Colon cancer screening in 2016

The evidence & the Belgium situation

Prof Dr Eric Van CutsemUZ Gasthuisberg Leuven

Eric.VanCutsem@uzleuven.be

De Standaard4-6-2015

Belgium: number of invasive tumours by primary site and age group in 2014

MALES FEMALES• Oesophagus 710 278• Stomach 898 584• Small intestine 188 160• Colon 3,823 3,091 • Rectosigmoid junction 108 82 COLON: 8748• Rectum 1,644 946• Anus and anal canal 65 115• Liver and IH bile ducts 596 268• Gallbladder 35 80• Biliary tract, NOS 159 129• Pancreas 871 844• Other digestive organs 27 24

Publication date: 07/10/2016

Cancer prevention

Primary prevention Secundary prevention

Screeningsurveillance

Life styleChemoprevention

Causes of colorectal cancer

• Multifactorial: many factors unknown – A few risk factors known: e.g. age– Genetic and hereditary predisposition– Enviromental factors: multifactorial !!

• High fat intake• Low fiber intake• Low physical activity• Overweight• Red meat• Low vitamine, calcium• Nicotine• Alcohol• ……..

Healthy life style : 25 % (?) reduction of cancer related mortality

Life style and cancer

COLON CANCER IN 2013 IN BELGIUM

Colorectal cancer: risk groups

FAP

5%

IBD1% FAP

1%HNPCC

5%

FH 15%-20%

Sporadic(Average Risk)

~75%

Colorectal cancer screening

CRC is very suitable for screening– Detectable and treatable pre-malignant lesions

(adenomas)– Early detection of CRC improves the prognosis– Benefits outweigh the potential harms

Brenner, BMJ, 2014; Hewitson, Am J Gastro, 2008; Lansdorp-Vogelaar, Epi Rev, 2011

Percentage of combined TNM stage -CRC by sex in Belgiium

Genes and growth factors who stimulate the progression till cancer

Adenoma – Carcinoma sequence

Knudsen A et al, JAMA 2016

Hereditary colorectal cancer“Traditional” approach for diagnosis has been phenotype/driven

Based on clinical presentationOne or few genes are analyzed based on clinical suspicion

EndoscopyClinical findings Pathology (HE) Molecular pathology (IHC/MSI/BRAF)

Hereditary factors in CRCGENETIC DISORDERS : Hereditary disorders: FAP and HNPCC (= Lynch syndroom): very high risk for colon cancer (however only ~3 of colon cancers)

Familial predisposition of colorectal cancer: in ~ 20 % of patients (other genetic abnormality – not yet revealed)

higher risk if 1st degree family member has colon cancer (RR 2,42) higher risk if 1st degree family member has colon cancer at the age < 45 year (RR 3,87) higher risk if more than one 1st degree family member has colon cancer (RR 4,25) higher risk if 1st degree family member has (advanced) adenoma(s) (RR 1,99)

Clinical phenotype Syndrome Hereditary CRC genes

Gene Mendelianpattern Chromosome Reference

Adenomatous polyposis

FAP APC AD 5q21-q22 Groden J, et al. Cell 1991

MAP MUTYH AR 1p34.1Al-Tassan N, et al. Nat Genet

2002Polymerase-proof reading-

associated polyposisPOLE AD 12q24.3 Palles C, et al. Nat Genet 2013

POLD1 AD 19q13.3 Palles C, et al. Nat Genet 2013

Hamartomatous polyposis

Peutz-Jeghers syndrome STK11 AD 19p13.3 Hemminki A, et al. Nature 1998

Juvenile polyposis

SMAD4 AD 18q21.1 Howe JR, et al. Science 1998BMPR1A AD 10q22.3 Howe J, et al. Nat Genet 2001

ENG AD 9q34.11Ngeow J, et al. Gastroenterology

2013Cowden syndrome PTEN AD 10q23.3 Liaw D, et al. Nature Genet 1997

Serrated polyposis

Serrated polyposis syndrome

??? ??

