Ann Hsing, Ph.D.

Biliary Tract Cancers

Hsing et al, Oxford University Press 2006

Biliary Tract Cancer Biliary Tract Cancer

•Rare cancer •Highly fatal •Etiology •Obscure•Three sub-sites – distinct

Age-adjusted Incidence, Worldwide

Shanghai

South and Central American

North American

Asia

Europe

Oceania

Hsing et al, Oxford University Press 2006

Chile

5

Gallbladder Cancer Incidence

Biliary Tract Cancer: Risk Factors Biliary Tract Cancer: Risk Factors

Bile duct Ampulla of Vater

Gallbladder

•Female excess •Obesity •Parity •Gallstones•Inflammation•Cholecystitis •Genetics •Typhoid? •Helicobacter?

•Obesity •Gallstones•Cholangitis •Infection •Inflammation

?

Hsing et al. Int J Cancer 1998

Incidence Trends in Shanghai 1972-74 to 1993-94

2/100,000

8

•What are the risk factors?

•Why are rates increasing?

Research Questions Research Questions

Genetics Infections Lifestyle Factors

Main Hypotheses

Shanghai Biliary Study

Shanghai Biliary Tract Cancer Study

•Interviews•Body size

•Blood •DNA •Gallstones•Bile•Tissue •Urine

Abdominal ultrasound

Shanghai

•539 cancer cases•280 gallbladder •191 bile duct •68 ampulla of Vater

•1,000 gallstone cases•1,000 population controls

Biological Samples

•Case ascertainment >95% •Response rate

Cases >95%

Controls 82%

Population-Based

Shanghai Biliary Study

Genetics Infection Lifestyle factors

Increased Risk •Gallstones (Hsing et al. BJC 2007)

•Cholecystitis (Andreotti et al. 2010, Submitted)

•Liver cirrhosis (Hsing et al. IJC 2007)

•Obesity (Hsing et al. BJC 2008)

•Diabetes (Shebl et al. BJC 2010)

•Metabolic syndrome (Shebl et al. 2010, Submitted)

•Parity (Andreotti et al. BJC 2010)

Decreased Risk•Aspirin use •Tea drinking

Genetics Infection Lifestyle Factors

Increased Risk •HBV (bile duct only, OR=2.4)

Hsing et al. IJC 2008

No Association•HCV •Chronic typhoid

Safaeian et al. CEBP (Submitted)

Investigation Ongoing •H. pylori•Helicobacter sp.

Shanghai Biliary Study

1.32.4

1.2

1.2 1.2 1.4

1 1 1

Gallbladder ampulla ofVater

Negative

Anti-HBc

HBsAg

(1.2-4.5)

Bile duct

HBV

Shanghai Biliary Study

Genetics Infection Lifestyle factors

•Family history of gallstones (Hsing et al. IJC 2007)

•Lipid metabolism (LPLR, APOE, ABCG8, etc.) (Andreotti et al. IJC 2008)

•Insulin signaling (PPAR, INS) (Chang et al. Carcinogenesis 2008)

•Hormone metabolism (ER, AR, CYP17, COMT, etc.)(Park et al. Carcinogenesis 2009) (Meyer et al. CEBP 2010) (Xu et al., Carcinogenesis 2010)

•Inflammation (PTGS2, IL8, TNF, VEGF, etc.)(Sakoda et al. Carcinogenesis 2006) (Hsing et al. Cancer Res 2008)

•Candidate SNP•Candidate gene •Candidate pathway •iSelect•GWAS

Inflammation

•HBsAg 2.4 (1.2-4.5)

Serology

Interview Data

Genetic •PTGS2, IL8, IL10, TNF, VEGF

Shanghai Biliary Study

OR Gallstones

4.28.1

23.8

1

10

100

Ampulla ofVater

Bile Duct Gallbladder

41

59

81

0

50

100

Ampulla ofVater

Bile Duct Gallbladder

Attributable Risk (%)

• 1% of gallstone patients develop gallbladder cancer

•Gallstones - necessary but not sufficient

What’s Next?

