Screening and prevention of ovarian cancer

Ovarian cancer remains the most lethal gynaecological malignancy with 314 000 cases and 207 000 deaths annually worldwide. Ovarian cancer cases and deaths are predicted to increase in Australia by 42% and 55% respectively by 2040. Earlier detection and significant downstaging of ovarian cancer have been demonstrated with multimodal screening in the largest randomised controlled trial of ovarian cancer screening in women at average population risk. However, none of the randomised trials have demonstrated a mortality benefit. Therefore, ovarian cancer screening is not currently recommended in women at average population risk. More frequent surveillance for ovarian cancer every three to four months in women at high risk has shown good performance characteristics and significant downstaging, but there is no available information on a survival benefit. Population testing offers an emerging novel strategy to identify women at high risk who can benefit from ovarian cancer prevention. Novel multicancer early detection biomarker, longitudinal multiple marker strategies, and new biomarkers are being investigated and evaluated for ovarian cancer screening. Risk‐reducing salpingo‐oophorectomy (RRSO) decreases ovarian cancer incidence and mortality and is recommended for women at over a 4–5% lifetime risk of ovarian cancer. Pre‐menopausal women without contraindications to hormone replacement therapy (HRT) undergoing RRSO should be offered HRT until 51 years of age to minimise the detrimental consequences of premature menopause. Currently risk‐reducing early salpingectomy and delayed oophorectomy (RRESDO) should only be offered to women at increased risk of ovarian cancer within the context of a research trial. Pre‐menopausal early salpingectomy is associated with fewer menopausal symptoms and better sexual function than bilateral salpingo‐oophorectomy. A Sectioning and Extensively Examining the Fimbria (SEE‐FIM) protocol should be used for histopathological assessment in women at high risk of ovarian cancer who are undergoing surgical prevention. Opportunistic salpingectomy may be offered at routine gynaecological surgery to all women who have completed their family. Long term prospective opportunistic salpingectomy studies are needed to determine the effect size of ovarian cancer risk reduction and the impact on menopause.


Screening and prevention of ovarian cancer
Michail Sideris 1 , Usha Menon 2 , Ranjit Manchanda 1,2,3,4 A round 314 000 women worldwide are diagnosed with ovarian cancer annually and 207 000 women die of it. 1GLOBOCAN, the World Health Organization Global Cancer Observatory, predicts the number of ovarian cancer cases and deaths will rise globally by 36% and 47% respectively over 20 years. 2 Correspondingly, the predicted increase in ovarian cancer cases and deaths in Australia is 42% and 55% respectively by 2040.Despite advances in treatment, ovarian cancer remains a lethal disease.High-grade serous ovarian cancer (HGSOC) is the commonest (> 80%) histological type.][5] The principles of a screening program described over 50 years ago 6 have subsequently been integrated into modern implementation frameworks, such as the Australian Population Based Screening Framework, to inform decision makers on key issues (criteria, principles of assessment, implementation, management) when assessing or considering screening programs in Australia. 7Ovarian cancer screening has been investigated in randomised controlled trials (RCTs) in women at average population risk and in cohort studies in women at high risk.These have included ultrasound, absolute cancer antigen 125 (Ca125), longitudinal Ca125, and multiple biomarker-based screening strategies.However, research so far has not led to the establishment of a national ovarian cancer screening program in Australia or elsewhere.Our improving ability to predict personalised ovarian cancer risk using complex modelling, the implementation of mainstreaming genetic testing at cancer diagnosis, and the unselected population-based approaches to identify women with moderate to high penetrance cancer susceptibility genes (CSGs) have broadened our ability to identify women at increased risk of ovarian cancer.This and the broad acceptance of the role of the fallopian tube in ovarian cancer etiopathogenesis have led to advances in preventive approaches to minimise ovarian cancer risk.These include broadening access for risk-reducing salpingo-oophorectomy (RRSO), along with implementing novel approaches such as risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) in women at high risk, and opportunistic bilateral salpingectomy (OBS) in women at average population risk.Our review summarises and appraises the spectrum of ovarian cancer screening and targeted preventive approaches for reducing ovarian cancer risk.

