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Molecular markers to aid in Molecular markers to aid in early diagnosis of early diagnosis of
pancreatic cancer pancreatic cancer Michael Goggins, MDMichael Goggins, MD
Professor of Pathology, Medicine and Professor of Pathology, Medicine and OncologyOncology
Johns Hopkins Medical Institutions, Johns Hopkins Medical Institutions, Baltimore, MDBaltimore, MD
“7th Annual Symposium on Gastrointestinal Cancers " St. Louis, Mo, 9/20/08
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DisclosureDisclosure
Dr. Goggins has licensing agreements Dr. Goggins has licensing agreements with Oncomethylome sciences for several with Oncomethylome sciences for several DNA methylation markersDNA methylation markers
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Early detection of Early detection of asymptomatic diseaseasymptomatic disease
Early diagnosis of Early diagnosis of symptomatic diseasesymptomatic disease
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0.1
.2.3
.4.5
.6.7
.8.9
1.0
Pro
port
ion
Sur
vivi
ng
0 12 24 36 48 60months
0.1
.2.3
.4.5
.6.7
.8.9
1.0
Pro
port
ion
Sur
vivi
ng
0 12 24 36 48 60months
0.1
.2.3
.4.5
.6.7
.8.9
1.0
Pro
port
ion
Sur
vivi
ng
0 12 24 36 48 60months
0.1
.2.3
.4.5
.6.7
.8.9
1.0
Pro
port
ion
Sur
vivi
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0 12 24 36 48 60months
positive margin
negative margin
poor or undifferentiated
well or moderate
no positive nodes
positive nodes
< 3 cm
≥ 3 cm
p<0.0001
p<0.0001
p<0.0001
p<0.0001
Survival for Ductal Pancreas AdenocarcinomaSurvival for Ductal Pancreas Adenocarcinoma
Tumor Diameter
Margin Status
Lymph Node Status
Histologic Grade
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Early detection of small asymptomatic Early detection of small asymptomatic neoplasms may result in cureneoplasms may result in cure
Best outcome: 79 patients wth small, Best outcome: 79 patients wth small, asymptomatic, asymptomatic,
<< 1 cm cancers 1 cm cancers
5- year survival 100% after surgery if 5- year survival 100% after surgery if PC limited to duct epithelium (CIS?)PC limited to duct epithelium (CIS?)
Ariyama 1997
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What is the natural history of What is the natural history of patients who present with patients who present with
symptoms and are ultimately symptoms and are ultimately diagnosed with pancreatic diagnosed with pancreatic
cancer?cancer?
We do not have much quantitative We do not have much quantitative information on the obstacles to information on the obstacles to
diagnosis for patients with diagnosis for patients with pancreatic cancerpancreatic cancer
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When there are delays in When there are delays in diagnosis, what are their diagnosis, what are their
causes?causes?
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Chari et al, AJR 2004;182:897
Pancreatic CT abnormalities up Pancreatic CT abnormalities up to 18 months prior to a to 18 months prior to a
diagnosis of pancreatic cancerdiagnosis of pancreatic cancer
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How many patients would have How many patients would have a significantly improved a significantly improved
outcome if they were optimally outcome if they were optimally diagnosed as soon as diagnosed as soon as symptoms presented?symptoms presented?
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Markers of Pancreatic Markers of Pancreatic NeoplasiaNeoplasia
What performance What performance characteristics are needed characteristics are needed
for a(serum) molecular for a(serum) molecular marker for the marker for the
DiagnosisDiagnosis of pancreatic of pancreatic cancercancer
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The performance The performance characteristics of a marker characteristics of a marker often vary by population often vary by population
(disease stage, heterogeneity): (disease stage, heterogeneity): Ca19-9Ca19-9
0
35
70
105
140
175
210
0 1 2 3 4 5 6
panc ca
amp cbd ca
pancreatitis/panc cyst
islet cell neoplasm
healthy
PC AmpCA CP islet ca controls JHU unpublished
Sensitivity for resectable PC =65%
(Sensitivity for unresectable PC=80%)
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900 (TP) 200 (FP)
100 (FN) 800 (TN)
Disease No Disease
Positive
Negative
Test Sensitivity: 90% Specificity: 80% (for cancer)
PPV: 900/1100=81% NPV: 800/900=91%1,0001,000
1,100
900
Disease prevalence 50% (e.g. pancreatic mass)
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182 (TP) 360 (FP)
18 (FN) 1540 (TN)
Disease No Disease
Positive
Negative
Sensitivity: 90% Specificity: 80% (for resectable cancer)
PPV: 182/542=34% NPV: 1540/1558=98%
1,800200
542
1558
Disease prevalence ~10%, e.g. mid-back pain, wt loss
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What performance What performance characteristics are needed characteristics are needed for a molecular marker forfor a molecular marker for
ScreeningScreening for pancreatic for pancreatic cancer?cancer?
