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Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG)
  1. Kevin J Monahan1,2,
  2. Nicola Bradshaw3,
  3. Sunil Dolwani4,
  4. Bianca Desouza5,
  5. Malcolm G Dunlop6,
  6. James E East7,8,
  7. Mohammad Ilyas9,
  8. Asha Kaur10,
  9. Fiona Lalloo11,
  10. Andrew Latchford12,
  11. Matthew D Rutter13,14,
  12. Ian Tomlinson15,16,
  13. Huw J W Thomas1,2,
  14. James Hill11
  15. Hereditary CRC guidelines eDelphi consensus group
    1. 1 Family Cancer Clinic, St Mark's Hospital, London, UK
    2. 2 Faculty of Medicine, Imperial College, London, UK
    3. 3 Clinical Genetics, West of Scotland Genetics Services, Glasgow, Glasgow, UK
    4. 4 Gastroenterology, Cardiff and Vale NHS Trust, Cardiff, UK
    5. 5 Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK
    6. 6 CCGG, University of Edinburgh, Edinburgh, UK
    7. 7 Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
    8. 8 Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
    9. 9 Faculty of Medicine & Health Sciences, Nottingham University, Nottingham, UK
    10. 10 Head of Policy and Campaigns, Bowel Cancer UK, London, UK
    11. 11 Genetic Medicine, Central Manchester University Hospitals Foundation Trust, Manchester, UK
    12. 12 Polyposis Registry, St Mark's Hospital, London, UK
    13. 13 Gastroenterology, University Hospital of North Tees, Stockton-on-Tees, UK
    14. 14 Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
    15. 15 Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Birmingham, UK
    16. 16 Cancer Research Centre, University of Edinburgh, Edinburgh, UK
    1. Correspondence to Dr Kevin J Monahan, Family Cancer Clinic, St Mark's Hospital, London, HA1 3UJ, UK; k.monahan{at}imperial.ac.uk

    Abstract

    Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual’s lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.

    • colorectal cancer
    • genetic testing
    • inherited cancers
    • surveillance
    • colorectal surgery
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    Objective

    To provide a clear strategy for the management of people at hereditary risk of colorectal cancer (CRC), which includes diagnosis, endoscopic management, prevention and surgical care.

    Aims and methods

    An estimated 35% of CRC is due to heritable factors,1 with approximately 29% of the UK population having a family history of a first-degree relative (FDR) or second degree relative (SDR) with CRC.2 While highly penetrant syndromes such as Lynch syndrome (LS), familial adenomatous polyposis (FAP) and other polyposis syndromes account for account for only 5–10% of all CRC diagnoses, advances in genetic diagnosis, improvements in endoscopic surgical control, and medical and lifestyle interventions provide opportunities for CRC prevention and effective treatment in susceptible individuals.

    The purpose of this guideline is to provide an evidence-based framework for the optimal management of hereditary CRC for clinicians involved in their management, including gastroenterologists, nurse practitioners, physicians, colorectal surgeons, clinical geneticists, genetic counsellors and pathologists. This guideline was commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG), via the colorectal section, and a guideline chair selected. It is an update of the previous iteration of the BSG/Association of Coloproctology of Great Britain and Ireland (ACPGBI) guideline published in 2010 and developed in accordance with the BSG National Institute for Health and Care Excellence (NICE)-compliant guideline process.

    The Guideline Development Group (GDG), which included gastroenterologists from the BSG, clinical geneticists from United Kingdom Cancer Genetics Group (UKCGG), colorectal surgeons from the ACPGBI, a pathologist, a genetic counsellor and a patient representative, was selected to ensure wide-ranging expertise across all relevant disciplines. Members of the GDG, and participants in the eDelphi process, completed a Declaration of Conflict of Interests (COI) form which was reviewed and vetted by the BSG.

    A scoping meeting was held on 13 October 2017, and in advance of this meeting the GDG was asked to develop key priorities and questions.

    The GDG determined that the primary measure of effectiveness of any intervention was a reduction of the lifetime risk of CRC, and the following secondary outcome measures:

    1. Reduction in the incidence of advanced adenomas at colonoscopy

    2. Prevention of CRC

    3. Reduced morbidity related to CRC, or morbidity secondary to complications of surveillance and treatment

    4. Improved identification of hereditary CRC syndromes

    5. Improved pathways from diagnosis to treatment in susceptible populations.

    We sought a consistent approach in our assessment of the relative effectiveness of interventions. In principle we agreed that surveillance should only be offered to individuals who remain at higher risk of developing CRC than the general population. As CRC risk is not always clearly defined, as a surrogate we accepted that advanced adenoma yield on surveillance should be approximately double that in susceptible populations compared with the average risk population.

