Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer.

BACKGROUND: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. METHODS: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. RESULTS: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year's testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. CONCLUSIONS: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.

Implementing Multifactorial Risk Assessment with Polygenic Risk Scores for Personalized Breast Cancer Screening in the Population Setting: Challenges and Opportunities.

Risk-stratified breast screening has been proposed as a strategy to overcome the limitations of age-based screening. A prospective cohort study was undertaken within the PERSPECTIVE I&I project, which will generate the first Canadian evidence on multifactorial breast cancer risk assessment in the population setting to inform the implementation of risk-stratified screening. Recruited females aged 40-69 unaffected by breast cancer, with a previous mammogram, underwent multifactorial breast cancer risk assessment. The adoption of multifactorial risk assessment, the effectiveness of methods for collecting risk factor information and the costs of risk assessment were examined. Associations between participant characteristics and study sites, as well as data collection methods, were assessed using logistic regression; all p-values are two-sided. Of the 4246 participants recruited, 88.4% completed a risk assessment, with 79.8%, 15.7% and 4.4% estimated at average, higher than average and high risk, respectively. The total per-participant cost for risk assessment was CAD 315. Participants who chose to provide risk factor information on paper/telephone (27.2%) vs. online were more likely to be older (p = 0.021), not born in Canada (p = 0.043), visible minorities (p = 0.01) and have a lower attained education (p < 0.0001) and perceived fair/poor health (p < 0.001). The 34.4% of participants requiring risk factor verification for missing/unusual values were more likely to be visible minorities (p = 0.009) and have a lower attained education (p ≤ 0.006). This study demonstrates the feasibility of risk assessment for risk-stratified screening at the population level. Implementation should incorporate an equity lens to ensure cancer-screening disparities are not widened.

Breast cancer risk assessment for prescription of menopausal hormone therapy in women with a family history of breast cancer: an epidemiological modelling study.

BACKGROUND: Menopausal hormone therapy (MHT) can alleviate menopausal symptoms but has been associated with an increased risk of breast cancer. MHT prescription should be preceded by individualised risk/benefit evaluation; however, data outlining the impact of family history alongside different MHT therapeutic approaches are lacking. AIM: To quantify the risks associated with MHT use in women with varying breast cancer family histories of developing and dying from breast cancer. DESIGN AND SETTING: An epidemiological modelling study for women in England using the BOADICEA breast cancer prediction model and data relating to MHT use and breast cancer risk taken from research by the Collaborative Group on Hormonal Factors in Breast Cancer. METHOD: The risk of developing and dying from breast cancer between the ages of 50 and 80 years was modelled in women with four different breast cancer family history profiles: 'average', 'modest', 'intermediate', and 'strong' by using 1) background risks of breast cancer by age and family history, 2) relative risks for breast cancer associated with MHT use, and 3) 10-year breast cancer-specific net mortality rates. This study modelled use of combined oestrogen-progestogen MHT (cyclical or continuous) and oestrogen-only MHT. RESULTS: For a woman of 'average' family history taking no MHT, the cumulative breast cancer risk (age 50-80 years) is 9.8%, and the risk of dying from the breast cancer is 1.7%. In this model, 5 years' exposure to combined-cyclical MHT (age 50-55 years) was calculated to increase these risks to 11.0% and 1.8%, respectively. For a woman with a 'strong' family history taking no MHT, the cumulative breast cancer risk is 19.6% (age 50-80 years), and the risk of dying from the breast cancer is 3.2%. With 5 years' exposure to MHT (age 50-55 years), this model showed that these risks increase to 22.4% and 3.5%, respectively. CONCLUSION: In this model, both family history and MHT are associated with increased risk of breast cancer. Estimates of the risks of breast cancer associated with MHT for women with different family histories can be used to support decision making around MHT prescription for women experiencing menopausal symptoms.

Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer.