Ovarian cancer screening in women at average population risk
The 2021 Cancer Australia position statement 8 advises against ovarian cancer screening for women at average population risk using any tests, including pelvic examination, blood biomarkers, ultrasound or a combination of the above (Box 1).This was based on results from two large RCTs: the United Kingdom Collaborative Trial on Ovarian Cancer Screening (UKCTOCS) 3 and the Prostate Lung Colorectal Ovarian (PLCO) 21 cancer screening trial, which demonstrated no mortality benefit.
Overall, three RCTs have reported on ovarian cancer screening in women at average population risk. 3,21,22The Shizuoka Cohort 1 Wolfson Institute of Population Health, Queen Mary University of London, London, UK. 2 Institute of Clinical Trials and Methodology, University College London, London, UK. 3 Barts Health NHS Trust, London, UK. 4 London School of Hygiene and Tropical Medicine, London, UK.

Summary
• Ovarian cancer remains the most lethal gynaecological malignancy with 314 000 cases and 207 000 deaths annually worldwide.Ovarian cancer cases and deaths are predicted to increase in Australia by 42% and 55% respectively by 2040.
• Earlier detection and significant downstaging of ovarian cancer have been demonstrated with multimodal screening in the largest randomised controlled trial of ovarian cancer screening in women at average population risk.However, none of the randomised trials have demonstrated a mortality benefit.Therefore, ovarian cancer screening is not currently recommended in women at average population risk.More frequent surveillance for ovarian cancer every three to four months in women at high risk has shown good performance characteristics and significant downstaging, but there is no available information on a survival benefit.
• Population testing offers an emerging novel strategy to identify women at high risk who can benefit from ovarian cancer prevention.Novel multicancer early detection biomarker, longitudinal multiple marker strategies, and new biomarkers are being investigated and evaluated for ovarian cancer screening.
• Risk-reducing salpingo-oophorectomy (RRSO) decreases ovarian cancer incidence and mortality and is recommended for women at over a 4-5% lifetime risk of ovarian cancer.Pre-menopausal women without contraindications to hormone replacement therapy (HRT) undergoing RRSO should be offered HRT until 51 years of age to minimise the detrimental consequences of premature menopause.
• Currently risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) should only be offered to women at increased risk of ovarian cancer within the context of a research trial.Pre-menopausal early salpingectomy is associated with fewer menopausal symptoms and better sexual function than bilateral salpingo-oophorectomy.
• A Sectioning and Extensively Examining the Fimbria (SEE- FIM) protocol should be used for histopathological assessment in women at high risk of ovarian cancer who are undergoing surgical prevention.
• Opportunistic salpingectomy may be offered at routine gynaecological surgery to all women who have completed their family.Long term prospective opportunistic salpingectomy studies are needed to determine the effect size of ovarian cancer risk reduction and the impact on menopause.

Narrative reviews
Study of Ovarian Cancer Screening (SCSOCS) 22   The UKCTOCS-trial 3     • Screening the general public for ovarian cancer using Ca125 and ultrasound does not save lives in the general population; and population screening, which can reduce mortality, is likely decades away • Screening women at average population risk is not recommended    • The USPSTF does not recommend routine screening for ovarian cancer using any method in asymptomatic women at average population risk        Narrative reviews [P = 0.36]; controls, 619 deaths).Thus, screening did not reduce mortality.The reasons are likely multiple and include the effect size of the downstaging achieved, poor ovarian cancer biology, and availability of less effective treatments for ovarian cancer in 2001-2012.UKCTOCS highlights the importance of using "cancer mortality" rather than surrogate outcomes such as downstaging as the primary outcome in ovarian cancer screening trials.Any successful future screening strategy will likely need a much larger reduction in advanced stage disease and/or improvements in the lead and sojourn time than observed in UKCTOCS.In addition, clinicians and multidisciplinary teams will need to operate on a rising biomarker or abnormal screening result without radiological corroboration of any abnormality.
Besides ROCA, other longitudinal biomarker algorithms (eg, method of mean trends and parametric empirical Bayes) have been evaluated for ovarian cancer screening.These have been found to have comparable performance characteristics. 24,25lthough other biomarkers have been evaluated along with Ca125 in ovarian cancer screening, these have not added significant value over Ca125 alone. 24

