Pancreatic Cancer: How to identify high-risk population

Núria Malats

Centro Nacional de Investigaciones Oncológicas (CNIO)

nmalats@cnio.es

1EDCD 2017 / NMalats

The Facts

Pancreas

5EDCD 2017 / NMalats

Looking into the future: hoping to be wrong

Pancreas

3EDCD 2017 / NMalats

Death rates from pancreatic cancer are rising while rates for all other cancers continue to fall in Europe

Malvezzi M, Ann Oncol 2014

Pancreatic Cancer

Ferlay J, Acta Oncol 2016

More deaths from pancreatic cancerthan breast cancer in the EU by 2017

4

PERSONALIZED PREVENTION OF PANCREATIC CANCER

Pancreas

EDCD 2017 / NMalats

90%sporadic

2%HPC

8%FPC

Pancreatic Cancer Aetiology: Complex

Sporadic cancer

Familial (unknown)

BRCA2

CDKN2A

STK11

MLH1, MSH2, MSH6

APC

PALB2

PRSS1, SPIN1

CFTR

Klein et al. Mol Carcinog 2012

64% attributed to environmental factors(Lichtenstein P et al. NEJM 2000)

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Pancreas

EDCD 2017 / NMalats

90%sporadic

2%HPC

8%FPC

Lifetime PC risk >16 %

Anticipating Pancreatic Cancer : Complex ???

High-risk

General Population

Lifetime PC risk = 0.7%

6EDCD 2017 / NMalats

GENOME

Periodontitis

PANCREASCANCER

Diabetes

A/BBlood group

Chronic pancreatitis

TobaccoObesity

Metals(Cd, As, Pb)

Allergy/Asthma

Vitamin D

Helicobacter pylori

StatinsMetformin

Selenium

Alcohol

ASANSAIDs

Familyhistory

MICROBIOME

Pancreas

EPIGENOME

PANCREATIC CANCER: A chronic inflammation-related disease

7

PAF: Population Attributable FractionLowenfels et al. Int J Epidemiol 2015

PAF<3%

PAF=1-16%

PAF=3-16%PAF=11-32%

PAF=13-19%

PAF=3-7%

PAF<9%

PAF=3-10%

EDCD 2017 / NMalats

Screening with

Enriching pancreatic cancer high-risk population: 2-step filter

8EDCD 2017 / NMalats

• Hospital-based case-control and cohort study

• Consensus pathology review

• Samples (uniform SOPs)• Blood• Saliva• Urine• Toenails• Tissue• Stool

• Information (EPIQUEST)• Epidemiologic • Clinical-pathological• Prospective follow-up

From 2009 to 201328 centres

External Scientific Advisors: D Silverman (NCI, USA)D Easton (Cambridge U, UK)

Cases Controls

Informed consent 2299 1450

Epi questionnaire 2246 1304

Clinical &FU data 1175 -

Blood 2036 1350

Saliva 1319 1008

Urine 1608 950

Toenails 636 669

European Study of Chronic Pancreas Diseases and Genetic

PanGenEU Study

9EDCD 2017 / NMalats

Periodontitis

PANCREASCANCER

Diabetes

A/BBlood group

Chronic pancreatitis

TobaccoObesity

Metals(Cd, As, Pb)

Allergy/Asthma

Vitamin D

Helicobacter pylori

StatinsMetformin

Selenium

Alcohol

ASANSAIDs

Familyhistory

Pancreas

PANCREATIC CANCER EXPOSOME

10Gómez-Rubio et al. Gut 2017EDCD 2017 / NMalats

Longstanding Conditions Recent Conditions

Cases Controls OR* 95%CI Cases Controls OR* 95%CI Cases Controls OR* 95%CI

N=1705 N=1084 N=1318 N=1037 N=1009 N=640

Gastric + Diabetes^

0 730 610 1 730 610 1 730 610 11 482 256 1.97 1.58 - 2.47 292 235 1.29 1.02 – 1.65 193 21 8.76 5.37 – 14.272 322 150 2.48 1.87 - 3.29 190 134 1.56 1.15 – 2.12 86 9 10 4.79 – 20.96

>=3 171 68 3.5 2.38 - 5.13 106 58 2.39 1.58 - 2.65P. of trend 4.39E-14 2.02E-05 1.14E-20^ Heartburn, Acid regurgitation, H. pylori, Ulcer, and T2D

* Adjusted for age, sex, country, pack/years, and number of morbidities

† Last two categories combined into one (>=2 conditions). Subjects with >=3 conditions: 13 cases and 3 controls