90% 20%

Cases Controls

Prevalence of Gallstones

Biliary Tract Cancer: Opportunities Biliary Tract Cancer: Opportunities

•International Consortium •19 studies from 12 countries (~2,000 cases and 5,000 controls) •Pooled analysis to evaluate the role of cofactors •GWAS

•Chile Gallbladder Study (proposed)

•4,000 cases and 6,000 controls

90% 20%

Larger N Cases Controls

17

Chile

Gallbladder Cancer

Pilot Study

18

US-Chile Gallbladder Study

•Highest gallbladder cancer incidence in the world

•Leading cause of cancer deaths in women

• Chile and NCI MOU

Rationale

19

6.0

8.0

10.0

12.0

14.0

16.0

18.0

20.0

ADJU

STED

DEA

TH R

ATES

/100

000 W

OM

EN

TOP CANCER KILLERS AMONG CHILEAN WOMEN

biliar &GBCervixBreast

Biliary Tract Cancer

Blood

Interview

Tissue

24-hour Urine

1,000-2,000

Gallstone cases

4,000-6,000

Population controls

4,000

Cases

Anthropometry

Chile Biliary Tract Cancer Study Study Design

Clinical Trial

SS Antofagasta= 1 hospital 38 GBC deaths 0,79 % mapuches

SS Valparaiso-San Antonio: 1 hospital34 GBC deaths 1,12 % mapuches

Santiago 3 hospitals

SS del Lib.Bdo O´Higgins: 1 hospital54 GBC deaths 1,17% mapuches

SS del Maule: 1 hospital102 GBC deaths 0,82 % mapuches

Concepción

SS Araucanía Sur: 1 hospital96 GBC deaths 24,28 % mapuches

Valdivia

•80 cases •80 controls

Chile Pilot Study

Test

•Case recruitment •Control selection •Response rate •Blood collection •Blood processing•Tissue collection

Acknowledgments Epidemiology Robert Hoover, M.D., NCI Lisa Chu, Ph.D., NCI Sabah Quraishi , M.P.H., NCI Tamra Meyer, Ph.D., DoD Christine Berg, M.D., NCI Alan Kristal, Ph.D., Fred Hutchinson Cancer Center Chris Haiman, Ph.D., USC Brian Henderson, M.D., USC Anand Chokkalingam, Ph.D., UC Berkeley Yu-Tang Gao, M.D., Shanghai Cancer Institute, China Richard Biritwum, M.D., University of Ghana Andrew Adjei, Ph.D., University of Ghana

Pathology Isabel Sesterhenn, M.D., AFIP Angelo DeMarzo, M.D., Ph.D., JHU George Netto, M.D., JHUYao Tetty, M.D., University of Ghana

Urology Alan Partin, M.D., JHUIan Thompson, M.D. , University of Texas Edward Yeboah, M.D., University of Ghana

Endocrinology Frank Stanczyk, Ph.D, USC Alain Belanger, Ph.D, Laval University

Epidemiology Joseph F. Fraumeni, Jr., M.D., NCI Gabriella Andreotti, Ph.D., NCI Fatma Shebl, M.D., NCI Mahboobeh Safaeian, Ph.D., NCI Yu-Tang Gao, M.D., Shanghai Cancer Institute, China

Pathology Asif Rashid, M.D., MD Anderson Cancer CenterMing-Chang Shen, M.D., Shanghai Tumor Hospital, China

Gastroenterology Tian-Quinn Han, M.D., Raijin Hospital, Shanghai, China Bai-He Zhang, M.D., First Military Hospital, Shanghai, China Bin-Sheng Wang, M.D., Fudan University, Shanghai, China

Virology/Microbiology Betty Conde, NCI-SAICJames Fox, DVM, MITTorkel Wadstrom, Ph,D., Lund University, Sweden

Genetics Stephen Chanock, M.D., NCI Juergen Reichardt, Ph.D., University of Sydney Jianfeng Xu, M.D., Ph.D., Wake Forest University Streamson Chu, M.D., Ph.D., Columbia University

Statistics Phil Rosenberg, Ph.D., NCI Kai Yu, Ph.D., NCIHong Zhang, Ph.D., NCI Jinbo Chen, Ph.D., University of PennsylvaniaCathy Tangen, Ph.D., Fred Hutchinson Cancer Center