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.

Patient decision aids in mainstreaming genetic testing for women with ovarian cancer: A prospective cohort study.

OBJECTIVE: To evaluate patient preference for short (gist) or detailed/extensive decision aids (DA) for genetic testing at ovarian cancer (OC) diagnosis. DESIGN: Cohort study set within recruitment to the Systematic Genetic Testing for Personalised Ovarian Cancer Therapy (SIGNPOST) study (ISRCTN: 16988857). SETTING: North-East London Cancer Network (NELCN) population. POPULATION/SAMPLE: Women with high-grade non-mucinous epithelial OC. METHODS: A more detailed DA was developed using patient and stakeholder input following the principles/methodology of IPDAS (International Patients Decision Aids Standards). Unselected patients attending oncology clinics evaluated both a pre-existing short and a new long DA version and then underwent mainstreaming genetic testing by a cancer clinician. Appropriate inferential descriptive and regression analyses were undertaken. MAIN OUTCOME MEASURES: Satisfaction, readability, understanding, emotional well-being and preference for long/short DA. RESULTS: The mean age of patients was 66 years (interquartile range 11), and 85% were White British ethnicity. Of the participants, 74% found DAs helpful/useful in decision-making. Women reported higher levels of satisfaction (86% versus 58%, p < 0.001), right amount of information provided (76.79% versus49.12%, p < 0.001) and improved understanding (p < 0.001) with the long DA compared with the short DA. There was no statistically significant difference in emotional outcomes (feeling worried/concerned/reassured/upset) between 'short' and 'long' DA; 74% of patients preferred the long DA and 24% the short DA. Patients undergoing treatment (correlation coefficient (coef) = 0.603; 95% CI 0.165-1.041, p = 0.007), those with recurrence (coef = 0.493; 95% CI 0.065-0.92, p = 0.024) and older women (coef = 0.042; 95% CI 0.017-0.066, p = 0.001) preferred the short DA. Ethnicity did not affect outcomes or overall preference for long/short DA. CONCLUSIONS: A longer DA in OC patients has higher satisfaction without increasing emotional distress. Older women and those undergoing treatment/recurrence prefer less extensive information, whereas those in remission preferred a longer DA.

Quality of life after risk-reducing surgery for breast and ovarian cancer prevention: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the impact of risk-reducing surgery for breast cancer and ovarian cancer prevention on quality of life. We considered risk-reducing mastectomy, risk-reducing salpingo-oophorectomy, and risk-reducing early salpingectomy and delayed oophorectomy. DATA SOURCES: We followed a prospective protocol (International Prospective Register of Systematic Reviews: CRD42022319782) and searched MEDLINE, Embase, PubMed, and Cochrane Library from inception to February 2023. STUDY ELIGIBILITY CRITERIA: We followed a PICOS (population, intervention, comparison, outcome, and study design) framework. The population included women at increased risk of breast cancer or ovarian cancer. We focused on studies reporting quality of life outcomes (health-related quality of life, sexual function, menopause symptoms, body image, cancer-related distress or worry, anxiety, or depression) after risk-reducing surgery, including risk-reducing mastectomy for breast cancer and risk-reducing salpingo-oophorectomy or risk-reducing early salpingectomy and delayed oophorectomy for ovarian cancer. METHODS: We used the Methodological Index for Non-Randomized Studies (MINORS) for study appraisal. Qualitative synthesis and fixed-effects meta-analysis were performed. RESULTS: A total of 34 studies were included (risk-reducing mastectomy: 16 studies; risk-reducing salpingo-oophorectomy: 19 studies; risk-reducing early salpingectomy and delayed oophorectomy: 2 studies). Health-related quality of life was unchanged or improved in 13 of 15 studies after risk-reducing mastectomy (N=986) and 10 of 16 studies after risk-reducing salpingo-oophorectomy (N=1617), despite short-term deficits (N=96 after risk-reducing mastectomy and N=459 after risk-reducing salpingo-oophorectomy). Sexual function (using the Sexual Activity Questionnaire) was affected in 13 of 16 studies (N=1400) after risk-reducing salpingo-oophorectomy in terms of decreased sexual pleasure (-1.21 [-1.53 to -0.89]; N=3070) and increased sexual discomfort (1.12 [0.93-1.31]; N=1400). Hormone replacement therapy after premenopausal risk-reducing salpingo-oophorectomy was associated with an increase (1.16 [0.17-2.15]; N=291) in sexual pleasure and a decrease (-1.20 [-1.75 to -0.65]; N=157) in sexual discomfort. Sexual function was affected in 4 of 13 studies (N=147) after risk-reducing mastectomy, but stable in 9 of 13 studies (N=799). Body image was unaffected in 7 of 13 studies (N=605) after risk-reducing mastectomy, whereas 6 of 13 studies (N=391) reported worsening. Increased menopause symptoms were reported in 12 of 13 studies (N=1759) after risk-reducing salpingo-oophorectomy with a reduction (-1.96 [-2.81 to -1.10]; N=1745) in the Functional Assessment of Cancer Therapy - Endocrine Symptoms. Cancer-related distress was unchanged or decreased in 5 of 5 studies after risk-reducing mastectomy (N=365) and 8 of 10 studies after risk-reducing salpingo-oophorectomy (N=1223). Risk-reducing early salpingectomy and delayed oophorectomy (2 studies, N=413) led to better sexual function and menopause-specific quality of life. CONCLUSION: Risk-reducing surgery may be associated with quality of life outcomes. Risk-reducing mastectomy and risk-reducing salpingo-oophorectomy reduce cancer-related distress, and do not affect health-related quality of life. Women and clinicians should be aware of body image problems after risk-reducing mastectomy, and of sexual dysfunction and menopause symptoms after risk-reducing salpingo-oophorectomy. Risk-reducing early salpingectomy and delayed oophorectomy may be a promising alternative to mitigate quality of life-related risks of risk-reducing salpingo-oophorectomy.

