Abstract
Background and Aims
The optimal algorithm to identify Lynch syndrome (LS) among patients with colorectal cancer (CRC) is unclear. The definitive test for LS, germline testing, is too expensive to be applied in all cases. Initial screening with the revised Bethesda Guidelines (RBG) cannot be applied in a considerable number of cases due to missing information.
Methods
We developed a model to evaluate the cost-effectiveness of 10 strategies for diagnosing LS. Three main issues are addressed: modeling estimates (20–40 %) of RBG applicability; comparing sequential or parallel use of microsatellite instability (MSI) and immunohistochemistry (IHC); and a threshold analysis of the charge value below which universal germline testing becomes the most cost-effective strategy.
Results
LS detection rates in RBG-based strategies decreased to 64.1–70.6 % with 20 % inapplicable RBG. The strategy that uses MSI alone had lower yield, but also lower cost than strategies that use MSI sequentially or in parallel with IHC. The use of MSI and IHC in parallel was less affected by variations in the sensitivity and specificity of these tests. Universal germline testing had the highest yield and the highest cost of all strategies. The model estimated that if charges for germline testing drop to $633–1,518, universal testing of all newly diagnosed CRC cases becomes the most cost-effective strategy.
Conclusions
The low applicability of RBG makes strategies employing initial laboratory-based testing more cost-effective. Of these strategies, parallel testing with MSI and IHC offers the most robust yield. With a considerable drop in cost, universal germline testing may become the most cost-effective strategy for the diagnosis of LS.
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Abbreviations
- LS:
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Lynch syndrome
- CRC:
-
Colorectal cancer
- RBG:
-
Revised Bethesda Guidelines
- MSI:
-
Microsatellite instability
- IHC:
-
Immunohistochemistry
- MMR:
-
Mismatch repair
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Acknowledgments
This work was supported in part by the Texas Digestive Disease Center NIH DK58338 and Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (CIN 13-413).
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No conflict of interests exist.
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Appendices
Appendix 1
Costs of tests used in the model for the base case scenario. The italic numbers are the ones used in the base case analysis
Test | Cost ($) | Reference |
---|---|---|
RBG—cost of genetic consultation | 150* | 1 |
MLH1, MSH2, MSH6 and PMS2 full gene sequencing | 4,000* | 2 |
MLH1, MSH2, and MSH6 deletion/duplication analysis | 2,200* | 2 |
MLH1 full gene sequencing | 1,150 | 2 |
1,018 | 3 | |
1,200 | 4 | |
900* | 5 | |
1,342 | 6 | |
1,290 | 7 | |
MLH1 deletion/duplication | 1,500 | 2 |
300* | 3 | |
470 | 4 | |
505 | 5 | |
474 | 6 | |
MLH1 hypermethylation analysis | 439 | 3 |
MSH2 full gene sequencing | 1,150 | 2 |
996 | 3 | |
1,200–900* | 4 | |
1,342 | 5 | |
1,090 | 67 | |
MSH2 deletion/duplication | 1,500 | 2 |
300* | 3 | |
470 | 4 | |
505 | 5 | |
474 | 6 | |
MSH6 full gene sequencing | 1,150 | 2 |
1,018 | 3 | |
1,200 | 4 | |
900* | 5 | |
1,102 | 6 | |
1,050 | 7 | |
MSH6 deletion/duplication | 1,500 | 2 |
300* | 3 | |
470 | 4 | |
505 | 5 | |
474 | 6 | |
PMS2 full gene sequencing | 1,400 | 2 |
1,870 | 4 | |
1,342 | 6 | |
980* | 7 | |
PMS2 deletion/duplication | 470* | 4 |
474 | 6 | |
IHC(MLK1, MSH2, MSH6, and PMS2) | 500* | 2 |
558 | 3 | |
MSI | 415* | 2 |
493 | 3 | |
BRAF mutation analysis | 314* | 3 |
Abbreviations: RBG Revised Bethesda Guidelines, IHC immunohistochemistry, MSI microsatellite instability
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Emory Genetics Labs
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BCM labs
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Harvard Partners
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University Hospitals Case Medical Center
-
7.
Prevention Genetics
Appendix 2
Estimates of transition probabilities used in the model for the base case scenario
Parameter | Percentage (%) | Reference |
---|---|---|
Prevalence of LS in CRC | 3 | 1 |
Proportion of LS with MSH2 mutation | 39 | 20 |
Proportion of LS with MLH1 mutation | 32 | 20 |
Proportion of LS with MSH6 mutation | 14 | 20 |
Proportion of LS with PMS2 mutation | 15 | 20 |
RBG sensitivity for LS | 91 | 21 |
RBG specificity for LS | 82 | 21 |
MSI specificity for LS | 90.2 | 20 |
MSI sensitivity for LS MLH1/MSH2 | 91 | 20 |
MSI sensitivity for LS MSH6/PMS2 | 77 | 20 |
IHC specificity for LS | 88.8 | 20 |
IHC sensitivity for LS | 83 | 20 |
BRAF V600E sensitivity for LS | 69 | 20 |
BRAF V600E specificity for LS | 99.5 | 20 |
MMR sensitivity for LS | 99.5 | 6 |
MMR specificity for LS | 99.96 | 6 |
Abbreviations: LS Lynch syndrome, CRC colorectal cancer, RBG Revised Bethesda Guidelines, MSI microsatellite instability, IHC immunohistochemistry, MMR mismatch repair gene testing
Appendix 3
HNPCC Ten Screening Strategies (Decision Trees)
Abbreviations: CRC colorectal cancer, RBG revised Bethesda guidelines, MMR4 mismatch repair testing (gene sequencing, deletion, and duplication testing of all 4 LS genes), MSI microsatellite instability, IHC immunohistochemistry
IHC4—indicates abnormal IHC or absence of MMR proteins.
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Gould-Suarez, M., El-Serag, H.B., Musher, B. et al. Cost-Effectiveness and Diagnostic Effectiveness Analyses of Multiple Algorithms for the Diagnosis of Lynch Syndrome. Dig Dis Sci 59, 2913–2926 (2014). https://doi.org/10.1007/s10620-014-3248-6
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DOI: https://doi.org/10.1007/s10620-014-3248-6