Chronic Pancreatitis and the Risk of Pancreatic Cancer

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1 Chronic Pancreatitis and the Risk of Pancreatic Cancer Albert B. Lowenfels, New York Medical College, Valhalla, NY Patrick Maisonneuve, European Institute of Oncology, Milan, Italy The Causes of Cancer: Then and Now 1802: Institution for Investigating the Nature of Cancer May other diseases degenerate into cancer? 2011 NCI Challenge Questions (24) What are the mechanisms by which some patients with chronic diseaseshave increased risks risksfor developing cancer? 1

2 Risk factors for Pancreatic Cancer Unknown Hereditary 10% Smoking 30% Benign diseases <5% (Diabetes, Pancreatitis) Diet ~20% Case-control studies Early studies found no / or non-significant association between Pancreatitis and pancreatic cancer risk Wynder et al., JNCI 1973 Lin and Kessler, JAMA, 1981 Gold et al. Cancer 1985 Mack et al JNCI 1986 Farrow and Davis, Int J Cancer, 1990 More recent studies tend to report elevated risk of pancreatic cancer in patients with past history of pancreatitis La Vecchia et al, 1990 RR =32(13 =3.2 (1.3-79) 7.9) 7 cases Kalapothaki et al RR= cases Fernandez et al., 1995 RR= 5.1 ( ) 24 cases Bansal et al., 1995 RR= 2.2 ( ) 93 cases Hassan et al., 2007 RR=10.9 ( ) 60 cases Bracci et al., 2009 RR= 7.2 ( ) 137 cases Maisonneuve et al., 2010 RR= 4.7 ( ) 36 cases 2

3 Case-control studies (-) Cases are not always histologically confirmed (-) Control group may not be representative of the population (hospital controls) (-) Past-medical history relies on patient interview - Recall bias - Confusion between Acute and Chronic pancreatitis (or even abdominal pain) (-) Use of proxy (spouse, children, friends,...) interview when patient is too sick to respond (+) possibility to adjust estimates for potential confounders (age, sex, smoking, obesity, family history,...) Cohort studies Study Year Cases RR Rocca et al., / 172 SIR=69 Lowenfels et al., / 2015 SIR=16.5 ( ) Ekbom et al., / 7956 SIR= 3.8 ( ) Karlson et al., / 4546 SIR= 7.6 ( ) Talamini et al., / 715 RR=18.5 ( ) Malka et al., / 373 RR=26.7 ( ) Goldacre et al / 1496 SIR=10.7 ( ) Tropical pancreatitis Chari et al., / 185 RR= 100 ( ) Follow-up of series of patients with CP Pancreas cancer rates compared to that observed in the general population 3

4 Cumulative incidence of pancreatic cancer 4%, 20 years after Pancreatitis Lowenfels et al., New Engl J Med, 1993 Hereditary Pancreatitis and Pancreatic Cancer Reviewing the Evidence 4

5 Hereditary Pancreatitis and Pancreatic Cancer Members of the American Pancreatic Association and the International Association of Pancreatology were invited to participate in a longitudinal study of this rare form of pancreatitis. Eligibility criteria: Early age (<30 years) at onset of symptoms, positive family history and absence of other cause of pancreatitis. Initially, 37 physicians from 10 countries contributed medical records of 246 patients thought to have hereditary pancreatitis. Lowenfels, JNCI, pancreas cancer observed (0.15 expected) SIR= Update 497 Patients with hereditary pancreatitis 19 Pancreas cancers (0.33 expected) SIR (95% CI) = 57 (35-90) 60% 40% Cumulative pancreas cancer risk N=16 20% N=239 N=146 N=92 N= Age Lowenfels, et al. J Natl Cancer Inst 1997 Med Clin North Am JAMA

6 Age at diagnosis of pancreas cancer in patients with Hereditary Pancreatitis 70 yrs On average, smokers developed their tumor 20 years before nonsmokers. 48 yrs Lowenfels et al., JAMA, 2001 Gene-Environment Interaction? Smoking and Hereditary Pancreatitis General Population Hereditary Pancreatitis Smoking NO YES RR=1 RR=2 RR=54 RR=154 Lowenfels et al., JAMA,

7 EUROPAC study 112 families in 14 countries (418 affected individuals) 58 (52%) families carried the R112H mutation 24 (21%) the N29I mutation 5 ( 4%) the A16V mutation 2 ( 2%) rare mutations 21 (19%) had No PRSS1 mutation The cumulative risk of pancreas cancer was 44% (8-80%) 80%) after 70 years from symptoms onset Standardized Incidence Ratio (SIR) = 67 (50-82) Howes et al., Clin Gastro Hepatol, 2004 Vitone et al., 2005 (Europac study) 7

8 All French genetic laboratories (response rate 100%), pediatricians, and gastroenterologists (response rate 84%) were contacted. Inclusion criteria: - mutation in the PRSS1 gene - recurrent, acute, or chronic pancreatitis, with no precipitating factors in two first-degree relatives or 3 second-degree relatives in 2 generations. Rebours et al., Am J Gastroenterol, 2008 French Study 78 families and 200 patients included 10 Pancreas cancer diagnosed > SIR=87 (42-113) Cumulative risk of PaCa at age 50: ~10% Cumulative risk of PaCa at age 70: ~50% Rebours et al., Am J Gastroenterol,

