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Guideline Summary
Guideline Title
Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives.
Bibliographic Source(s)
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009 Jan;11(1):35-41. PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)
  • Colorectal cancer (CRC)
  • Lynch syndrome

Note: Lynch syndrome is defined as a hereditary predisposition to CRC and certain other malignancies (e.g., endometrial and gastric cancer) as a result of a germline mismatch repair (MMR) gene mutation. Lynch syndrome includes both individuals with an existing cancer and those who have not yet developed cancer.

Guideline Category
Counseling
Evaluation
Prevention
Risk Assessment
Screening
Technology Assessment
Clinical Specialty
Colon and Rectal Surgery
Gastroenterology
Internal Medicine
Medical Genetics
Oncology
Pathology
Surgery
Intended Users
Advanced Practice Nurses
Health Care Providers
Health Plans
Managed Care Organizations
Physician Assistants
Physicians
Utilization Management
Guideline Objective(s)

To provide recommendations concerning genetic testing to detect Lynch syndrome in individuals with newly diagnosed colorectal cancer (CRC) as a strategy to reduce CRC morbidity and mortality in their relatives

Target Population

All individuals with a new diagnosis of colorectal cancer (CRC)

Interventions and Practices Considered
  1. Genetic testing for Lynch syndrome (i.e., mismatch repair [MMR] gene mutations):
    • DNA sequencing and deletion testing
    • Microsatellite instability (MSI) testing
    • Immunohistochemical (IHC) testing
    • BRAF mutation testing
  2. Counsel all newly diagnosed colorectal cancer (CRC) patients who test positive for Lynch syndrome on contacting blood relatives to offer:
    • Counseling
    • Targeted testing to diagnose Lynch syndrome
  3. Relatives diagnosed with Lynch syndrome:
    • Increased surveillance
    • Earlier and more frequent colonoscopies
    • Female surveillance for endometrial cancer (may be considered for both probands and relatives)
  4. Informed consent
Major Outcomes Considered

Analytic Validity

Analytic sensitivity and specificity for preliminary and diagnostic tests

Clinical Validity

Clinical sensitivity and specificity for preliminary tests and selected testing strategies.

Clinical Utility

  • Testing uptake rates
  • Adherence to recommended surveillance activities
  • Number of relatives approachable
  • Harms associated with additional follow-up
  • Effectiveness of routine colonoscopy

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Searches of Unpublished Data
Description of Methods Used to Collect/Select the Evidence

Note from the National Guideline Clearinghouse (NGC): An evidence review commissioned by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) and funded by the Office of Public Health Genomics (OPHG) Centers for Disease Control and Prevention (CDC), was prepared by the Tufts University Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ). (See the "Availability of Companion Documents" field).

In addition, a technical contractor with experience in evidence review collaborated with EGAPP staff and consultants to conduct a supplementary targeted evidence review based on EGAPP methodology. (See the "Availability of Companion Documents" field). This supplementary review was initiated because Lynch syndrome emerged as being of more specific interest than the less well-defined clinical constellation of hereditary nonpolyposis colorectal cancer (HNPCC), and because EWG members requested additional information to address questions dealing with impact of testing strategies on relatives.

Key Questions Addressed in the Original Evidence Review

Key questions were proposed through AHRQ on behalf of the CDC EGAPP Project.

Key Question 1: Does risk assessment and hereditary nonpolyposis colorectal cancer (HNPCC) mutation testing in patients with newly diagnosed colorectal cancer (CRC) lead to improved outcomes for the patient or family members, or is it useful in medical, personal, or public health decision making? (Over-arching question).

Key Question 2a: Assuming a clinical definition of the Lynch Syndrome, what proportion of patients has a mismatch repair gene mutation?

2b: Assuming a clinical definition of the Lynch Syndrome, what proportion of patients has microsatellite instability (MSI)?

2c: Assuming a clinical definition of the Lynch Syndrome, what proportion of patients has abnormal protein expression by immunohistochemistry?

2d: How accurate are various predictors, assuming a genetic definition of Lynch Syndrome?

Key Question 3: What are the harms associated with screening high-risk individuals for HNPCC?

