Predicting Risk of Post-Operative Morbidity and Mortality following Gynaecological Oncology Surgery (PROMEGO): A Global Gynaecological Oncology Surgical Outcomes Collaborative Led Study.

The medical complexity of surgical patients is increasing, and surgical risk calculators are crucial in providing high-value, patient-centered surgical care. However, pre-existing models are not validated to accurately predict risk for major gynecological oncology surgeries, and many are not generalizable to low- and middle-income country settings (LMICs). The international GO SOAR database dataset was used to develop a novel predictive surgical risk calculator for post-operative morbidity and mortality following gynecological surgery. Fifteen candidate features readily available pre-operatively across both high-income countries (HICs) and LMICs were selected. Predictive modeling analyses using machine learning methods and linear regression were performed. The area-under-the-receiver-operating characteristic curve (AUROC) was calculated to assess overall discriminatory performance. Neural networks (AUROC 0.94) significantly outperformed other models (p < 0.001) for evaluating the accuracy of prediction across three groups, i.e., minor morbidity (Clavien-Dindo I-II), major morbidity (Clavien-Dindo III-V), and no morbidity. Logistic-regression modeling outperformed the clinically established SORT model in predicting mortality (AUROC 0.66 versus 0.61, p < 0.001). The GO SOAR surgical risk prediction model is the first that is validated for use in patients undergoing gynecological surgery. Accurate surgical risk predictions are vital within the context of major cytoreduction surgery, where surgery and its associated complications can diminish quality-of-life and affect long-term cancer survival. A model that requires readily available pre-operative data, irrespective of resource setting, is crucial to reducing global surgical disparities.

Prognosis Following Surgery for Recurrent Ovarian Cancer and Diagnostic Criteria Predictive of Cytoreduction Success: A Systematic Review and Meta-Analysis.

For women achieving clinical remission after the completion of initial treatment for epithelial ovarian cancer, 80% with advanced-stage disease will develop recurrence. However, the standard treatment of women with recurrent platinum-sensitive diseases remains poorly defined. Secondary (SCS), tertiary (TCS) or quaternary (QCS) cytoreduction surgery for recurrence has been suggested to be associated with increased overall survival (OS). We searched five databases for studies reporting death rate, OS, cytoreduction rates, post-operative morbidity/mortality and diagnostic models predicting complete cytoreduction in a platinum-sensitive disease recurrence setting. Death rates calculated from raw data were pooled based on a random-effects model. Meta-regression/linear regression was performed to explore the role of complete or optimal cytoreduction as a moderator. Pooled death rates were 45%, 51%, 66% for SCS, TCS and QCS, respectively. Median OS for optimal cytoreduction ranged from 16-91, 24-99 and 39-135 months for SCS, TCS and QCS, respectively. Every 10% increase in complete cytoreduction rates at SCS corresponds to a 7% increase in median OS. Complete cytoreduction rates ranged from 9-100%, 35-90% and 33-100% for SCS, TCS and QCS, respectively. Major post-operative thirty-day morbidity was reported to range from 0-47%, 13-33% and 15-29% for SCS, TCS and QCS, respectively. Thirty-day post-operative mortality was 0-6%, 0-3% and 0-2% for SCS, TCS and QCS, respectively. There were two externally validated diagnostic models predicting complete cytoreduction at SCS, but none for TCS and QCS. In conclusion, our data confirm that maximal effort higher order cytoreductive surgery resulting in complete cytoreduction can improve survival.

International Variations in Surgical Morbidity and Mortality Post Gynaecological Oncology Surgery: A Global Gynaecological Oncology Surgical Outcomes Collaborative Led Study (GO SOAR1).

