Surveillance of Individuals At High Risk For Developing Pancreatic Cancer

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

2. 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, non-specific symptoms and high metastatic potential • Poor response to chemo- and radiotherapy • Poor 5 year survival rates, even after potentially curative surgical resection

3. 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

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

5. Hereditary Pancreatic Cancer Genetic factors II • 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

6. Hereditary Pancreatic Cancer Genetic factors III

7. Familial Pancreatic Cancer Without a known mutation • 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

8. 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

9. 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)

10. Carcinogenesis Genetic model adapted from Fearon and Vogelstein

11. Pancreatic Intrapithelial Neoplasia Stages PanIn-1A to PanIn-2 • Wendt et al. 2007

12. Pancreatic Intrapithelial Neoplasia Stages PanIn-2 to PanIn-3 • Wendt et al. 2007

13. 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

14. 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 • has the ability to identify early lesions • despite invasiveness, low risk for adverse effects • operator-dependent

15. Surveillance in HereditaryPancreatic 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; 766-81

16. Surveillance in HereditaryPancreatic 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

17. Surveillance in HereditaryPancreatic CancerInclusion 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

18. Surveillance in HereditaryPancreatic CancerInclusion 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

19. Surveillance in HereditaryPancreatic 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

20. Surveillance in HereditaryPancreatic 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

21. Hereditary Pancreatic Cancer Study Case example I

22. Hereditary Pancreatic Cancer Study Case example II

23. Surveillance in HereditaryPancreatic 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%)

24. Surveillance in HereditaryPancreatic 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.

25. Surveillance in HereditaryPancreatic 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

26. Surveillance in HereditaryPancreatic 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

27. Surveillance in HereditaryPancreatic Cancer Conclusion & summary II • 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?