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Molecular markers to aid in early diagnosis of pancreatic cancer

Molecular markers to aid in early diagnosis of pancreatic cancer. Michael Goggins, MD Professor of Pathology, Medicine and Oncology Johns Hopkins Medical Institutions, Baltimore, MD. “7th Annual Symposium on Gastrointestinal Cancers " St. Louis, Mo, 9/20/08. Disclosure.

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Molecular markers to aid in early diagnosis of pancreatic cancer

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  1. Molecular markers to aid in early diagnosis of pancreatic cancer Michael Goggins, MD Professor of Pathology, Medicine and Oncology Johns Hopkins Medical Institutions, Baltimore, MD “7th Annual Symposium on Gastrointestinal Cancers " St. Louis, Mo, 9/20/08

  2. Disclosure • Dr. Goggins has licensing agreements with Oncomethylome sciences for several DNA methylation markers

  3. Early detection of asymptomatic disease Early diagnosis of symptomatic disease

  4. Survival for Ductal Pancreas Adenocarcinoma Tumor Diameter Lymph Node Status p<0.0001 p<0.0001 no positive nodes < 3 cm positive nodes ≥ 3 cm Margin Status Histologic Grade p<0.0001 p<0.0001 negative margin well or moderate positive margin poor or undifferentiated

  5. Early detection of small asymptomatic neoplasms may result in cure Best outcome: 79 patients wth small, asymptomatic, < 1 cm cancers 5- year survival 100% after surgery if PC limited to duct epithelium (CIS?) Ariyama 1997

  6. What is the natural history of patients who present with symptoms and are ultimately diagnosed with pancreatic cancer? We do not have much quantitative information on the obstacles to diagnosis for patients with pancreatic cancer

  7. When there are delays in diagnosis, what are their causes?

  8. Pancreatic CT abnormalities up to 18 months prior to a diagnosis of pancreatic cancer Chari et al, AJR 2004;182:897

  9. How many patients would have a significantly improved outcome if they were optimally diagnosed as soon as symptoms presented?

  10. Markers of Pancreatic Neoplasia What performance characteristics are needed for a(serum) molecular marker for the Diagnosis of pancreatic cancer

  11. The performance characteristics of a marker often vary by population (disease stage, heterogeneity): Ca19-9 Sensitivity for resectable PC =65% (Sensitivity for unresectable PC=80%) PC AmpCA CP islet ca controls JHU unpublished

  12. Disease prevalence 50% (e.g. pancreatic mass) Disease No Disease Positive 1,100 Negative 900 1,000 1,000 PPV: 900/1100=81% NPV: 800/900=91% Test Sensitivity: 90% Specificity: 80% (for cancer)

  13. Disease prevalence ~10%, e.g. mid-back pain, wt loss Disease No Disease Positive 542 Negative 1558 1,800 200 PPV: 182/542=34% NPV: 1540/1558=98% Sensitivity: 90% Specificity: 80% (for resectable cancer)

  14. What performance characteristics are needed for a molecular marker for Screening for pancreatic cancer?

  15. General Population: Age 65: 5 year Risk PPV NPV Surveillance Epidemiology and End Result

  16. Disease prevalence, 1% Disease No Disease 414 Positive Negative 1586 20 1,980 PPV: 18/414=4.3% NPV: 1584/81856=99.8% Sensitivity:90% Specificity: 80%

  17. New Onset Diabetics: 3 yr PC risk PPV NPV Chari et al. Gasto 2005

  18. Family Hx PC 3 1st-degree relatives: 3-yr PC risk PPV NPV Klein et al. Cancer Research 2004

  19. Family Hx PC 2 1st-degree relatives: 3-yr PC risk PPV NPV Klein et al. Cancer Research 2004

  20. Is this the right question to ask of our markers?What performance characteristics are needed for a molecular marker to Screen for pancreatic cancer?

