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Update on Cholangiocarcinoma: What we have learned from the

Update on Cholangiocarcinoma: What we have learned from the International Hepatobiliary Neoplasia Biorepository. Roon Chaiteerakij , MD Mayo Clinic, Rochester, MN Chaiteerakij.roongruedee@mayo.edu. Outline. International Hepatobiliary Neoplasia Biorepository (IHNB)

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Update on Cholangiocarcinoma: What we have learned from the

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  1. Update on Cholangiocarcinoma: What we have learned from the International Hepatobiliary Neoplasia Biorepository RoonChaiteerakij, MD Mayo Clinic, Rochester, MN Chaiteerakij.roongruedee@mayo.edu

  2. Outline • International Hepatobiliary Neoplasia Biorepository (IHNB) • Studies on cholangiocarcinoma • How we use liver tissues collected from the IHNB to conduct research

  3. The IHNB Collects Data and Samples of Patients with Liver, Bile duct and Gallbladder Cancer and Controls Cancer cases Blood DNA plasma & serum Benign Liver Disease controls Healthy controls Urine, Stool & Bile Tumor & Benign tissue Clinical data Questionnaire

  4. Our Goal is to Improve Prevention, Diagnosis and Treatment of Liver, Bile Duct and Gallbladder Cancers Tumor Biology Clinical outcome Epidemiology study Hepatobiliary cancer Personalized oncology Early diagnosis Novel therapeutics

  5. Epidemiology: Understanding the Risk Factors for Hepatobiliary Cancers Tumor Biology Clinical outcome Epidemiologystudy Cholangiocarcinoma Personalized oncology Early diagnosis Novel therapeutics

  6. Epidemiology Studies use Clinical Data, Risk Factor Questionnaires, and Blood Samples Benign Liver Disease controls Cancer cases Blood DNA plasma & serum Healthy controls Urine, Stool & Bile Tumor & Benign tissue Clinical data Questionnaire

  7. Current Epidemiology Studies on Cholangiocarcinoma (CCA) • Classification of CCA • Incidence of CCA • Clinical risk factors for CCA • Genetic risk factors for CCA

  8. Classification of CCA CCA is not a single disease but a group of three separate diseases The three have similarities, but also distinct differences

  9. Classification of Cholangiocarcinoma (CCA) 103 iCCA (intrahepatic) 71 pCCA (perihilar) Gallbladder Cystic duct 22 dCCA (distal) Pancreas Image Courtesy of Dr. Gregory Gores

  10. The Incidence Rate of Intrahepatic Cholangiocarcinoma in Olmsted County, MN, US has Increased 7-fold Incidence rates (Per 100,000 person-year) 2.1 P trend = 0.02 0.8 0.3 2001-2008 1976-1990 1991-2000 Year Yang JD, et al. Am J Gastro 2012

  11. Classification of Cholangiocarcinoma (CCA) 103 iCCA (intrahepatic) 71 pCCA (perihilar) Gallbladder Cystic duct 22 dCCA (distal) Pancreas Image Courtesy of Dr. Gregory Gores

  12. The Incidence Rate of Distal CCA has Decreased by 35% Incidence rates (Per 100,000 person-year) 2.2 iCCA 2.1 1.9 pCCA 1.5 1.3 1.4 dCCA 0.8 0.6 0.3 2001-2008 1976-1990 1991-2000 Year Yang JD, et al. Am J Gastro 2012

  13. Demographics of 1267 CCA Patients Distribution of location (%) Proportion of Males 63% 60% 50% iCCA pCCA dCCA iCCA (Year) Mean age pCCA 67 62 61 dCCA iCCA pCCA dCCA Data from IHNB

  14. Factors associated with iCCA development Risk (fold) 82 8 4 3 1.5 Diabetes PSC Cirrhosis Hepatitis C Smoking Primary Sclerosing Cholangitis Chaiteerakij, et al. Hepatology. 2013

  15. Factors associated with iCCA development Risk (fold) 82 8 5 4 3 2 1.5 Diabetes PSC Cirrhosis Diabetes No Metformin use Diabetes Metformin use Metformin use was associated with 60% reduction in risk for iCCA Chaiteerakij, et al. Hepatology. 2013

  16. Study of Effect of Metformin Treatment on Cholangiocarcinoma in Mice Control Metformin Manuscript, in preparation

  17. Epidemiologic study • Current classification of CCA • Clinical risk factors for CCA • Genetic risk factors for CCA • Planned GWAS for CCA • Future directions

  18. Is genetic variation associated with risk of CCA development? Cancer cases Healthy controls G A * * Single nucleotide polymorphism (SNP)

  19. Is genetic variation associated with risk of CCA development? C G A G C T G C G C C G Adenine (A) – Thymine (T) Cytosine (C) – Guanine (G) Single nucleotide polymorphism (SNP)

  20. Is genetic variation associated with risk of CCA development? Cancer cases Blood DNA Blood DNA (N = 740) (N = 370) Healthy controls G A * * Single nucleotide polymorphism

  21. Genetic Variation in COX-2 Gene is Associated with CCA Risk % Increases in Risk 300% 50% 40% rs689466 both rs2143417 Manuscript, submitted

  22. 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)

  23. GWAS for CCA Healthy controls Cancer cases Blood DNA Blood DNA (N = 4000) (N = 2000) * * * * * * * * * * * * * * * * * * * *

  24. 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

  25. Future Directions of Genetic Risk Studies in CCA GWAS Discovery phase:Complete accrual, Grant application Validation phase: Begin accrual GWAS Validation phase: Genotyping 2014 2015 2017 2016 2018 Genetic risk study in young-onset CCA Whole exome sequencing Proportion of CCA patients aged < 50 11.5% 18.4% 17.3% pCCA dCCA iCCA

  26. 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

  27. Clinical Outcomes study: Developing a New Clinical Staging System for pCCA Tumor Biology Clinical staging system Epidemiologic study Cholangiocarcinoma Personalized oncology Early diagnosis Novel therapeutics

  28. Stage I Single mass ≤ 3 cm

  29. Stage II Single mass ≤ 3 cm Vascular encasement

  30. Stage III Mass > 3 cm Intrahepatic and/or lymph node metastasis

  31. Stage IV Peritoneal metastasis

  32. Survival of pCCA Patients Classified by the New Staging System Survival (%) P<0.0001 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) Years Manuscript, submitted

  33. The International Hepatobiliary Neoplasia Biorepository Collects Liver Tissues Benign Liver Disease controls Cancer cases Blood DNA plasma & serum Healthy controls Urine, Stool & Bile Tumor & Benign tissue Clinical data Questionnaire

  34. * * Next Generation Sequencing * Key driver mutations in CCA genome are identified Cancer tissue 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

  35. Summary of Current Projects in the International Hepatobiliary Neoplasia Biorepository Novel gene mutations Clinical staging system Genetic markers and biomarkers Cholangiocarcinoma Patient-derived xenograft mouse model Clinical & genetic risk factors Targeted therapies

  36. 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, BiodonostiaResearch Institute, Spain • All CCA patients and family members

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