    A relative threshold for genetic testing was agreed for people with a 10% or greater probability of having a germline pathogenic variant in a cancer susceptibility gene in accordance with previous UK guidelines.3 4 However the GDG agreed that the arbitrary nature of this threshold meant that it could be modified in cases where objective risk assessment was difficult to attain, and clinicians had sufficient clinical suspicion of risk.

    Key questions we sought to cover included the following:

    1. Which aspects of the previous guidelines require updating?

    2. What is the lifetime CRC risk and optimal surveillance for those with a family history of CRC (where LS and polyposis syndromes have been excluded)?

    3. What is the diagnostic yield of genetic testing and/or surveillance for high-risk populations?

    4. What is the optimal gastrointestinal (GI) surveillance for patients at hereditary risk GI cancer?

    5. What is the impact of high-quality endoscopy in patients with known or suspected hereditary cancer syndromes?

    6. Should we develop gene- or gender-specific guidelines for surveillance?

    7. What is the optimal diagnostic assessment and surveillance interval for ‘Lynch-like’ syndrome patients?

    8. How can we improve recognition, diagnosis and treatment of patients at hereditary risk of CRC?

    9. Which diagnostic genetic tests should we offer serrated polyposis syndrome (SPS), multiple colorectal adenoma (MCRA) and early onset CRC (EOCRC) patients (if any)?

    10. When should colonoscopic surveillance for familial risk patients stop, because it is no longer necessary, or because the patient should be referred for surgery?

    11. Which are the optimal surgical approaches in patients with hereditary CRC syndromes?

    12. What is the evidence for chemoprophylaxis in patients who are at hereditary risk of CRC?

    13. What is the evidence for the effect of lifestyle modification on hereditary risk of CRC?

    14. What information do we need to share with our patients at inherited risk of GI cancer?

    Twenty-three PICOs (Patients, Interventions, Controls and Outcomes) were developed which considered these questions. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument provided a methodological framework.5

    A literature search was commissioned externally, with search strategies agreed, and was performed by the Yorkshire Healthcare Consortium, which returned 10 189 publications. Returned abstracts were reviewed for relevance. Additional references were obtained by cross-referencing and by recommendation from the GDG. Relevant published national and international guidelines were also scrutinised. After each round of Delphi, and before the guideline was finalised, the search was repeated and any important studies published since the initial evidence search were incorporated.

    A modified electronic Delphi process6 was used to develop and refine statements. Initial draft statements formulated by the writing committee were reviewed by the GDG to allow for modification and to identify additional references. After a preliminary discussion, formal anonymous voting rounds were undertaken using SurveyMonkey. Each statement was scored by each member of the GDG using a five-point scale. We also invited key national and international opinion leaders from the UKCGG steering group, ACPGBI, BSG, the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE) to participate in the modified Delphi process. We included additional patient and public involvement in the Delphi process by inviting participants through the national charities Bowel Cancer UK and Lynch Syndrome UK. Consensus required at least 80% agreement, and consensus of over 70% was accepted if the GDG felt a statement was required for clinical practice. Where consensus was not reached, feedback from the GDG members was disseminated after each round to allow members to reconsider their original position.7 Where appropriate, revisions to statements were made and a further voting round was undertaken in second and third rounds. A final (fourth) round of voting for statements where consensus had not been reached for 11 statements was performed within the GDG only.

    Surveillance and molecular testing recommendations are summarised in table 1 and table 2 respectively. The GDG also developed 10 research recommendations (online supplementary file 1) which were prioritised by electronic voting.

    Table 1

    Summary of surveillance recommendations

    Table 2

    Molecular testing strategies in hereditary colorectal cancer (CRC)

    The GRADE (Grading of Recommendations, Assessment, Development and Evaluations) tool8 was used to evaluate the strength of evidence and the strength of recommendations made (see executive summary). The GRADE system specifically separates the strength of evidence from the strength of a recommendation. While the strength of a recommendation may often reflect the evidence base, the GRADE system allows for occasions where this is not the case—for example, where it seems good sense to make a recommendation despite the absence of high-quality scientific evidence such as a large randomised controlled trial (RCT).