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General Population: Age 65: 5 year RiskGeneral Population: Age 65: 5 year Risk
PPV
NPV
Surveillance Epidemiology and End Result
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18 (TP) 396 (FP)
2 (FN) 1584 (TN)
Disease No Disease
Positive
Negative
Sensitivity:90% Specificity: 80%PPV: 18/414=4.3% NPV: 1584/81856=99.8%
1,98020
1586
414
Disease prevalence, 1%
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New Onset Diabetics: 3 yr PC riskNew Onset Diabetics: 3 yr PC risk
PPV
NPV
Chari et al. Gasto 2005
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Family Hx PC 3 1Family Hx PC 3 1stst-degree relatives: 3-yr PC risk-degree relatives: 3-yr PC risk
PPV
NPV
Klein et al. Cancer Research 2004
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PPV
NPV
Klein et al. Cancer Research 2004
Family Hx PC 2 1Family Hx PC 2 1stst-degree relatives: 3-yr PC risk-degree relatives: 3-yr PC risk
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Is this the right question to Is this the right question to ask of our markers?ask of our markers?
What performance What performance characteristics are needed for characteristics are needed for a molecular marker to Screen a molecular marker to Screen
for pancreatic cancer?for pancreatic cancer?
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What about the performance What about the performance characteristics for a characteristics for a molecular marker of molecular marker of
neoplastic precursors?neoplastic precursors?
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95 10
5 90
Disease No Disease
Positive
Negative
Test: Sensitivity: 95% Specificity: =90% (EUS or MRI)
PPV: 95/105=91% NPV: 90/95=95%
100100
105
95
Strong Family Hx of PC, prevalence: 10% (IPMN)
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Cancer of the Pancreas Cancer of the Pancreas ScreeningScreening
(CAPS) clinical trials(CAPS) clinical trialsWho are we screening?Who are we screening?
Asymptomatic High risk individuals with a Asymptomatic High risk individuals with a strong family history of pancreatic cancer strong family history of pancreatic cancer and certain germline mutation carriersand certain germline mutation carriers
CAPS1:1999CAPS1:1999
CAPS2: 2001CAPS2: 2001
CAPS3: 2006CAPS3: 2006
CAPS4: 2008CAPS4: 2008
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Familial PC Screening ProgramsFamilial PC Screening ProgramsPopn Screening
TestsDiagnostic
Yield (IPMN/PC)
Canto, CGH 2004,n=36
FPC (> 3)
PJS
EUS 5.8%
Canto, CGH 2006,n=78
FPC (> 3)
PJS
EUS + CT 10.2%
Kurtz, DDW 2007,n=66
FPC CT/MRI
+/- EUS
7.6%
Poley, DDW 2007,n=46
FPC, PJS, FAMM,
BRCA1/2
EUS 23.9%
Other studies ongoing, eg. Brentnall et al (Seattle), Europac, U Pitt, Zubarik et al, (Vt)
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Cancer of the Pancreas Screening Cancer of the Pancreas Screening Study (CAPS) 3Study (CAPS) 3
CAPS 3 – 1CAPS 3 – 1stst national American multicenter national American multicenter screening studyscreening study
EUS/CT/MRI + biomarkers (juice)EUS/CT/MRI + biomarkers (juice) Hopkins, Mayo, MDACC, Dana Farber, Hopkins, Mayo, MDACC, Dana Farber,
UCLAUCLA www.clinicaltrials.gov Email: [email protected]: [email protected] lizst.onc.jhmi.edu/caps3lizst.onc.jhmi.edu/caps3
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CAPS 4CAPS 4
Single center, long-term screening and Single center, long-term screening and surveillance (V foundation)surveillance (V foundation)Evaluate expanded eligibility Evaluate expanded eligibility – 1 FDR, 1 SDR (eg. parent and 1 FDR, 1 SDR (eg. parent and
grandparent)grandparent)– BRCA2 mutation carriersBRCA2 mutation carriersBiomarker discoveryBiomarker discovery
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3 months10 mm
12 months18 mm
baseline
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Lobular CP like changes on EUSLobular CP like changes on EUS
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Extensive PanINExtensive PanINLobulocentric Lobulocentric atrophyatrophy
Brune et al, AJSP, 2006
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Is the identification of IPMNs Is the identification of IPMNs and PanINs in asymptomatic and PanINs in asymptomatic individuals justified when we individuals justified when we
have not proven that have not proven that surveillance of these lesions surveillance of these lesions leads to improved outcome?leads to improved outcome?
