Incidence Rate of Distal CCA has
Decreased by 35%
Incidence rates
(Per 100,000 2.5
person-year)
2.2
1.9
2.0
1.5
2.1 iCCA
1.5 pCCA
1.3
1.4 dCCA
1.0
0.5
0.8
0.3
0.6
0.0
1976-1990
Yang JD, et al. Am J Gastro 2012
1991-2000
Year
2001-2008
Demographics of 1267 CCA Patients
Distribution of location
(%)
Proportion of Males
50%
iCCA
(Year)
iCCA
60%
63%
pCCA
dCCA
Mean age
61
62
iCCA
pCCA
67
pCCA
dCCA
Data from IHNB
dCCA
Factors associated with iCCA development
Risk (fold)
82
8
4
3
1.5
PSC
Cirrhosis
Diabetes
Hepatitis C Smoking
Primary Sclerosing Cholangitis
Chaiteerakij, et al. Hepatology. 2013
Factors associated with iCCA development
Risk (fold)
82
8
5
4
3
1.5
PSC
Cirrhosis
Diabetes
Diabetes
No Metformin use
2
Diabetes
Metformin use
Metformin use was associated with
60% reduction in risk for iCCA
Chaiteerakij, et al. Hepatology. 2013
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?
A
*
G
*
Single nucleotide polymorphism
(SNP)
Is genetic variation associated
with risk of CCA development?
GAC
CTG
G GC
C CG
Adenine (A) – Thymine (T)
Cytosine (C) – Guanine (G)
Single nucleotide polymorphism
(SNP)
Is genetic variation associated
with risk of CCA development?
Blood DNA
(N = 370)
A
*
Blood DNA
(N = 740)
G
*
Single nucleotide polymorphism
Genetic Variation in COX-2 Gene is
Associated with CCA Risk
% Increases in Risk
300%
50%
rs2143417
Manuscript, submitted
40%
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
Blood DNA
(N = 2000)
** **
*** ***
Blood DNA
(N = 4000)
** **
*** ***
Accrual for Phase I (n=1974)
Alberta Health Services (44)
University Health Network (62)
Imperial College, UK (140)
Biodonostia Research Institute, Spain (31)
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
Future Directions of Genetic Risk Studies in CCA
GWAS
Discovery phase: Complete accrual,
Grant application
Validation phase: Begin accrual
2014
2015
2016
Genetic risk study in young-onset CCA
Proportion of CCA
patients aged < 50
18.4%
iCCA
GWAS
Validation phase: Genotyping
2017
2018
Whole exome sequencing
17.3%
pCCA
11.5%
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
Clinical Outcomes study:
Developing a New Clinical Staging System for pCCA
Tumor
Biology
Clinical
staging
system
Epidemiologic
study
Cholangio
carcinoma
Early
diagnosis
Personalized
oncology
Novel
therapeutics
©2013 MFMER | 3299636-27
Stage I
Single mass ≤ 3 cm
Stage II
Single mass ≤ 3 cm
Vascular encasement
Stage III
Mass > 3 cm
Intrahepatic and/or lymph node metastasis
Stage IV
Peritoneal metastasis
Survival of pCCA Patients Classified by
the New Staging System
Survival
(%) 100
P<0.0001
75
Stage I: 45.7 months (n=57)
50
Stage II: 13.8 months (n=89)
25
Stage III: 8.0 months (n=79)
Stage IV: 2.1 months (n=38)
0
1
Manuscript, submitted
2
Years
3
4
5
©2013 MFMER | 3299636-32
The International Hepatobiliary Neoplasia
Biorepository Collects Liver Tissues
Questionnaire
Blood DNA
plasma & serum
Tumor & Benign tissue
Clinical data
Urine, Stool & Bile
Next Generation Sequencing
* **
Key driver mutations in CCA genome
Cancer tissue
are identified
Candidate targeted drugs are tested in mice
Implant
into mice
Best candidate drug is used for
clinical therapy of the patient
Complete
response
Partial
response
No
response
Summary of Current Projects in
the International Hepatobiliary Neoplasia Biorepository
Novel gene
mutations
Clinical
staging
system
Patientderived
xenograft
mouse
model
Genetic
markers and
biomarkers
Cholangio
carcinoma
Clinical &
genetic
risk factors
Targeted
therapies
©2013 MFMER | 3299636-35
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