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Colon cancer screening in 2016
The evidence & the Belgium situation
Prof Dr Eric Van CutsemUZ Gasthuisberg Leuven
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De Standaard4-6-2015
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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
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Cancer prevention
Primary prevention Secundary prevention
Screeningsurveillance
Life styleChemoprevention
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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• ……..
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Healthy life style : 25 % (?) reduction of cancer related mortality
Life style and cancer
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COLON CANCER IN 2013 IN BELGIUM
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Colorectal cancer: risk groups
FAP
5%
IBD1% FAP
1%HNPCC
5%
FH 15%-20%
Sporadic(Average Risk)
~75%
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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
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Percentage of combined TNM stage -CRC by sex in Belgiium
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Genes and growth factors who stimulate the progression till cancer
Adenoma – Carcinoma sequence
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Knudsen A et al, JAMA 2016
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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)
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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)
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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
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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
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Familial Adenomatous Polyposis syndrome
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FAPIntestinal >100 adenomatous polyps
>20 in AFAP Other cancers
Duodenum Thyroid
Ampulla of Vater
Pancreas
Liver
Brain
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Duodenal adenoma in FAP
sessile +/- 90% of FAP 4% duodenal cancer leading cause of death
in colectomized patients
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familial adenomatous polyposis (FAP) prevention:
Colectomy with ileorectal or ileo-anal anastomosisat young adult age
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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
?
? ? ??
?
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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
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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
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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
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illustration: HNPCC, mutation MLH1
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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?
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Population screening for colon cancer
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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
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Cost-effective Screening methods
FOBTChemical test (gFOBT)Immunochemical test (iFOBT)Stool DNA tests
EndoscopySigmoidoscopyColonoscopy
Virtual colonoscopy - CTCCapsule endoscopy
Lansdorp-Vogelaar Epidemiol Rev 2011
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A Positive FOBT
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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)
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COLON POLYPS
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Polypectomy
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COLONOSCOPY
polypectomy
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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
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CRC screening
Making screening effective depends on several factors;
Scientific evidence
Solid organisation/ efficacy of the program
Uptake/participation
Quality assurance on all levels
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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
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Authors: L Van Karsa… Van Cutsem E…..et al February 2011
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2008: Creation of ESDO with W Havel CRC awareness lobying at EU Parliament
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Schreuders Gut 2015 (WEO),
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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)
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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
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De Standaard
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Darmkanker best zo vroeg mogelijk opgespoord: Artsen
hopen op‘Termont-effect’ 04 juni 2015 | Maxie Eckert
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Samenwerking
Voorbereidende pilootprojecten: Samenwerking Overheden (Vlaanderen, Wallonië, Federaal, lokale overheden – provincie, gemeenten), KCE, Wetenschappelijke verenigingen, Universiteiten, huisartsen, Stichting Kankerregister, RIZIV, mutualiteiten,…
Artsenkrant
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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
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Conclusion: screening for CRC in Flanders
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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
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One Should Take No Risks
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Lin J et al, JAMA 2016
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Lin J et al, JAMA 2016
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Life style Screening