Erasmus Medical Center, Rotterdam Marco Bruno Surveillance of Individuals At High Risk For Developing Pancreatic Cancer

Erasmus Medical Center, Rotterdam

Marco Bruno

Surveillance of Individuals At High Risk

For Developing Pancreatic Cancer

• One of the most fatal malignancies

• Overall 5-year survival rates < 3%

• Median survival 6 months

• Irresectable at diagnosis due to late, non-specific symptoms and high metastatic potential

• Poor response to chemo- and radiotherapy

• Poor 5 year survival rates, even after potentially curative surgical resection

Pancreatic CancerFacts & figures

• Main risk factor: cigarette smoking 2- to 3-fold elevated risk accounts for 25% all cases dose-response relationship ↓ age of onset

• Less well established: fat, meat, salt exposure to certain chemicals diabetes mellitus, obesity

• Possibly protective: fresh fruits and vegetables, dietary fiber, vitamin C

Pancreatic CancerEnvironmental factors

In about 10 to 15% of pancreatic cancers genetic factors seem to play a prominent

role

Hereditary Pancreatic CancerGenetic factors I

• Inherited (tumor) syndromes which predispose to pancreatic cancer (syndromal)

(FAMMM, HBOC, HNPCC or Lynch syndrome, Peutz-Jeghers syndrome, ataxia-teleangiectasia, FAP, Li-Fraumeni syndrome)

• Hereditary pancreatitis (trypsinogen mutations)

• Accumulation of pancreatic cancer within a family without a known mutation

Hereditary Pancreatic CancerGenetic factors II

Syndrome Gene Locus Lifetime risk

RR

FAMMM P16INK4a/ CDKN2A/MTS1

9p21 10-15% 20-34

HBOC BRCA2 13q12 5% 10

HBOC BRCA1 17q21 ?? 2

Hereditary pancreatitis

PRSS1/TRY1 7q35 30-70% 50

HNPCC MMR 2p21-22, 3p21 e.a. ?? ??

PJS 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

Hereditary Pancreatic CancerGenetic factors III

• Autosomal dominant inheritance

• Variable penetrance

• No known susceptibility genes

• Risk of pancreatic cancer increases with an increasing number of affected members: RR reaching a maximum of 57-fold in ≥ 3 affected family members

• Cancerous genotype: penetrance of the gene environmental factors

Familial Pancreatic CancerWithout a known mutation

Prevention of early death by:

Detection of a precursor lesion before progression towards invasive carcinoma

or

Detection of an ‘early’ asymptomatic potentially curable malignancy

Surveillance in Hereditary Pancreatic Cancer

Ultimate goal

• 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)

Pancreatic Cancer(Benign) precursor lesions

CarcinogenesisGenetic model adapted from Fearon and Vogelstein

Pancreatic Intrapithelial NeoplasiaStages PanIn-1A to PanIn-2

Wendt et al. 2007

Wendt et al. 2007

Pancreatic Intrapithelial NeoplasiaStages PanIn-2 to PanIn-3

• 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

Pancreatic Cancer(Benign) precursor lesions

• MRI non-invasive sensitivity 83-87%, specificity 81-100% for diagnosing

pancreatic cancer no radiation exposure

• EUS 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

Imaging in Pancreatic CancerPotentially promising techniques


Literature data

• Prospective controlled study

• 78 ‘high’ risk individuals6 peutz-Jeghers patients72 individuals with 3 or more affected relatives

• 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 lesionbenign IPMN (n=6)malignant IPMN (n=1)pancreatic intraepithelial neoplasia (n=1)

Canto et al. Clin Gastroenterol 2006: 4; 766-81


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

• PC prone hereditary syndromes with a cumulative lifetime risk >10%

carriers of mutations in CDKN2A, PRSS1 and STK11 genespatients 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%

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 I

• Familial pancreatic cancer (site-specific), i.e.

a. ≥ 2 first-degree relatives with PC orb. ≥ 3 relatives of any degree with PC orc. ≥ 2 relatives of any degree with PC, one of whom was

aged 50 years or younger at the time of diagnosis;

- with at least one histologically confirmed PC in all subcategories and without obvious relation to any currently recognized hereditary

syndrome

- screening of first degree relatives of family members with PC

Surveillance in Hereditary Pancreatic Cancer Inclusion criteria II


Prospective study

• Main outcome parameter: number (percentage) of patients in whom a pancreatic cancer or precursor lesions are detected

• Secondary outcome parameters (among others)

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


Prospective study: first results

• 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: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 StudyCase example I

Hereditary Pancreatic Cancer StudyCase example II


Ongoing study; interesting observations I

• 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%)


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.


Psychological burden• For weeks after the intake surveillance

investigations

•Response rate of 83%

•Main reasons to participate in programchance of early detection and better treatment

prospects (100%)contribution to scientific research

•Major concernschance 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


Conclusion & summary I

• 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

• Many questions remain:

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?


Conclusion & summary II

Documents

Erasmus Medical Center, Rotterdam Marco Bruno Surveillance of Individuals At High Risk For Developing Pancreatic Cancer