Ovarian cancer screening for women at high risk
Similarly, the Cancer Australia position statement on ovarian cancer screening does not recommend any form of screening for women at high risk and, hence, there is no national surveillance program for Australian women at high risk of ovarian cancer (Box 1). 8In the UK, the National Institute for Health and Care Excellence (NICE) is reviewing this issue within a guideline on familial ovarian cancer under development (GID-NG10225). 26ost of the evidence comes from prospective single-arm interventional trials in women who have a lifetime risk of ovarian cancer of 10% or more, and included predominantly BRCA1 and BRCA2 carriers, but also women with a strong family history of ovarian cancer.These trials include the UK Familial Ovarian Cancer Screening Study (UKFOCSS phase 1 27 and phase 2 28 ), the United States Cancer Genetics Network (CGN) and the Gynaecological Oncology Group (GOG) studies, 29,30 and the Avoiding Late Diagnosis of Ovarian Cancer (ALDO) pilot trial. 31l these studies used a Ca125-based multimodal screening strategy, interpreted using the longitudinal Ca125 algorithm ROCA along with transvaginal ultrasound as a second line test.Annual screening using absolute serum Ca125 (single cutoff) and transvaginal ultrasound is not effective in women at high risk of ovarian cancer and is not recommended.This was evaluated in the UKFOCSS phase 1 study 27 (n = 3563), in which only 31% of screen-detected cancers were early stage.However, it needs to be noted that screening was associated with significant delays in diagnosis.The UKFOCSS phase 2 study 28  Ovarian cancer treatment outcome studies indicate that primary cytoreductive surgery has better survival than interval surgery following neoadjuvant chemotherapy and is recommended in treatment guidelines.Similar performance characteristics from ROCA-based screening every three months were demonstrated in the US CGN/GOG trials (3692 women; 13 080 women screenyears). 29,30The UK ALDO pilot study evaluated ROCA-based surveillance every four months in 767 BRCA1 and BRCA2 carriers across 12 centres in the UK. 31 ALDO demonstrated similar performance characteristics (sensitivity, specificity, negative predictive value, positive predictive value) of a Ca125 ROCA-based screening strategy in a real-world clinical setting to UKFOCSS phase 2, although the sample size and number of cancers detected were much smaller.Downstaging can lead to less radical surgery, with lesser morbidity and cost savings of poly (ADP-ribose) polymerase (PARP)-inhibitor treatment costs.The evidence from key trials in ovarian cancer screening for average and high risk populations is summarised in Box 2. 3,21,22,[27][28][29]31,32 Data on ovarian cancer screening for women with Lynch syndrome are limited, as the aforementioned trials mainly recruited BRCA1 and BRCA2 carriers. In adition, Lynch syndrome-related ovarian cancer is biologically different to BRCA-related HGSOC, being less aggressive and predominantly early stage at clinical diagnosis.33 Ovarian cancer screening in women with Lynch syndrome needs more research and is not currently recommended in Australia.9 Although findings from these trials on women at high risk appear encouraging, these are non-randomised and demonstration of a survival and mortality benefit is not possible.This makes drawing clear conclusions of benefit with respect to screening in women at high risk challenging.Screening is therefore not an alternative to risk-reducing surgery, which remains the mainstay of ovarian cancer prevention and risk management in women at high risk.However, there may be a potential role as an interim risk management strategy in women delaying riskreducing surgery following careful counselling, as an option compared with symptom awareness alone.These issues are under review by a NICE Guideline Committee, with a draft guideline in preparation.34 A summary of published guideline recommendations regarding ovarian cancer screening in women at average population risk and at high risk is presented in Box 1.

