Pancreas Cancer Screening in 2018. Pancrea2c Cysts and Beyond - James Farrell, MD Director, Yale Pancreas Disease Program Interven7onal Endoscopy ...
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Pancreas Cancer Screening in 2018.
Pancrea2c Cysts and Beyond
James Farrell, MD
Director, Yale Pancreas Disease Program
Interven7onal Endoscopy and Pancreas Diseases
2018 Yale Pancreas Cancer Symposium
Mul7disciplinary Management of Pancrea7c Cancer
50 year old lady with recurrent pancrea22s
Intraductal Papillary Mucinous Neoplasm
with High Grade Dysplasia
Farrell et al Gastrointest Endosc. 2009 Jan;69(1):176-7
What? Early stage, preinvasive
Pancrea2c Ductal
Adenocarcinoma
(More Common)
IPMN related
Adenocarcinoma
(Less Common)
“A successful screening program should detect and treat :
• T1N0M0 margin-nega7ve PC (asymptoma7c)
• High-grade dysplas7c precursor lesions
(PanINs, IPMNs and MCNs)”
Cancer of Pancreas Screening Consor7um Gut. 2013 Mar;62(3):339-47
How? No Simple Blood Test!
Farrell/Zhang et al.Gastroenterology. 2010 Mar;138(3):949
CancerSEEK:
“Single blood test for 8 cancers: $500”
• 1005 8 common cancers including 92 PDAC
• Early resectable stages
• Cell-free DNA: 16 genes
• Circula7ng proteins: 8 proteins
• Sensi7vity for PDAC: 70%
• Specificity for PDAC >99%
• 7 of 812 healthy controls scored “posi7ve”
• Localized the pancrea7c cancer in 87% of pa7ents
Cohen et al. Science 2018 Jan 18.
General Popula2on Screening?:
Lots of “false” posi2ve tests…sleepless nights
Prevalence 0.00202 Prevalence 0.00202 Prevalence 0.00202
1.0 1.0 1.0
NPV
Predictive Value
Predictive Value
Predictive Value
0.8 0.8 0.8
0.6 0.6 0.6
PPV
0.4 0.4 0.4
0.2 0.2 0.2
0.0 0.0 0.0
0.90 0.94 0.99 0.90 0.94 0.99 0.90 0.94 0.99
Sensitivity Sensitivity Sensitivity
Spec: 0.9 Spec: 0.95 Spec: 0.99
Incidence 9(General) to 300(3 FDR) per 100,000
Klein AP et al. Cancer Res 2004; 64:2634-38
Pancrea2c Cancer Screening
High Risk Groups
• Diabetes Mellitus
• ClinicalTrials.gov Iden7fier: NCT03250078
• Richard Frank, MD, Western CTHealth Network
• Familial Pancrea7c Cancer (10%)
• Pancrea7c Cysts
Pancrea2c Cancer Screening
High Risk Groups
• Diabetes Mellitus
• ClinicalTrials.gov Iden7fier: NCT03250078
• Richard Frank, MD, Western CTHealth Network
• Familial Pancrea2c Cancer (10%)
• Pancrea7c Cysts
Familial Syndromes Associated with
Pancrea2c Cancer
Syndrome Affected Genes Fold Increase in
Relative Risk
Hereditary Breast Ovary BRCA1, BRCA2,PALB2 6-10
Cancer
Peutz Jeghers STK11/LKB1 132
Hereditary NonPolyposis HMLH1,HMSH2 8-9
Colon Cancer
Hereditary Pancreatitis PRSS1,PRSS2, SPINK, 26-60
CTRC
Familial atypical multiple CDKN2A(P16) 13-22
melanoma
Familial Adenomatous APC 4-6
polyposis
Ataxia telangiectasia ATM 2.7
Familial Pancreatic ??? 4.5-32
Cancer
Arch Pathol Lab Med 2009;133:365-74. Gastroenterology 2000;119:1447-53, 3. JAMA 2009;302:1790-5. ; J Natl Cancer Inst 1997
Gut 2007;56:1327-8. Fam Cancer 2008;7:103-12. Gut 1993;34:1394-6. Clin Cancer Res 2009;15:1907-1914Risk in Familial Pancrea2c Cancer
Affected 1st degree Relative risk BRCA2
relatives mutations
3 32 (95% CI: 10-75) 17%
2 6.4 (CI: 2-16) 19%
1 4.6 (CI: 0.5-16) ?
Klein, Cancer Res, 2004 Apr, 2634-8
Murphy, Cancer Res, 2002 Jul, 3789-93, Hahn, J Natl Cancer Inst, 2003 Feb, 214-21Who?
Familial Pancreas Cancer Screening
1. Peutz-Jeghers Syndrome
• At least 30 yrs old
2. Familial pancreaCc cancer relaCves
• > 55 years old or 10 years younger than the age of youngest rela7ve with pancrea7c
cancer, and
• 2 or more members with a history of pancrea7c cancer or one with a first degree rela7ve
with PDAC.
