A systematic review and economic evaluation of diagnostic strategies for Lynch syndrome

Abstract

BackgroundLynch syndrome (LS) is an inherited autosomal dominant disorder characterised by an increased risk of colorectal cancer (CRC) and other cancers, and caused by mutations in the deoxyribonucleic acid (DNA) mismatch repair genes.ObjectiveTo evaluate the accuracy and cost-effectiveness of strategies to identify LS in newly diagnosed early-onset CRC patients (aged < 50 years). Cascade testing of relatives is employed in all strategies for individuals in whom LS is identified.Data sources and methodsSystematic reviews were conducted of the test accuracy of microsatellite instability (MSI) testing or immunohistochemistry (IHC) in individuals with CRC at risk of LS, and of economic evidence relating to diagnostic strategies for LS. Reviews were carried out in April 2012 (test accuracy); and in February 2012, repeated in February 2013 (economic evaluations). Databases searched included MEDLINE (1946 to April week 3, 2012), EMBASE (1980 to week 17, 2012) and Web of Science (inception to 30 April 2012), and risk of bias for test accuracy was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) quality appraisal tool. A de novo economic model of diagnostic strategies for LS was developed.ResultsInconsistencies in study designs precluded pooling of diagnostic test accuracy results from a previous systematic review and nine subsequent primary studies. These were of mixed quality, with significant methodological concerns identified for most. IHC and MSI can both play a part in diagnosing LS but neither is gold standard. No UK studies evaluated the cost-effectiveness of diagnosing and managing LS, although studies from other countries generally found some strategies to be cost-effective compared with no testing.The de novo model demonstrated that all strategies were cost-effective compared with no testing at a threshold of £20,000 per quality-adjusted life-year (QALY), with the most cost-effective strategy utilising MSI andBRAFtesting [incremental cost-effectiveness ratio (ICER) = £5491 per QALY]. The maximum health benefit to the population of interest would be obtained using universal germline testing, but this would not be a cost-effective use of NHS resources compared with the next best strategy. When the age limit was raised from 50 to 60 and 70 years, the ICERs compared with no testing increased but remained below £20,000 per QALY (except for universal germline testing with an age limit of 70 years). The total net health benefit increased with the age limit as more individuals with LS were identified. Uncertainty was evaluated through univariate sensitivity analyses, which suggested that the parameters substantially affecting cost-effectiveness: were the risk of CRC for individuals with LS; the average number of relatives identified per index patient; the effectiveness of colonoscopy in preventing metachronous CRC; the cost of colonoscopy; the duration of the psychological impact of genetic testing on health-related quality of life (HRQoL); and the impact of prophylactic hysterectomy and bilateral salpingo-oophorectomy on HRQoL (this had the potential to make all testing strategies more expensive and less effective than no testing).LimitationsThe absence of high-quality data for the impact of prophylactic gynaecological surgery and the psychological impact of genetic testing on HRQoL is an acknowledged limitation.ConclusionsResults suggest that reflex testing for LS in newly diagnosed CRC patients aged < 50 years is cost-effective. Such testing may also be cost-effective in newly diagnosed CRC patients aged < 60 or < 70 years. Results are subject to uncertainty due to a number of parameters, for some of which good estimates were not identified. We recommend future research to estimate the cost-effectiveness of testing for LS in individuals with newly diagnosed endometrial or ovarian cancer, and the inclusion of aspirin chemoprevention. Further research is required to accurately estimate the impact of interventions on HRQoL.Study registrationThis study is registered as PROSPERO CRD42012002436.FundingThe National Institute for Health Research Health Technology Assessment programme.

Which Lynch syndrome screening programs could be implemented in the “real world”? A systematic review of economic evaluations

“…62,63 Our systematic review can help inform health decision makers of the opportunities and challenges involved in integrating LS screening in public health policies. 10,64 Compared with previous reviews, 12,13 ours is a more comprehensive classification of all cost-effective LS screening programs and we assessed their feasibility within the related health-care contexts. We considered all target populations examined in the economic studies to provide a broad overview of the various available LS screening programs.…”

“…10 As evidenced by the results of a systematic review on BRCA genetic testing programs, economic evaluations may allow an assessment of genetic screening programs in terms of both their cost and effectiveness and their readiness for implementation. 11 Two previous systematic reviews 12,13 of LS economic evaluations have argued that universal LS screening is costeffective compared with not performing genetic testing (no screening), but not necessarily compared with selective or age-targeted testing strategies. Accordingly, there are still several issues that need to be clarified: the cost-effectiveness of universal screening relative to age-targeted screening, the comparative cost-effectiveness of different diagnostic strategies, the implications of the use of preventive strategies for endometrial and ovarian cancer in females with LS, and the cost-effectiveness of LS screening programs for other potential target populations, such as women newly diagnosed with endometrial cancer or primary care patients.…”

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…Diagnoses of Lynch Syndrome using clinical strategies, such as the Amsterdam criteria, have a lower sensitivity and specificity than those incorporating the use of MSI/MMR testing within the algorithm, such as the Bethesda guidelines (Gologan and Sepulveda, 2005;Jass, 2007;Peterlongo et al, 2003). Universal tumor screening further increases the sensitivity compared to selective testing strategies, with more at risk relatives undergoing genetic evaluation and receiving appropriate cancer surveillance (EGAPP, 2009;Palomaki et al, 2009;Snowsill et al, 2014). Strict, intensive life-saving cancer surveillance is recommended for any individual with Lynch syndrome .…”

“…Tumours with absent MLH1 and who are BRAF mutation negative and/or who are MLH1 promoter hypermethylation negative, and tumours with absent MSH2, MSH6 or PMS2 should be referred for genetic testing. Molecular assays based on sequence alterations between methylated and non-methylated DNA after bisulfite modification may be used to directly analyze methylation status (Pai et al, 2014;Snowsill et al, 2014). Alternatively an antibody for BRAF V600E is now commercially available.…”

“…The 8 strategies ranged from no testing to genetic testing of the entire CRC population (Snowsill et al, 2014). When the age limit was extended to ≤60 years, all incremental cost-effectiveness ratios (ICERs) compared with no testing remained below the £20,000-per-QALY threshold, and at ≤70 years only the ICER for strategy 8 (germline mutation analysis for the entire population) was above the £20,000-per-QALY threshold.…”