Two self-sampling strategies for HPV primary cervical cancer screening compared with clinician-collected sampling: an economic evaluation.

OBJECTIVE: To compare the costs and effects of three sampling strategies for human papillomavirus (HPV) primary screening. DESIGN: Cost-consequence analysis from a health system perspective using a deterministic decision tree model. SETTING: England. PARTICIPANTS: A cohort of 10 000 women aged 25-65 years eligible for the National Health Service Cervical Screening Programme (NHSCSP). METHODS: The model was based on the NHSCSP HPV primary screening pathway and adapted for self-sampling. It used a 3-year cycle: routine screening (year 1) and recall screening (years 2/3). Parameter inputs were informed using published studies, NHSCSP reports and input from experts and manufacturers. Costs were from 2020/2021, British pound sterling (£). INTERVENTIONS: Three sampling strategies were implemented: (1) routine clinician-collected cervical sample, (2) self-collected first-void (FV) urine, (3) self-collected vaginal swab. The hypothetical self-sampling strategies involved mailing women a sampling kit. MAIN OUTCOME MEASURES: Primary outcomes: overall costs (for all screening steps to colposcopy), number of complete screens and cost per complete screen. SECONDARY OUTCOMES: number of women screened, number of women lost to follow-up, cost per colposcopy and total screening costs for a plausible range of uptake scenarios. RESULTS: In the base case, the average cost per complete screen was £56.81 for clinician-collected cervical sampling, £38.57 for FV urine self-sampling and £40.37 for vaginal self-sampling. In deterministic sensitivity analysis, the variables most affecting the average cost per screen were the cost of sample collection for clinician-collected sampling and the cost of laboratory HPV testing for the self-sampling strategies. Scaled to consider routine screening in England, if uptake in non-attenders increased by 15% and 50% of current screeners converted to self-sampling, the NHSCSP would save £19.2 million (FV urine) or £16.5 million (vaginal) per year. CONCLUSION: Self-sampling could provide a less costly alternative to clinician-collected sampling for routine HPV primary screening and offers opportunities to expand the reach of cervical screening to under-screened women.

Targeting lung cancer screening to individuals at greatest risk: the role of genetic factors.

Lung cancer (LC) is the most common global cancer. An individual's risk of developing LC is mediated by an array of factors, including family history of the disease. Considerable research into genetic risk factors for LC has taken place in recent years, with both low-penetrance and high-penetrance variants implicated in increasing or decreasing a person's risk of the disease. LC is the leading cause of cancer death worldwide; poor survival is driven by late onset of non-specific symptoms, resulting in late-stage diagnoses. Evidence for the efficacy of screening in detecting cancer earlier, thereby reducing lung-cancer specific mortality, is now well established. To ensure the cost-effectiveness of a screening programme and to limit the potential harms to participants, a risk threshold for screening eligibility is required. Risk prediction models (RPMs), which provide an individual's personal risk of LC over a particular period based on a large number of risk factors, may improve the selection of high-risk individuals for LC screening when compared with generalised eligibility criteria that only consider smoking history and age. No currently used RPM integrates genetic risk factors into its calculation of risk. This review provides an overview of the evidence for LC screening, screening related harms and the use of RPMs in screening cohort selection. It gives a synopsis of the known genetic risk factors for lung cancer and discusses the evidence for including them in RPMs, focusing in particular on the use of polygenic risk scores to increase the accuracy of targeted lung cancer screening.

Assessment of mismatch repair deficiency in ovarian cancer.

BACKGROUND: Hereditary causes of ovarian cancer include Lynch syndrome, which is due to inherited pathogenic variants affecting one of the four mismatch repair genes involved in DNA repair. The aim of this study was to evaluate tumour mismatch repair deficiency and prevalence of Lynch syndrome in high-risk women referred to the Manchester Centre for Genomic Medicine with ovarian cancer over the past 20 years. METHODS: Women with ovarian cancer diagnosed before the age of 35 years and/or with a suggestive personal or family history of Lynch syndrome cancers underwent tumour testing with immunohistochemistry for mismatch repair deficiency and, where indicated, MLH1 promoter methylation testing followed by constitutional testing for Lynch syndrome. RESULTS: In total, 261 ovarian cancers were tested and 27 (10.3%; 95% CI 6.9% to 14.7%) showed mismatch repair deficiency by immunohistochemistry. Three of 7 with MLH1 loss showed MLH1 promoter hypermethylation, and 18 of the remaining 24 underwent constitutional testing for Lynch syndrome. A further 15 women with mismatch repair proficient tumours underwent constitutional testing because of a strong family history of Lynch syndrome cancers. Pathogenic variants were identified in 9/33 (27%) women who underwent constitutional testing, aged 33-59 years (median 48 years), including one whose tumour was mismatch repair proficient. Most Lynch syndrome tumours were of endometrioid histological subtype. CONCLUSIONS: Tumour mismatch repair deficiency identified by immunohistochemistry is a useful prescreen for constitutional testing in women with ovarian cancer with personal or family histories suggestive of Lynch syndrome.