Gynaecological malignancies affect women in low and middle income countries (LMICs) at disproportionately higher rates compared with high income countries (HICs) with little known about variations in access, quality, and outcomes in global cancer care. Our study aims to evaluate international variation in post-operative morbidity and mortality following gynaecological oncology surgery between HIC and LMIC settings. Study design consisted of a multicentre, international prospective cohort study of women undergoing surgery for gynaecological malignancies (NCT04579861). Multilevel logistic regression determined relationships within three-level nested-models of patients within hospitals/countries. We enrolled 1820 patients from 73 hospitals in 27 countries. Minor morbidity (Clavien-Dindo I-II) was 26.5% (178/672) and 26.5% (267/1009), whilst major morbidity (Clavien-Dindo III-V) was 8.2% (55/672) and 7% (71/1009) for LMICs/HICs, respectively. Higher minor morbidity was associated with pre-operative mechanical bowel preparation (OR = 1.474, 95%CI = 1.054-2.061, p = 0.023), longer surgeries (OR = 1.253, 95%CI = 1.066-1.472, p = 0.006), greater blood loss (OR = 1.274, 95%CI = 1.081-1.502, p = 0.004). Higher major morbidity was associated with longer surgeries (OR = 1.37, 95%CI = 1.128-1.664, p = 0.002), greater blood loss (OR = 1.398, 95%CI = 1.175-1.664, p ≤ 0.001), and seniority of lead surgeon, with junior surgeons three times more likely to have a major complication (OR = 2.982, 95%CI = 1.509-5.894, p = 0.002). Of all surgeries, 50% versus 25% were performed by junior surgeons in LMICs/HICs, respectively. We conclude that LMICs and HICs were associated with similar post-operative major morbidity. Capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention.

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.

Patient outcomes following interval and delayed cytoreductive surgery in advanced ovarian cancer: protocol for a multicenter, international, cohort study (Global Gynaecological Oncology Surgical Outcomes Collaborative).

BACKGROUND: The Global Gynecological Oncology Surgical Outcomes Collaborative (GO SOAR) has developed a network of gynecological oncology surgeons, surgical departments, and other interested parties that have the long-term ability to collaborate on outcome studies. Presented is the protocol for the GO SOAR2 study. PRIMARY OBJECTIVES: To compare survival following interval and delayed cytoreductive surgery, between delayed cytoreductive surgery and no surgery (chemotherapy alone); and international variations in access to cytoreductive surgery for women with stage III-IV epithelial ovarian cancer. STUDY HYPOTHESES: There is no difference in survival following interval and delayed cytoreductive surgery; there is poorer survival with no surgery compared with delayed cytoreductive surgery; and there are international disparities in prevalent practice and access to cytoreductive surgery in women with stage III-IV epithelial ovarian cancer. TRIAL DESIGN: International, multicenter, mixed-methods cohort study. Participating centers, will review medical charts/electronic records of patients who had been consecutively diagnosed with stage III-IV ovarian cancer between January 1, 2006 and December 31, 2021. Qualitative interviews will be conducted to identify factors determining international variations in prevalent practice and access to cytoreductive surgery. MAJOR INCLUSION/EXCLUSION CRITERIA: Inclusion criteria include women with stage III-IV epithelial ovarian cancer, undergoing interval (after 3-4 cycles of chemotherapy) or delayed (≥5 cycles of chemotherapy) cytoreductive surgeries or no cytoreductive surgery (≥5 cycles of chemotherapy alone). PRIMARY ENDPOINTS: Overall survival (defined from date of diagnosis to date of death); progression-free survival (defined from date of diagnosis to date of first recurrence); facilitator/barriers to prevalent practice and access to cytoreductive surgery. SAMPLE SIZE: In order to determine whether there is a difference in survival following interval and delayed cytoreductive surgery and no surgery, data will be abstracted from 1000 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: It is estimated that recruitment will be completed by 2023, and results published by 2024. TRIAL REGISTRATION: NCT05523804.

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.

Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors.