Importance: Pathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BRIP1 cancer susceptibility genes (CSGs) confer an increased ovarian cancer (OC) risk, with BRCA1, BRCA2, PALB2, RAD51C, and RAD51D PVs also conferring an elevated breast cancer (BC) risk. Risk-reducing surgery, medical prevention, and BC surveillance offer the opportunity to prevent cancers and deaths, but their cost-effectiveness for individual CSGs remains poorly addressed. Objective: To estimate the cost-effectiveness of prevention strategies for OC and BC among individuals carrying PVs in the previously listed CSGs. Design, Setting, and Participants: In this economic evaluation, a decision-analytic Markov model evaluated the cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) and, where relevant, risk-reducing mastectomy (RRM) compared with nonsurgical interventions (including BC surveillance and medical prevention for increased BC risk) from December 1, 2022, to August 31, 2023. The analysis took a UK payer perspective with a lifetime horizon. The simulated cohort consisted of women aged 30 years who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. Appropriate sensitivity and scenario analyses were performed. Exposures: CSG-specific interventions, including RRSO at age 35 to 50 years with or without BC surveillance and medical prevention (ie, tamoxifen or anastrozole) from age 30 or 40 years, RRM at age 30 to 40 years, both RRSO and RRM, BC surveillance and medical prevention, or no intervention. Main Outcomes and Measures: The incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained. OC and BC cases and deaths were estimated. Results: In the simulated cohort of women aged 30 years with no cancer, undergoing both RRSO and RRM was most cost-effective for individuals carrying BRCA1 (RRM at age 30 years; RRSO at age 35 years), BRCA2 (RRM at age 35 years; RRSO at age 40 years), and PALB2 (RRM at age 40 years; RRSO at age 45 years) PVs. The corresponding ICERs were -£1942/QALY (-$2680/QALY), -£89/QALY (-$123/QALY), and £2381/QALY ($3286/QALY), respectively. RRSO at age 45 years was cost-effective for RAD51C, RAD51D, and BRIP1 PV carriers compared with nonsurgical strategies. The corresponding ICERs were £962/QALY ($1328/QALY), £771/QALY ($1064/QALY), and £2355/QALY ($3250/QALY), respectively. The most cost-effective preventive strategy per 1000 PV carriers could prevent 923 OC and BC cases and 302 deaths among those carrying BRCA1; 686 OC and BC cases and 170 deaths for BRCA2; 464 OC and BC cases and 130 deaths for PALB2; 102 OC cases and 64 deaths for RAD51C; 118 OC cases and 76 deaths for RAD51D; and 55 OC cases and 37 deaths for BRIP1. Probabilistic sensitivity analysis indicated both RRSO and RRM were most cost-effective in 96.5%, 89.2%, and 84.8% of simulations for BRCA1, BRCA2, and PALB2 PVs, respectively, while RRSO was cost-effective in approximately 100% of simulations for RAD51C, RAD51D, and BRIP1 PVs. Conclusions and Relevance: In this cost-effectiveness study, RRSO with or without RRM at varying optimal ages was cost-effective compared with nonsurgical strategies for individuals who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. These findings support personalizing risk-reducing surgery and guideline recommendations for individual CSG-specific OC and BC risk management.

Feasibility and acceptability of offering breast cancer risk assessment to general population women aged 30-39 years: a mixed-methods study protocol.

INTRODUCTION: Breast cancer incidence starts to increase exponentially when women reach 30-39 years, hence before they are eligible for breast cancer screening. The introduction of breast cancer risk assessment for this age group could lead to those at higher risk receiving benefits of earlier screening and preventive strategies. Currently, risk assessment is limited to women with a family history of breast cancer only. The Breast CANcer Risk Assessment in Younger women (BCAN-RAY) study is evaluating a comprehensive breast cancer risk assessment strategy for women aged 30-39 years incorporating a questionnaire of breast cancer risk factors, low-dose mammography to assess breast density and polygenic risk. This study will assess the feasibility and acceptability of the BCAN-RAY risk assessment strategy. METHODS AND ANALYSIS: This study involves women undergoing risk assessment as part of the BCAN-RAY case-control study (n=750). They will be aged 30-39 years without a strong family history of breast cancer and invited to participate via general practice. A comparison of uptake rates by socioeconomic status and ethnicity between women who participated in the BCAN-RAY study and women who declined participation will be conducted. All participants will be asked to complete self-report questionnaires to assess key potential harms including increased state anxiety (State Trait Anxiety Inventory), cancer worry (Lerman Cancer Worry Scale) and satisfaction with the decision to participate (Decision Regret Scale), alongside potential benefits such as feeling more informed about breast cancer risk. A subsample of approximately 24 women (12 at average risk and 12 at increased risk) will additionally participate in semistructured interviews to understand the acceptability of the risk assessment strategy and identify any changes needed to it to increase uptake. ETHICS AND DISSEMINATION: Ethical approval was granted by North West-Greater Manchester West Research Ethics Committee (reference: 22/NW/0268). Study results will be disseminated through peer-reviewed journals, conference presentations and charitable organisations. TRIAL REGISTRATION NUMBER: NCT05305963.