PANCREASCANCERLongstanding condition

2yr

Recent condition

Multimorbidity patterns and pancreatic cancer risk Time-dependence

Early manifestations ?Risk factors

Gómez-Rubio et al. Ann Oncol 2017

Pancreas

11EDCD 2017 / NMalats

Pancreas

http://www.disgenet.org/web/DisGeNET

Autoimmune disease and pancreatic cancer risk

Gómez-Rubio et al. Submitted

Any AID

1 AID

>2 AIDs

Systemic

Localized

Both

GI AIDs

PanGenEU Study1705 cases & 1084 controls

OR, 95%CI

12EDCD 2017 / NMalats

GENOME

Periodontitis

PANCREASCANCER

Diabetes

A/BBlood group

Chronic pancreatitis

TobaccoObesity

Metals(Cd, As, Pb)

Allergy/Asthma

Vitamin D

Helicobacter pylori

StatinsMetformin

Selenium

Alcohol

ASANSAIDs

Familyhistory

Pancreas

PANCREATIC CANCER and GENOME

13EDCD 2017 / NMalats

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Amundadottir L. Int J Biol Sci 2016

Pancreas

PANCREATIC CANCER and GENOME

https://www.ebi.ac.uk/gwas/

EDCD 2017 / NMalats

Periodontitis

PANCREASCANCER

Diabetes

A/BBlood group

Chronic pancreatitis

TobaccoObesity

Metals(Cd, As, Pb)

Allergy/Asthma

Vitamin D

Helicobacter pylori

StatinsMetformin

Selenium

Alcohol

ASANSAIDs

Familyhistory

Pancreas

GENOMEBlood

(SNP, CNV, Rare variants)

GWAS (PanGenEU)WES/WGS (ICGC)

PANCREATIC CANCER and GENOME

15López de Maturana E, et al. Work in progressEDCD 2017 / NMalats

Periodontitis

PANCREASCANCER

Diabetes

A/BBlood group

Chronic pancreatitis

TobaccoObesity

Metals(Cd, As, Pb)

Allergy/Asthma

Vitamin D

Helicobacter pylori

StatinsMetformin

Selenium

Alcohol

ASANSAIDs

Familyhistory

Pancreas

GENOMEBlood

(SNP, CNV, Rare variants)

GWAS (PanGenEU)WES/WGS (ICGC)

EPIGENOMEBlood

(mCpG)850K Illumina

Col. M Fraga, UNIOVI

PANCREATIC CANCER and METHYLATION

16Alonso L, et al. Work in progressEDCD 2017 / NMalats

Periodontitis

PANCREASCANCER

Diabetes

A/BBlood group

Chronic pancreatitis

TobaccoObesity

Metals(Cd, As, Pb)

Allergy/Asthma

Vitamin D

Helicobacter pylori

StatinsMetformin

Selenium

Alcohol

ASANSAIDs

Familyhistory

Pancreas

GENOMEBlood

(SNP, CNV, Rare variants)

GWAS (PanGenEU)WES/WGS (ICGC)

EPIGENOMEBlood

(mCpG)850K Illumina

Col. M Fraga, UNIOVI

MICROBIOMEOral – Gut

(pathogens)MetaG, 16S

Col. P Bork, EMBL

PANCREATIC CANCER and MICROBIOME

17Molina E & Gómez P. Work in progressEDCD 2017 / NMalats

Periodontitis

PANCREASCANCER

Diabetes

A/BBlood group

Chronic pancreatitis

TobaccoObesity

Metals(Cd, As, Pb)

Allergy/Asthma

Vitamin D

Helicobacter pylori

StatinsMetformin

Selenium

Alcohol

ASANSAIDs

Familyhistory

Pancreas

GENOMEBlood

(SNP, CNV, Rare variants)

GWAS (PanGenEU)WES/WGS (ICGC)

EPIGENOMEBlood

(mCpG)850K Illumina

Col. M Fraga, UNIOVI

MICROBIOMEOral – Gut

(pathogens)MetaG, 16S

Col. P Bork, EMBL

18Molina E & Gómez P. Work in progress

Multifactorial PANCREATIC CANCER aetiology

EDCD 2017 / NMalats

Take-home Messages1. Pancreatic cancer aetiology is complex with highly-correlated genomic

and non-genomic factors involved

2. Definition of high-risk populations should mirror such complexity bybuilding multifactorial algorithms

3. Multimorbidity patterns associate with pancreatic cancer, highlightingthe importance of the systems concept (diseasome)

4. Hyper-reactivity of the immune system (asthma, allergies, andautoimmune diseases) reduces the risk of pancreatic cancer

5. Medical conditions included in the multimorbidity patterns have acommon genetic background partly shared with pancreatic cancer

6. Genomics, methylomics, and microbiomics patterns associated withpancreatic cancer risk

19EDCD 2017 / NMalats

90%sporadic

2%HPC

8%FPC

Lifetime PC risk >16 %

Anticipating Pancreatic Cancer : Complex ???