BACKGROUND: Epithelial tubo-ovarian cancer (EOC) has high mortality partly due to late diagnosis. Prevention is available but may be associated with adverse effects. A multifactorial risk model based on known genetic and epidemiological risk factors (RFs) for EOC can help identify women at higher risk who could benefit from targeted screening and prevention. METHODS: We developed a multifactorial EOC risk model for women of European ancestry incorporating the effects of pathogenic variants (PVs) in BRCA1, BRCA2, RAD51C, RAD51D and BRIP1, a Polygenic Risk Score (PRS) of arbitrary size, the effects of RFs and explicit family history (FH) using a synthetic model approach. The PRS, PV and RFs were assumed to act multiplicatively. RESULTS: Based on a currently available PRS for EOC that explains 5% of the EOC polygenic variance, the estimated lifetime risks under the multifactorial model in the general population vary from 0.5% to 4.6% for the first to 99th percentiles of the EOC risk distribution. The corresponding range for women with an affected first-degree relative is 1.9%-10.3%. Based on the combined risk distribution, 33% of RAD51D PV carriers are expected to have a lifetime EOC risk of less than 10%. RFs provided the widest distribution, followed by the PRS. In an independent partial model validation, absolute and relative 5-year risks were well calibrated in quintiles of predicted risk. CONCLUSION: This multifactorial risk model can facilitate stratification, in particular among women with FH of cancer and/or moderate-risk and high-risk PVs. The model is available via the CanRisk Tool (www.canrisk.org).

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.

Determining post-operative morbidity and mortality following gynecological oncology surgery: protocol for a multicenter, international, prospective cohort study (Global Gynaecological Oncology Surgical Outcomes Collaborative-GO SOAR).

BACKGROUND: The Global Gynaecological Oncology Surgical Outcomes Collaborative (GO SOAR) aims to develop a network of gynecological oncology surgeons, surgical departments, and other interested parties that will have the long-term ability to collaborate on outcome studies. The protocol for the first collaborative study is presented here. PRIMARY OBJECTIVE: To evaluate international variation in 30-day post-operative morbidity and mortality following gynecological oncology surgery between very high/high and medium/low human development index country settings. HYPOTHESIS: There is no variation in post-operative morbidity and mortality following gynecological oncology surgery between very high/high and medium/low human development index country settings. STUDY DESIGN: International, multicenter, prospective cohort study. Patient data will be collected over a consecutive 30-day period through gynecological oncology multidisciplinary teams/tumor boards and clinics across different human development index country groups. All data are collected on a customized, secure, password protected, central REDCap database. MAJOR INCLUSION/EXCLUSION CRITERIA: Inclusion criteria include women aged ≥18 years undergoing elective/emergency, curative/palliative surgery for primary/recurrent tubo-ovarian/peritoneal, endometrial, cervical, vulval, vaginal, gestational trophoblastic malignancies. Surgical modality may be open, minimal access (laparoscopic/robotic), or vaginal. PRIMARY ENDPOINT: 30-day post-operative morbidity and mortality defined as per Clavien-Dindo classification system. SAMPLE SIZE: 1100 (550/arm). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: It is estimated recruitment will be completed by 2022 and results published by 2023. TRIAL REGISTRATION: ClinicalTrials.gov registry: NCT04579861 (https://clinicaltrials.gov/ct2/show/NCT04579861).

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.

Impact of SARS-CoV-2 on training and mental well-being of surgical gynecological oncology trainees.

