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 Cancer Facts & 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 Cancer Environmental factors

In about 10 to 15% of pancreatic cancers genetic factors seem to play a prominent role Hereditary Pancreatic Cancer Genetic 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 Cancer Genetic factors II

SyndromeGeneLocus Lifetime risk RR FAMMM P16INK4a/ CDKN2A/MTS1 9p %20-34 HBOCBRCA213q125%10 HBOCBRCA117q21??2 Hereditary pancreatitis PRSS1/TRY17q %50 HNPCCMMR2p21-22, 3p21 e.a.?? PJSSTK11/LKB119p1336%136 ATATM11q22?? FAPAPC5q21-22??4 Li-Fraumeni syndrome p5317p13?? FPC??4q32-34Up to 50%18-57 Hereditary Pancreatic Cancer Genetic 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 Cancer Without 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

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

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 % 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 Cancer Potentially promising techniques

Surveillance in Hereditary Pancreatic Cancer Literature data Prospective controlled study 78 ‘high’ risk individuals 6 peutz-Jeghers patients 72 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 lesion benign IPMN (n=6) malignant IPMN (n=1) pancreatic intraepithelial neoplasia (n=1) Canto et al. Clin Gastroenterol 2006: 4;

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

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

Surveillance in Hereditary Pancreatic Cancer 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

Surveillance in Hereditary Pancreatic Cancer 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 Study Case example I

Hereditary Pancreatic Cancer Study Case example II

Surveillance in Hereditary Pancreatic Cancer 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%)

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 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 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? Surveillance in Hereditary Pancreatic Cancer Conclusion & summary II