High-risk population:- Precursor Conditions (NODM, Chronic pancreatitis)- Precursor Lesions (IPMN)- Risk/Protective Factors

High-risk

General Population

Lifetime PC risk = 0.7%

20EDCD 2017 / NMalats

Larger investment in primary & secondary prevention

• Need to apply a “systems thinking”

• Large & international standardized studies

• Longitudinal data and sample collection

• e-medical records

• novel “smart” technologies: e-exposures

• associated biobanks using same SOPs

• Omics data generation: adequate platforms

• Next-generation database platforms and Quantum-computing

• Algorithms allowing Omics and non-omics data integration

• Multidisciplinary approaches involving health professionals

Present/Future challenges in pancreatic cancer aetiology research

21EDCD 2017 / NMalats

PanGenEU Study

CNIO, Madrid (Genetic and Molecular Epidemiology, Epithelial Carcinogenesis (FX Real), Structural Computational Biology, Bioinformatics Unit, Human Genotyping Unit-CEGEN)

Institut Municipal d’Investigació Mèdica, Barcelona

Hospital del Mar, Barcelona (I Poves, L Ilzarbe)

Hospital de Sant Pau, Barcelona (A Farré)

Hospital Vall d‘Hebron, Barcelona (X Molero, L Guarner)

Hospital Universitario de Oviedo (A Tardón)

Hospital CLínico de Salamanca (L Muñoz-Bellvis)

Hospital Universitario de Santiago C. (E Dominguez-Muñoz)

Hospital Universitario de Elche (V Barberá)

Hospital 12 de Octubre, Madrid (P Peláez)

Hospital Ramón y Cajal, Madrid (A Carrato)

Centro Oncológico Integral “Clara Campal”, Madrid (M Hidalgo)

Philipps-Universität Marburg (T Gress, M Buchholz)

Technische Universität Munchen (C Michalski)

University of Liverpool (B Greenhalf)

Queen Mary University of London (T Crnogorac-Jurcevic)

Universita di Verona (A Scarpa, R Lawlor)

Karolinska Institute, Stockholm (M Löhr)

PanCAM, Ireland (L Sharp, L Murray)

External Scientific Advisors: D Silverman (NCI,US), D Easton (Sanger, UK)

Patients, monitors, technicians, doctors, and researchers

Acknowledgments Multimorbidity studies InvestigatorsV Rosato A Gutierrez

C Bosetti J Piñero

C La Vecchia L Furlong

Chronic Pancreatitis Team: D Whitcomb, L Amundadottir, M Lehr, W Greenhalf, A Ferré, X Molero

Pancreas cancer studies collaboratorsMicrobiome: P Bork (EMBL, Germany)

Methylome: M Fraga (UniOvi, Spain)

ICGC: A Biankin (Glasgow U, UK), S Gallinger (OICR, Canada)

PanGenFAM: A Carrato (HRyC, Spain)

Pancreatic Cancer Europe // PancreOS Registry

PANSCAN & PanC4: L Amundadottir (NCI, US), G Petersen (Mayo C, US), A Klein

(JHU, US)

EUPancreas COST ActionVice-Chair: C La Vecchia (U. Milan, Italy)

WG Coordinators: I Esposito (U. Düsseldorf, Germany), K Van Steen (U. Liège, Belgium), S Hahn (U. Bohum), A Brand (U Maastricht)

Action coordination: E Molina (CNIO, Spain)

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24 of September

Periodontitis

PANCREASCANCER

Diabetes

Chronic pancreatitis

Obesity

Allergy/Asthma

Helicobacter pylori

Pancreas

PANCREATIC CANCER and MICROBIOME

Neisseria elongataStreptococcus mitis

Porphyromona gingivalisMICROBIOME Porphyromona gingivalisAggregatibacter actinomycetemcomitansPhylum FusobacteriaLeptotrichia

24CRG 2017 / NMalats