Key Question 4: What is known about the analytic (sensitivity, specificity, reproducibility, reliability) and clinical validity of tests that identify HNPCC mutations?

Key Question 5: What are the harms associated with screening for high-risk individuals?

Key Question 6a: What are the management options for CRC patients who are HNPCC positive?

6b: Does the identification of HNPCC mutations lead to improved patient outcomes in terms of early detection, mortality/morbidity or management decisions (e.g., counseling, surveillance, treatment, other decision making) by patients and providers?

Key Question 7: What are the harms associated with subsequent management options after identification of HNPCC mutations in CRC patients?

Key Question 8a: What is the efficacy of pre-test genetic counseling for informing family members of potential risks and benefits of testing?

8b: What is the accuracy of HNPCC testing in family members in predicting the risk of CRC?

8c: Do other factors, such as race/ethnicity, age, gender, or co-morbidities affect the accuracy of the testing?

Key Question 9: What are the harms associated with informing/counseling family members or with subsequent testing for HNPCC mutations?

Key Question 10a: What are the management options for family members of CRC patients who have a positive HNPCC test?

10b1: Does the identification of HNPCC mutations lead to improved outcomes in terms of decision making by patients, family members and providers, or public health policy?

10b2: Does the identification of HNPCC mutations lead to improved outcomes in terms of early detection and mortality/morbidity of patients, family members?

Key Question 11: What are the harms associated with subsequent actions or interventions for family members?

Literature Search Strategy – Original Evidence Review

A literature search of MEDLINE® using PubMed was conducted on January 10, 2006, using MEDLINE® subject headings and text words to capture relevant English language publications of human studies. Additional sources of potentially relevant studies included technical experts and hand searching of bibliographic references of reviews. An automatic updated search results from PubMed was received on April 1, 2006 after which additional studies were included only if the investigators or Technical Expert Panel (TEP) considered them to provide substantive new information that might influence the conclusions.

All abstracts were reviewed for their relevance to the Key Questions and the full-text article of potentially relevant citations were retrieved. Bibliographies of studies included in the report (as well as previous review articles or meta-analyses, which were not included) were reviewed to identify additional citations, all of which were retrieved for review. Duplicate reports of the same patients were identified by comparing authors and study centers. Duplicate reports were excluded unless they provided complementary information (such as outcomes at different time points) in which case they were considered together.

Inclusion/Exclusion Criteria and Data Extraction – Original Evidence Review

Prespecified inclusion and exclusion criteria were applied in considering each study. The criteria corresponded to the three domains of analytic validity, clinical validity, and benefits and harms.

Supplemental Evidence Review – Targeted 5 Specific Areas

  1. Clarifying how to define the clinical disorder—Lynch syndrome
  2. Removing family history from consideration as a preliminary test
  3. Documenting the clinical validity of DNA-based preliminary tests
  4. Benefits and harms to probands and relatives with Lynch syndrome
  5. Economic modeling of programmatic costs and costs per Lynch syndrome detected using four different testing strategies

Specific details regarding the identification of data are contained within each section of the Supplemental Evidence Review (see "Availability of Companion Documents" field). In general, data identification was based on explicit search strategies for each question of interest, with occasional use of gray data, referral to the original evidence report, and in some instances, existing structured reviews. Although the analytic framework used for the original evidence review remains relevant, the present review does not address all aspects of the overarching question.

Number of Source Documents

Original Evidence Review

104 studies were included of which 40 addressed issues related to clinical validity, 3 to analytic validity, and 61 to benefits and harms.

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Original Report

Interpretation of Overall Quality Grading of Individual Studies

Grade Explanation for Quality Scoring
A Most or all of the criteria are fulfilled and the conclusions of the study would be very unlikely to be affected by those that are not.
B Some of the criteria are fulfilled and the conclusions of the study would be unlikely to be affected by those that are not
C Few or no criteria were fulfilled and the conclusions of the study would be thought likely or very likely to be altered by multiple omissions in the required criteria for an acceptable study

Supplemental Review

The EGAPP Working Group (EWG) has explicit methods for both identifying published and gray data, and for ranking the quality of data sources (1 being the highest quality and 4 being the lowest) and quality of evidence (convincing being the highest, adequate, and inadequate being the lowest). Criteria for both the quality of data sources and quality of evidence differ for analytic validity, clinical validity, and clinical utility.