9 Why is chronic pancreatitis associated with pancreatic cancer? Inflammation and Cancer Inflammatory agents Asbestos Schistosomiasis Chronic urinary bladder catheterization Tobacco, silica Liver fluke Helicobacter Pylori Viruses (HBV, HCV, HPV,Herpes) Inflammatory conditions Barrett s metaplasia Pelvic inflammatory disease Inflammatory bowel disease Crohn s disease, ulcerative colitis Cirrhosis, hematochromatosis Chronic pancreatitis Cancer Mesothelioma Bladder Bladder Virchow Lung Liver Stomach, MALT Liver, Cervix, Kaposi Esophageal Ovary Colon-rectum Colon-rectum Liver Pancreas Rudolf Virchow 9

10 112 patients with CP followed for 42 months K-ras mutation in pancreatic duct brushing in 39% of CP 4/44 patients with k-ras mutation developed PaCa None of the 68 with wild genotype p= (Endoscopy 2004) Arvanitakis et al., Endoscopy 2004 Pancreatitis-Induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence* Pancreatic acinar cells yield panins and ductal adenocarcinomas when exposed to bouts of pancreatitis, if they harbor K-Ras oncogenes. The findings suggest that anti-inflammatory therapy of people diagnosed with pancreatitis may reduce the risk of pancreatic cancer. *Guerra et al., Cancer cell,june,

11 (Ji, Gastroenterology 2009) Aspirin and GI Cancer Mortality Pooled analysis of 25,000 patients, 7 RCT s. Daily aspirin, with follow up > 5 Years.* Tumor Site (n) Hazard Ratio (HR) P value Esophagus (23) Pancreas (45) Colorectal (54) Stomach (36) *Rothwell et al: Lancet

12 Conclusions There is strong evidence that pancreas cancer risk is increased in patients with chronic pancreatitis, but CP accounts for only a small proportion of PDAC. The risk is highest in the first years following the diagnosis of chronic pancreatitis. Because of the long duration of inflammation, the risk is particularly high in patients with hereditary pancreatitis. Smoking cessation in CP patients is important! Could long-term aspirin reduce the risk of pancreatic cancer in patients with hereditary pancreatitis? Conclusions Past-history of chronic pancreatitis is a rare (~ 5%) event in pancreas cancer patients Only a small proportion of patients with non-hereditary chronic pancreatitis develop pancreatic cancer (<5% after 20 years) CHRONIC PANCREATITIS IS RESPONSIBLE FOR A SMALL PROPORTION OF PANCREATIC CANCERS 12

13 Death on the Internet IN NTERNET HITS (Million ns) Chocolate PanCA Pancreatitis Powerpoint CAUSE OF DEATH 2.3 Sub-group analysis Bracci et al.,

14 Duration of Pancreatitis 109 of 137 cases (80%) and5of28controls(18%) reported that their first episode of pancreatitis occurred <3 years before their pancreatic cancer diagnosis or interview (controls). (n=109) (n= 18) (n= 10) P for trend <.0001 Bracci et al., 2009 Multicentre historical cohort study of 2015 subjects with chronic pancreatitis who were recruited from 7 clinical centres in six countries. Recruitment: Patients studied between Denmark (Copenhagen), Germany (Göttingen-Lüneburg), Italy (Verona), Sweden (Lund and Orebro), Switzerland (Zurich), and the United States (Rochester, Minnesota.) Information was abstracted from the patients' clinical records or transferred directly from existing computer files Lowenfels et al., New Engl J Med,

15 After a mean duration of follow up of 7.4 years Patients Obs/exp SIR (95% CI) All patients / ( ) excl first 2 years / ( ) - Italy 18.0 ( ) - Switzerland 19.9 ( ) - Germany 17.8 ( ) - Sweden 9.7 ( ) - Denmark 15.9 ( ) - USA ( ) 36 9) - Alcoholic 15.1 ( ) - Non alcoholic 18.7 ( ) excl first 5 years 18/ ( ) Histological confirmation of PaCa for 83% of the pancreas cancer Pancreas cancer risk in patients with chronic pancreatitis according to time interval between pancreatitis and cancer: 1-4 years ( ) 5-9 years ( ) years ( ) Overall ( ) A persistent excess risk after 10 years was restricted to patients with associated alcohol abuse (SIR 3.8; ) suggesting potential confounding with alcohol/tobacco Karlson et al., Gastroenterology,

16 Record linkage study: Analysis of statistical database of linked hospital and mortality data in an area in southern England Reference cohort of 599,308 subjects Acute pancreatitis n= Paca SIR= 5.7 ( ) 3.0 ( )* Chronic pancreatitis n= Paca SIR=27.0 ( ) 10.7 ( )* *Omitting pancreas cancers in the first year Goldacre et al., Eur J Gastro Hepatol, 2008 Maisonneuve et al., Ann Epidemiol,

17 Genetic susceptibility to Pancreatic Cancer in CP The SPINK 1 gene N34S mutation (present in 8% of CP patients), is associated with pancreatic cancer development SPINK1: Serine protease inhibitor Kazal type 1 Shimosegawa et al, Clin Gastro and Hepato, 2009 Aoun et al., Am J Gastroenterol Aspirin and Cancer Prevention* *Rothwell, Lancet, Jan

18 Ras activity levels and development of pancreatic diseases Ras activity in pancreatic acinii induces several important pancreatic disease manifestations and supports a potential direct linkage between chronic pancreatitis, cystic papillary carcinoma, and PDAC. Ji, B. Gastroenterology Sep;137(3): , 18