Non-polyposisCRC

Lynch syndrome

MLH1 AD 3p21.3Papadopoulos N, et al. Science

1994MSH2 AD 2p21 Fishel R, et al. Cell 1993MSH6 AD 2p16 Miyaki M, et al. Nat Genet 1997PMS2 AD 7p22.2 Nicolaides N, et al. Nature 1994

EPCAM AD 2p21 Ligtenberg MJ et al. Nat Genet 2009

MUTYH associated CRC MUTYH AD 1p34.1Al-Tassan N, et al. Nat Genet

2002

Hereditary CRC type XSEMA4A AD 1q22 Nat Commun. 2014RPS20 AD 8q12.1 Gastroenterology. 2014

GALNT12 AD 9q22.33 Guda K, et al. PNAS 2009

Hereditary CRC syndromes

Familial Adenomatous Polyposis (FAP)

Definition:colorectal adenomas:More than 100 in one individualorLess than 100 in an individual withfirst degree family member with FAP

Frequency: ~1%

Mutated genes:APC: dominant - detected in ~80% of FAP patientsMutYH: recessive form

www.belgianfapa.be

Familial Adenomatous Polyposis syndrome

FAPIntestinal >100 adenomatous polyps

>20 in AFAP Other cancers

Duodenum Thyroid

Ampulla of Vater

Pancreas

Liver

Brain

Duodenal adenoma in FAP

sessile +/- 90% of FAP 4% duodenal cancer leading cause of death

in colectomized patients

familial adenomatous polyposis (FAP) prevention:

Colectomy with ileorectal or ileo-anal anastomosisat young adult age

Genetic test in FAP

Predictive test for at-risk persons– via Centres Human Genetics– Genetic and Psychosocial counselling

FAPIAA 22y

FAPsurg 35y

FAPDeath at 16y

30yno colo

17y 13y 9y

FAPstoma at 47y

18ynl colo

7y

?

? ? ??

?

Lynch syndrome (formerly known as HNPCC)

• Most common hereditary CRC syndrome (1-5%)

• Cause: Germline mutations in MMR genes (MLH1/MSH2/MSH6/PMS2/Epcam)

Autosomal dominant pattern of inheritance (50% probability of transmission)

• Clinical phenotype: cancer predisposition (early-onset, but not always…..)

– Lifetime risk of CRC: 25-80%

– Lifetime risk of endometrial cancer: 20-70%

– Others: stomach, urinary tract, ovary, small bowel

• Tumor phenotype:

– Characteristic pathology: tumor infiltrating lymphocytes, mucinous features

– Microsatellite instability (MSI) (PCR-based assay)

– Loss of protein expression (immunohistochemistry)

Hampel et al. NEJM 2005Piñol et al. JAMA 2005Bessa X et a. JCO 2011

Hallmarks of MMR deficiencyDiagnostic markers

Lynch syndrome

definition: OLD (too) strict Amsterdam criteria I (of II)colon cancer (endometrium, urothelial, small bowel):

in at least 3 family members, in at least 2 generationsof which 1 is first degree relative of the 2 othersAnd at least 1 patient is <50 yearsFAP is excluded

NEW (more realistic) Bethesda criteria

molecular genetics:Mutation in gens involved in mismatch repair (MMR)

MLH1, MSH2, MSH6, PMS2MSI phenotype and immunehistochemical examination

Tumour Cumulative risk

colorectal adenocarcinoma 80%

Endometrium carcinoma till 60%

Ovarian carcinoma 12%

Stomach- and small bowell cancer till 13%

transitional cel carcinoma (ureter andkidney)

Brain tumors Turcot syndrome

sebaceous adenoma en carcinoma Muir-Torre syndrom

Lynch syndrome

illustration: HNPCC, mutation MLH1

Recommendation in Lynch syndrome Preventive Examinations:

– Total Colosconopy every 2 years– Starting at 25 year

– Gynecologic examination with intravaginalultrasonography and CA 125 determation, yearly

– Starting at 30 years

– If other tumours occurs in the family, starting at 35 years:

– Gastroscopy every 2 years– Ultrasonography or urinary bladder and kidneys and

urine cytology, every year

Treatment– Prophylactic Colectomie? Hysterectomie?

Population screening for colon cancer

CRC screening is cost-effective compared to no screening (cost-saving)

No single strategy found to be the most effective or preferred for a given willingness to pay per LYG

Cost-effectiveness of CRC screening

Lansdorp-Vogelaar Epidemiol Rev 2011

Cost-effective Screening methods

FOBTChemical test (gFOBT)Immunochemical test (iFOBT)Stool DNA tests

EndoscopySigmoidoscopyColonoscopy

Virtual colonoscopy - CTCCapsule endoscopy

Lansdorp-Vogelaar Epidemiol Rev 2011

A Positive FOBT

Guaiac FOBT

Detects peroxidase activity of heme

Diet/drug restrictions 3 samples Low cost Lower sensitivity

Immunochemical FOBT

Antibody reacts to human globin No dietary restrictions 1 sample Moderate cost Leads to higher participation, higher

sensitivity, more colonoscopies (cut of)

COLON POLYPS

Polypectomy

COLONOSCOPY

polypectomy

How to screen?