  21. What about the performance characteristics for a molecular marker of neoplastic precursors?

  22. Strong Family Hx of PC, prevalence: 10% (IPMN) Test: Sensitivity: 95% Specificity: =90% (EUS or MRI) Disease No Disease 105 Positive 95 Negative 100 100 PPV: 95/105=91% NPV: 90/95=95%

  23. Cancer of the Pancreas Screening(CAPS) clinical trials Who are we screening? Asymptomatic High risk individuals with a strong family history of pancreatic cancer and certain germline mutation carriers CAPS1:1999 CAPS2: 2001 CAPS3: 2006 CAPS4: 2008

  24. Familial PC Screening Programs Other studies ongoing, eg. Brentnall et al (Seattle), Europac, U Pitt, Zubarik et al, (Vt)

  25. Cancer of the Pancreas Screening Study (CAPS) 3 CAPS 3 – 1st national American multicenter screening study • EUS/CT/MRI + biomarkers (juice) • Hopkins, Mayo, MDACC, Dana Farber, UCLA • www.clinicaltrials.gov • Email: caps3@jhmi.edu • lizst.onc.jhmi.edu/caps3

  26. CAPS 4 • Single center, long-term screening and surveillance (V foundation) • Evaluate expanded eligibility • 1 FDR, 1 SDR (eg. parent and grandparent) • BRCA2 mutation carriers • Biomarker discovery

  27. baseline 3 months 10 mm 12 months 18 mm

  28. Lobular CP like changes on EUS

  29. Extensive PanINLobulocentric atrophy Brune et al, AJSP, 2006

  30. Is the identification of IPMNs and PanINs in asymptomatic individuals justified when we have not proven that surveillance of these lesions leads to improved outcome?

  31. What molecular markers are on the horizon and can they help identify cancer or advanced neoplasia?

  32. Molecular alterations in pancreatic cancer • DNA: Somatic mutations Aberrant DNA methylation Chromosomal losses/gains • RNAs: RNAs and microRNAs • Proteins Peptides, glycopeptides • Other eg. Autoantibodies Infiltrating pancreatic ca

  33. Normal Duct PanIN 2 PanIN 3 PanIN 1A PanIN 1B Invasive AdenoCa Intraductal Papillary Mucinous Neoplasm (IPMN) Cystic Lesion Adenoma Carcinoma in situ Invasive AdenoCa Mucinous Cystic Neoplasm (MCN)

  34. Pancreatic cancer research:Era of systematic discovery 100% Research Activity Translational Evaluation of markers Systematic Discovery (“Omics”) Candidate Markers 0% 1985 1990 1995 2000 2005 2010 2015 2020 Time

  35. The Pancreatic Cancer Genome

  36. Number of somatic mutations in pancreatic cancer Data figure on the pc genome

  37. Pancreatic cancer chromosomal gains + losses Gains Losses Walter et al, Cancer Biol Ther, 2008

  38. Quantifying mutant KRAS in Pancreatic juice: LigAMP PC CP Shi et al, Cancer Biol Ther, 2008

  39. Discovering the cancer methylome Methylome = genome wide DNA methylation patterns

  40. Log ratio Chr1 Chr7 Chr2 Chr8 Chr3 Chr9 Chr4 Chr10 Chr5 Chr11 Chr6 Chr12

  41. Aberrant DNA methylation in IPMNs % Hong et al, Modern Path in press

  42. Quantitative Methylation analysis of ERCP Brushings of common bile duct strictures

  43. QMSP of biliary and Pancreatic duct Brushings performed to diagnose strictures Parsi et al, Clin Gastro Hep, 2008

  44. Pancreas juice sampling for markers

  45. Quantifying pancreatic juice DNA methylation alterations 5 gene panel, quantified by QMSP, CAPS2 study population Cancer Res 2006:66:1208

  46. Discovering Pancreatic cancer expression patterns Marker

  47. Candidate pancreatic cancer markers: Serum Macrophage inhibitory cytokine-1 (MIC-1) ELISA PC=pancreatic cancer CP=chronic pancreatitis Nl=normal Clin Cancer Res 2006;12:442

  48. MicroRNA alterations in pancreatic cancer Hahn et al, Oncogene 2007;264442

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