The EWG ranks individual studies as Good, Fair, or Marginal based on critical appraisal using the criteria in Tables 3 and 4 (of Teutsch et al., 2009; see "Availability of Companion Documents" field). The designation Marginal (rather than Poor) acknowledges that some studies may not have been "poor" in overall design or conduct, but may not have been designed to address the specific key question in the evidence review.

An interpretation of the data was provided for each question of interest that includes an assessment of quality of data and quality of evidence and identification of possible biases and gaps in knowledge.

Methods Used to Analyze the Evidence
Meta-Analysis of Randomized Controlled Trials
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

Note from the National Guideline Clearinghouse (NGC): An evidence review, commissioned by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) and funded by the Office of Public Health Genomics (OPHG) at the Centers for Disease Control and Prevention (CDC), was prepared by the Tufts University Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ). (See the "Availability of Companion Documents" field). The final report, Hereditary Nonpolyposis Colorectal Cancer: Accuracy of Diagnostic Strategies and Implications to Patients with Colorectal Cancer and Their Families, is available online. (See the "Availability of Companion Documents" field).

The review focused on the accuracy of diagnostic strategies for hereditary non-polyposis colorectal cancer (HNPCC), and the implications of testing to individuals with colorectal cancer (CRC) and their families. It was anticipated that data might not be available to directly answer the overarching question. The EGAPP Working Group (EWG), therefore, constructed an analytic framework and key questions to address different components of evaluation (e.g., analytic and clinical validity, intermediate outcomes of interest, and clinical utility) for the purpose of providing relevant indirect evidence of efficacy. Established methods were followed in conducting this review. A Technical Expert Panel that included three EWG members was available to provide expert guidance during the course of the review.

Each included study was reviewed for its quality. Reviewers assigned an overall quality score (A, B or C) to provide a short hand appraisal of the overall validity of the study but also performed analysis of specific components of study quality that may have influenced the conclusions. Reviewers combined data in studies that used similar methodology and definitions of endpoints in similarly selected CRC populations using meta-analysis to provide a point estimate and 95% confidence interval, mainly for questions pertaining to clinical validity. Decision trees models were constructed to calculate the reported outcomes of various strategies for identifying HNPCC among patients with colorectal cancer. The models were based upon parameters estimated from data presented in the full technical report.

In addition, a technical contractor with experience in evidence review collaborated with EGAPP staff and consultants to conduct a supplementary targeted evidence review based on EGAPP methodology. This supplementary review was initiated because Lynch syndrome emerged as being of more specific interest than the less well-defined clinical constellation of HNPCC, and because EWG members requested additional information to address questions dealing with impact of testing strategies on relatives. Refer to the full Supplementary Evidence Review for details of this review. (See the "Availability of Companion Documents" field).

Based on the evidence available, the overall level of certainty of net health benefit is categorized as High, Moderate, or Low.* High certainty is associated with consistent and generalizable results from well-designed and conducted studies, making it unlikely that estimates and conclusions will change based on future studies. When the level of certainty is Moderate, some data are available, but limitations in data quantity, quality, consistency, or generalizability reduce confidence in the results, and, as more information becomes available, the estimate or effect may change enough to alter the conclusion. Low certainty is associated with insufficient or poor quality data, results that are not consistent or generalizable, or lack of information on important outcomes of interest; as a result, conclusions are likely to change based on future studies.

Teutsch SM, Bradley LA, Palomaki GE, Haddow JE, Piper M, Calonge N, Dotson WD, Douglas MP, Berg AO; EGAPP Working Group. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative: methods of the EGAPP Working Group. Genet Med. 2009 Jan;11(1):3-14.

*Sawaya GF, Guirguis-Blake J, LeFevre M, et al. Update on methods of the U.S. Preventive Services Task Force: estimating certainty and magnitude of net benefit. Ann Intern Med 2007;147:871-5.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

Note from the National Guideline Clearinghouse (NGC): An evidence review, commissioned by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) and funded by the Office of Public Health Genomics (OPHG) at the Centers for Disease Control and Prevention (CDC), was prepared by the Tufts University Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ). (See the "Availability of Companion Documents" field).