Persons with hereditary syndrome: DNA test + colonoscopy www.belgianfapa.be

Persons with elevated (familial) risk: colonoscopy

Persons at normal risk:

Population screening program: stool blood test (iFOBT) followed by a colonoscopy between 50-74 years

Take into account age distribution and individual perception

CRC screening

Making screening effective depends on several factors;

Scientific evidence

Solid organisation/ efficacy of the program

Uptake/participation

Quality assurance on all levels

European level

December 2003: European Code against Cancer and EU councilrecommendation "Men and women from 50 years of age shouldparticipate in colorectal screening. This should be withinprogrammes with built-in quality assurance procedures“"Faecal occult blood testing is actually the only recommendedscreening strategy“

December 2010: Declaration on relevance of screening in EUparliament signed by majority of members of parliament

February 2011: presentation of new guidelines by EU commission

Authors: L Van Karsa… Van Cutsem E…..et al February 2011

2008: Creation of ESDO with W Havel CRC awareness lobying at EU Parliament

Schreuders Gut 2015 (WEO),

Pilootprojecten in de Vlaamse Gemeenschap• Werkgroep colonkanker 2006

– Installatie op 2 februari 2006• Minister Inge Vervotte en Mevrouw Karine Moykens (adjunct

Kabinetschef); later Minister Steven Vanackere, later Minister Jo Van Deurzen en Dr Dirk Dewolf (adjunct kabinetschef)

– Samenstelling: • Eric Van Cutsem (voorzitter) (maagdarm ziekten & digestieve

oncologie)• Johan Pauwels, Dirk Dewolf, Pieter Vandenbulcke, Jessy Hoste &

Karen Colaert (Vlaamse Gemeenschap)• Frans Goovaerts & Jos Desmedt (Huisartsen)• Joost Weyler (Epidemioloog)• Michiel Callens, Patrick Galloo, Raf Mertens (IMA)• Liesbeth Van Eycken (Kankerregister)• Erwin Declerck (VLK)• Luc Colemont, Elisabeth Macken, Marc Peeters & Sabine Tejpar

(Maagdarm ziekten)• Gerrie Kiebooms (psychologe, ethicus)• Ad hoc: Dr Bielen (radioloog)

Vlaanderen

Piloot project in Vlaanderen: 3 gemeenten in provincie Antwerpen

FOBT in average risk bevolking van 50 – 74 jaar 2 sporen

FOBT vanaf 40 jaar of colonoscopie bij hoog risico personen

Bevolkingsonderzoek Vlaams Brabant: UZ Leuven, LUCK, Provincie Vlaams Brabant, MCH, Huisartsen

Samenwerking Overheden (Vlaanderen, Wallonië, Federaal, lokale overheden – provincie, gemeenten), KCE, Wetenschappelijke verenigingen, Universiteiten, huisartsen, WIV, RIZIV, mutualiteiten

De Standaard

Darmkanker best zo vroeg mogelijk opgespoord: Artsen

hopen op‘Termont-effect’ 04 juni 2015 | Maxie Eckert

Samenwerking

Voorbereidende pilootprojecten: Samenwerking Overheden (Vlaanderen, Wallonië, Federaal, lokale overheden – provincie, gemeenten), KCE, Wetenschappelijke verenigingen, Universiteiten, huisartsen, Stichting Kankerregister, RIZIV, mutualiteiten,…

Artsenkrant

Selectie en uitnodiging: 56 – 74 jaar Exclusielijst via Stichting Kankerregister Tweejaarlijkse brief met test per post Reden van niet-deelname opgeven via

antwoordformulier/website

Onderzoek Zelf stoelgangstest uitvoeren en opsturen per

post Bij positieve test: resultaat naar

deelnemer en huisarts en coloscopie te plannen

Organisatie

Conclusion: screening for CRC in Flanders

Flemish

communityFrench - German

community

* **

Pilot study 2009 Population study 2009

~20.000 535.740

i-FOB-test g-FOB-test

44 % participation rate 8 % participation rate

bevolkingsscreening sinds 10/2013 Participatie: * 48.7% in 2013

* 50.3% in 2014* 51.4% in 2015

One Should Take No Risks

Lin J et al, JAMA 2016

Lin J et al, JAMA 2016

Life style Screening