Online Provision of BRCA1 and BRCA2 Health Information: A Search Engine Driven Systematic Web-Based Analysis.

BRCA genetic testing is available for UK Jewish individuals but the provision of information online for BRCA is unknown. We aimed to evaluate online provision of BRCA information by UK organisations (UKO), UK Jewish community organisations (JCO), and genetic testing providers (GTP). Google searches for organisations offering BRCA information were performed using relevant sets of keywords. The first 100 website links were categorised into UKOs/JCOs/GTPs; additional JCOs were supplemented through community experts. Websites were reviewed using customised questionnaires for BRCA information. Information provision was assessed for five domains: accessibility, scope, depth, accuracy, and quality. These domains were combined to provide a composite score (maximum score = 5). Results were screened (n = 6856) and 45 UKOs, 16 JCOs, and 18 GTPs provided BRCA information. Accessibility was high (84%,66/79). Scope was lacking with 35% (28/79) addressing >50% items. Most (82%, 65/79) described BRCA-associated cancers: breast and/or ovarian cancer was mentioned by 78%(62/79), but only 34% (27/79) mentioned ≥1 pancreatic, prostate, melanoma. Few websites provided carrier frequencies in the general (24%,19/79) and Jewish populations (20%,16/79). Only 15% (12/79) had quality information with some/minimal shortcomings. Overall information provision was low-to-moderate: median scores UKO = 2.1 (IQR = 1), JCO = 1.6 (IQR = 0.9), and GTP = 2.3 (IQR = 1) (maximum-score = 5). There is a scarcity of high-quality BRCA information online. These findings have implications for UK Jewish BRCA programmes and those considering BRCA testing.

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.

Utility Scores for Risk-Reducing Mastectomy and Risk-Reducing Salpingo-Oophorectomy: Mapping to EQ-5D.

BACKGROUND: Risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) are the most effective breast and ovarian cancer preventive interventions. EQ-5D is the recommended tool to assess the quality of life and determine health-related utility scores (HRUSs), yet there are no published EQ-5D HRUSs after these procedures. These are essential for clinicians counselling patients and for health-economic evaluations. METHODS: We used aggregate data from our published systematic review and converted SF-36/SF-12 summary scores to EQ-5D HRUSs using a published mapping algorithm. Study control arm or age-matched country-specific reference values provided comparison. Random-effects meta-analysis provided adjusted disutilities and utility scores. Subgroup analyses included long-term vs. short-term follow-up. RESULTS: Four studies (209 patients) reported RRM outcomes using SF-36, and five studies (742 patients) reported RRSO outcomes using SF-12/SF-36. RRM is associated with a long-term (>2 years) disutility of -0.08 (95% CI -0.11, -0.04) (I2 31.4%) and a utility of 0.92 (95% CI 0.88, 0.95) (I2 31.4%). RRSO is associated with a long-term (>1 year) disutility of -0.03 (95% CI -0.05, 0.00) (I2 17.2%) and a utility of 0.97 (95% CI 0.94, 0.99) (I2 34.0%). CONCLUSIONS: We present the first HRUSs sourced from patients following RRM and RRSO. There is a need for high-quality prospective studies to characterise quality of life at different timepoints.

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.

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.

A systematic review of the cost-effectiveness of interventions to increase cervical cancer screening among underserved women in Europe.

BACKGROUND: This study aimed to conduct a systematic review of the cost-effectiveness studies of interventions to increase cervical cancer screening uptake rates in underserved women in Europe. METHODS: A search of Embase, Medline, Global Health, PsychINFO, and NHS Economic Evaluation Database was conducted for studies published between January 2000 and September 2022. Studies were eligible if they analysed the cost-effectiveness of any interventions to improve participation in cervical cancer screening among underserved women of any age eligible to participate in cervical cancer screening in European countries, in any language. Study characteristics and cost-effectiveness results were summarised. Study quality was assessed using the Drummond Checklist, and methodological choices were further compared. RESULTS: The searches yielded 962 unique studies, with 17 of these (from twelve European countries) meeting the eligibility criteria for data extraction. All studies focused on underscreened women as an overarching group, with no identified studies focusing on specific subgroups of underserved women. Generally, self-HPV testing and reminder interventions were shown to be cost-effective to increase the uptake rates. There was also research showing that addressing access issues and adopting different screening modalities could be economically attractive in some settings, but the current evidence is insufficient due to the limited number of studies. CONCLUSION: This systematic review has revealed a gap in the literature on the cost-effectiveness of interventions to improve uptake rates of cervical cancer screening through tailored provision for specific groups of underserved women.

