Erasmus Medical Center, Rotterdam Marco Bruno Surveillance of Individuals At High Risk For...

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

Surveillance in Hereditary Pancreatic Cancer

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

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 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

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 StudyCase example I

Hereditary Pancreatic Cancer StudyCase 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 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

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