Socio-economic burden of TB and its impact on child contacts in The Gambia.

OBJECTIVE: To determine the social impact of adult TB on child household contacts living in the Greater Banjul Area, The Gambia. METHODS: This was a prospective observational cohort study among adults (≥18 years) starting treatment for drug-susceptible pulmonary TB between June 2019 and July 2021 who reported having at least one child household contact. We collected data from 51 adults and 180 child contacts at the start of TB treatment (baseline) and again at 6 months of treatment. Participants were asked about expenses for school fees, healthcare, festivities and food security of child contacts. RESULTS: While school attendance of the child contacts remained largely unaffected, there was a significant drop in school performance at 6 months (P < 0.001). Furthermore, child contacts faced significant food insecurity in terms of food quantity and variety available, with up to a four-fold increase in some instances at 6 months compared to baseline (P < 0.001). CONCLUSION: Child contacts face a potential decline in school performance and risk of food insecurity. While a plethora of work is being undertaken to alleviate costs of care for TB patients, further emphasis is needed to ensure educational and social prosperity for child contacts, as adults with TB have socio-economic implications for the wider household.

OBJECTIF: Déterminer l'impact social de la TB de l'adulte sur les contacts familiaux de l'enfant vivant dans la région du Grand Banjul, en Gambie. MÉTHODES: Il s'agissait d'une étude de cohorte observationnelle prospective auprès d'adultes (≥18 ans) commençant un traitement contre la TB pulmonaire sensible aux médicaments entre juin 2019 et juillet 2021 et qui ont déclaré avoir au moins un contact domestique avec un enfant. Nous avons recueilli des données auprès de 51 adultes et 180 enfants contacts au début du traitement contre la TB, puis à nouveau après 6 mois de traitement. Les participants ont été interrogés sur les dépenses liées aux frais de scolarité, aux soins de santé, aux célébrations et à la sécurité alimentaire des enfants contacts. RÉSULTATS: Alors que la fréquentation scolaire des enfants contacts n'a pratiquement pas été affectée, on a constaté une baisse significative des résultats scolaires 6 mois plus tard (P < 0,001). Par ailleurs, les enfants contacts ont été confrontés à une insécurité alimentaire importante en termes de quantité et de variété de nourriture disponible, avec une augmentation d'au moins quatre fois après le traitement de la TB (P < 0,001). CONCLUSION: Les enfants contacts sont confrontés à une baisse potentielle de leurs résultats scolaires et à un risque d'insécurité alimentaire. Alors qu'une multitude de travaux sont entrepris pour réduire les coûts des soins pour les patients atteints de TB, il est nécessaire de mettre davantage l'accent sur la prospérité éducative et sociale des enfants contacts, étant donné que les adultes atteints de TB ont des implications socio-économiques pour l'ensemble du ménage.

Estimating the Cost of 3 Risk Prediction Strategies for Potential Use in the United Kingdom National Breast Screening Program.

Background: Economic evaluations have suggested that risk-stratified breast cancer screening may be cost-effective but have used assumptions to estimate the cost of risk prediction. The aim of this study was to identify and quantify the resource use and associated costs required to introduce a breast cancer risk-stratification approach into the English national breast screening program. Methods: A micro-costing study, conducted alongside a cohort-based prospective trial (BC-PREDICT), identified the resource use and cost per individual (£; 2021 price year) of providing a risk-stratification strategy at a woman's first mammography. Costs were calculated for 3 risk-stratification approaches: Tyrer-Cuzick survey, Tyrer-Cuzick with Volpara breast-density measurement, and Tyrer-Cuzick with Volpara breast-density measurement and testing for 142 single nucleotide polymorphisms (SNP). Costs were determined for the intervention as implemented in the trial and in the health service. Results: The cost of providing the risk-stratification strategy was calculated to be £16.45 for the Tyrer-Cuzick survey approach, £21.82 for the Tyrer-Cuzick with Volpara breast-density measurement, and £102.22 for the Tyrer-Cuzick with Volpara breast-density measurement and SNP testing. Limitations: This study did not use formal expert elicitation methods to synthesize estimates. Conclusion: The costs of risk prediction using a survey and breast density measurement were low, but adding SNP testing substantially increases costs. Implementation issues present in the trial may also significantly increase the cost of risk prediction. Implications: This is the first study to robustly estimate the cost of risk-stratification for breast cancer screening. The cost of risk prediction using questionnaires and automated breast density measurement was low, but full economic evaluations including accurate costs are required to provide evidence of the cost-effectiveness of risk-stratified breast cancer screening. Highlights: Economic evaluations have suggested that risk-stratified breast cancer screening may be a cost-effective use of resources in the United Kingdom.Current estimates of the cost of risk stratification are based on pragmatic assumptions.This study provides estimates of the cost of risk stratification using 3 strategies and when these strategies are implemented perfectly and imperfectly in the health system.The cost of risk stratification is relatively low unless single nucleotide polymorphisms are included in the strategy.