INTRODUCTION: The SARS-CoV-2 global pandemic has caused a crisis disrupting health systems worldwide. While efforts are being made to determine the extent of the disruption, the impact on gynecological oncology trainees/training has not been explored. We conducted an international survey of the impact of SARS-CoV-2 on clinical practice, medical education, and mental well-being of surgical gynecological oncology trainees. METHODS: In our cross-sectional study, a customized web-based survey was circulated to surgical gynecological oncology trainees from national/international organizations from May to November 2020. Validated questionnaires assessed mental well-being. The Wilcoxon rank-sum test and Fisher's exact test were used to analyse differences in means and proportions. Multiple linear regression was used to evaluate the effect of variables on psychological/mental well-being outcomes. Outcomes included clinical practice, medical education, anxiety and depression, distress, and mental well-being. RESULTS: A total of 127 trainees from 34 countries responded. Of these, 52% (66/127) were from countries with national training programs (UK/USA/Netherlands/Canada/Australia) and 48% (61/127) from countries with no national training programs. Altogether, 28% (35/125) had suspected/confirmed COVID-19, 28% (35/125) experienced a fall in household income, 20% (18/90) were self-isolated from households, 45% (57/126) had to re-use personal protective equipment, and 22% (28/126) purchased their own. In total, 32.3% (41/127) of trainees (16.6% (11/66) from countries with a national training program vs 49.1% (30/61) from countries with no national training program, p=0.02) perceived they would require additional time to complete their training fellowship. The additional training time anticipated did not differ between trainees from countries with or without national training programs (p=0.11) or trainees at the beginning or end of their fellowship (p=0.12). Surgical exposure was reduced for 50% of trainees. Departmental teaching continued throughout the pandemic for 69% (87/126) of trainees, although at reduced frequency for 16.1% (14/87), and virtually for 88.5% (77/87). Trainees reporting adequate pastoral support (defined as allocation of a dedicated mentor/access to occupational health support services) had better mental well-being with lower levels of anxiety/depression (p=0.02) and distress (p<0.001). Trainees from countries with a national training program experienced higher levels of distress (p=0.01). Mean (SD) pre-pandemic mental well-being scores were significantly higher than post-pandemic scores (8.3 (1.6) vs 7 (1.8); p<0.01). CONCLUSION: SARS-CoV-2 has negatively impacted the surgical training, household income, and psychological/mental well-being of surgical gynecological oncology trainees. The overall clinical impact was worse for trainees in countries with no national training program than for those in countries with a national training program, although national training program trainees reported greater distress. COVID-19 sickness increased anxiety/depression. The recovery phase must focus on improving mental well-being and addressing lost training opportunities.

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).

Economic Evaluation of Population-Based BRCA1/BRCA2 Mutation Testing across Multiple Countries and Health Systems.

Clinical criteria/Family history-based BRCA testing misses a large proportion of BRCA carriers who can benefit from screening/prevention. We estimate the cost-effectiveness of population-based BRCA testing in general population women across different countries/health systems. A Markov model comparing the lifetime costs and effects of BRCA1/BRCA2 testing all general population women ≥30 years compared with clinical criteria/FH-based testing. Separate analyses are undertaken for the UK/USA/Netherlands (high-income countries/HIC), China/Brazil (upper-middle income countries/UMIC) and India (low-middle income countries/LMIC) using both health system/payer and societal perspectives. BRCA carriers undergo appropriate screening/prevention interventions to reduce breast cancer (BC) and ovarian cancer (OC) risk. Outcomes include OC, BC, and additional heart disease deaths and incremental cost-effectiveness ratio (ICER)/quality-adjusted life year (QALY). Probabilistic/one-way sensitivity analyses evaluate model uncertainty. For the base case, from a societal perspective, we found that population-based BRCA testing is cost-saving in HIC (UK-ICER = $-5639/QALY; USA-ICER = $-4018/QALY; Netherlands-ICER = $-11,433/QALY), and it appears cost-effective in UMIC (China-ICER = $18,066/QALY; Brazil-ICER = $13,579/QALY), but it is not cost-effective in LMIC (India-ICER = $23,031/QALY). From a payer perspective, population-based BRCA testing is highly cost-effective in HIC (UK-ICER = $21,191/QALY, USA-ICER = $16,552/QALY, Netherlands-ICER = $25,215/QALY), and it is cost-effective in UMIC (China-ICER = $23,485/QALY, Brazil-ICER = $20,995/QALY), but it is not cost-effective in LMIC (India-ICER = $32,217/QALY). BRCA testing costs below $172/test (ICER = $19,685/QALY), which makes it cost-effective (from a societal perspective) for LMIC/India. Population-based BRCA testing can prevent an additional 2319 to 2666 BC and 327 to 449 OC cases per million women than the current clinical strategy. Findings suggest that population-based BRCA testing for countries evaluated is extremely cost-effective across HIC/UMIC health systems, is cost-saving for HIC health systems from a societal perspective, and can prevent tens of thousands more BC/OC cases.

Population Study of Ovarian Cancer Risk Prediction for Targeted Screening and Prevention.

