Transcript B04 Bruno (type , size 1.27 MB)

Surveillance of Individuals
At High Risk For Developing
Pancreatic Cancer
Marco Bruno
Erasmus Medical Center, Rotterdam
Pancreatic Cancer
Facts & figures
• One of the most fatal malignancies
• Overall 5-year survival rates < 3%
• Median survival 6 months
• Irresectable at diagnosis due to late, nonspecific symptoms and high metastatic
potential
• Poor response to chemo- and radiotherapy
• Poor 5 year survival rates, even after
potentially curative surgical resection
Pancreatic Cancer
Environmental factors
• Main risk factor: cigarette smoking
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2- to 3-fold elevated risk
accounts for 25% all cases
dose-response relationship
↓ age of onset
• Less well established:
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fat, meat, salt
exposure to certain chemicals
diabetes mellitus, obesity
• Possibly protective: fresh fruits and
vegetables, dietary fiber, vitamin C
Hereditary Pancreatic Cancer
Genetic factors I
In about 10 to 15% of pancreatic cancers
genetic factors seem to play a prominent
role
Hereditary Pancreatic Cancer
Genetic factors II
• Inherited (tumor) syndromes which
predispose to pancreatic cancer (syndromal)
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(FAMMM, HBOC, HNPCC or Lynch syndrome, PeutzJeghers syndrome, ataxia-teleangiectasia, FAP, LiFraumeni syndrome)
• Hereditary pancreatitis (trypsinogen
mutations)
• Accumulation of pancreatic cancer within a
family without a known mutation
Hereditary Pancreatic Cancer
Genetic factors III
Syndrome
Gene
Locus
Lifetime
risk
RR
P16INK4a/
CDKN2A/MTS1
9p21
10-15%
20-34
HBOC
BRCA2
13q12
5%
10
HBOC
BRCA1
17q21
??
2
PRSS1/TRY1
7q35
30-70%
50
MMR
2p21-22, 3p21 e.a.
??
??
STK11/LKB1
19p13
36%
136
AT
ATM
11q22
??
??
FAP
APC
5q21-22
??
4
Li-Fraumeni
syndrome
p53
17p13
??
??
FPC
??
4q32-34
Up to 50%
18-57
FAMMM
Hereditary
pancreatitis
HNPCC
PJS
Familial Pancreatic Cancer
Without a known mutation
• Autosomal dominant inheritance
• Variable penetrance
• No known susceptibility genes
• Risk of pancreatic cancer increases with an
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increasing number of affected members: RR
reaching a maximum of 57-fold in ≥ 3 affected
family members
Cancerous genotype:
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penetrance of the gene
environmental factors
Surveillance in Hereditary Pancreatic Cancer
Ultimate goal
Prevention of early death by:
Detection of a precursor lesion before
progression towards invasive carcinoma
or
Detection of an ‘early’ asymptomatic potentially
curable malignancy
Pancreatic Cancer
(Benign) precursor lesions
• Stepwise, cumulative pathogenesis;
activation K-ras, over-expression Her-2/neu
(early), inactivation p16 and p53 (later)
• Adenoma-carcinoma like sequence with
curable, non-invasive precursor lesions:
PanIN I-III, IPMN (SB – MB type)
Carcinogenesis
Genetic model adapted from Fearon and Vogelstein
Pancreatic Intrapithelial Neoplasia
Stages PanIn-1A to PanIn-2
Wendt et al. 2007
Pancreatic Intrapithelial Neoplasia
Stages PanIn-2 to PanIn-3
Wendt et al. 2007
Pancreatic Cancer
(Benign) precursor lesions
• Stepwise, cumulative pathogenesis;
activation K-ras, over-expression Her-2/neu
(early), inactivation p16 and p53 (later)
• Adenoma-carcinoma like sequence with
curable, non-invasive precursor lesions:
PanIN I-III, IPMN (SB – MB type)
• IntraPancreatic Mucinous Neoplasia (IPMN)
• Unknown interval of progression to invasive
carcinoma; between 1 and 10 years
Imaging in Pancreatic Cancer
Potentially promising techniques
• MRI
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non-invasive
sensitivity 83-87%, specificity 81-100% for diagnosing
pancreatic cancer
no radiation exposure
• EUS
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invasive
sensitivity 95%, specificity 80% for diagnosing
pancreatic cancer
has the ability to identify early lesions
despite invasiveness, low risk for adverse effects
operator-dependent
Surveillance in Hereditary Pancreatic Cancer
Literature data
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Prospective controlled study
78 ‘high’ risk individuals
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6 peutz-Jeghers patients
72 individuals with 3 or more affected relatives
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not belonging to p16, herid pancreatitis or HNPCC
families
4 patients with known BRCA2 mutation
31 suspected of possibly having BRCA2 mutation based
on Ashkenazi Jewish ancestery
Yield: 8 patients with neoplastic lesion
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benign IPMN (n=6)
malignant IPMN (n=1)
pancreatic intraepithelial neoplasia (n=1)
Canto et al. Clin Gastroenterol 2006: 4; 766-81
Surveillance in Hereditary Pancreatic Cancer
Prospective study
• Partnership between Erasmus MC, AMC,
AvL, and UMCG
• Design: multi-centre, prospective, cohort
study
• Aim: to evaluate the feasibility and
effectiveness of surveillance for early
pancreatic neoplasia in high-risk individuals
• Methods: one-yearly repeated investigations
with EUS and MRI
Surveillance in Hereditary Pancreatic Cancer
Inclusion criteria I
•
PC prone hereditary syndromes with a cumulative lifetime
risk >10%
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carriers of mutations in CDKN2A, PRSS1 and STK11 genes
patients with a clinical diagnosis of Peutz-Jeghers syndrome but
without a known gene mutation
PC prone hereditary syndromes with an unknown
cumulative lifetime risk, or <10%
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carriers of a germline mutation in BRCA2, BRCA1, MLH1, MSH2,
APC or p53 in families with PC
at any age in ≥ 2 relatives who are (proven, obligate or supposed)
carriers of these mutations;
with at least one histologically confirmed PC
Surveillance in Hereditary Pancreatic Cancer
Inclusion criteria II
•
Familial pancreatic cancer (site-specific), i.e.