Cost-Effectiveness of the Manchester Approach to Identifying Lynch Syndrome in Women with Endometrial Cancer.

Lynch syndrome (LS) is a hereditary cancer syndrome responsible for 3% of all endometrial cancer and 5% in those aged under 70 years. It is unclear whether universal testing for LS in endometrial cancer patients would be cost-effective. The Manchester approach to identifying LS in endometrial cancer patients uses immunohistochemistry (IHC) to detect mismatch repair (MMR) deficiency, incorporates testing for MLH1 promoter hypermethylation, and incorporates genetic testing for pathogenic MMR variants. We aimed to assess the cost-effectiveness of the Manchester approach on the basis of primary research data from clinical practice in Manchester. The Proportion of Endometrial Tumours Associated with Lynch Syndrome (PETALS) study informed estimates of diagnostic performances for a number of different strategies. A recent microcosting study was adapted and was used to estimate diagnostic costs. A Markov model was used to predict long-term costs and health outcomes (measured in quality-adjusted life years, QALYs) for individuals and their relatives. Bootstrapping and probabilistic sensitivity analysis were used to estimate the uncertainty in cost-effectiveness. The Manchester approach dominated other reflex testing strategies when considering diagnostic costs and Lynch syndrome cases identified. When considering long-term costs and QALYs the Manchester approach was the optimal strategy, costing £5459 per QALY gained (compared to thresholds of £20,000 to £30,000 per QALY commonly used in the National Health Service (NHS)). Cost-effectiveness is not an argument for restricting testing to younger patients or those with a strong family history. Universal testing for Lynch syndrome in endometrial cancer patients is expected to be cost-effective in the U.K. (NHS), and the Manchester approach is expected to be the optimal testing strategy.

Variation in the initial assessment and investigation for ovarian cancer in symptomatic women: a systematic review of international guidelines.

BACKGROUND: Women with ovarian cancer can present with a variety of symptoms and signs, and an increasing range of tests are available for their investigation. A number of international guidelines provide advice for the initial assessment of possible ovarian cancer in symptomatic women. We systematically identified and reviewed the consistency and quality of these documents. METHODS: MEDLINE, Embase, guideline-specific databases and professional organisation websites were searched in March 2018 for relevant clinical guidelines, consensus statements and clinical pathways, produced by professional or governmental bodies. Two reviewers independently extracted data and appraised documents using the Appraisal for Guidelines and Research Evaluation 2 (AGREEII) tool. RESULTS: Eighteen documents from 11 countries in six languages met selection criteria. Methodological quality varied with two guidance documents achieving an AGREEII score ≥ 50% in all six domains and 10 documents scoring ≥50% for "Rigour of development" (range: 7-96%). All guidance documents provided advice on possible symptoms of ovarian cancer, although the number of symptoms included in documents ranged from four to 14 with only one symptom (bloating/abdominal distension/increased abdominal size) appearing in all documents. Fourteen documents provided advice on physical examinations but varied in both the examinations they recommended and the physical signs they included. Fifteen documents provided recommendations on initial investigations. Transabdominal/transvaginal ultrasound and the serum biomarker CA125 were the most widely advocated initial tests. Five distinct testing strategies were identified based on the number of tests and the order of testing advocated: 'single test', 'dual testing', 'sequential testing', 'multiple testing options' and 'no testing'. CONCLUSIONS: Recommendations on the initial assessment and investigation for ovarian cancer in symptomatic women vary considerably between international guidance documents. This variation could contribute to differences in the way symptomatic women are assessed and investigated between countries. Greater research is needed to evaluate the assessment and testing approaches advocated by different guidelines and their impact on ovarian cancer detection.

Cost-effectiveness analysis of reflex testing for Lynch syndrome in women with endometrial cancer in the UK setting.

