Molecular testing for Lynch syndrome in people with colorectal cancer: Systematic reviews and economic evaluation
Background: Inherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests - microsatellite instability (MSI) and MMR immunohistochemistry (IHC) - are used in CRC patients to identify individuals at high risk of LS for genetic testing. MLH1 (MutL homologue 1) promoter methylation and BRAF V600E testing can be conducted on tumour material to rule out certain sporadic cancers. Objectives: To investigate whether testing for LS in CRC patients using MSI or IHC (with or without MLH1 promoter methylation testing and BRAF V600E testing) is clinically effective (in terms of identifying Lynch syndrome and improving outcomes for patients) and represents a cost-effective use of NHS resources. Review methods: Systematic reviews were conducted of the published literature on diagnostic test accuracy studies of MSI and/or IHC testing for LS, end-to-end studies of screening for LS in CRC patients and economic evaluations of screening for LS in CRC patients. A model-based economic evaluation was conducted to extrapolate long-term outcomes from the results of the diagnostic test accuracy review. The model was extended from a model previously developed by the authors. Results: Ten studies were identified that evaluated the diagnostic test accuracy of MSI and/or IHC testing for identifying LS in CRC patients. For MSI testing, sensitivity ranged from 66.7% to 100.0% and specificity ranged from 61.1% to 92.5%. For IHC, sensitivity ranged from 80.8% to 100.0% and specificity ranged from 80.5% to 91.9%. When tumours showing low levels of MSI were treated as a positive result, the sensitivity of MSI testing increased but specificity fell. No end-to-end studies of screening for LS in CRC patients were identified. Nine economic evaluations of screening for LS in CRC were identified. None of the included studies fully matched the decision problem and hence a new economic evaluation was required. The base-case results in the economic evaluation suggest that screening for LS in CRC patients using IHC, BRAF V600E and MLH1 promoter methylation testing would be cost-effective at a threshold of £20,000 per quality-adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was £11,008 per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective. Limitations: Most of the diagnostic test accuracy studies identified were rated as having a risk of bias or were conducted in unrepresentative samples. There was no direct evidence that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted. Conclusions: Systematic review evidence suggests that MSI- and IHC-based testing can be used to identify LS in CRC patients, although there was heterogeneity in the methods used in the studies identified and the results of the studies. There was no high-quality empirical evidence that screening improves long-term outcomes and so an evidence linkage approach using modelling was necessary. Key determinants of whether or not screening is cost-effective are the accuracy of tumour-based tests, CRC risk without surveillance, the number of relatives identified for cascade testing, colonoscopic surveillance effectiveness and the acceptance of genetic testing. Future work should investigate screening for more causes of hereditary CRC and screening for LS in endometrial cancer patients.
Citation
@article{t.2017,
author = {Snowsill, T. and Coelho, H. and Huxley, N. and Jones-Hughes,
T. and Briscoe, S. and Frayling, I. M. and Hyde, C.},
title = {Molecular Testing for {Lynch} Syndrome in People with
Colorectal Cancer: {Systematic} Reviews and Economic Evaluation},
journal = {Health Technology Assessment},
volume = {21},
number = {51},
date = {2017-09-01},
url = {https://tristansnowsill.co.uk/molecular-testing-for-lynch-syndrome-in-people-with.html},
doi = {10.3310/hta21510},
langid = {en},
abstract = {Background: Inherited mutations in deoxyribonucleic acid
(DNA) mismatch repair (MMR) genes lead to an increased risk of
colorectal cancer (CRC), gynaecological cancers and other cancers,
known as Lynch syndrome (LS). Risk-reducing interventions can be
offered to individuals with known LS-causing mutations. The
mutations can be identified by comprehensive testing of the MMR
genes, but this would be prohibitively expensive in the general
population. Tumour-based tests - microsatellite instability (MSI)
and MMR immunohistochemistry (IHC) - are used in CRC patients to
identify individuals at high risk of LS for genetic testing. MLH1
(MutL homologue 1) promoter methylation and BRAF V600E testing can
be conducted on tumour material to rule out certain sporadic
cancers. Objectives: To investigate whether testing for LS in CRC
patients using MSI or IHC (with or without MLH1 promoter methylation
testing and BRAF V600E testing) is clinically effective (in terms of
identifying Lynch syndrome and improving outcomes for patients) and
represents a cost-effective use of NHS resources. Review methods:
Systematic reviews were conducted of the published literature on
diagnostic test accuracy studies of MSI and/or IHC testing for LS,
end-to-end studies of screening for LS in CRC patients and economic
evaluations of screening for LS in CRC patients. A model-based
economic evaluation was conducted to extrapolate long-term outcomes
from the results of the diagnostic test accuracy review. The model
was extended from a model previously developed by the authors.
Results: Ten studies were identified that evaluated the diagnostic
test accuracy of MSI and/or IHC testing for identifying LS in CRC
patients. For MSI testing, sensitivity ranged from 66.7\% to 100.0\%
and specificity ranged from 61.1\% to 92.5\%. For IHC, sensitivity
ranged from 80.8\% to 100.0\% and specificity ranged from 80.5\% to
91.9\%. When tumours showing low levels of MSI were treated as a
positive result, the sensitivity of MSI testing increased but
specificity fell. No end-to-end studies of screening for LS in CRC
patients were identified. Nine economic evaluations of screening for
LS in CRC were identified. None of the included studies fully
matched the decision problem and hence a new economic evaluation was
required. The base-case results in the economic evaluation suggest
that screening for LS in CRC patients using IHC, BRAF V600E and MLH1
promoter methylation testing would be cost-effective at a threshold
of £20,000 per quality-adjusted life-year (QALY). The incremental
cost-effectiveness ratio for this strategy was £11,008 per QALY
compared with no screening. Screening without tumour tests is not
predicted to be cost-effective. Limitations: Most of the diagnostic
test accuracy studies identified were rated as having a risk of bias
or were conducted in unrepresentative samples. There was no direct
evidence that screening improves long-term outcomes. No
probabilistic sensitivity analysis was conducted. Conclusions:
Systematic review evidence suggests that MSI- and IHC-based testing
can be used to identify LS in CRC patients, although there was
heterogeneity in the methods used in the studies identified and the
results of the studies. There was no high-quality empirical evidence
that screening improves long-term outcomes and so an evidence
linkage approach using modelling was necessary. Key determinants of
whether or not screening is cost-effective are the accuracy of
tumour-based tests, CRC risk without surveillance, the number of
relatives identified for cascade testing, colonoscopic surveillance
effectiveness and the acceptance of genetic testing. Future work
should investigate screening for more causes of hereditary CRC and
screening for LS in endometrial cancer patients.}
}