In addition, a technical contractor with experience in evidence review collaborated with EGAPP staff and consultants to conduct a supplementary targeted evidence review based on EGAPP methodology. (See the "Availability of Companion Documents" field).

The EGAPP Working Group (EWG) members reviewed the AHRQ evidence report, the supplementary targeted review, and key primary publications in detail, and examined other sources of information to address specific gaps in the evidence. The writers of the supplementary report and the EGAPP panel members further collaborated in constructing simple economic models to assist in analyzing the limited evidence available on clinical utility and in estimating how various testing strategies might function in practice. The final EGAPP recommendation statement regarding the use of testing strategies aimed at reducing morbidity and mortality from Lynch syndrome was formulated based on magnitude of effect, certainty of evidence, and consideration of contextual factors (e.g., severity of disorder, family considerations, and costs).

Key factors considered in the development of a recommendation are: the relative importance of the outcomes selected for review; the benefits (e.g., improved clinical outcome, reduction of risk) that result from the use of the test and subsequent actions or interventions (or if not available, maximum potential benefits); the harms (e.g., adverse clinical outcome, increase in risk or burden) that result from the use of the test and subsequent actions/interventions (or if not available, largest potential harms); and the efficacy and effectiveness of the test and follow-up compared with currently used interventions (or doing nothing). Simple decision models or outcomes tables may be used to assess the magnitudes of benefits and harms, and estimate the net effect. Consistent with the terminology used by the USPSTF, the magnitude of net benefit (benefit minus harm) may be classified as Substantial, Moderate, Small, or Zero.*

Standard EGAPP language for recommendation statements uses the terms: Recommend For, Recommend Against, or Insufficient Evidence (Table 6 in Teutsch et al., 2009). Because the types of emerging genomic tests addressed by EGAPP are more likely to have findings of Insufficient Evidence, three additional qualifiers may be added. Based on the existing evidence and consideration of contextual issues and modeling, Insufficient Evidence could be considered "Neutral" (not possible to predict with current evidence), "Discouraging" (discouraged until specific gaps in knowledge are filled or not likely to meet evidentiary standards even with further study), and "Encouraging" (likely to meet evidentiary standards with further studies or reasonable to use in limited situations based on existing evidence while additional evidence is gathered).

Teutsch SM, Bradley LA, Palomaki GE, Haddow JE, Piper M, Calonge N, Dotson WD, Douglas MP, Berg AO; EGAPP Working Group. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative: methods of the EGAPP Working Group. Genet Med. 2009 Jan;11(1):3-14.

*Sawaya GF, Guirguis-Blake J, LeFevre M, et al. Update on methods of the U.S. Preventive Services Task Force: estimating certainty and magnitude of net benefit. Ann Intern Med 2007;147:871-5.

Rating Scheme for the Strength of the Recommendations

Recommendations Based on Certainty of Evidence, Magnitude of Net Benefit, and Contextual Issues

High or Moderate Recommend for:
  • If the magnitude of net benefit is Substantial, Moderate, or Small, unless additional considerations warrant caution.
  • Consider the importance of each relevant contextual factor and its magnitude or finding.
Recommend against:
  • If the magnitude of net benefit is Zero or there are net harms.
  • Consider the importance of each relevant contextual factor and its magnitude or finding.
Low Insufficient evidence:
  • If the evidence for clinical utility or clinical validity is insufficient in quantity or quality to support conclusions or make a recommendation.
  • Consider the importance of each contextual factor and its magnitude or finding.
  • Determine whether the recommendation should be Insufficient (neutral), Insufficient (encouraging), or Insufficient (discouraging).
  • Provide information on key information gaps to drive a research agenda.

Teutsch SM, Bradley LA, Palomaki GE, Haddow JE, Piper M, Calonge N, Dotson WD, Douglas MP, Berg AO; EGAPP Working Group. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative: methods of the EGAPP Working Group. Genet Med. 2009 Jan;11(1):3-14.