    Executive summary of key recommendations

    Service provision, communication and management principles

    • We recommend that the moderate risk category of family history of CRC (FHCC) is the minimum threshold for referral from primary care (GRADE of evidence: very low; Strength of recommendation: strong)

    • We recommend that individuals with a FHCC, which meets this referral criteria, be referred to a specialist familial CRC clinic in secondary or tertiary care (GRADE of evidence: low; Strength of recommendation: weak)

    • We recommend that patients should be referred to a specialist service which includes access to constitutional genetic testing in the presence of either deficient mismatch repair (MMR) (with no evidence of MLH1 promoter methylation or BRAF V600E), or polyposis. (GRADE of evidence: low; Strength of recommendation: strong)

    • There are insufficient clinical data to develop specific guidance for patients with very rare conditions such as polymerase proofreading associated polyposis (PPAP), or NTHL1-associated polyposis (NAP); therefore, we suggest patients with these syndromes should be referred to multidisciplinary expert centres for clinical management. (GRADE of evidence: low; Strength of recommendation: weak)

    • We recommend that hospitals which diagnose or manage patients at hereditary CRC risk should ensure clinical pathways to facilitate their care, and processes to monitor the quality of the service. (GRADE of evidence: low; Strength of recommendation: strong)

    • We recommend that individuals at increased familial CRC risk receive specialist knowledge and are aware of patient/support organisations and discussion with regard to lifestyle and participation in research projects. (GRADE of evidence: very low; Strength of recommendation: strong)

    Family history of CRC (FHCC)

    • We recommend that for all patients referred from primary care for assessment for a FHCC, MMR status should be assessed in tumour tissue from a close affected family member. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We recommend that a reported family history of polyposis should be verified by review of histopathology and/or endoscopy reports which confirm the presence of a minimum of 10 adenomas or serrated lesions in a FDR. (GRADE of evidence: low; Strength of recommendation: strong)

    • We recommend that patients with a moderate familial CRC risk should have a one-off colonoscopy at age 55 years. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We recommend that subsequent colonoscopic surveillance should be performed as determined by post-polypectomy surveillance guidelines. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We suggest that in high-risk families (a cluster of 3× FDRs with CRC across >1 generation) a 5 yearly colonoscopy should be performed from age 40 years until age 75 years. (GRADE of evidence: moderate; Strength of recommendation: weak)

    Prevention and lifestyle modification in familial CRC

    • We recommend that individuals with LS should be advised that regular use of daily aspirin reduces CRC risk. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We suggest that people with LS should be offered research opportunities to take aspirin daily at different dosages. If they decline research participation they may be advised on their choices regarding dose of aspirin, risks and benefits of long-term aspirin use and ensure their medical practitioner is aware of their intake. (GRADE of evidence: low; Strength of recommendation: weak)

    • There is insufficient evidence of the benefit of chemoprophylaxis in polyposis syndromes. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We suggest that individuals at increased familial risk of CRC should be strongly encouraged not to smoke, to maintain a normal body mass index (BMI), to moderate their consumption of red and processed meat, and to exercise regularly. (GRADE of evidence: low; Strength of recommendation: weak)

    Quality and advanced endoscopic imaging in colonoscopic surveillance

    • We recommend that colonoscopy is the gold standard diagnostic and preventative method of surveillance for people with hereditary risk of CRC. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We recommend that all surveillance colonoscopies are performed by endoscopists who consistently achieve BSG colonoscopy KPI (key performance indicators) minimum standards, specifically caecal intubation rate, adenoma/polyp detection rate and comfort score. (GRADE of evidence: low; Strength of recommendation: strong)

    • We suggest high-quality, high-definition white light endoscopy as the preferred modality for colonoscopy surveillance. Chromoendoscopy (virtual or dye-based) does not offer a clear advantage over high definition white light examination for colonoscopic surveillance, apart from in the context of determining the multiple polyp phenotype. (GRADE of evidence: moderate; Strength of recommendation: weak)

    • We suggest a repeat colonoscopy performed by an expert endoscopist is indicated in the event of a previously failed colonoscopy, with efforts made to both improve patient experience and to ensure procedure completion, given the advantages of colonoscopic surveillance. If colonoscopy is not possible then consider CT colonography. (GRADE of evidence: low; Strength of recommendation: weak)

    • We suggest that if the bowel preparation for colonoscopy is inadequate or if the examination is incomplete then a repeat colorectal surveillance procedure should be arranged within 3 months. (GRADE of evidence: low; Strength of recommendation: weak)

