Familial Risk and Surveillance of Colon and Rectum

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Academic Coloproctology & Colon Cancer Genetics Group University of Edinburgh & Western General Hospital. Familial Risk and Surveillance of Colon and Rectum. Malcolm Dunlop. Doing harm. Providing benefit. Know your enemy!. Colorectal Cancer Aetiology. Diet Age/Sex - PowerPoint PPT Presentation

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  • Familial Risk and Surveillance of Colon and RectumMalcolm Dunlop

  • Providing benefitDoing harm

  • Know your enemy!

  • Colorectal Cancer AetiologyDiet Age/SexLifestyle factorsChronic inflammatory bowel disease Genetic factors High penetrance dominant/recessive gene disordersLow penetrance dominant/recessive alleles Genetic risk factors, gene-environment & gene-gene interaction

  • Colorectal cancer age distribution

  • Absolute 5-year Colorectal Cancer Risk

  • Age-specific incidence rate(per 100,000 person-years)204326OR = 1.6, M vs F

  • Relative Contributions to Colorectal Cancer Incidence35% -Lichtenstein NEJ M 2000

  • GeneContributionFamilial adenomatous polyposis APC0.07%Rare dominant genetic syndromes
  • HNPCC kindred

  • HNPCC is due to mutations in DNA mismatch repair genes

  • Lifetime cancer risk for people with HNPCC gene mutationsLarge bowel Male80%Female30%

    Uterus (endometrium)40%Ovary9%

    Stomach19%Upper Urinary Tract10%Small intestine1%

  • MMR gene penetranceAge (years)Cumulative risk %**Dunlop et al 1997

  • Effect of Surveillance on Colorectal Cancer Incidence and MortalityRetrospective case-control study colonoscopic surveillance vs no screen

    62% colorectal cancer incidence 65% colorectal cancer mortality Jarvinen 2000

  • Effectiveness of Polypectomyby Risk Group

    Sporadic CRC

    (Winawer)

    HNPCC

    (Jarvinen)

    Polypectomies

    1178

    22

    Expected CRC

    20-48

    12.8

    Observed CRC

    5

    5

    CRC prevented

    15-43

    7.8

    PolypX/CRC prevented

    48

    2.8

  • Evidence Base for Cancer Surveillance in HNPCC/MMR CarriersBeneficial?Grade of evidenceColorectal cancerYesB/CEndometrialNoB/COvarian?CUrothelial?CGastricNoB/CBrain?C

  • Empiric FH Criteria to Guide Surveillance

  • Familial aggregation due to chanceFamilial aggregation due shared environmentRecall inaccuracy (+ve or ve)Effect of family sizeInability to determine risk at the individual levelInherent limitations of FH information

  • Heterogeneity of CRC RiskAggregate risk 1:10

  • Population Prevalence of Colorectal Cancer FH Published data*Any affected relative 4 - 10%1 affected under 45yrs0.4%2 affected relatives0.2%Combined0.5%*St John. Ann Int Med 1993. Fuchs NEJM 1994. Bonelli Int J C 1988. Slattery JNCI 1994. Ponz de Leon Cancer 1987. Stephenson. BJS 1991

  • Edinburgh FH StudyPopulation Prevalence of Family HistoryAll relatives traced of healthy control subjects (n = 160) (age 30-70 years)Mitchell & Dunlop 2004 unpublished.

    Family History CriteriaAny affected relative46 28.8% (95% CI = 21.7, 35.8)Affected first degree relative15 9.4% (95% CI = 4.9, 13.9) More than one affected relative14 8.8% (95% CI = 4.4, 13.1)

  • Accuracy of FH ReportingKnowledge of Family Members Health

  • Accuracy of FH Reporting Reporting of Colorectal Cancer in Relatives

  • FH Criteria (ACP/BSG) Two affected first degree relatives or One first degree relative affected at
  • Family history of colorectal cancer is common in population

    FH of colorectal cancer is substantially under-reported

    Interviewee reports are subject to considerable inaccuracy

    Interview data should be interpreted with cautionFH Reporting at Interview Conclusions

  • Degree of empirical lifetime CRC riskRR and OR

    Risk group

    Houlston

    (lifetime risk CRC death)

    St John

    (OR)

    Fuchs

    (RR)

    Slattery

    (OR)

    Male Female

    Population

    1:50

    -

    -

    -

    -

    Any FH

    1:17

    1.8

    1.72

    2.1

    2.43

    One affected relative

  • Absolute 10yr RiskCumulative risk for each age group

  • Absolute 10yr Colorectal Cancer Risk

  • Competing Causes of Death10-year risks by age-group50-69yrs70yrs+

    All cause death17%41%

    Developing CRC 1.7%4.2%

    Death from CRC0.95%2.6%

  • Colonoscopy adverse eventsOutcomeRisk/examination

    Adenoma miss rate(Rex et al 1997)Overall27%6-9mm13%>1cm6%

    Serious morbidity0.3%

    Mortality1/5000-1/10,000

  • Projected effect of surveillanceACP/BSG Moderate Risk GuidelinesProjected benefit Single colonoscopy 35-45yrs 55yrs

    Early CRC detection 1:1660 1:180 Prevention CRC death 1:3600 1:220Detect polyposis syndromes ++ +/-Reduce anxiety ++ +/-Identify polyp formers for surveillance + ++Sporadic CRC incidence reduction - +/-

  • Edinburgh FH Genetic DatabaseHighModerateLowUnclear18%40%33%9%N = 882

  • Prevalence colonoscopy screen(n=448 consultands. 176 Medium/High Risk)Bradshaw et al. Gut 2003; 52: 1748-51

    High Risk

    Median Age

    Moderate Risk

    Median Age

    Screened

    53

    43

    123

    43

    Normal

    45

    41

    104

    43

    Any Polyp

    8

    49

    19

    45

    adenoma

    4 (8%)

    46

    5 (4%)

    54

    hyperplastic

    4 (8%)

    54

    14 (11%)

    44

  • Possession of a technology requires that you keep your eye on the horizon!

  • ConclusionsLimited high quality data available to inform practice

    Centralised management of FH+ cases facilitates risk assignment and audit of outcomes

    People fulfilling moderate risk criteria merit surveillance on two occasions, aged 35-45 and at 55yrsWhole colon should be imagedPeople assigned low risk can be reassured and population interventions advised