Novel biomarkers and ovarian cancer screening strategies
Several novel biomarkers and screening strategies are currently being investigated globally and may hold promise for the future.
Examples include DNA methylation biomarkers (eg, Women's Risk Identification for Ovarian Cancer [WID-OC] Index), 35 cellfree DNA, 36 circulating tumour DNA (ctDNA), 37,38 glycosylated Ca125, 39 Olink biomarkers, 40 other novel biomarkers, 41 use of multimarker longitudinal algorithms, 24 and multicancer early detection (MCED) biomarker strategies. 42MCED uses nextgeneration genetic and epigenetic technologies involving a range of potential platforms to screen for multiple cancer types at the same time.Screening strategies using MCED tests use second line positron emission tomography-computed tomography (PET-CT), 43 along with DNA patterns to identify cancer site 44 and machine learning algorithms to improve performance. 45A number of MCED studies are investigating a range of biomarkers and tests for pan-cancer early detection.A particular challenge is the low prevalence of most cancer types in populations at average risk (Box 3). 38,44,45Although the MCED approach is Narrative reviews       Narrative reviews associated with better aggregate sensitivity or positive predictive value for multiple cancers, the accuracy or performance for individual cancer types varies and may be limited.Moreover, sensitivity for early stage disease, in particular early stage ovarian cancer, remains limited. 46Other challenges that need resolving include accuracy of tissue of origin; testing pathway and strategy, including frequency, triage and follow-up; level of over diagnosis; and impact on mortality and cost-effectiveness.
It is important for the adoption of an effective general population ovarian cancer screening strategy that screening trials have mortality as a primary outcome, given that surrogate markers such as downstaging or R0 resection rate have not proved reliable in predicting mortality reduction.
Studies have evaluated multiple biomarkers in addition to Ca125 in pre-diagnostic samples of women developing ovarian cancer, but these additional markers did not improve screening performance compared with Ca125 alone. 24,47A longitudinal multiple biomarker-based early diagnosis strategy may identify cancers missed by Ca125 alone and, therefore, earlier than routine clinical detection, or may detect ovarian cancer before detection by Ca125 and thereby enable a greater reduction in incidence of late stage disease. 48Some new biomarkers with potential include glycovariants of Ca125, 49 Copenhagen Index, 50 Olink panel, 51 and long interspersed nuclear element (LINE-1) open reading frame 1 protein (ORF1p) 52 biomarkers.There is growing consensus that most HGSOC cancers arise from serous tubular intraepithelial carcinoma (STIC) lesions in the fallopian tubes.Modelling studies suggest a fallopian tube STIC lesion takes six to seven years to develop into invasive ovarian cancer. 53 validated STIC biomarker is urgently needed and may lead to huge strides in the quest for an effective ovarian cancer screening strategy.

Improving identification of women at increased risk of ovarian cancer
Women with one first degree relative have an estimated 2.96 familial relative risk (95% CI, 2.35-3.72) of developing ovarian cancer, 54 while women with two or three first degree relatives with ovarian cancer have significantly higher familial relative risk.In addition to the traditional BRCA1 and BRCA2 CSGs, a number of newer moderate penetrance ovarian cancer CSGs (RAD51C, RAD51D, BRIP1, PALB2), with lifetime ovarian cancer risks ranging from 5% to 13%, have been identified and are now routinely tested along with mismatch repair (Lynch syndrome) genes.Surgical prevention to minimise ovarian cancer risk is now recommended and offered to these CSG carriers.Narrative reviews essential to reduce future burden of disease.In the UK, Australia and in other health systems, individuals are offered genetic testing dependent on fulfilling established clinical or family historybased criteria. 8A probability of 10% or greater of carrying a BRCA pathogenic variant is the current clinical threshold for being offered genetic testing.This approach is plagued by restricted access and underutilisation of testing.Importantly, an estimated 50-80% of pathogenic variant carriers for these ovarian cancer CSGs do not fulfil current clinical genetic testing criteria, [57][58][59] and 97% of individuals carrying high penetrance monogenic CSGs (eg, BRCA carriers) remain unidentified despite 25 years of criteria-driven genetic testing. 60fering unselected genetic testing at cancer diagnosis increases the identification of individuals carrying CSGs who can benefit from secondary cancer prevention, along with identification through cascade testing of unaffected family members who can opt for primary cancer prevention.2][63] It is likely that this will become available for all