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2.

BACKGROUND: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. RESULTS: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY. CONCLUSION: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery.

Cost-effectiveness model of renal cell carcinoma (RCC) surveillance in hereditary leiomyomatosis and renal cell carcinoma (HLRCC).

PURPOSE: To determine the cost-effectiveness of annual renal imaging surveillance (RIS) in hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is associated with a 21% risk to age 70 years of RCC. Presentations with advanced renal cell cancer (RCC) are associated with poor outcomes whereas RIS detects early-stage RCC; however, evidence for the cost-effectiveness of RIS is lacking. METHODS: We developed a decision-analytic model to compare, at different age starting points (11 years, 18 years, 40 years, 60 years), the costs and benefits of lifetime contrast-enhanced renal MRI surveillance (CERMRIS) vs no surveillance in HLRCC. Benefits were measured in life-years gained (LYG), quality-adjusted life years (QALYs) and costs in British Pounds Sterling (GBP). Net monetary benefit (NMB) was calculated using a cost-effectiveness threshold of £20 000/QALY. One-way sensitivity and probabilistic analyses were also performed. RESULTS: In the base-case 11-year age cohort, surveillance was cost-effective (Incremental_NMB=£3522 (95% CI -£2747 to £7652); Incremental_LYG=1.25 (95% CI 0.30 to 1.86); Incremental_QALYs=0.29 (95% CI 0.07 to 0.43)] at an additional mean discounted cost of £2185/patient (95% CI £430 to £4144). Surveillance was also cost-effective in other age cohorts and dominated a no surveillance strategy in the 40 year cohort [Incremental_NMB=£12 655 (95% CIs -£709 to £21 134); Incremental_LYG=1.52 (95% CI 0.30 to 2.26); Incremental_QALYs=0.58 (95% CI 0.12 to 0.87) with a cost saving of £965/patient (95% CI -£4202 to £2652). CONCLUSION: Annual CERMRI in HLRCC is cost-effective across age groups modelled.

The household economic burden of drug-susceptible TB diagnosis and treatment in The Gambia.

OBJECTIVE: To determine the costs and catastrophic costs incurred by drug-susceptible (DS) pulmonary TB patients in The Gambia.METHODS: This observational study collected cost and socio-economic data using a micro-costing approach from the household perspective from 244 adult DS-TB patients with pulmonary TB receiving treatment through the national treatment programme in The Gambia. We used data collected between 2017 and 2020 using an adapted version of the WHO generic patient cost survey instrument to estimate costs and the proportion of patients experiencing catastrophic costs (≥20% of household income).RESULTS: The mean total cost of the TB episode was $104.11 (2018 USD). Direct costs were highest before treatment ($22.93). Indirect costs accounted for over 50% of the entire episode costs. Using different income estimation approaches and catastrophic cost thresholds, 0.4-75% of participants encountered catastrophic costs, showing the variability of results given the different assumptions we utilised.CONCLUSIONS: We show that despite the benefits of free TB care and treatment, DS-TB patients still incur substantial direct and indirect costs, and cases of impoverishing expenditure varied vastly depending on the income estimation approaches used.

Implementing Risk-Stratified Breast Screening in England: An Agenda Setting Meeting.

It is now possible to accurately assess breast cancer risk at routine NHS Breast Screening Programme (NHSBSP) appointments, provide risk feedback and offer risk management strategies to women at higher risk. These strategies include National Institute for Health and Care Excellence (NICE) approved additional breast screening and risk-reducing medication. However, the NHSBSP invites nearly all women three-yearly, regardless of risk. In March 2022, a one-day agenda setting meeting took place in Manchester to discuss the feasibility and desirability of implementation of risk-stratified screening in the NHSBSP. Fifty-eight individuals participated (38 face-to-face, 20 virtual) with relevant expertise from academic, clinical and/or policy-making perspectives. Key findings were presented from the PROCAS2 NIHR programme grant regarding feasibility of risk-stratified screening in the NHSBSP. Participants discussed key uncertainties in seven groups, followed by a plenary session. Discussions were audio-recorded and thematically analysed to produce descriptive themes. Five themes were developed: (i) risk and health economic modelling; (ii) health inequalities and communication with women; (iii); extending screening intervals for low-risk women; (iv) integration with existing NHSBSP; and (v) potential new service models. Most attendees expected some form of risk-stratified breast screening to be implemented in England and collectively identified key issues to be resolved to facilitate this.