The Evolving Nature of Health Technology Assessment: A Critical Appraisal of NICE's New Methods Manual.

OBJECTIVES: The National Institute for Health and Care Excellence (NICE) recently completed a review of its methods for health technology assessment, involving a 2-stage public consultation. We appraise proposed methodological changes and analyze key decisions. METHODS: We categorize all changes proposed in the first consultation as "critical," "moderate" or "limited" updates, considering the importance of the topic and the degree of change or the level of reinforcement. Proposals were followed through the review process, for their inclusion, exclusion, or amendment in the second consultation and the new manual. RESULTS: The end-of-life value modifier was replaced with a new "disease severity" modifier and other potential modifiers were rejected. The usefulness of a comprehensive evidence base was emphasized, clarifying when nonrandomized studies can be used, with further guidance on "real-world" evidence developed separately. A greater degree of uncertainty was accepted in circumstances when evidence generation raised challenges, in particular for children, rare diseases, and innovative technologies. For some topics, such as health inequality, discounting, unrelated healthcare costs, and value of information, significant changes were possibly warranted, but NICE decided not to make any revisions at present. CONCLUSION: Most of the changes to NICE's health technology assessment methods are appropriate and modest in impact. Nevertheless, some decisions were not well justified and further research is needed on several topics, including investigation of societal preferences. Ultimately, NICE's role of protecting National Health Services resources for valuable interventions that can contribute toward improving overall population health must be safeguarded, without accepting weaker evidence.

Surgical decision making in premenopausal BRCA carriers considering risk-reducing early salpingectomy or salpingo-oophorectomy: a qualitative study.

BACKGROUND: Acceptance of the role of the fallopian tube in 'ovarian' carcinogenesis and the detrimental sequelae of surgical menopause in premenopausal women following risk-reducing salpingo-oophorectomy (RRSO) has resulted in risk-reducing early-salpingectomy with delayed oophorectomy (RRESDO) being proposed as an attractive alternative risk-reducing strategy in women who decline/delay oophorectomy. We present the results of a qualitative study evaluating the decision-making process among BRCA carriers considering prophylactic surgeries (RRSO/RRESDO) as part of the multicentre PROTECTOR trial (ISRCTN:25173360). METHODS: In-depth semistructured 1:1 interviews conducted using a predeveloped topic-guide (development informed by literature review and expert consultation) until informational saturation reached. Wording and sequencing of questions were left open with probes used to elicit additional information. All interviews were audio-recorded, transcribed verbatim, transcripts analysed using an inductive theoretical framework and data managed using NVIVO-v12. RESULTS: Informational saturation was reached following 24 interviews. Seven interconnected themes integral to surgical decision making were identified: fertility/menopause/cancer risk reduction/surgical choices/surgical complications/sequence of ovarian-and-breast prophylactic surgeries/support/satisfaction. Women for whom maximising ovarian cancer risk reduction was relatively more important than early menopause/quality-of-life preferred RRSO, whereas those more concerned about detrimental impact of menopause chose RRESDO. Women managed in specialist familial cancer clinic settings compared with non-specialist settings felt they received better quality care, improved hormone replacement therapy access and were more satisfied. CONCLUSION: Multiple contextual factors (medical, physical, psychological, social) influence timing of risk-reducing surgeries. RRESDO offers women delaying/declining premenopausal oophorectomy, particularly those concerned about menopausal effects, a degree of ovarian cancer risk reduction while avoiding early menopause. Care of high-risk women should be centralised to centres with specialist familial gynaecological cancer risk management services to provide a better-quality, streamlined, holistic multidisciplinary approach.

Randomised trial of population-based BRCA testing in Ashkenazi Jews: long-term secondary lifestyle behavioural outcomes.

