Testing tumours for deficient DNA mismatch repair (dMMR) has been identified as a practice that is potentially over-utilized. According to clinical experts, dMMR tumour testing appears to be transitioning from an approach aimed at identifying patients and families with Lynch syndrome (LS) into a tumour phenotyping procedure that can be used to predict the prognosis of colorectal cancer (CRC) and to guide for adjuvant chemotherapy decisions. The use of a test with a prognostic and predictive value falls under the realm of “personalized medicine.” According to oncology and pathology experts, this recent application of dMMR tumour testing is the major driver of new test requisitions. This transition has led to an increased demand for the test, with unclear benefits for the patient or family members. In general, there is a lack of clarity regarding when the tests should be ordered and the impact of tumour dMMR status on CRC outcomes in the current era of oxaliplatin- and irinotecan-based chemotherapy. The central question, however, is whether universal dMMR tumour testing of CRC tumours is a viable and desirable option, given the known limitations of LS pre-selection criteria based on age, history, and pathology, and recognizing the potential utility of tumour dMMR status for personalizing cancer therapy. Missed cases of LS resulting from a targeted tumour dMMR testing strategy that is restricted to pre-selected high-risk individuals (e.g., selected based on the rBG) can be problematic and costly for the system, which would potentially support broader (universal) dMMR tumour testing of all CRC tumours. Alternatively, universal tumour testing carries with it additional costs associated with testing all CRC patients, most of whom will not have LS.

In summary, there is uncertainty regarding:

• Optimal eligibility criteria for dMMR tumour testing in:
  • CRC patients to identify new families with LS
  • CRC patients to inform prognosis or prediction of response to chemotherapy.
• The cost-effectiveness of tumour screening strategies and algorithms in:
  • CRC patients to identify new families with LS
  • CRC patients to inform prognosis or prediction of response to chemotherapy.