    • There is insufficient evidence to recommend other methods of surveillance for those with familial CRC risk such as FIT (faecal immunochemical test), MR or CT colonography. (GRADE of evidence: low; Strength of recommendation: strong)

    Lynch syndrome (LS)

    • We recommend that for all people when first diagnosed with CRC, testing using immunohistochemistry (IHC) for MMR proteins or microsatellite instability is used to identify tumours with deficient DNA MMR, and to guide further sequential testing for LS. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We recommend that colonoscopic surveillance should be performed at a 2 yearly interval for all LS patients. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We recommend that age of onset of surveillance colonoscopy should be stratified according to the LS-associated gene. We recommend colonoscopy from age 25 years for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. There are insufficient data to support stratifying age of onset of surveillance by gender. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We suggest that for LS patients with MLH1 or MSH2 mutations who develop colon cancer or colonic neoplasia not amenable to endoscopic control, the decision to perform segmental versus total/near total colectomy should balance the risks of metachronous cancer, the functional consequences of surgery, the patient’s age and patient’s wishes. (GRADE of evidence: Moderate; Strength of recommendation: strong)

    • We recommend that for LS patients with MSH6 or PMS2 mutations there is insufficient evidence for oncological benefit of extended colectomy over segmental resection. (GRADE of evidence: low; Strength of recommendation: strong)

    • We suggest that when abdominal-perineal excision can be avoided, a standard low anterior resection is a reasonable option to treat rectal cancers in LS patients, even though the residual colon is at high-risk of metachronous neoplasia. (GRADE of evidence: low; Strength of recommendation: weak)

    • We recommend that gastric, small bowel, or pancreatic surveillance in LS patients is only performed in the context of a clinical trial. (GRADE of evidence: low; Strength of recommendation: strong)

    • We recommend screening for H elicobacter pylori in patients with LS and subsequent eradication therapy if indicated. (GRADE of evidence: low; Strength of recommendation: strong)

    Lynch-like syndrome (LLS)

    • We recommend that deficient MMR tumours without hypermethylation/BRAF mutation and without a germline pathogenic variant in MMR genes should undergo somatic tumour testing with a CRC gene panel. (GRADE of evidence: low; Strength of recommendation: strong)

    • We recommend that if double somatic MMR pathogenic variants are identified, manage proband and their FDRs based on the FHCC. (GRADE of evidence: low; Strength of recommendation: strong)

    • We suggest that if no or one somatic mutations are identified, the proband and their FDRs should be managed as per LS. (GRADE of evidence: low; Strength of recommendation: weak)

    Early onset CRC (EOCRC)

    • We recommend that in patients under 30 years of age with dMMR CRC, an LS constitutional panel test should be performed, followed by tumour testing for somatic testing if constitutional testing is negative. (GRADE of evidence: low; Strength of recommendation: strong)

    • We recommend that in patients under 30 years of age with pMMR CRC, a constitutional CRC multiple gene panel test should be performed. (GRADE of evidence: low; Strength of recommendation: strong)

    • We suggest that people diagnosed with CRC under age 50 years, where hereditary CRC syndromes have been excluded, undergo standard post-CRC surveillance for 3 years, then continue 5 yearly colonoscopic surveillance until the age they are eligible for national screening. (GRADE of evidence: low; Strength of recommendation: weak)

    Serrated polyposis syndrome (SPS)

    • We recommend a diagnosis of SPS should be made in accordance with the new WHO 2019 criteria for SPS. Since causative gene pathogenic variants for SPS have not been identified, a definitive diagnosis of SPS should be phenotype-driven. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • Other intestinal polyposis syndromes may present with serrated lesions. If (i) the patient is under 50 or (ii) there are multiple affected individuals within kindred or (iii) there is dysplasia within any of the polyps, then we suggest that other polyposis syndromes should be excluded by gene panel testing before making a definitive diagnosis of SPS. (GRADE of evidence: very low; Strength of recommendation: weak)