OBJECTIVE: Ashkenazi-Jewish (AJ) population-based BRCA testing is acceptable, cost-effective and amplifies primary prevention for breast & ovarian cancer. However, data describing lifestyle impact are lacking. We report long-term results of population-based BRCA testing on lifestyle behaviour and cancer risk perception. DESIGN: Two-arm randomised controlled trials (ISRCTN73338115, GCaPPS): (a) population-screening (PS); (b) family history (FH)/clinical criteria testing. SETTING: North London AJ-population. POPULATION/SAMPLE: AJ women/men >18 years. EXCLUSIONS: prior BRCA testing or first-degree relatives of BRCA-carriers. METHODS: Participants were recruited through self-referral. All participants received informed pre-test genetic counselling. The intervention included genetic testing for three AJ BRCA-mutations: 185delAG(c.68_69delAG), 5382insC(c.5266dupC) and 6174delT(c.5946delT). This was undertaken for all participants in the PS arm and participants fulfilling FH/clinical criteria in the FH arm. Patients filled out customised/validated questionnaires at baseline/1-year/2-year/3-year follow-ups. Generalised linear-mixed models adjusted for covariates and appropriate contrast tests were used for between-group/within-group analysis of lifestyle and behavioural outcomes along with evaluating factors associated with these outcomes. Outcomes are adjusted for multiple testing (Bonferroni method), with P < 0.0039 considered significant. OUTCOME MEASURES: Lifestyle/behavioural outcomes at baseline/1-year/2-year/3-year follow-ups. RESULTS: 1034 participants were randomised to PS (n = 530) or FH (n = 504) arms. No significant difference was identified between PS- and FH-based BRCA testing approaches in terms of dietary fruit/vegetable/meat consumption, vitamin intake, alcohol quantity/ frequency, smoking behaviour (frequency/cessation), physical activity/exercise or routine breast mammogram screening behaviour, with outcomes not affected by BRCA test result. Cancer risk perception decreased with time following BRCA testing, with no difference between FH/PS approaches, and the perception of risk was lowest in BRCA-negative participants. Men consumed fewer fruits/vegetables/vitamins and more meat/alcohol than women (P < 0.001). CONCLUSION: Population-based and FH-based AJ BRCA testing have similar long-term lifestyle impacts on smoking, alcohol, dietary fruit/vegetable/meat/vitamin, exercise, breast screening participation and reduced cancer risk perception.

Cost-Utility Analysis of a Complex Intervention to Reduce School-Based Bullying and Aggression: An Analysis of the Inclusive RCT.

OBJECTIVES: Bullying and aggression among children and young people are key public mental health priorities. In this study, we evaluated the cost-effectiveness of a complex school-based intervention to address these outcomes within a large-cluster randomized trial (Inclusive). METHODS: Forty state secondary schools were randomly allocated (1:1) to receive the intervention or continue with current practice as controls. Data were collected using paper questionnaires completed in classrooms including measures of their health-related quality of life using the Childhood Utility Index and police and National Health Service resource use. Further detailed data were collected on the cost of delivering the intervention. We calculated incremental cost-effectiveness ratios following the intention-to-treat principle using multilevel linear regression models that allowed for clustering of pupils at the school level. RESULTS: Overall, we found that the intervention was highly cost-effective, with cost-per quality-adjusted life year thresholds of £13 284 and £1875 at 2 years and 3 years, respectively. Analysis of uncertainty in the result at 2 years revealed a 65% chance of being cost-effective, but after 3 years there was a 90% chance that it was cost-effective. CONCLUSION: This study provides strong evidence collected prospectively from a randomized study that this school-based intervention is highly cost-effective. Education- and health-sector policy makers should consider investment in scaling up this intervention.

Preventing Ovarian Cancer through early Excision of Tubes and late Ovarian Removal (PROTECTOR): protocol for a prospective non-randomised multi-center trial.