Contents

• Reviewers
• Authorship
• Conflicts of Interest
• 1. Protocol Deviations
• 2. Context and Policy Issues
  • 2.1 Disease and Technology Background
  • 2.2 Policy and Practice Issues
• 3. Research Questions
• Clinical Review: Clinical Validity of dMMR Testing
  • 4. Methods
    • 4.1 Literature Search Strategies
    • 4.2 Selection Criteria and Methods
    • 4.3 Exclusion Criteria
    • 4.4 Data Extraction
    • 4.5 Critical Appraisal of Individual Studies
    • 4.6 Data Analyses and Synthesis
  • 5. Summary of Clinical Evidence
    • 5.1 Quantity of Research Available
    • 5.2 Summary of Study Characteristics
    • 5.3 Summary of Critical Appraisal
    • 5.4 Summary of Findings
• Clinical Review: Health Outcomes of dMMR Testing for Family Members
  • 6. Methods
    • 6.1 Literature Search Strategies
    • 6.2 Selection Criteria and Methods
    • 6.3 Exclusion Criteria
    • 6.4 Data Extraction
    • 6.5 Critical Appraisal of Individual Studies
    • 6.6 Data Analyses and Synthesis
  • 7. Summary of Clinical Evidence
    • 7.1 Quantity of Research Available
    • 7.2 Summary of Study Characteristics
    • 7.3 Summary of Critical Appraisal
    • 7.4 Summary of Findings
• Clinical Review: Clinical Validity of Tests Subsequent to dMMR Testing
  • 8. Methods
    • 8.1 Literature Search Strategies
    • 8.2 Selection Criteria and Methods
    • 8.3 Exclusion Criteria
    • 8.4 Data Extraction
    • 8.5 Critical Appraisal of Individual Studies
    • 8.6 Data Analyses and Synthesis
  • 9. Summary of Clinical Evidence
    • 9.1 Quantity of Research Available
    • 9.2 Summary of Study Characteristics
    • 9.3 Summary of Critical Appraisal
    • 9.4 Summary of Findings
• Clinical Review: Clinical Utility of dMMR Testing
  • 10. Methods
    • 10.1 Literature Search Strategies
    • 10.2 Selection Criteria and Methods
    • 10.3 Exclusion Criteria
    • 10.4 Data Extraction
    • 10.5 Critical Appraisal of Individual Studies
    • 10.6 Data Analyses and Synthesis
    • 10.7 Meta-analysis
    • 10.8 Heterogeneity
    • 10.9 Missing Data
  • 11. Summary of Clinical Evidence
    • 11.1 Quantity of Research Available
    • 11.2 Summary of Study Characteristics
    • 11.3 Summary of Critical Appraisal
    • 11.4 Summary of Findings
• Economic Review: Cost-Effectiveness of dMMR Testing
  • 12. Methods
    • 12.1 Literature Search Strategies
  • 13. Summary of Evidence
    • 13.1 Quantity of Research Available
    • 13.2 Summary of Study Characteristics
    • 13.3 Summary of Critical Appraisal
    • 13.4 Summary of Findings
• Primary Economic Evaluation
  • 14. Methods
    • 14.1 Type of Economic Evaluation
    • 14.2 Target Population
    • 14.3 Comparators
    • 14.4 Perspective
    • 14.5 Time Horizon
    • 14.6 Modelling
    • 14.7 Resource Costs Model Variables
    • 14.8 Discount Rate
    • 14.9 Uncertainty and Variability
    • 14.10 List of Assumptions
  • 15. Results
    • 15.1 Base-Case Results
    • 15.2 Sensitivity Analysis
• Patient Experience and Preferences
  • 16. Methods
    • 16.1 Literature Search Strategy
    • 16.2 Eligibility Criteria
    • 16.3 Screening and Selecting Studies for Inclusion
    • 16.4 Data Collection and Extraction
    • 16.5 Quality Assessment
    • 16.6 Data Analysis
  • 17. Results
    • 17.1 Descriptive Analysis
    • 17.2 Thematic Analysis
    • 17.3 Summary of Quality Assessment
• 18. Discussion
  • 18.1 Summary of Main Findings
  • 18.2 Strengths and Limitations
• 19. Conclusions
• Abbreviations
• References
• Appendix 1 Literature Search Strategies
• Appendix 2 Results From Search Update (March 1, 2016)
• Appendix 3 Title and Abstract Screening Checklist (Question 1)
• Appendix 4 Title and Abstract Screening Checklist (Question 2)
• Appendix 5 Title and Abstract Screening Checklist (Question 3)
• Appendix 6 Title and Abstract Screening Checklist (Questions 4 and 5)
• Appendix 7 Title and Abstract Screening Checklist (Question 6)
• Appendix 8 Full-Text Screening Checklist (Question 1)
• Appendix 9 Full-Text Screening Checklist (Question 2)
• Appendix 10 Full-Text Screening Checklist (Question 3)
• Appendix 11 Full-Text Screening Checklist (Questions 4 and 5)
• Appendix 12 Full-Text Screening Checklist (Question 6)
• Appendix 13 QUADAS-2 Tool for the Quality Assessment of Diagnostic Accuracy Studies
• Appendix 14 Quality Assessment Form (Questions 4 and 5)
• Appendix 15 Clinical Data Abstraction Form (Question 1)
• Appendix 16 Clinical Data Abstraction Form (Question 3)
• Appendix 17 Clinical Data Abstraction Form (Questions 4 and 5)
• Appendix 18 Data Abstraction Form (Question 6)
• Appendix 19 Details of Outcome Measures for Assessment of Diagnostic Test Performance
• Appendix 20 Selection of Included Studies (Question 1)
• Appendix 21 Selection of Included Studies (Question 2)
• Appendix 22 Selection of Included Studies (Question 3)
• Appendix 23 Selection of Included Studies (Question 4 and 5)
• Appendix 24 Selection of Included Studies (Question 6)
• Appendix 25 Characteristics of Included Studies (Question 1)
• Appendix 26 Characteristics of Included Studies (Question 3)
• Appendix 27 Characteristics of Included Studies (Question 4)
• Appendix 28 Characteristics of Included Studies (Question 5)
• Appendix 29 Characteristics of Included Studies (Question 6)
• Appendix 30 Critical Appraisal of Included Studies (Question 1)
• Appendix 31 Critical Appraisal of Included Studies (Question 3)
• Appendix 32 Critical Appraisal of Included Studies (Question 4)
• Appendix 33 Critical Appraisal of Included Studies (Question 5)
• Appendix 34 Outcomes Reported by the Included Studies (Question 4)
• Appendix 35 Outcomes Reported by the Included Studies (Question 5)
• Appendix 36 Forest Plots of Outcome Comparisons Reported by the Included Studies (Question 4)
• Appendix 37 Forest Plots of Outcome Comparisons Reported by the Included Studies (Question 5)
• Appendix 38 Detailed Summary of Relevant Economic Evaluations
• Appendix 39 List of Different Strategies Compared in the Model
• Appendix 40 Overview of Screening and Reflex Testing Strategies in Patients With Colorectal Cancer and Subsequent Carrier Testing in Their Relatives
• Appendix 41 Proportion of Patients With Diagnosed Colorectal Cancer, According to Dukes Staging
• Appendix 42 Detailed Calculation to Determine Parameter Estimates for Relative Identification Submodel
• Appendix 43 Detailed Cost Breakdown for a Year of Adjuvant Chemotherapy
• Appendix 44 Background Age- and Sex-Specific Utility Values
• Appendix 45 Detailed Deterministic Results From the Economic Model
• Appendix 46 Literature Search Strategy (Question 7)
• Appendix 47 Data Abstraction Form (Question 7)
• Appendix 48 Quality Assessment Instrument — Qualitative Studies
• Appendix 49 Quality Assessment Instrument — Cross-Sectional Studies
• Appendix 50 Selection of Included Studies (Question 7)
• Appendix 51 List of Included Studies (Question 7)
• Appendix 52 List of Excluded Studies, With Reasons (Question 7)
• Appendix 53 Characteristics of Included Studies (Question 7)
• Appendix 54 Characteristics of Included Study Participants (Question 7)
• Appendix 55 Acceptance of Genetic Testing
• Appendix 56 Medical Management and Screening Post-Test Result by Study
• Appendix 57 Critical Appraisal of the Included Studies: Cross-Sectional (Question 7)
• Appendix 58 Critical Appraisal of the Included Studies: Qualitative (Question 7)

Suggested citation:

DNA mismatch repair deficiency tumour testing for patients with colorectal cancer: a health technology assessment. Ottawa: CADTH; 2016 Aug. (CADTH optimal use report; vol.5, no.3b).

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