3. Germline mutaCon carriers with > 1 pancreaCc cancer in family
• 10% + EsCmated lifeCme risk of pancreaCc cancer
• FAMMM (p16/CDKN2A), BRCA2, PALB2, ATM muta7on
• 5% EsCmated lifeCme risk of pancreaCc cancer
• BRCA1, or HNPCC ( hMLH1, hMSH2, PMS1, hMSH6, EpCAM) gene muta7on
4. Hereditary PancreaCCs
• Gene muta7ons that predispose to chronic pancrea77s, such as PRSS1, PRSS2, CTRC
Cancer of Pancreas Screening Consor7um Gut. 2013 Mar;62(3):339-47CAPS5 Pancreas Cancer Screening
Research Protocol
• Cancer Gene7cs Counselling
• Blood for research
• MRI Pancreas
• Endoscopic Ultrasound with secre7n injec7on
• Pancrea7c mass
• Pancrea7c Cyst
• Chronic Pancrea77sOutcomes of Pancreas Cancer
Screening Programs in HRIs
Diagnos7c Yield: 2-40%: PDAC, IPMN, PANIN1-3
Proven Impact on Survival?Pancrea2c Juice P53/SMAD4 DNA
Muta2ons Present 4-61 months before
PDAC diagnosed
Suenaga M, et al. Gastrointest Endosc. 2017 Dec;86(6):1152-1156
Yu J et al. Gut 2017 Sep;66(9):1677-1687Pancrea2c Cancer Screening
High Risk Groups
• Diabetes Mellitus
• Familial Pancrea7c Cancer
• Pancrea2c CystsPancrea2c Cysts and Cancer
The prevalence of pancrea2c cysts in asymptoma2c individuals is about 2.5-40%
• Pseudocyst
• Serous cystadenoma
• Solid Pseudopapillary
Neoplasm (SPEN)
• Cys7c pancrea7c endocrine
neoplasm (CPEN)
• Mucinous cys7c neoplasm
• Intraductal Papillary Mucinous
Neoplasm (IPMN)
Farrell, Fernandez-del Castillo Gastroenterology 2013Pancrea2c Cysts and Cancer
The prevalence of pancrea2c cysts in asymptoma2c individuals is about 2.5-40%
• Pseudocyst
• Serous cystadenoma
• Solid Pseudopapillary
Neoplasm (SPEN)
• Cys7c pancrea7c endocrine
neoplasm (CPEN)
• Mucinous cys7c neoplasm
• Intraductal Papillary Mucinous
Neoplasm (IPMN)
Farrell, Fernandez-del Castillo Gastroenterology 2013Intraductal Papillary Mucinous Neoplasm
(IPMN)
Main Duct Type Branch Duct Type
67% 5-10%
5 year actuarial risk of CIS or Invasive CancerBranch Duct Intraductal Papillary Mucinous Neoplasm
(BD-IPMN) - The Real Challenge
Deciding Between Surgery and Surveillance
High Risk Stigmata Worriesome Features
•Jaundice •
•
Mural nodule
MPD 5-9mm
•MPD≥10mm • Size >3cm
• Abrupt change in
•Solid duct caliber
• Pancreatitis
Branch Duct Type
5-10%Where does Endoscopic Ultrasound
fit in?
• Superior Imaging
• Ductal Anatomy
• Addi7onal cysts
• “Solid Component”
• Mural nodules
• Cyst fluid analysis
• Cytology
• Low sensi7vity
• Tumor MarkersEUS Pancrea2c Cyst Fluid CEA:
Not a predictor of malignancy
Non Mucinous Mucinous
(incl IPMN)
Van Der Waal et al. Gastrointest Endosc. 2005Major Differences between
Fukuoka and AGA Guidelines
Fukuoka 2012 AGA 2015
Pa7ents Suspected IPMN or MCN All Incidental Pancrea7c
Cysts
Imaging CT/MRI MRI+/- MRCP
Unecessary
Threshold for EUS
Surveillance
Pancreas2 panel pancrea2c cyst fluid methyla2on marker
Low Grade Dysplasia vs. HGD/Cancer
Methylated TBX15 and BMP3 more sensi7ve
than either K-ras or CEA
Majumder S et al DDW 2017Endoscopic Molecular Imaging
Contrast Enhanced Ultrasound of Small PDAC:1-2 mm
Thymocyte differen7a7on an7gen 1 (Thy1):
A specific biomarker of PDAC neovasculature
Juergen Willmann
Abou-Elkacem L, et al. Willmann JK. Clin Cancer Res. 2018 Jan 4.2057.2017
Foygel K, et al, Willmann JK. Gastroenterology. 2013 Oct;145(4):885-894Summary
• No General Popula7on Screening Indicated
• Diabetes
• Opportunity for pancreas cancer screening
• Pancreas Cancer Screening
• Should be performed in high-risk individuals
• CAPS5 Study
• Aim to find advanced precursor lesions or early PDAC
• MRI/MRCP and EUS are main surveillance modali7es
• Benefit of a surveillance program remains to be proven!!
• Pancrea7c Cysts
• High Disease Specific Survival in low risk BDIPMNs
• Beter cyst fluid markers for cancer on the way?
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