    • We recommend the cumulative number of serrated polyps from all endoscopic examinations should be used when applying the WHO 2019 diagnostic criteria for SPS. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We recommend that patients with SPS should have colonoscopic surveillance yearly once the colon has been cleared of all lesions >5 mm in size. If no polyps ≥10 mm in size are identified at subsequent surveillance examinations the interval can be extended to 2 yearly. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We recommend all FDRs of patients with SPS on the basis of the new WHO 2019 SPS criteria, one or two should be offered an index colonoscopic screening examination at age 40 years or 10 years before the diagnosis of the index case. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We suggest all FDRs of SPS patients have a surveillance examination every 5 years unless polyp burden indicates an examination is required earlier according to post-polypectomy surveillance guidelines. (GRADE of evidence: low; Strength of recommendation: strong)

    Multiple colorectal adenoma (MCRA) patients

    • We suggest an individualised approach to germline testing of patients with MCRA (defined as having 10 or more metachronous adenomas). Consider this testing for:

      • Patients under 60 years of age with lifetime total of ≥10 adenomas; or

      • Patients from 60 years of age with lifetime total of:

        • ≥20 adenomas, or

        • ≥10 adenomas and a FHCC or polyposis

    (GRADE of evidence: low; Strength of recommendation: weak)

    • We suggest that patients with a finding of 10 or more polyps (adenomas or serrated lesions) should, at their next colonoscopy, have a high-quality colonoscopic assessment with pancolonic dye spray in order to define accurately the multiple polyp phenotype. (GRADE of evidence: very low; Strength of recommendation: weak)

    • We suggest that the endoscopic management of patients with 10 or more metachronous adenomas, without MUTYH or APC gene mutations, should be individualised according to phenotype. (GRADE of evidence: very low; Strength of recommendation: weak)

    • We suggest annual colonoscopic surveillance for patients with 10 or more metachronous adenomas after the colon has been cleared of all lesions >5 mm in size. If no polyps 10 mm or greater in size are identified at subsequent surveillance examinations the interval can be extended to 2 yearly. (GRADE of evidence: very low; Strength of recommendation: weak)

    Familial adenomatous polyposis (FAP)

    • We recommend that colonic surveillance should normally commence age 12–14 years in those confirmed to have FAP on predictive genetic testing. (GRADE of evidence: low; Strength of recommendation: strong)

    • We suggest that for those with FAP, intervals between surveillance colonoscopy may be individualised depending on colonic phenotype every 1–3 years. (GRADE of evidence: low; Strength of recommendation: weak)

    • We suggest that colonoscopy screening is performed for individuals who have an FDR with a clinical diagnosis of FAP (ie, “at-risk”) and in whom an APC mutation has not been identified, starting at age 12–14 years, and should continue on 5 yearly surveillance until either a clinical diagnosis is made and they are then managed as FAP, or they reach the age at which they can enrol in national screening. (GRADE of evidence: very low; Strength of recommendation: weak)

    • We recommend upper GI surveillance for FAP patients starting at age 25 years. (GRADE of evidence: low; Strength of recommendation: strong)

    • We suggest that for those considered at risk, where predictive genetic testing is not possible, screening with upper GI endoscopy is not routinely recommended but should be started if/when a clinical diagnosis of FAP is made based on colorectal phenotype. (GRADE of evidence: very low; Strength of recommendation: weak)

    • We suggest that patients with congenital hypertrophy retinal pigmentation epithelium (CHRPE) be referred for a specialist ophthalmic review. Patients with bilateral and multiple CHRPE lesions should be referred for screening for FAP and considered for genetic testing and colonoscopy. (GRADE of evidence: low; Strength of recommendation: weak)

    FAP: Surgery, and desmoid disease

    • We recommend that for patients with FAP who are undergoing colonoscopic surveillance, relative indications for surgery are: polyps >10 mm in diameter, high grade dysplasia within polyps and a significant increase in polyp burden between screening examinations. (GRADE of evidence: low; Strength of recommendation: strong)

    • We recommend that absolute indications for immediate colorectal surgery in FAP include: documented or suspected cancer or significant symptoms attributable to the polyposis. (GRADE of evidence: low; Strength of recommendation: strong)

    • We suggest that FAP patients should be counselled about the risk of postoperative desmoid disease formation. (GRADE of evidence: low; Strength of recommendation: weak)

    • Consider, for FAP patients before colectomy, determining genotypes or family history of desmoid disease which may be predictive of desmoid formation. (GRADE of evidence: very low; Strength of recommendation: weak)

    • We suggest that sulindac in combination with high-dose selective oestrogen receptor modulators may be effective in FAP patients with intra-abdominal desmoids and desmoids located at the abdominal wall. (GRADE of evidence: low; Strength of recommendation: weak)