Cost Analysis

Existing economic analyses that included relatives with Lynch syndrome were reviewed and found to be inadequate (e.g., variability in assumptions and initial values, no consideration of impact on relatives, no assessment of immunohistochemical [IHC] testing as the primary screening test or refined testing strategies that involve BRAF or methylation testing). The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) commissioned a basic economic analysis comparing selected strategies of combining microsatellite instability (MSI), IHC, BRAF, and mismatch repair (MMR) gene mutation testing for the identification of Lynch syndrome among individuals with colorectal cancer (CRC) and their relatives. Four selected sample testing strategies were included. The outcome of interest was the cost per Lynch syndrome case detected (proband, and proband and relatives), total program costs through identification of Lynch syndrome individuals, and the associated incremental costs. Although this cost consequences analysis did not allow the EWG to recommend a specific strategy, the results were used in context with the other findings to inform its recommendation.

Costs per Lynch syndrome case detected depend on the testing strategy selected; higher costs are associated with higher sensitivity. Total program costs are highest when no preliminary tests are employed (e.g., all individuals with newly diagnosed colorectal cancer are offered deoxyribonucleic acid [DNA] sequencing). See the companion document "Hereditary nonpolyposis colorectal cancer: diagnostic strategies and their implications," Evidence Report/Technology Assessment No. 150, for more details. (See the "Availability of Companion Documents" field).

Method of Guideline Validation
Comparison with Guidelines from Other Groups
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation

Recommendations concerning laboratory and genetic testing in colorectal cancer from the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncologists (ASCO) were reviewed.

Recommendations

Major Recommendations

Summary of Recommendations

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer (CRC) to reduce morbidity and mortality in relatives. The EWG found insufficient evidence to recommend a specific genetic testing strategy among the several examined.

Rationale

Genetic testing to detect Lynch syndrome in individuals with newly diagnosed CRC is proposed as a strategy to reduce CRC morbidity and mortality in their relatives (see Clinical Considerations section for definition of Lynch syndrome). The EWG constructed a chain of evidence that linked genetic testing for Lynch syndrome in patients with newly diagnosed CRC with improved health outcomes in their relatives. They found that assessing patients who have newly diagnosed CRC with a series of genetic tests could lead to the identification of Lynch syndrome. Relatives of patients with Lynch syndrome could then be offered genetic testing, and, where indicated, colorectal, and possibly endometrial, cancer surveillance, with the expectation of improved health outcome. The EWG concluded that there is moderate certainty that such a testing strategy would provide moderate population benefit.

Analytic Validity: The EWG found adequate evidence to conclude that the analytic sensitivity and specificity for preliminary and diagnostic tests were high.

Clinical Validity: After accounting for the specific technologies and numbers of markers used, the EWG found at least adequate evidence to describe the clinical sensitivity and specificity for three preliminary tests, and for four selected testing strategies. These measures of clinical validity varied with each test and each strategy (see Clinical Considerations section).

Clinical Utility: The EWG found adequate evidence for testing uptake rates, adherence to recommended surveillance activities, number of relatives approachable, harms associated with additional follow-up, and effectiveness of routine colonoscopy. This chain of evidence supported the use of genetic testing strategies to reduce morbidity/mortality in relatives with Lynch syndrome. Several genetic testing strategies were potentially effective, but none was clearly superior. The evidence for or against effectiveness of identifying mismatch repair (MMR) gene mutations in reducing endometrial cancer morbidity or mortality was inadequate.

Contextual Issues: CRC is a common disease responsible for an estimated 52,000 deaths in the United States in 2007. In about 3% of newly diagnosed CRC, the underlying cause is a mutation in a MMR gene (Lynch syndrome) that can be reliably identified with existing laboratory tests. Relatives inheriting the mutation have a high (about 45% by age 70) risk of developing CRC. Evidence suggests these relatives will often accept testing and increased surveillance.

