Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation

This is the final version of the article. Available from the publisher via the DOI in this record.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. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016033879. FUNDING: The National Institute for Health Research Health Technology Assessment programme.Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Researc

Socio-economic inequalities in the incidence of four common cancers: a population-based registry study

Objectives: To investigate the relationship between socio-economic circumstances and cancer incidence in Scotland in recent years. Study design: Population-based study using cancer registry data. Methods: Data on incident cases of colorectal, lung, female breast, and prostate cancer diagnosed between 2001 and 2012 were obtained from a population-based cancer registry covering a population of approximately 2.5 million people in the West of Scotland. Socio-economic circumstances were assessed based on postcode of residence at diagnosis, using the Scottish Index of Multiple Deprivation (SIMD). For each cancer, crude and age-standardised incidence rates were calculated by quintile of SIMD score, and the number of excess cases associated with socio-economic deprivation was estimated. Results: 93,866 cases met inclusion criteria, comprising 21,114 colorectal, 31,761 lung, 23,757 female breast, and 15,314 prostate cancers. Between 2001 and 2006, there was no consistent association between socio-economic circumstances and colorectal cancer incidence, but 2006–2012 saw an emerging deprivation gradient in both sexes. The incidence rate ratio (IRR) for colorectal cancer between most deprived and least deprived increased from 1.03 (95% confidence interval [CI] 0.91–1.16) to 1.24 (95% CI 1.11–1.39) during the study period. The incidence of lung cancer showed the strongest relationship with socio-economic circumstances, with inequalities widening across the study period among women from IRR 2.66 (95% CI 2.33–3.05) to 2.91 (95% CI 2.54–3.33) in 2001–03 and 2010–12, respectively. Breast and prostate cancer showed an inverse relationship with socio-economic circumstances, with lower incidence among people living in more deprived areas. Conclusion: Significant socio-economic inequalities remain in cancer incidence in the West of Scotland, and in some cases are increasing. In particular, this study has identified an emerging, previously unreported, socio-economic gradient in colorectal cancer incidence among women as well as men. Actions to prevent, mitigate, and undo health inequalities should be a public health priority