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.

Factors influencing the participation of groups identified as underserved in cervical cancer screening in Europe: a scoping review of the literature.

Background: Cervical cancer is a preventable and inequitably distributed disease. Screening plays a vital role in prevention, but many women face barriers to participation. The aims of this scoping review, undertaken to inform the co-design of interventions to equitably increase screening uptake, were to: (1) identify barriers and facilitators to cervical cancer screening for underserved populations, and (2) identify and describe the effectiveness of interventions aimed at improving participation in cervical cancer screening among underserved groups in Europe. Methods: Qualitative, quantitative, and mixed methods studies focusing on barriers and facilitators to cervical screening participation and interventions to improve uptake undertaken in Europe and published after 2000 were included. Four electronic databases were searched to identify relevant papers. Titles and abstracts were screened, full text reviewed, and key findings extracted. Data were extracted and analyzed according to different health system strata: system-wide (macro), service specific (meso) and individual/community specific (micro). Within these categories, themes were identified, and the population groups impacted were recorded. All findings are presented in accordance with (PRISMA) guidelines. Results: 33 studies on barriers and facilitators and eight intervention studies met the inclusion criteria. Collectively, the findings of these studies presented a wide array of screening uptake barriers, facilitators, and interventions, predominantly related to screening service and individual/community factors. However, although diverse, certain core themes around information provision, prompts for participation and the need for inclusive spaces were apparent. Implementation of screening programs should focus on: (1) reducing identifiable barriers, (2) increasing public awareness, and (3) providing patient reminders and measures to promote engagement by healthcare providers. Conclusion: There are many barriers to uptake of cervical cancer screening and this review, nested within a larger study, will inform work to devise a solution alongside groups identified in three European countries.

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.

Breast Cancer Risk and Breast-Cancer-Specific Mortality following Risk-Reducing Salpingo-Oophorectomy in BRCA Carriers: A Systematic Review and Meta-Analysis.

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard method of ovarian cancer risk reduction, but the data are conflicting regarding the impact on breast cancer (BC) outcomes. This study aimed to quantify BC risk/mortality in BRCA1/BRCA2 carriers after RRSO. METHODS: We conducted a systematic review (CRD42018077613) of BRCA1/BRCA2 carriers undergoing RRSO, with the outcomes including primary BC (PBC), contralateral BC (CBC) and BC-specific mortality (BCSM) using a fixed-effects meta-analysis, with subgroup analyses stratified by mutation and menopause status. RESULTS: RRSO was not associated with a significant reduction in the PBC risk (RR = 0.84, 95%CI: 0.59-1.21) or CBC risk (RR = 0.95, 95%CI: 0.65-1.39) in BRCA1 and BRCA2 carriers combined but was associated with reduced BC-specific mortality in BC-affected BRCA1 and BRCA2 carriers combined (RR = 0.26, 95%CI: 0.18-0.39). Subgroup analyses showed that RRSO was not associated with a reduction in the PBC risk (RR = 0.89, 95%CI: 0.68-1.17) or CBC risk (RR = 0.85, 95%CI: 0.59-1.24) in BRCA1 carriers nor a reduction in the CBC risk in BRCA2 carriers (RR = 0.35, 95%CI: 0.07-1.74) but was associated with a reduction in the PBC risk in BRCA2 carriers (RR = 0.63, 95%CI: 0.41-0.97) and BCSM in BC-affected BRCA1 carriers (RR = 0.46, 95%CI: 0.30-0.70). The mean NNT = 20.6 RRSOs to prevent one PBC death in BRCA2 carriers, while 5.6 and 14.2 RRSOs may prevent one BC death in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers, respectively. CONCLUSIONS: RRSO was not associated with PBC or CBC risk reduction in BRCA1 and BRCA2 carriers combined but was associated with improved BC survival in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers and a reduced PBC risk in BRCA2 carriers.

Impact of Multiple COVID-19 Waves on Gynaecological Cancer Services in the UK.