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a. ≥ 2 first-degree relatives with PC or
b. ≥ 3 relatives of any degree with PC or
c. ≥ 2 relatives of any degree with PC, one of whom was
aged 50 years or younger at the time of diagnosis;
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with at least one histologically confirmed PC in all subcategories and
without obvious relation to any currently recognized hereditary
syndrome
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screening of first degree relatives of family members with PC
Surveillance in Hereditary Pancreatic Cancer
Prospective study
• Main outcome parameter: number
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(percentage) of patients in whom a
pancreatic cancer or precursor lesions are
detected
Secondary outcome parameters (among others)
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comparison between yield EUS and MRI
inter-observer agreement (video recordings)
psychological burden of surveillance
(long-term) outcome of operated patients
• In addition: yearly collection of blood and
fecal samples for future biomarker studies
Surveillance in Hereditary Pancreatic Cancer
Prospective study: first results
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48 patients included (20 M / 28 F, 51 y 27-75)
First time surveillance of asymptomatic individuals
14 FAMMM, 22 familial pancreatic cancer, 3
hereditary pancreatitis, 2 Peutz-Jeghers, 3
BRCA1 and 2 BRCA2 mutation carriers with
familial clustering of PC, and 2 p53 mutation
Yield:
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3 patients (6%) with pancreatic masses (12, 27, 55
mm)
sidebranch IPMN-like lesions in 7 patients (15%)
[precursor lesions??]
Poley et al. AM J Gastroenterol 2009:104; 2175
Hereditary Pancreatic Cancer Study
Case example I
Hereditary Pancreatic Cancer Study
Case example II
Surveillance in Hereditary Pancreatic Cancer
Ongoing study; interesting observations I
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n=82
46% male, median age 51y (SD 9.6)
47.6% FPC, 26.8% p16-Leiden,
14.6% BRCA2, 4.9% BRCA1, 3.7%
PJS, 2.4% p53
Focal lesions detected n=29
(45.4%)
 mass n=3 (3.7%)
 cyst n=20 (24.7%)
 focal area of hypoechogenicity n=6
(7.3%)
Surveillance in Hereditary Pancreatic Cancer
Ongoing study; interesting observations II
• Interval-EUS was performed in all cases
with a focal area of hypoechogenicity of
undetermined significance
 spontaneous disappearance n=4
 persistent lesion n=2
• In 3/4 cases FU EUS after 12 months
confirmed the absence of the previously
detected lesions. In 1/4 cases FU12
months investigations are still pending.
Surveillance in Hereditary Pancreatic Cancer
Psychological burden
• For weeks after the intake surveillance
investigations
• Response rate of 83%
• Main reasons to participate in program
 chance of early detection and better treatment
prospects (100%)
 contribution to scientific research
• Major concerns
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 chance that a relative develops cancer: 34%
 often or almost always concerned about
developing cancer themselves: 31%
17% of respondents have clinically relevant
levels of depression and/or anxiety
Surveillance in Hereditary Pancreatic Cancer
Conclusion & summary I
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EUS and MR are promising techniques for
surveillance being able to detect “precursor”
lesions and/or small carcinoma’s
We are only at the beginning of exploring the
possibilities and prospects of pancreatic cancer
surveillance
By no means it has been proven yet that we are
doing good for the individuals at this point in time
The only sensible thing to do is to do surveillance
within well defined research protocols and learn
from its results
Surveillance in Hereditary Pancreatic Cancer
Conclusion & summary II
• Many questions remain:
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more accurate risk assessment of pancreatic cancer in
various syndromes?
which individuals should be surveyed?
what is the most optimal (and feasible) surveillance
interval?
is a non-invasive diagnostic modality (MRI) equally
effective in detecting these early lesions?
at which time should a resection be performed?
is a total pancreatectomy indicated?
does early detection change the course of the disease;
do patients survive and is mortality actually lowered?