BACKGROUND: Risk-reducing salpingo-oophorectomy is the 'gold standard' for preventing tubo-ovarian cancer in women at increased risk. However, when performed in pre-menopausal women, it results in premature menopause and associated detrimental health consequences. This, together with acceptance of the central role of the fallopian tube in etiopathogenesis of high-grade serous carcinoma, by far the most common type of tubo-ovarian cancer, has led to risk-reducing early salpingectomy with delayed oophorectomy being proposed as a two-step surgical alternative for pre-menopausal women declining/delaying oophorectomy. PRIMARY OBJECTIVE: To evaluate the impact on sexual function of risk-reducing early salpingectomy, within a two-step, risk-reducing, early salpingectomy with delayed oophorectomy tubo-ovarian cancer prevention strategy in pre-menopausal women at increased risk of tubo-ovarian cancer. STUDY HYPOTHESIS: Risk-reducing early salpingectomy is non-inferior for sexual and endocrine function compared with controls; risk-reducing early salpingectomy is superior for sexual/endocrine function, non-inferior for quality-of-life, and equivalent in satisfaction to the standard risk-reducing salpingo-oophorectomy. TRIAL DESIGN: Multi-center, observational cohort trial with three arms: risk-reducing early salpingectomy with delayed oophorectomy; risk-reducing salpingo-oophorectomy; controls (no surgery). Consenting individuals undergo an ultrasound, serum CA125, and follicle-stimulating hormone measurements and provide information on medical history, family history, quality-of-life, sexual function, cancer worry, psychological well-being, and satisfaction/regret. Follow-up by questionnaire takes place annually for 3 years. Women receiving risk-reducing early salpingectomy can undergo delayed oophorectomy at a later date of their choosing, or definitely by the menopause. MAJOR INCLUSION/EXCLUSION CRITERIA: Inclusion criteria: pre-menopausal; aged >30 years; at increased risk of tubo-ovarian cancer (mutation carriers or on the basis of a strong family history); completed their family (for surgical arms). EXCLUSION CRITERIA: post-menopausal; previous bilateral salpingectomy or bilateral oophorectomy; pregnancy; previous tubal/ovarian/peritoneal malignancy; <12 months after cancer treatment; clinical suspicion of tubal/ovarian cancer at baseline. PRIMARY ENDPOINT: Sexual function measured by validated questionnaires. SAMPLE SIZE: 1000 (333 per arm). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: It is estimated recruitment will be completed by 2023 and results published by 2027. TRIAL REGISTRATION NUMBER: ISRCTN registry: 25 173 360 (https://doi.org/10.1186/ISRCTN25173360).

Costs of Early Invasive Breast Cancer in England Using National Patient-Level Data.

OBJECTIVES: This study aimed to use patient-level data to provide up-to-date estimates of early invasive breast cancer care costs by stage in England and to explore to what extent these costs varied based on patients' ages and geographic regions. METHODS: This study identified women aged 50 years and older who had been diagnosed with early invasive breast cancer between January 1, 2014, and December 31, 2015, using linked cancer registrations and routine hospital data sets generated from the usual care for all National Health Service trusts in England. Cost estimates were derived from hospital records in Hospital Episodes Statistics with additional chemotherapy and radiotherapy information from the national data sets. We fitted general linear regression models to analyze the cost data. The model that best fit the data was selected using the model selection criteria of Akaike information criterion. RESULTS: 55 662 women with early invasive breast cancer in England were included. The generalized linear model with log-gamma distribution fit the data best. The costs of breast cancer care for 1 year after diagnosis were strongly dependent on stage at diagnosis, controlling for other covariates. The estimated average per-patient hospital-related costs were £5167 at stage I, £7613 at stage II, and £13 330 at stage IIIA. Costs decreased with increasing age (P < .001) and varied across region (P < .001), deprivation level (P < .001), referral source (P < .01), presence of comorbidities (P< .001), and tumor receptor (ER/PR/HER2) status (P < .001). CONCLUSIONS: In England, the costs of breast cancer care increased with advancing stage of the disease at diagnosis. Breast cancer costs varied by age and geographic region.

Cost-effectiveness of breast cancer screening programme for women in rural China.

In low and middle-income countries mammographic breast cancer screening is prohibitively expensive and a cheaper alternative option is to use ultrasound as the primary screening test. In 2009, China launched a breast cancer screening programme for rural women aged 35-64 years with clinical breast examination coupled with ultrasound as the primary tool. Our study aimed to analyse the cost-effectiveness of breast screening compared to no screening among Chinese rural women. We developed a Markov model to estimate the lifetime costs and effects for rural women aged 35 years from a societal perspective. Asymptomatic women in the intervention arm were screened every 3 years before age 64 years. Breast cancer in the non-screening arm can only be diagnosed on presentation of symptoms. Parameter uncertainty was explored using one-way and probabilistic sensitivity analyses. Compared to no screening, breast cancer screening cost $186.7 more and led to a loss of 0.20 quality-adjusted life years (QALYs). Breast screening was more expensive and did harm to health among rural women with an incremental cost-effectiveness ratio (ICER) of $-916/QALY. The sensitivity analysis identified utility loss from false positives as the factor that most influenced the results, but this did not affect the conclusions. In a rural setting with such low breast cancer incidence, screening for asymptomatic disease is not cost-effective with current screening tools. Priority should be given to ensure that symptomatic women have proper access to diagnosis and treatment at an early stage as this will lead to mortality reductions without the usual screening harms.

Effects of the Learning Together intervention on bullying and aggression in English secondary schools (INCLUSIVE): a cluster randomised controlled trial.