BACKGROUND: Lynch syndrome is a hereditary cancer syndrome caused by constitutional pathogenic variants in the DNA mismatch repair (MMR) system, leading to increased risk of colorectal, endometrial and other cancers. The study aimed to identify the incremental costs and consequences of strategies to identify Lynch syndrome in women with endometrial cancer. METHODS: A decision-analytic model was developed to evaluate the relative cost-effectiveness of reflex testing strategies for identifying Lynch syndrome in women with endometrial cancer taking the NHS perspective and a lifetime horizon. Model input parameters were sourced from various published sources. Consequences were measured using quality-adjusted life years (QALYs). A cost-effectiveness threshold of £20 000/QALY was used. RESULTS: Reflex testing for Lynch syndrome using MMR immunohistochemistry and MLH1 methylation testing was cost-effective versus no testing, costing £14 200 per QALY gained. There was uncertainty due to parameter imprecision, with an estimated 42% chance this strategy is not cost-effective compared with no testing. Age had a significant impact on cost-effectiveness, with testing not predicted to be cost-effective in patients aged 65 years and over. CONCLUSIONS: Testing for Lynch syndrome in younger women with endometrial cancer using MMR immunohistochemistry and MLH1 methylation testing may be cost-effective. Age cut-offs may be controversial and adversely affect implementation.

A Micro-Costing Study of Screening for Lynch Syndrome-Associated Pathogenic Variants in an Unselected Endometrial Cancer Population: Cheap as NGS Chips?

Background: Lynch syndrome is the most common inherited cause of endometrial cancer. Identifying individuals affected by Lynch syndrome enables risk-reducing interventions including colorectal surveillance, and cascade testing of relatives. Methods: We conducted a micro-costing study of screening all women with endometrial cancer for Lynch syndrome using one of four diagnostic strategies combining tumor microsatellite instability testing (MSI), immunohistochemistry (IHC), and/or MLH1 methylation testing, and germline next generation sequencing (NGS). Resource use (consumables, capital equipment, and staff) was identified through direct observation and laboratory protocols. Published sources were used to identify unit costs to calculate a per-patient cost (£; 2017) of each testing strategy, assuming a National Health Service (NHS) perspective. Results: Tumor triage with MSI and reflex MLH1 methylation testing followed by germline NGS of women with likely Lynch syndrome was the cheapest strategy at £42.01 per case. Tumor triage with IHC and reflex MLH1 methylation testing of MLH1 protein-deficient cancers followed by NGS of women with likely Lynch syndrome cost £45.68. Tumor triage with MSI followed by NGS of all women found to have tumor microsatellite instability cost £78.95. Immediate germline NGS of all women with endometrial cancer cost £176.24. The cost of NGS was affected by the skills and time needed to interpret results (£44.55/patient). Conclusion: This study identified the cost of reflex screening all women with endometrial cancer for Lynch syndrome, which can be used in a model-based cost-effectiveness analysis to understand the added value of introducing reflex screening into clinical practice.

The prevalence of Lynch syndrome in women with endometrial cancer: a systematic review protocol.

BACKGROUND: Lynch syndrome is the most common inherited cancer syndrome, which predisposes individuals to a number of different cancers, principally colorectal and endometrial cancer. The early diagnosis of Lynch syndrome enables colorectal surveillance, which has been shown to save lives through the detection and removal of premalignant polyps and earlier detection of invasive disease. Endometrial cancer, which is often the sentinel cancer in women, provides an opportunity to diagnose Lynch syndrome and thus enable colorectal surveillance as well as the cascade testing for Lynch syndrome in other family members. These potential benefits have led to a call for the universal screening of women with endometrial cancer for Lynch syndrome, a practice that is now commonplace in colorectal cancer. Healthcare providers and clinicians are however restricted by insufficient knowledge about the prevalence of Lynch syndrome in women with endometrial cancer, with estimates varying as widely as 1-10%. The aim of this study is to perform a systematic review with a meta-analysis of the current literature base in order to estimate the prevalence of Lynch syndrome among women with endometrial cancer to inform this discussion. METHODS: Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register, NHS Health and Technology Assessment Database and the Web of Science will be systematically searched for relevant studies via the Ovid platform. Two authors will review the titles and abstracts independently, with discrepancy settled by a third author. Data extraction will be completed to record demographic, pathological and clinical data, as well as the diagnostic methods used for estimating the prevalence of Lynch syndrome in women with endometrial cancer. Bias will be assessed and recorded using the Newcastle-Ottawa Scale and that of the International Cochrane Collaboration. Dependent on the heterogeneity of the data, we aim to produce a cumulative incidence in addition to subgroup analyses as to investigate secondary outcomes. DISCUSSION: The aim of this systematic review is to provide a robust estimate of the prevalence of Lynch syndrome in women with endometrial cancer. This will enable resource allocation and decision-making regarding the appropriateness of screening all women, or certain women, with endometrial cancer for Lynch syndrome. Such a policy could enable the earlier diagnosis of Lynch syndrome in women and, through the application of colorectal cancer surveillance, improve their survival outcomes. SYSTEMATIC REVIEW REGISTRATION: This systematic review has been registered on PROSPERO (ref CRD42017081707 ).