Opportunities to engage health system leaders in whole systems approaches to physical activity in England.

BACKGROUND: Physical activity plays an important role in maintaining good health and wellbeing, non-communicable disease prevention and can improve healthcare outcomes. Some progress is being made on incorporating physical activity into routine care, but less on engaging health system leaders in the 'whole systems' approaches which are increasingly recognised as important for addressing complex public health challenges such as physical inactivity. This commentary builds upon the findings of a recent study and aims to identify opportunities for engaging National Health Service (NHS) systems leaders in whole systems approaches to physical activity. OPPORTUNITIES FOR ACTION IN ENGLAND: Pockets of good practice exist from which lessons can be learned, but there are systemic issues that discourage and create barriers, and a need for meaningful engagement, leadership and action at national, regional and local levels. National and regional actors like Sport England, NHS England, health professional bodies, Active Partnerships, the Local Government Association and the Office for Health Improvement and Disparities can encourage and support government and the NHS to change policy drivers, culture and practices. Emerging opportunities include the 2021 White Paper Integration and Innovation, development of local integrated care systems, leadership from health charities and investment in non-clinical interventions ('social prescribing'). At local level, public health and physical activity specialists and other organisations have a key role as champions and facilitators of local whole systems approaches and engagement of local NHS leaderships. Finally, although whole systems action is about collaborative leadership, individual champions of physical activity can make a difference in influencing NHS leaders at every level towards whole systems working.

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.

A mismatch in care: results of a United Kingdom-wide patient and clinician survey of gynaecological services for women with Lynch syndrome.

OBJECTIVE: To describe the current testing practice, referral pathways and gynaecological services available to women with Lynch syndrome (LS) in the UK. DESIGN: Cross-sectional nationwide survey of gynaecological oncologists and women with LS. SETTING: United Kingdom. METHODS: Gynaecological oncologists were contacted directly. Women with LS were identified from national and regional clinical databases and the patient support group, Lynch syndrome UK. MAIN OUTCOME MEASURES: Gynaecological oncologists were asked to report rates of LS testing and current practice regarding risk-reducing strategies and gynaecological surveillance for women with LS. Women with LS were asked to describe their experiences of gynaecological care. RESULTS: In total, 41 gynaecological oncologists and 298 women with LS responded to the survey. Of the gynaecological oncologists surveyed, 37% were unfamiliar with any clinical guidelines for the management of LS. Only 29% of gynaecological oncologists supported universal testing of endometrial cancer for LS; one centre routinely performed such testing. In all, 83% said they perform risk-reducing gynaecological surgery and 43% were aware of a local gynaecological surveillance service for women with LS. Of women with LS, most had undergone a hysterectomy (n = 191/64.1%), most frequently to reduce their gynaecological cancer risk (n = 86/45%). A total of 10% were initially referred for LS testing by their gynaecologist and 55% of those eligible regularly attended gynaecological surveillance; however, 62% wanted more regular surveillance. Regional variation was evident across all standards of care. CONCLUSIONS: There is widespread variation in the services offered to women with LS in the UK. As a community, gynaecological oncologists should move towards a nationally agreed provision of services. TWEETABLE ABSTRACT: A mismatch in care for mismatch repair. Survey finds significant variation in gynaecological care for #Lynchsyndrome in the UK.

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.

What are the benefits and harms of risk stratified screening as part of the NHS breast screening Programme? Study protocol for a multi-site non-randomised comparison of BC-predict versus usual screening (NCT04359420).