BACKGROUND: Bullying, aggression, and violence among children and young people are some of the most consequential public mental health problems. We tested the Learning Together intervention, which involved students in efforts to modify their school environment using restorative practice and by developing social and emotional skills. METHODS: We did a cluster randomised trial, with economic and process evaluations, of the Learning Together intervention compared with standard practice (controls) over 3 years in secondary schools in south-east England. Learning Together consisted of staff training in restorative practice; convening and facilitating a school action group; and a student social and emotional skills curriculum. Primary outcomes were self-reported experience of bullying victimisation (Gatehouse Bullying Scale; GBS) and perpetration of aggression (Edinburgh Study of Youth Transitions and Crime (ESYTC) school misbehaviour subscale) measured at 36 months. We analysed data using intention-to-treat longitudinal mixed-effects models. This trial was registered with the ISRCTN registry (10751359). FINDINGS: We included 40 schools (20 in each group); no schools withdrew. 6667 (93·6%) of 7121 students participated at baseline and 5960 (83·3%) of 7154 at 36 months. Mean GBS bullying score at 36 months was 0·34 (SE 0·02) in the control group versus 0·29 (SE 0·02) in the intervention group, with a significant adjusted mean difference (-0·03, 95% CI -0·06 to -0·001; adjusted effect size -0·08). Mean ESYTC score at 36 months was 4·33 (SE 0·20) in the control group versus 4·04 (0·21) in the intervention group, with no evidence of a difference between groups (adjusted difference -0·13, 95% CI -0·43 to 0·18; adjusted effect size -0·03). Costs were an additional £58 per pupil in intervention schools than in control schools. INTERPRETATION: Learning Together had small but significant effects on bullying, which could be important for public health, but no effect on aggression. Interventions to promote student health by modifying the whole-school environment are likely to be one of the most feasible and efficient ways of addressing closely related risk and health outcomes in children and young people. FUNDING: National Institute for Health Research, Educational Endowment Foundation.

Current detection rates and time-to-detection of all identifiable BRCA carriers in the Greater London population.

BACKGROUND: BRCA carrier identification offers opportunities for early diagnoses, targeted treatment and cancer prevention. We evaluate BRCA- carrier detection rates in general and Ashkenazi Jewish (AJ) populations across Greater London and estimate time-to-detection of all identifiable BRCA carriers. METHODS: BRCA carrier data from 1993 to 2014 were obtained from National Health Service genetic laboratories and compared with modelled predictions of BRCA prevalence from published literature and geographical data from UK Office for National Statistics. Proportion of BRCA carriers identified was estimated. Prediction models were developed to fit BRCA detection rate data. BRCA carrier identification rates were evaluated for an 'Angelina Jolie effect'. Maps for four Greater London regions were constructed, and their relative BRCA detection rates were compared. Models developed were used to predict future time-to-identify all detectable BRCA carriers in AJ and general populations. RESULTS: Until 2014, only 2.6% (3072/111 742 estimated) general population and 10.9% (548/4985 estimated) AJ population BRCA carriers have been identified in 16 696 608 (AJ=190 997) Greater London population. 57% general population and 54% AJ mutations were identified through cascade testing. Current detection rates mirror linear fit rather than parabolic model and will not identify all BRCA carriers. Addition of unselected ovarian/triple-negative breast cancer testing would take >250 years to identify all BRCA carriers. Doubling current detection rates can identify all 'detectable' BRCA carriers in the general population by year 2181, while parabolic and triple linear rates can identify 'detectable' BRCA carriers by 2084 and 2093, respectively. The linear fit model can identify 'detectable' AJ carriers by 2044. We did not find an Angelina Jolie effect on BRCA carrier detection rates. There was a significant difference in BRCA detection rates between geographical regions over time (P<0.001). CONCLUSIONS: The majority of BRCA carriers have not been identified, missing key opportunities for prevention/earlier diagnosis. Enhanced and new strategies/approaches are needed.

Economic burden of HIV and TB/HIV coinfection in a middle-income country: a costing analysis alongside a pragmatic clinical trial in Brazil.

OBJECTIVE: The objective of this study was to measure the costs of people living with HIV (PLHIV) as well as active tuberculosis (TB/HIV), latent tuberculosis infection (LTBI/HIV) or without TB (HIV/AIDS). METHODS: We analysed the costs through the entire pathway of care during the prediagnosis and treatment periods from the Brazilian public health system perspective. We applied a combination of bottom-up and top-down approaches to capture and estimate direct medical and non-medical costs. We measured the mean cost per patient per type of care (inpatient, outpatient and emergency care) and disease category (HIV/AIDS, HIV/AIDS death, TB/HIV, TB/HIV death and LTBI/HIV). RESULTS: Between March 2014 and March 2016 we recruited 239 PLHIV. During the follow-up 26 patients were diagnosed and treated for TB and 5 received chemoprophylaxis for LTBI. During the prediagnosis and treatment period, the mean total costs for HIV or AIDS and AIDS death categories were US$1558 and US$2828, respectively. The mean total costs for TB/HIV and TB/HIV death categories were US$5289.0 and US$8281, respectively. The mean total cost for the LTBI/HIV category was US$882. CONCLUSIONS: Patients with TB/HIV impose a higher economic burden on the health system than HIV/AIDS and LTBI/HIV. Patients with LTBI/HIV were the lowest cost group among all disease categories, indicating that preventive TB treatment can avoid the further costs treating active TB. TRIAL REGISTRATION NUMBER: RBR-22t943, Results.