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What molecular markers are What molecular markers are on the horizon and can they on the horizon and can they
help identify cancer or help identify cancer or advanced neoplasia?advanced neoplasia?
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Molecular alterations in pancreatic Molecular alterations in pancreatic cancercancer
DNA: DNA:
Somatic mutationsSomatic mutations
Aberrant DNA methylationAberrant DNA methylation
Chromosomal losses/gainsChromosomal losses/gains
RNAs:RNAs:
RNAs and microRNAsRNAs and microRNAs
ProteinsProteins
Peptides, glycopeptidesPeptides, glycopeptides
Other Other
eg. Autoantibodieseg. Autoantibodies
Infiltrating pancreatic ca
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Normal Duct PanIN 1A PanIN 1B PanIN 2 PanIN 3 Invasive AdenoCa
Intraductal Papillary Mucinous Neoplasm (IPMN)
Mucinous Cystic Neoplasm (MCN)
Cystic Lesion
Adenoma Carcinoma in situ
Invasive AdenoCa
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ResearchActivity
Time
1985 1990 1995 2000 2005 2010 2015 2020
CandidateMarkers
Pancreatic cancer research:Pancreatic cancer research:Era of systematic discoveryEra of systematic discovery
TranslationalEvaluation of markers
100%
0%
Systematic Discovery(“Omics”)
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The Pancreatic Cancer Genome
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Data figure on the pc genomeData figure on the pc genome
Number of somatic mutations in pancreatic cancer
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Walter et al, Cancer Biol Ther, 2008
Gains
Losses
Pancreatic cancer chromosomal gains + losses
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Quantifying mutant Quantifying mutant KRASKRAS in in Pancreatic juice: LigAMPPancreatic juice: LigAMP
Shi et al, Cancer Biol Ther, 2008
PC
CP
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Discovering the cancer Discovering the cancer methylomemethylome
Methylome = genome wide Methylome = genome wide DNA methylation patternsDNA methylation patterns
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Chr1
Chr2
Chr3
Chr4
Chr5
Chr6
Chr7
Chr8
Chr9
Chr10
Chr11
Chr12
Log
ratio
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Hong et al, Modern Path in press
Aberrant DNA methylation in IPMNs
%
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Quantitative Methylation analysis of Quantitative Methylation analysis of ERCP Brushings of common bile ERCP Brushings of common bile
duct stricturesduct strictures
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QMSP ≥1 gene +
3 gene panel, >3% conc. n Sens (CI) Spec (CI) Accuracy (CI)
Pancreatic adenocarcinoma 41 73.2 (58-84)a 86.4 (7-24) 81 (73-88) i
Biliary tract cancer 10 80 (49-94)b 86.4 (7-24) 86 (76-92)
Cytology
Pancreatic adenocarcinoma 41 19.5 (14-34)c 100 (95-100) 69 (60-77)
Biliary tract cancer 10 30 (11-60)d 100 (95-100) 92 (84-96)
Cytology + QMSP
Pancreatic adenocarcinoma 41 76 (61-76)e 86.4 (7-24) 82 (74-88) h
Biliary tract cancer 10 90 (60-96)f 86.4 (7-24) 88 (79-94)
QMSP of biliary and Pancreatic duct Brushings QMSP of biliary and Pancreatic duct Brushings performed to diagnose stricturesperformed to diagnose strictures
Parsi et al, Clin Gastro Hep, 2008
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Pancreas juice sampling for markersPancreas juice sampling for markers
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Quantifying pancreatic juice DNA methylation alterationsQuantifying pancreatic juice DNA methylation alterations5 gene panel, quantified by QMSP, CAPS2 study population
Cancer Res 2006:66:1208
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B .
Hs766T
MiaPaca2
Panc1
PL45
PL 12
PL 1
BxP
C3
CAPAN1
CFPA
C1
CAPAN2
PL 8
PL 11
Su86.86
AsP
C1
PL 3
PC 16
PC 17
PC 15
PC 12a
PC 11
PM 1
Normal 1
Normal 2
Normal 3
Marker
Discovering Pancreatic cancer expression patterns
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MIC-1
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
0 0 .5 1 1 .5 2 2 .5 3 3 .5
PC CP Nl
S e rie s1
Clin Cancer Res 2006;12:442
Candidate pancreatic cancer Candidate pancreatic cancer markers: markers: Serum Macrophage Serum Macrophage inhibitory cytokine-1 (MIC-1)inhibitory cytokine-1 (MIC-1)
PC=pancreatic cancer CP=chronic pancreatitis Nl=normal
ELISA
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MicroRNA alterations in pancreatic cancer
Hahn et al, Oncogene 2007;264442