Surveillance of Individuals At High Risk For Developing Pancreatic Cancer

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 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

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

Hereditary Pancreatic Cancer Genetic factors 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

Surveillance in Hereditary Pancreatic Cancer Ultimate goal Detection of a precursor lesion before progression towards invasive carcinoma or Detection of an early 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) Often multifocal Unknown interval of progression to invasive carcinoma; between 1 and 10 years

Imaging in Pancreatic Cancer Potentially promising techniques 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 effective in the identification of early lesions despite invasiveness, low risk for adverse effects operator-dependent

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 Hepatol 2006:4;766-81

Surveillance in Hereditary Pancreatic Cancer Prospective study Partnership between AMC, AvL, and Erasmus MC 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% 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 II 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 Prospective study Main outcome parameter: number (percentage) of patients in whom a pancreatic cancer or precursor lesions is 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 faecal 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??]

Hereditary Pancreatic Cancer Study Case example

Hereditary Pancreatic Cancer Study Case example

Surveillance in Hereditary Pancreatic Cancer Conclusion & summary EUS is a promising technique for surveillance EUS is able to detect precursor lesions and small carcinoma s With this strategy it may possible to lower the mortality of pancreatic cancer However,

Surveillance in Hereditary Pancreatic Cancer Conclusion & summary Many questions remain: 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 actually survive and is mortality lowered?