Cost-effectiveness of risk-based breast cancer screening programme, China.

OBJECTIVE: To model the cost-effectiveness of a risk-based breast cancer screening programme in urban China, launched in 2012, compared with no screening. METHODS: We developed a Markov model to estimate the lifetime costs and effects, in terms of quality-adjusted life years (QALYs), of a breast cancer screening programme for high-risk women aged 40-69 years. We derived or adopted age-specific incidence and transition probability data, assuming a natural history progression between the stages of cancer, from other studies. We obtained lifetime direct and indirect treatment costs in 2014 United States dollars (US$) from surveys of breast cancer patients in 37 Chinese hospitals. To calculate QALYs, we derived utility scores from cross-sectional patient surveys. We evaluated incremental cost-effectiveness ratios for various scenarios for comparison with a willingness-to-pay threshold. FINDINGS: Our baseline model of annual screening yielded an incremental cost-effectiveness ratio of US$ 8253/QALY, lower than the willingness-to-pay threshold of US$ 23 050/QALY. One-way and probabilistic sensitivity analyses demonstrated that the results are robust. In the exploration of various scenarios, screening every 3 years is the most cost-effective with an incremental cost-effectiveness ratio of US$ 6671/QALY. The cost-effectiveness of the screening is reduced if not all diagnosed women seek treatment. Finally, the economic benefit of screening women aged 45-69 years with both ultrasound and mammography, compared with mammography alone, is uncertain. CONCLUSION: High-risk population-based breast cancer screening is cost-effective compared with no screening.

Cost effectiveness of population based BRCA1 founder mutation testing in Sephardi Jewish women.

BACKGROUND: Population-based BRCA1/BRCA2 founder-mutation testing has been demonstrated as cost effective compared with family history based testing in Ashkenazi Jewish women. However, only 1 of the 3 Ashkenazi Jewish BRCA1/BRCA2 founder mutations (185delAG[c.68_69delAG]), 5382insC[c.5266dupC]), and 6174delT[c.5946delT]) is found in the Sephardi Jewish population (185delAG[c.68_69delAG]), and the overall prevalence of BRCA mutations in the Sephardi Jewish population is accordingly lower (0.7% compared with 2.5% in the Ashkenazi Jewish population). Cost-effectiveness analyses of BRCA testing have not previously been performed at these lower BRCA prevalence levels seen in the Sephardi Jewish population. Here we present a cost-effectiveness analysis for UK and US populations comparing population testing with clinical criteria/family history-based testing in Sephardi Jewish women. STUDY DESIGN: A Markov model was built comparing the lifetime costs and effects of population-based BRCA1 testing, with testing using family history-based clinical criteria in Sephardi Jewish women aged ≥30 years. BRCA1 carriers identified were offered magnetic resonance imaging/mammograms and risk-reducing surgery. Costs are reported at 2015 prices. Outcomes include breast cancer, ovarian cancer, and excess deaths from heart disease. All costs and outcomes are discounted at 3.5%. The time horizon is lifetime, and perspective is payer. The incremental cost-effectiveness ratio per quality-adjusted life-year was calculated. Parameter uncertainty was evaluated through 1-way and probabilistic sensitivity analysis. RESULTS: Population testing resulted in gain in life expectancy of 12 months (quality-adjusted life-year = 1.00). The baseline discounted incremental cost-effectiveness ratio for UK population-based testing was £67.04/quality-adjusted life-year and for US population was $308.42/quality-adjusted life-year. Results were robust in the 1-way sensitivity analysis. The probabilistic sensitivity analysis showed 100% of simulations were cost effective at £20,000/quality-adjusted life-year UK and the $100,000/quality-adjusted life-year US willingness-to-pay thresholds. Scenario analysis showed that population testing remains cost effective in UK and US populations, even if premenopausal oophorectomy does not reduce breast cancer risk or if hormone replacement therapy compliance is nil. CONCLUSION: Population-based BRCA1 testing is highly cost effective compared with clinical criteria-driven approach in Sephardi Jewish women. This supports changing the paradigm to population-based BRCA testing in the Jewish population, regardless of Ashkenazi/Sephardi ancestry.

Cost of Tuberculosis Diagnosis and Treatment in Patients with HIV: A Systematic Literature Review.