    • We recommend the role of elective surgery for intra-abdominal desmoids should be restricted to treating secondary effects of the desmoid disease, and this surgery should be performed in expert centres. (GRADE of evidence: low; Strength of recommendation: strong)

    MUTYH-associated polyposis (MAP)

    • We recommend that colorectal surveillance is commenced in MAP commencing age 18–20 years. If surgery is not undertaken then annual surveillance is suggested. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We recommend that for monoallelic MUTYH pathogenic variant carriers, the risk of CRC is not sufficiently different to population risk to meet thresholds for screening and routine colonoscopy is not recommended. (GRADE of evidence: moderate; Strength of recommendation: strong)

    • We suggest that upper GI surveillance should be considered starting at the age of 35 years in MAP. We recommend that the surveillance interval is determined as outlined for FAP. (GRADE of evidence: low; Strength of recommendation: weak).

    Peutz-Jeghers syndrome (PJS)

    • We suggest that in an asymptomatic patient with PJS, GI surveillance by upper GI endoscopy, colonoscopy and video capsule endoscopy commence at age 8 years. We recommend that small bowel surveillance should continue 3 yearly. If baseline colonoscopy and oesophago-gastro-duodenoscopy (OGD) are normal, then they can be safely deferred until age 18 years; however, if polyps are found at baseline examination, then they should be repeated 3 yearly. Earlier investigation of the GI tract should be performed in symptomatic patients. (GRADE of evidence: low; Strength of recommendation: weak)

    • We suggest elective polypectomy to prevent polyp related complications. Small bowel polyps greater than 1.5–2 cm in size (or smaller if symptomatic) should be considered for elective resection to prevent intussusception. (GRADE of evidence: low; Strength of recommendation: weak)

    Juvenile polyposis syndrome (JPS)

    • We suggest colonoscopic surveillance should commence from the age of 15 years or earlier if symptomatic. The surveillance interval should be 1–3 yearly, personalised according to colorectal phenotype. (GRADE of evidence: low; Strength of recommendation: weak)

    • We suggest that for those with a confirmed clinical or genetic diagnosis, upper GI endoscopic surveillance should start at the age of 18 years for SMAD4 mutation carriers and 25 years for BMPR1A mutation carriers and those without an identified constitutional. The surveillance interval should be 1–3 yearly, personalised according to upper GI tract phenotype. (GRADE of evidence: low; Strength of recommendation: weak)

    • We suggest that for those with an FDR with a clinical diagnosis of JPS and in whom a mutation has not been identified, screening of the upper GI tract is not required routinely but should be initiated if/when a clinical diagnosis is made on the basis of colonic phenotype. It may, however, be considered if there is a family history suggestive of hereditary haemorrhagic telangiectasia (HHT), even in the absence of colonic polyps. (GRADE of evidence: low; Strength of recommendation: weak)

    • We suggest that patients with SMAD4 pathogenic variant should be evaluated for HHT, and that those at risk of, or with a confirmed diagnosis of, HHT are best managed in conjunction with a specialist HHT centre. (GRADE of evidence: low; Strength of recommendation: weak)

    • Patients with JPS and a microdeletion involving BMPR1A and PTEN are at risk of the clinical manifestations of both JPS and PTEN-hamartoma tumour syndrome (PHTS). We suggest that they should be referred to their local genetics centre for further advice and to coordinate their surveillance needs. (GRADE of evidence: low; Strength of recommendation: weak)

    Service provision, communication and management principles

    We recommend that moderate risk of FHCC is the minimum threshold for referral from primary care

    (GRADE of evidence: very low; Strength of recommendation: strong)

    Consensus reached: 100% agreement.

    We recommend that individuals with an FHCC, which meets this referral criteria, be referred to a specialist familial CRC clinic in secondary or tertiary care.

    ​(GRADE of evidence: low; Strength of recommendation: weak)

    Consensus reached: 82% agreement.

    We recommend that patients should be referred to a specialist service which includes access to constitutional genetic testing in the presence of defective MMR (with no evidence of MLH1 promoter methylation or BRAF V600E), or polyposis.

    (GRADE of evidence: low; Strength of recommendation: strong)

    There are insufficient clinical data to develop specific guidance for patients with very rare conditions such as polymerase proofreading associated polyposis (PPAP), or NTHL1 associated polyposis (NAP), therefore patients with these syndromes should be referred to multidisciplinary expert centres for clinical management.

    (GRADE of evidence: low; Strength of recommendation: weak)

    Consensus reached: 91% agreement.