Clinical Considerations

Definitions

  • Lynch syndrome is defined as a hereditary predisposition to CRC and certain other malignancies (e.g., endometrial and gastric cancer) as a result of a germline mismatch repair (MMR) gene mutation. Lynch syndrome includes both individuals with an existing cancer and those who have not yet developed cancer.
  • The associated MMR gene mutations are inherited in an autosomal dominant manner.
  • Analytic validity refers to a test's ability to accurately and reliably measure the genetic characteristic (e.g., genotype, mutation, polymorphism) of interest.
  • Clinical validity defines how well test results correlate with the intermediate or final outcomes of interest. This is usually reported as a clinical sensitivity/specificity.

Patient Population under Consideration

These recommendations apply to all individuals with a new diagnosis of CRC. An estimated 2-4% can be identified as having Lynch syndrome.

Preliminary (Screening) Tests

Microsatellite instability (MSI) testing or immunohistochemical (IHC) testing (with or without BRAF mutation testing) of the tumor tissue are examples of preliminary testing strategies that could be used to select patients for subsequent diagnostic testing. Diagnostic testing involves mismatch repair (MMR) gene mutation (and deletion/duplication) testing of the proband, usually using a blood sample. Lynch syndrome is most commonly caused by mutations in the two MMR genes MLH1 and MSH2; less commonly by mutations in MSH6 and PMS2. (See the original guideline document for a more detailed discussion of the tests relevant for Lynch syndrome.)

Treatment/Follow-up of Probands and Relatives

Evidence does not exist to make specific recommendations for changes in CRC treatment in probands. The EWG recommends that probands be informed of the advantages of contacting blood relatives to offer counseling and targeted testing to diagnose Lynch syndrome. Among relatives diagnosed with Lynch syndrome (MMR positive), more frequent colonoscopies are indicated and should begin at an earlier age than recommended for average risk individuals. Increased surveillance results in reduced rates of colon cancer and death from all causes. Among women with Lynch syndrome (both probands and relatives), additional surveillance for early identification of endometrial cancer may be considered, but there is less evidence to support it.

Other Considerations

  • The general debate on the issue of consent is acknowledged. However, because of the potential impact on the patient's relatives, the EWG recommends that individuals with newly diagnosed CRC should be routinely offered counseling and educational materials aimed at informing them and their relatives of the potential benefits and harms associated with genetic testing to identify Lynch syndrome.
  • Protocols for sample collection, laboratory testing, and reporting of results need to be instituted, as well as for contacting, educating, testing, and following relatives with Lynch syndrome.

Other Approaches

Family history is an important risk factor for CRC in the general population. Among individuals with newly diagnosed CRC, however, family history is less useful as the first step in identifying Lynch syndrome than strategies involving the analysis of tumor samples (e.g., MSI, IHC). The application of Amsterdam and Bethesda criteria has resulted in variable and generally poor performance in identifying Lynch syndrome. Therefore, the EWG does not recommend the use of family history to exclude individuals with newly diagnosed cancer from the offer of genetic testing.

Economic Considerations

Costs per Lynch syndrome case detected depend on the testing strategy selected; higher costs are associated with higher sensitivity. Total program costs are highest when no preliminary tests are employed (e.g., all individuals with newly diagnosed CRC are offered DNA sequencing).

Contextual Issues Important to the Recommendations

Major contextual issues considered by the EWG included:

  • With limited benefit of genetic testing to the CRC patient, the EWG recommends that informed consent should be obtained before microsatellite instability (MSI) or immunohistochemical (IHC) testing.
  • Results of several studies comparing psychosocial outcomes between MMR gene mutation carriers and noncarriers, and changes in outcomes over time, have provided no indication of adverse events related to genetic testing. Furthermore, changes in distress seem to be short lived among mutation carriers, and there may be decreases in colon cancer worry, general anxiety, and depression among noncarriers who do not have Lynch syndrome. The EWG found no substantial evidence to show that identifying Lynch syndrome via routine genetic testing would lead to adverse psychosocial outcomes.
  • Evidence shows relatively high levels of uptake for counseling among first-degree relatives contacted, subsequent MMR gene mutation testing, and adherence to increased surveillance among relatives found to have Lynch syndrome. The EWG concludes that the level of participation among relatives is sufficient to justify the resources needed to implement routine genetic testing strategies.