OBJECTIVES: To summarize the costs of tuberculosis (TB) diagnosis and treatment in human immunodeficiency virus (HIV)-infected patients and to assess the methodological quality of these studies. METHODS: We included cost, cost-effectiveness, and cost-utility studies that reported primary costing data, conducted worldwide and published between 1990 and August 2016. We retrieved articles in PubMed, Embase, EconLit, CINAHL plus, and LILACS databases. The quality assessment was performed using two guidelines-the Consolidated Health Economic Evaluation Reporting Standards and the Tool to Estimate Patient's Costs. TB diagnosis was reported as cost per positive result or per suspect case. TB treatment was reported as cost of TB drugs, TB/HIV hospitalization, and treatment. We analyzed the data per level of TB/HIV endemicity and perspective of analysis. RESULTS: We included 34 articles, with 24 addressing TB/HIV treatment and 10 addressing TB diagnosis. Most of the studies were carried out in high TB/HIV burden countries (82%). The cost of TB diagnosis per suspect case varied from $0.5 for sputum smear microscopy to $175 for intensified case finding. The cost of TB/HIV hospitalization was higher in low/medium TB/HIV burden countries than in high TB/HIV burden countries ($75,406 vs. $2,474). TB/HIV co-infection presented higher costs than TB from the provider perspective ($814 vs. $604 vs. $454). Items such as "choice of discount rate," "patient interview procedures," and "methods used for valuing indirect costs" did not achieve a good score in the quality assessment. CONCLUSIONS: Our findings point to the need of generation of more standardized methods for cost data collection to generate more robust estimates and thus, support decision-making process.

Cost-effectiveness of population based BRCA testing with varying Ashkenazi Jewish ancestry.

BACKGROUND: Population-based BRCA1/BRCA2 testing has been found to be cost-effective compared with family history-based testing in Ashkenazi-Jewish women were >30 years old with 4 Ashkenazi-Jewish grandparents. However, individuals may have 1, 2, or 3 Ashkenazi-Jewish grandparents, and cost-effectiveness data are lacking at these lower BRCA prevalence estimates. We present an updated cost-effectiveness analysis of population BRCA1/BRCA2 testing for women with 1, 2, and 3 Ashkenazi-Jewish grandparents. STUDY DESIGN: Decision analysis model. METHODS: Lifetime costs and effects of population and family history-based testing were compared with the use of a decision analysis model. 56% BRCA carriers are missed by family history criteria alone. Analyses were conducted for United Kingdom and United States populations. Model parameters were obtained from the Genetic Cancer Prediction through Population Screening trial and published literature. Model parameters and BRCA population prevalence for individuals with 3, 2, or 1 Ashkenazi-Jewish grandparent were adjusted for the relative frequency of BRCA mutations in the Ashkenazi-Jewish and general populations. Incremental cost-effectiveness ratios were calculated for all Ashkenazi-Jewish grandparent scenarios. Costs, along with outcomes, were discounted at 3.5%. The time horizon of the analysis is "life-time," and perspective is "payer." Probabilistic sensitivity analysis evaluated model uncertainty. RESULTS: Population testing for BRCA mutations is cost-saving in Ashkenazi-Jewish women with 2, 3, or 4 grandparents (22-33 days life-gained) in the United Kingdom and 1, 2, 3, or 4 grandparents (12-26 days life-gained) in the United States populations, respectively. It is also extremely cost-effective in women in the United Kingdom with just 1 Ashkenazi-Jewish grandparent with an incremental cost-effectiveness ratio of £863 per quality-adjusted life-years and 15 days life gained. Results show that population-testing remains cost-effective at the £20,000-30000 per quality-adjusted life-years and $100,000 per quality-adjusted life-years willingness-to-pay thresholds for all 4 Ashkenazi-Jewish grandparent scenarios, with ≥95% simulations found to be cost-effective on probabilistic sensitivity analysis. Population-testing remains cost-effective in the absence of reduction in breast cancer risk from oophorectomy and at lower risk-reducing mastectomy (13%) or risk-reducing salpingo-oophorectomy (20%) rates. CONCLUSION: Population testing for BRCA mutations with varying levels of Ashkenazi-Jewish ancestry is cost-effective in the United Kingdom and the United States. These results support population testing in Ashkenazi-Jewish women with 1-4 Ashkenazi-Jewish grandparent ancestry.

Specifying the ovarian cancer risk threshold of 'premenopausal risk-reducing salpingo-oophorectomy' for ovarian cancer prevention: a cost-effectiveness analysis.