    We recommend that hospitals that diagnose or manage patients at hereditary CRC risk should ensure clinical pathways to facilitate their care, and processes to monitor the quality of the service.

    (GRADE of evidence: low; Strength of recommendation: strong)

    Consensus reached: 100% agreement.

    We recommend that individuals at increased familial CRC risk receive specialist knowledge and are aware of patient/support organisations and discussion with regard to lifestyle and participation in research projects.

    (GRADE of evidence: very low; Strength of recommendation: strong)

    Consensus reached: 95% agreement

    People at hereditary CRC risk require coordinated, timely and high-quality care to reduce their cancer risk and should have access to a full range of management options that minimise the risk of morbidity and mortality.9 A structured referral pathway may ensure better inter-specialty communication and timely, efficient management of hereditary risk from primary through to tertiary care provision. It also facilitates an audit trail and subsequent monitoring of performance. Patients should have access to a full range of management options that minimise the risk of morbidity and mortality.9

    Moreover, studies consistently report that high quality screening and surveillance services result in a reduction of CRC incidence and mortality in individuals with FAP and LS.10 Registries of high-risk patients should be linked to robust quality assurance mechanisms for interventions, such as colonoscopy, with effective recall mechanisms in place to ensure high-risk individuals receive surveillance procedures on schedule.

    Awareness of hereditary conditions may be inadequate, resulting in an inconsistent approach to the management of these individuals.9 11 Many patients do not have personalised management strategies and there is a failure to provide adequate follow-up.12 13 Patient advocacy organisations recommend improvements in the detection of pre-cancerous polyps, early diagnosis of CRC, and personalised treatment options for LS individuals, who should be seen by a team of specialists.14 The relevance of genomics is growing in clinical practice, and is increasingly relevant across the cancer multidisciplinary teams, with improving access to constitutional genetic testing.15 Genetic testing and/or counselling may resolve uncertainty about personal and familial cancer risk and provide information to guide and personalise decisions about future health care in anyone with an FHCC.16 17 It has been recommended that a dedicated clinical champion for hereditary CRC should be established in each colorectal multidisciplinary team (MDT) to oversee service coordination and to ensure patient pathways.9 18 The establishment of these champions will be another critical component in establishing equity of care. We recommend the establishment of family cancer specialist services by CRC teams in secondary care to ensure local pathways for patients at hereditary risk of CRC, and which can arrange testing of relatives for MMR status. This service should be supported by commissioners and incorporate a multidisciplinary approach involving geneticists, gastroenterologists and colorectal surgeons with links between secondary and tertiary care. Adherence to surveillance recommendations should be monitored at least annually. We suggest a minimum standard of ≥90% compliance. Non-compliant cases should be reviewed to determine whether reason for deviation from surveillance recommendations was clearly documented and clinically appropriate. Thus patients with a family history of CRC may be managed by their local hospital, and patients who require constitutional gene testing be managed by a tertiary care clinic, for example, in clinical genetics, either locally or regionally.

    Family history of CRC (FHCC)

    Definitions and terminology

    A substantial proportion of the UK population have an FHCC without evidence of an inherited CRC syndrome. These individuals have a moderately increased relative risk (RR) of CRC (2–6 fold) compared with the general population.19 Lifetime CRC risk may be inferred from the age of onset of CRC in affected relatives, and familial aggregation, that is, the number of family members affected with CRC.

    This section refers to asymptomatic patients referred for optimal management of a family history of either CRC or multiple polyps. The GDG agreed three categories of familial risk (in the absence of known hereditary CRC syndromes) which were determined according to lifetime CRC risk and the diagnostic yield of colorectal surveillance (box 1). Familial clusters (or aggregations) are of affected family members with CRC who are FDRs of each other. The individual referred for assessment should be an FDR of at least one affected member of such families.

    Box 1

    Categories of risk in patients with a family history of colorectal cancer (FHCC)

    Categories of risk – FHCC

    • Average risk: No FHCC, or a FHCC which does not fulfil moderate or high-risk categories.

    • Moderate risk FHCC:

      • One FDR diagnosed with CRC under 50 years, or

      • Two FDRs (in first degree kinship) diagnosed with CRC at any age, of whom the patient under assessment is an FDR of at least one affected individual.

    • High risk FHCC: Families with a cluster of at least three affected FDRs with CRC diagnosed at any age, across at least two generations, of whom the patient under assessment is an FDR of at least one affected individual.