BACKGROUND: This study aimed to assess the impact of multiple COVID-19 waves on UK gynaecological-oncology services. METHODS: An online survey was distributed to all UK-British-Gynaecological-Cancer-Society members during three COVID-19 waves from 2020 to2022. RESULTS: In total, 51 hospitals (including 32 cancer centres) responded to Survey 1, 42 hospitals (29 centres) to Survey 2, and 39 hospitals (30 centres) to Survey 3. During the first wave, urgent referrals reportedly fell by a median of 50% (IQR = 25-70%). In total, 49% hospitals reported reduced staffing, and the greatest was noted for trainee doctors, by a median of 40%. Theatre capacity was reduced by a median of 40%. A median of 30% of planned operations was postponed. Multidisciplinary meetings were completely virtual in 39% and mixed in 65% of the total. A median of 75% of outpatient consultations were remote. By the second wave, fewer hospitals reported staffing reductions, and there was a return to pre-pandemic urgent referrals and multidisciplinary workloads. Theatre capacity was reduced by a median of 10%, with 5% of operations postponed. The third wave demonstrated worsening staff reductions similar to Wave 1, primarily from sickness. Pre-pandemic levels of urgent referrals/workload continued, with little reduction in surgical capacity. CONCLUSION: COVID-19 led to a significant disruption of gynaecological-cancer care across the UK, including reduced staffing, urgent referrals, theatre capacity, and working practice changes. Whilst disruption eased and referrals/workloads returned to normal, significant staff shortages remained in 2022, highlighting persistent capacity constraints.

Quality of Life after Risk-Reducing Hysterectomy for Endometrial Cancer Prevention: A Systematic Review.

BACKGROUND: Risk-reducing hysterectomy (RRH) is the gold-standard prevention for endometrial cancer (EC). Knowledge of the impact on quality-of-life (QoL) is crucial for decision-making. This systematic review aims to summarise the evidence. METHODS: We searched major databases until July 2022 (CRD42022347631). Given the paucity of data on RRH, we also included hysterectomy as treatment for benign disease. We used validated quality-assessment tools, and performed qualitative synthesis of QoL outcomes. RESULTS: Four studies (64 patients) reported on RRH, 25 studies (1268 patients) on hysterectomy as treatment for uterine bleeding. There was moderate risk-of-bias in many studies. Following RRH, three qualitative studies found substantially lowered cancer-worry, with no decision-regret. Oophorectomy (for ovarian cancer prevention) severely impaired menopause-specific QoL and sexual-function, particularly without hormone-replacement. Quantitative studies supported these results, finding low distress and generally high satisfaction. Hysterectomy as treatment of bleeding improved QoL, resulted in high satisfaction, and no change or improvements in sexual and urinary function, although small numbers reported worsening. CONCLUSIONS: There is very limited evidence on QoL after RRH. Whilst there are benefits, most adverse consequences arise from oophorectomy. Benign hysterectomy allows for some limited comparison; however, more research is needed for outcomes in the population of women at increased EC-risk.

Cost-Effectiveness of Risk-Reducing Surgery for Breast and Ovarian Cancer Prevention: A Systematic Review.

Policymakers require robust cost-effectiveness evidence of risk-reducing-surgery (RRS) for decision making on resource allocation for breast cancer (BC)/ovarian cancer (OC)/endometrial cancer (EC) prevention. We aimed to summarise published data on the cost-effectiveness of risk-reducing mastectomy (RRM)/risk-reducing salpingo-oophorectomy (RRSO)/risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) for BC/OC prevention in intermediate/high-risk populations; hysterectomy and bilateral salpingo-oophorectomy (BSO) in Lynch syndrome women; and opportunistic bilateral salpingectomy (OBS) for OC prevention in baseline-risk populations. Major databases were searched until December 2021 following a prospective protocol (PROSPERO-CRD42022338008). Data were qualitatively synthesised following a PICO framework. Twenty two studies were included, with a reporting quality varying from 53.6% to 82.1% of the items scored in the CHEERS checklist. The incremental cost-effectiveness ratio/incremental cost-utility ratio and cost thresholds were inflated and converted to US$2020, using the original currency consumer price index (CPI) and purchasing power parities (PPP), for comparison. Eight studies concluded that RRM and/or RRSO were cost-effective compared to surveillance/no surgery for BRCA1/2, while RRESDO was cost-effective compared to RRSO in one study. Three studies found that hysterectomy with BSO was cost-effective compared to surveillance in Lynch syndrome women. Two studies showed that RRSO was also cost-effective at ≥4%/≥5% lifetime OC risk for pre-/post-menopausal women, respectively. Seven studies demonstrated the cost-effectiveness of OBS at hysterectomy (n = 4), laparoscopic sterilisation (n = 4) or caesarean section (n = 2). This systematic review confirms that RRS is cost-effective, while the results are context-specific, given the diversity in the target populations, health systems and model assumptions, and sensitive to the disutility, age and uptake rates associated with RRS. Additionally, RRESDO/OBS were sensitive to the uncertainty concerning the effect sizes in terms of the OC-risk reduction and long-term health impact. Our findings are relevant for policymakers/service providers and the design of future research studies.