Definitions:

Recommendations Based on Certainty of Evidence, Magnitude of Net Benefit, and Contextual Issues

High or Moderate Recommend for:
  • If the magnitude of net benefit is Substantial, Moderate, or Small, unless additional considerations warrant caution.
  • Consider the importance of each relevant contextual factor and its magnitude or finding.
Recommend against:
  • If the magnitude of net benefit is Zero or there are net harms.
  • Consider the importance of each relevant contextual factor and its magnitude or finding.
Low Insufficient evidence:
  • If the evidence for clinical utility or clinical validity is insufficient in quantity or quality to support conclusions or make a recommendation.
  • Consider the importance of each contextual factor and its magnitude or finding.
  • Determine whether the recommendation should be Insufficient (neutral), Insufficient (encouraging), or Insufficient (discouraging).
  • Provide information on key information gaps to drive a research agenda.

Teutsch SM, Bradley LA, Palomaki GE, Haddow JE, Piper M, Calonge N, Dotson WD, Douglas MP, Berg AO; EGAPP Working Group. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative: methods of the EGAPP Working Group. Genet Med. 2009 Jan;11(1):3-14.

Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is not specifically stated for the recommendation.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Timely identification of Lynch syndrome in relatives of patients with newly diagnosed colorectal cancer, with resulting reduction in morbidity and mortality

Potential Harms

Studies reporting psychosocial sequelae of mutation testing find that distress among mutation carriers is usually short term and that noncarriers experience significant relief.

Qualifying Statements

Qualifying Statements
  • The recommendation statement is a product of the independent Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Although the Centers for Disease Control and Prevention (CDC) provides support to the EGAPP Working Group, including staff support in the preparation of this document, recommendations made by the EGAPP Working Group should not be construed as official positions of the CDC or the U.S. Department of Health and Human Services.
  • Research gaps were identified in four areas (analytic validity, clinical validity, clinical utility, and cost-effectiveness analyses). Further studies in these areas could contribute substantially to refining recommendations. See the original guideline document for a detailed discussion of these research gaps.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Staying Healthy
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009 Jan;11(1):35-41. PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2009 Jan
Guideline Developer(s)
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group - Independent Expert Panel
Guideline Developer Comment

This recommendation statement is a product of the independent EGAPP Working Group. Although the Centers for Disease Control and Prevention (CDC) provides support to the EGAPP Working Group, including staff support in the preparation of this document, recommendations made by the EGAPP Working Group should not be construed as official positions of the CDC or the U.S. Department of Health and Human Services.

Source(s) of Funding

United States Government

Guideline Committee

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group

Composition of Group That Authored the Guideline

Group Members: Alfred O. Berg, MD, MPH (University of Washington) (Chair); Katrina Armstrong, MD, MSCE (University of Pennsylvania School of Medicine); Jeffrey Botkin, MD, MPH (University of Utah); Ned Calonge, MD, MPH (Colorado Department of Public Health and Environment); James Haddow, MD (The Warren Alpert Medical School of Brown University); Maxine Hayes, MD, MPH (Washington State Department of Health); Celia Kaye, MD, PhD (University of Colorado School of Medicine); Kathryn A. Phillips, PhD (University of California, San Francisco); Margaret Piper, PhD, MPH (Blue Cross/Blue Shield Association Technology Evaluation Center); Carolyn Sue Richards, PhD, FACMG (Oregon Health & Science University); Joan A. Scott, MS, CGC (Johns Hopkins University); Ora L. Strickland, PhD, DSc (Hon.), RN, FAAN (Emory University); Steven Teutsch, MD, MPH (Merck & Co.)

Financial Disclosures/Conflicts of Interest

Steven Teutsch is an employee, option and stock holder in Merck & Co., Inc.

Guideline Status

This is the current release of the guideline.

Guideline Availability
Availability of Companion Documents

The following are available:

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on February 20, 2009. The information was verified by the guideline developer on July 23, 2009.

Copyright Statement

This NGC summary is based on the original guideline: Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 2009 Jan;11(1):35-41. ©American College of Medical Genetics. Reprinted with permission of Lippincott Williams & Wilkins.

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