Update on Cholangiocarcinoma: What we have learned from the International Hepatobiliary Neoplasia...

Update on Cholangiocarcinoma: What we have learned from the

International Hepatobiliary Neoplasia Biorepository

Roon Chaiteerakij, MDMayo Clinic, Rochester, MN

Chaiteerakij.roongruedee@mayo.edu

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

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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

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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

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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