BACKGROUND: In principle, risk-stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) should produce a better balance of benefits and harms. The main benefit is the offer of NICE-approved more frequent screening and/ or chemoprevention for women who are at increased risk, but are unaware of this. We have developed BC-Predict, to be offered to women when invited to NHSBSP which collects information on risk factors (self-reported information on family history and hormone-related factors via questionnaire; mammographic density; and in a sub-sample, Single Nucleotide Polymorphisms). BC-Predict produces risk feedback letters, inviting women at high risk (≥8% 10-year) or moderate risk (≥5 to < 8% 10-year) to have discussion of prevention and early detection options at Family History, Risk and Prevention Clinics. Despite the promise of systems such as BC-Predict, there are still too many uncertainties for a fully-powered definitive trial to be appropriate or ethical. The present research aims to identify these key uncertainties regarding the feasibility of integrating BC-Predict into the NHSBSP. Key objectives of the present research are to quantify important potential benefits and harms, and identify key drivers of the relative cost-effectiveness of embedding BC-Predict into NHSBSP. METHODS: A non-randomised fully counterbalanced study design will be used, to include approximately equal numbers of women offered NHSBSP (n = 18,700) and BC-Predict (n = 18,700) from selected screening sites (n = 7). In the initial 8-month time period, women eligible for NHSBSP will be offered BC-Predict in four screening sites. Three screening sites will offer women usual NHSBSP. In the following 8-months the study sites offering usual NHSBSP switch to BC-Predict and vice versa. Key potential benefits including uptake of risk consultations, chemoprevention and additional screening will be obtained for both groups. Key potential harms such as increased anxiety will be obtained via self-report questionnaires, with embedded qualitative process analysis. A decision-analytic model-based cost-effectiveness analysis will identify the key uncertainties underpinning the relative cost-effectiveness of embedding BC-Predict into NHSBSP. DISCUSSION: We will assess the feasibility of integrating BC-Predict into the NHSBSP, and identify the main uncertainties for a definitive evaluation of the clinical and cost-effectiveness of BC-Predict. TRIAL REGISTRATION: Retrospectively registered with clinicaltrials.gov (NCT04359420).

Managing multidrug-resistant tuberculosis in South Africa: a budget impact analysis.

SETTING: In South Africa prior to 2016, the standard treatment regimen for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) was 24 months long and required daily injectable aminoglycoside (IA) treatment during the first 6 months. Recent evidence supports the replacement of IA with well-tolerated oral bedaquiline (BDQ) and a shortened 9-12 month regimen.DESIGN: Using a Markov model, we analyzed the 5-year budgetary impact and cost per successful treatment outcome of four regimens: 1) IA long-course, 2) oral long-course, 3) IA short-course, and 4) oral short-course. We used the South African MDR/RR-TB case register (2013-2015) to assess treatment outcomes for the then-standard IA long-course. Data on the improvement in outcomes for BDQ-based regimens were based on the literature. Costs were estimated from the provider perspective using costs incurred to provide decentralized treatment for MDR-TB at a Johannesburg hospital.RESULTS: Based on our analysis, by 2023, the cost/successful outcome for the four regimens was respectively 1) US$7374, 2) US$7860, 3) US$5149, and 4) US$4922. The annual total cost of each regimen was US$37 million, US$43 million, US$26 million, and US$28 million.CONCLUSION: Despite the high cost of BDQ, a BDQ-based shortened regimen for the treatment of MDR/RR-TB will result in improved treatment outcomes and cost savings for South Africa.

Li-Fraumeni Exploration Consortium Data Coordinating Center: Building an Interactive Web-Based Resource for Collaborative International Cancer Epidemiology Research for a Rare Condition.

BACKGROUND: The success of multisite collaborative research relies on effective data collection, harmonization, and aggregation strategies. Data Coordination Centers (DCC) serve to facilitate the implementation of these strategies. The utility of a DCC can be particularly relevant for research on rare diseases where collaboration from multiple sites to amass large aggregate datasets is essential. However, approaches to building a DCC have been scarcely documented. METHODS: The Li-Fraumeni Exploration (LiFE) Consortium's DCC was created using multiple open source packages, including LAM/G Application (Linux, Apache, MySQL, Grails), Extraction-Transformation-Loading (ETL) Pentaho Data Integration Tool, and the Saiku-Mondrian client. This document serves as a resource for building a rare disease DCC for multi-institutional collaborative research. RESULTS: The primary scientific and technological objective to create an online central repository into which data from all participating sites could be deposited, harmonized, aggregated, disseminated, and analyzed was completed. The cohort now include 2,193 participants from six contributing sites, including 1,354 individuals from families with a pathogenic or likely variant in TP53. Data on cancer diagnoses are also available. Challenges and lessons learned are summarized. CONCLUSIONS: The methods leveraged mitigate challenges associated with successfully developing a DCC's technical infrastructure, data harmonization efforts, communications, and software development and applications. IMPACT: These methods can serve as a framework in establishing other collaborative research efforts. Data from the consortium will serve as a great resource for collaborative research to improve knowledge on, and the ability to care for, individuals and families with Li-Fraumeni syndrome.