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.

Unselected Population Genetic Testing for Personalised Ovarian Cancer Risk Prediction: A Qualitative Study Using Semi-Structured Interviews.

Unselected population-based personalised ovarian cancer (OC) risk assessments combining genetic, epidemiological and hormonal data have not previously been undertaken. We aimed to understand the attitudes, experiences and impact on the emotional well-being of women from the general population who underwent unselected population genetic testing (PGT) for personalised OC risk prediction and who received low-risk (<5% lifetime risk) results. This qualitative study was set within recruitment to a pilot PGT study using an OC risk tool and telephone helpline. OC-unaffected women ≥ 18 years and with no prior OC gene testing were ascertained through primary care in London. In-depth, semi-structured and 1:1 interviews were conducted until informational saturation was reached following nine interviews. Six interconnected themes emerged: health beliefs; decision making; factors influencing acceptability; effect on well-being; results communication; satisfaction. Satisfaction with testing was high and none expressed regret. All felt the telephone helpline was helpful and should remain optional. Delivery of low-risk results reduced anxiety. However, care must be taken to emphasise that low risk does not equal no risk. The main facilitators were ease of testing, learning about children's risk and a desire to prevent disease. Barriers included change in family dynamics, insurance, stigmatisation and personality traits associated with stress/worry. PGT for personalised OC risk prediction in women in the general population had high acceptability/satisfaction and reduced anxiety in low-risk individuals. Facilitators/barriers observed were similar to those reported with genetic testing from high-risk cancer clinics and unselected PGT in the Jewish population.

Cost-Effectiveness of Genetic Testing for All Women Diagnosed with Breast Cancer in China.

Unselected multigene testing for all women with breast cancer (BC) identifies more cancer susceptibility gene (CSG) carriers who can benefit from precision prevention compared with family history (FH)/clinical-criteria-based guidelines. Very little CSG testing is undertaken in middle-income countries such as China, and its cost-effectiveness remains unaddressed. We aimed to estimate cost-effectiveness and population impact of multigene testing for all Chinese BC patients. Data from 8085 unselected BC patients recruited to a Peking University Cancer Hospital study were used for microsimulation modeling, comparing three strategies in the Chinese setting: all BC women undergo BRCA1/BRCA2/PALB2 genetic testing, only BC women fulfilling FH/clinical criteria undergo BRCA testing, and no genetic testing. Prophylactic mastectomy and salpingo-oophorectomy would be adopted where appropriate. Societal and payer perspectives with a lifetime horizon along with sensitivity analyses were presented. Incremental cost-effectiveness ratio (ICER): incremental cost per quality-adjusted life-year (QALY) gained is compared to the USD 10,260/QALY (one-times GDP per capita) willingness-to-pay threshold. BC incidence, ovarian cancer (OC) incidence, and related deaths were also estimated. FH/clinical-criteria-based BRCA testing was ruled out on the principle of extensive dominance. Compared with no genetic testing, multigene testing for all BC patients had an ICER = USD 4506/QALY (societal perspective) and USD 7266/QALY (payer perspective), well below our threshold. Probabilistic sensitivity analysis showed unselected multigene testing remained cost-effective for 94.2%/86.6% of simulations from the societal and payer perspectives. One year's unselected multigene testing could prevent 7868 BC/OC cases and 5164 BC/OC deaths in China. Therefore, unselected multigene testing is extremely cost-effective and should be offered to all Chinese women with BC.

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.

Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study.

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p < 0.001). The median age was 54 (IQR = 51-62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51-71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.