    • CRC, colorectal cancer; FDR, first degree relative.

    • ­

    Patients with average risk include those without an FHCC, or with an FHCC which does not significantly increase their lifetime CRC risk, that is, below the level of the moderate risk population. For the average risk populations surveillance may be effectively managed via national bowel cancer screening programmes. Those people in moderate- or high-risk categories require additional surveillance above and beyond national screening however (figure 1).

    Figure 1

    Management of people with a family history of colorectal cancer. BSG, British Society of Gastroenterology; CRC, colorectal cancer; FHCC, family history of colorectal cancer; FDR, first degree relative; MMR, mismatch repair.

    Assessment of tumours in the affected relatives of those with an FHCC

    We recommend that for all patients referred from primary care for assessment for an FHCC, MMR status should be assessed in tumour tissue from a close affected family member.

    ​(GRADE of evidence: Moderate; Strength of recommendation: strong)

    Consensus reached: 82% agreement.

    We recommend that a reported family history of polyposis should be verified by review of histopathology and/or endoscopy reports which confirm the presence of a minimum of 10 adenomas or serrated lesions in an FDR.

    ​(GRADE of evidence: low; Strength of recommendation: strong)

    Consensus reached: 90% agreement.

    Histopathological confirmation of CRC alters management of familial CRC surveillance in 20% of UK patients through verification of a diagnosis of CRC, multiple adenomas or other relevant features.20 Similarly review of endoscopy reports may assist in identification of patients with suspected familial risk such as those with polyposis syndromes.

    When LS and Lynch-like tumours are excluded in families, their lifetime risk of CRC decreases. To quantify familial CRC risks associated with MMR deficient (dMMR) or MMR proficient (pMMR) tumours, a UK group analysed 2941 population-based cases of CRC.21 CRC risks in FDRs were strongly associated with dMMR tumours, early-onset disease and more than one affected FDR.

    In a study by Bapat et al of 3143 CRC patients, dMMR tumours were associated with increasing numbers of FDRs with CRC (p=0.002); this association disappeared, however, when dMMR cases meeting Amsterdam criteria were removed from the analysis.22

    A multicentre international registry based study23 assessed MMR status in 33 496 FDRs of 4853 cases of CRC. In comparison with the FDRs of pMMR CRC cases the FDRs of CRC cases with suspected ‘Lynch-like’ syndrome and with LS had a higher risk of CRC, but not those with dMMR non-LS. There was a greater risk of CRC in FDRs if CRC cases were diagnosed under 50 years of age, or if the tumours had clinicopathological features suggestive of LS.

    Surveillance for colorectal neoplasia in those with a moderate risk FHCC

    We recommend that patients with a moderate familial CRC risk should have a one-off colonoscopy at the age of 55 years.

    (GRADE of evidence: moderate; Strength of recommendation: strong)

    Consensus reached: 85% agreement.

    We recommend that subsequent colonoscopic surveillance should be performed as determined by post-polypectomy surveillance guidelines.

    ​(GRADE of evidence: moderate; Strength of recommendation: strong)

    Consensus reached: 95% agreement.

    An important question is whether the adenoma detection rate in those with an FHCC is higher than the detection rate in the general population. Most CRCs develop from adenomas and “advanced” adenomas (AAs, defined as either an adenoma size of at least 10 mm, villous architecture of at least 25%, or high grade dysplasia24) are considered to be the precursors of CRC. The term “advanced neoplasia” (AN) refers to the identification of either AAs or CRC.

    The effectiveness and requirement for familial risk surveillance may be best determined by comparing the long-term CRC risk of a defined cohort of at-risk patients not undergoing surveillance with that of the general population. Theoretical relative risks of CRC <2 may be dominated by other genetic or environmental effects (and may require complex and validated risk modelling tools to determine suitability for surveillance).25 Where long-term CRC data are not available, the findings at surveillance may be used as a surrogate means to determine the need for post-polypectomy surveillance, although this method is inferior. In this context, that surveillance procedure may not have been warranted where the AA yield on that surveillance was less than doubled compared with a comparable yield in a control population.

    There is a low prevalence of CRC in studies of surveillance in familial risk populations. There are limited data suggesting that metachronous CRC risk may be higher in patients at moderate familial risk versus population risk.26 As AAs are strongly associated with CRC development, AAs may be considered a proxy for CRC risk. In studies of patients with a moderate familial risk the