Unselected population-based personalised ovarian cancer (OC) risk assessment combining genetic/epidemiology/hormonal data has not previously been undertaken. We aimed to perform a feasibility study of OC risk stratification of general population women using a personalised OC risk tool followed by risk management. Volunteers were recruited through London primary care networks. INCLUSION CRITERIA: women ≥18 years. EXCLUSION CRITERIA: prior ovarian/tubal/peritoneal cancer, previous genetic testing for OC genes. Participants accessed an online/web-based decision aid along with optional telephone helpline use. Consenting individuals completed risk assessment and underwent genetic testing (BRCA1/BRCA2/RAD51C/RAD51D/BRIP1, OC susceptibility single-nucleotide polymorphisms). A validated OC risk prediction algorithm provided a personalised OC risk estimate using genetic/lifestyle/hormonal OC risk factors. Population genetic testing (PGT)/OC risk stratification uptake/acceptability, satisfaction, decision aid/telephone helpline use, psychological health and quality of life were assessed using validated/customised questionnaires over six months. Linear-mixed models/contrast tests analysed impact on study outcomes. MAIN OUTCOMES: feasibility/acceptability, uptake, decision aid/telephone helpline use, satisfaction/regret, and impact on psychological health/quality of life. In total, 123 volunteers (mean age = 48.5 (SD = 15.4) years) used the decision aid, 105 (85%) consented. None fulfilled NHS genetic testing clinical criteria. OC risk stratification revealed 1/103 at ≥10% (high), 0/103 at ≥5%-<10% (intermediate), and 100/103 at <5% (low) lifetime OC risk. Decision aid satisfaction was 92.2%. The telephone helpline use rate was 13% and the questionnaire response rate at six months was 75%. Contrast tests indicated that overall depression (p = 0.30), anxiety (p = 0.10), quality-of-life (p = 0.99), and distress (p = 0.25) levels did not jointly change, while OC worry (p = 0.021) and general cancer risk perception (p = 0.015) decreased over six months. In total, 85.5-98.7% were satisfied with their decision. Findings suggest population-based personalised OC risk stratification is feasible and acceptable, has high satisfaction, reduces cancer worry/risk perception, and does not negatively impact psychological health/quality of life.

Population-based genetic testing for Women's cancer prevention.

Germline mutations in cancer-susceptibility-genes (CSG) can dramatically increase womens' lifetime risk of ovarian, endometrial, breast and bowel cancers. Identification of unaffected carriers is important to enable proactive engagement with highly effective screening and preventive options to minimise cancer risk. Currently, a family-history model is used to identify individuals with CSGs. Complex regional referral guidelines specify the family-history criteria required before an individual is eligible for genetic-testing. This model is ineffective, resource intense, misses >50% CSG carriers, is associated with underutilisation of genetic-testing services and delays detection of mutation carriers. Although awareness and detection of CSG-carriers has improved, over 97% carriers remain unidentified. This reflects significant missed opportunities for precision-prevention. Population-based genetic-testing (PBGT) represents a novel healthcare strategy with the potential to dramatically improve detection of unaffected CSG-carriers along with enabling population risk-stratification for cancer precision-prevention. Several research studies have assessed the impact, feasibility, acceptability, long-term psychological outcomes and cost-effectiveness of population-based BRCA-testing in the Ashkenazi-Jewish population. Initial data on PBGT in the general-population is beginning to emerge and large implementation studies investigating PBGT in the general-population are needed. This review will summarise the current research into the clinical, psycho-social, health-economic, societal and ethical consequences of a PBGT model for women's cancer precision-prevention.

Population Screening for Inherited Predisposition to Breast and Ovarian Cancer.

The discovery of genes underlying inherited predisposition to breast and ovarian cancer has revolutionized the ability to identify women at high risk for these diseases before they become affected. Women who are carriers of deleterious variants in these genes can undertake surveillance and prevention measures that have been shown to reduce morbidity and mortality. However, under current strategies, the vast majority of women carriers remain undetected until they become affected. In this review, we show that universal testing, particularly of the BRCA1 and BRCA2 genes, fulfills classical disease screening criteria. This is especially true for BRCA1 and BRCA2 in Ashkenazi Jews but is translatable to all populations and may include additional genes. Utilizing genetic information for large-scale precision prevention requires a paradigmatic shift in health-care delivery. To address this need, we propose a direct-to-patient model, which is increasingly pertinent for fulfilling the promise of utilizing personal genomic information for disease prevention.