Identifying High-Risk Women for Endometrial Cancer Prevention Strategies: Proposal of an Endometrial Cancer Risk Prediction Model.

Already the fourth most common cancer in women in the developed world, the incidence of endometrial cancer is increasing rapidly, in line with the increasing prevalence of obesity. Relatively few studies have been undertaken of risk-reducing interventions aimed at limiting the impact of the disease on both individuals and the health service. Those that have been performed have demonstrated only modest results due to their application in relatively unselected populations. A validated risk prediction model is therefore urgently required to identify individuals at particularly high risk of endometrial cancer who may benefit from targeted primary prevention strategies and to guide trial eligibility. On the basis of a systematic review of the literature, the evidence for inclusion of measures of obesity, reproduction, insulin resistance, and genetic risk in such a model is discussed, and the strength of association between these risk factors and endometrial cancer is used to guide the development of a pragmatic risk prediction scoring system that could be implemented in the general population. Provisional cutoff values are described pending refinement of the model and external validation in large prospective cohorts. Potential risk-reducing interventions are suggested, highlighting the need for future studies in this area if the increasing tide of endometrial cancer is to be stemmed. Cancer Prev Res; 10(1); 1-13. ©2016 AACR.

A cluster randomised trial of strategies to increase cervical screening uptake at first invitation (STRATEGIC).

BACKGROUND: Falling participation by young women in cervical screening has been observed at a time that has seen an increase in the incidence of cervical cancer in the UK in women aged < 35 years. Various barriers to screening have been documented, including fear, embarrassment and inconvenience. OBJECTIVES: To measure the feasibility, clinical effectiveness and cost-effectiveness of a range of interventions to increase the uptake of cervical screening among young women. DESIGN: A cluster randomised trial based on general practices performed in two phases. SETTING: Primary care in Greater Manchester and the Grampian region in Scotland. PARTICIPANTS: Phase 1: 20,879 women receiving their first invitation for cervical screening. Phase 2: 10,126 women who had not attended by 6 months. INTERVENTIONS: Phase 1: pre-invitation leaflet or not, and access to online booking (Manchester only). Phase 2: (1) vaginal self-sampling kits (SSKs) sent unrequested (n = 1141); or (2) offered on request (n = 1290); (3) provided with a timed appointment (n = 1629); (4) offered access to a nurse navigator (NN) (n = 1007); or (5) offered a choice between a NN or a SSK (n = 1277); and 3782 women in control practices. MAIN OUTCOME MEASURES: Uplift in screening compared with control practices, cost-effectiveness of interventions, and the women's preferences explored in a discrete choice experiment. RESULTS: The pre-invitation leaflet and offer of online booking were ineffective when compared with control practices at 3 months, 18.8% versus 19.2% [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.88 to 1.06; p = 0.485] and 17.8% versus 17.2% (OR 1.02, 95% CI 0.87 to 1.20; p = 0.802), respectively. The uptake of screening at 3 months was higher among previously human papillomavirus (HPV)-vaccinated women than unvaccinated women, 23.7% versus 11% (OR 2.07, 95% CI 1.69 to 2.53; p < 0.001). Among non-attenders, the SSK sent intervention showed a statistically significant increase in uptake at 12 months post invitation, 21.3% versus 16.2% (OR 1.51, 95% CI 1.20 to 1.91; p = 0.001), as did timed appointments, 19.8% versus 16.2% (OR 1.41, 95% CI 1.14 to 1.74; p = 0.001). The offer of a NN, a SSK on request, and a choice between timed appointments and NN were ineffective. Overall, there was a gradual rather than prompt response, as demonstrated by uptake among control practices. A discrete choice experiment indicated that women invited who had not yet attended valued the attributes inherent in self-sampling. The health economic analysis showed that both timed appointments and unsolicited SSK sent were likely to be cost-effective at a cost per quality-adjusted life-year (QALY) gained of £7593 and £8434, respectively, if extended across the national 25-year-old cohort throughout the duration of screening. The certainty of these being cost-effective at a ceiling ratio of £20,000 per QALY gained was > 90%. CONCLUSION: Women receiving their initial screening invitation frequently delay taking up the offer and the net impact of interventions was small. Timed appointments and SSKs sent to non-attenders at 6 months are likely to be a cost-effective means of increasing uptake and should be considered further. HPV vaccination in the catch-up programme was associated with an increased uptake of cervical screening. Future work should focus on optimising self-sampling in terms of age range, timing of offer for non-attenders and use of urine testing instead of vaginal samples. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52303479. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 68. See the NIHR Journals Library website for further project information.