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is the most effective intervention to prevent ovarian cancer (OC). It is only available to high-risk women with >10% lifetime OC risk. This threshold has not been formally tested for cost-effectiveness. OBJECTIVE: To specify the OC risk thresholds for RRSO being cost-effective for preventing OC in premenopausal women. METHODS: The costs as well as effects of surgical prevention ('RRSO') were compared over a lifetime with 'no RRSO' using a decision analysis model. RRSO was undertaken in premenopausal women >40 years. The model was evaluated at lifetime OC risk levels: 2%, 4%, 5%, 6%, 8% and 10%. Costs and outcomes are discounted at 3.5%. Uncertainty in the model was assessed using both deterministic sensitivity analysis and probabilistic sensitivity analysis (PSA). Outcomes included in the analyses were OC, breast cancer (BC) and additional deaths from coronary heart disease. Total costs and effects were estimated in terms of quality-adjusted life-years (QALYs); incidence of OC and BC; as well as incremental cost-effectiveness ratio (ICER). DATA SOURCES: Published literature, Nurses Health Study, British National Formulary, Cancer Research UK, National Institute for Health and Care Excellence guidelines and National Health Service reference costs. The time horizon is lifetime and perspective: payer. RESULTS: Premenopausal RRSO is cost-effective at 4% OC risk (life expectancy gained=42.7 days, ICER=£19 536/QALY) with benefits largely driven by reduction in BC risk. RRSO remains cost-effective at >8.2% OC risk without hormone replacement therapy (ICER=£29 071/QALY, life expectancy gained=21.8 days) or 6%if BC risk reduction=0 (ICER=£27 212/QALY, life expectancy gained=35.3 days). Sensitivity analysis indicated results are not impacted much by costs of surgical prevention or treatment of OC/ BC or cardiovascular disease. However, results were sensitive to RRSO utility scores. Additionally, 37%, 61%, 74%, 84%, 96% and 99.5% simulations on PSA are cost-effective for RRSO at the 2%, 4%, 5%, 6%, 8% and 10% levels of OC risk, respectively. CONCLUSIONS: Premenopausal RRSO appears to be extremely cost-effective at ≥4% lifetime OC risk, with ≥42.7 days gain in life expectancy if compliance with hormone replacement therapy is high. Current guidelines should be re-evaluated to reduce the RRSO OC risk threshold to benefit a number of at-risk women who presently cannot access risk-reducing surgery.

Cluster-randomised non-inferiority trial comparing DVD-assisted and traditional genetic counselling in systematic population testing for BRCA1/2 mutations.

BACKGROUND: Newer approaches to genetic counselling are required for population-based testing. We compare traditional face-to-face genetic counselling with a DVD-assisted approach for population-based BRCA1/2 testing. METHODS: A cluster-randomised non-inferiority trial in the London Ashkenazi Jewish population. INCLUSION CRITERIA: Ashkenazi Jewish men/women >18 years; exclusion criteria: (a) known BRCA1/2 mutation, (b) previous BRCA1/2 testing and (c) first-degree relative of BRCA1/2 carrier. Ashkenazi Jewish men/women underwent pre-test genetic counselling prior to BRCA1/2 testing in the Genetic Cancer Prediction through Population Screening trial (ISRCTN73338115). Genetic counselling clinics (clusters) were randomised to traditional counselling (TC) and DVD-based counselling (DVD-C) approaches. DVD-C involved a DVD presentation followed by shorter face-to-face genetic counselling. Outcome measures included genetic testing uptake, cancer risk perception, increase in knowledge, counselling time and satisfaction (Genetic Counselling Satisfaction Scale). Random-effects models adjusted for covariates compared outcomes between TC and DVD-C groups. One-sided 97.5% CI was used to determine non-inferiority. SECONDARY OUTCOMES: relevance, satisfaction, adequacy, emotional impact and improved understanding with the DVD; cost-minimisation analysis for TC and DVD-C approaches. RESULTS: 936 individuals (clusters=256, mean-size=3.6) were randomised to TC (n=527, clusters=134) and DVD-C (n=409, clusters=122) approaches. Groups were similar at baseline, mean age=53.9 (SD=15) years, women=66.8%, men=33.2%. DVD-C was non-inferior to TC for increase in knowledge (d=-0.07; lower 97.5% CI=-0.41), counselling satisfaction (d=-0.38, 97.5% CI=1.2) and risk perception (d=0.08; upper 97.5% CI=3.1). Group differences and CIs did not cross non-inferiority margins. DVD-C was equivalent to TC for uptake of genetic testing (d=-3%; lower/upper 97.5% CI -7.9%/1.7%) and superior for counselling time (20.4 (CI 18.7 to 22.2) min reduction (p<0.005)). 98% people found the DVD length and information satisfactory. 85-89% felt it improved their understanding of risks/benefits/implications/purpose of genetic testing. 95% would recommend it to others. The cost of genetic counselling for DVD-C=£7787 and TC=£17 307. DVD-C resulted in cost savings=£9520 (£14/volunteer). CONCLUSIONS: DVD-C is an effective, acceptable, non-inferior, time-saving and cost-efficient alternative to TC. TRIAL REGISTRATION NUMBER: ISRCTN 73338115.