Narrative reviews
individuals with breast cancer and other solid cancers in the future. 64,65wever, why should we wait for someone to develop cancer in order to identify people in whom we can prevent cancer?Altering this paradigm to unselected population testing can address these limitations and provides a strategy to maximise prevention.The largest evidence base for population testing currently comes from BRCA testing studies in the Jewish population.Jewish population-based BRCA testing more than doubles the number of BRCA carriers identified; is safe, feasible and acceptable; has high satisfaction; reduces anxiety; does not detrimentally affect quality of life or lifestyle; and is cost-saving for the health system. 58,66-69As a result, population-based BRCA testing was introduced in Israel in 2022 70 and was recently launched as a pilot National Health Service program for the UK Jewish population in February 2023. 71phisticated ovarian cancer risk models incorporating multiple risk factors, including a polygenic risk score (PRS), family history, and epidemiological, hormonal and reproductive factors, have recently been validated. 72These can be used to predict a personalised ovarian cancer risk.Women with ovarian cancer risk greater than 4-5% can be offered surgical prevention. 56,73he PROMISE pilot study on population genetic testing showed acceptability, feasibility, high satisfaction and reduced cancer worry with personalised ovarian cancer risk prediction. 74[77] Finding unaffected people at increased ovarian cancer risk in the general population, including pathogenic variant carriers for monogenic ovarian cancer CSGs, should be an urgent priority for population genomics and health systems.Prospective general

Summary of practice points
Practice points

Average risk individuals High risk individuals
Screening for ovarian cancer • Screening for ovarian cancer with Ca125 and/or transvaginal ultrasound is not currently recommended for asymptomatic women at average population risk • Annual Ca125 and transvaginal ultrasound should not be undertaken for women at high risk • Screening is not currently routinely recommended in women at high risk • The potential role of interim surveillance every 4 months as a risk management strategy in women who prefer to defer or delay surgical prevention is currently being evaluated by NICE (UK)

Genetic testing
• Women with high grade epithelial ovarian cancer should be offered panel genetic testing for ovarian cancer susceptibility genes • BRCA testing should be offered to all Jewish individuals (unselected population testing), irrespective of family history, following informed consent • Unselected general population-based genetic testing studies are being undertaken in Australia (DNA Screen) 78,80,81 and the UK (PROTECT-C) 79 • Individuals with a strong family history of cancer should be referred for counselling and testing for an ovarian cancer susceptibility gene if the overall pre-test probability is ≥ 10% • Opportunistic bilateral salpingectomy (OBS) may be offered at routine gynaecological surgery to all women who have completed their family following informed counselling of advantages and disadvantages • Provided no contraindication, women undergoing premature menopause following pre-menopausal RRSO should be offered HRT until 51 years (age of natural menopause) • The HRT plan should be discussed and agreed before surgical prevention (RRSO) • Ongoing trials are assessing the impact of OBS on patients' reported outcomes.Prospective studies with long term follow-up are needed to assess the impact on cancer risk reduction and menopause • Patients are best managed with multidisciplinary team input in a specialist high risk clinic.They should receive evidence-based advice on HRT, symptom management, as well as specialist counselling and ongoing support to manage potential physical, emotional and long term health consequences • In women with good prognosis triple negative breast cancer, short term HRT use on an individualised basis should be discussed with a breast oncologist and menopause specialist with a special interest in this area • A SEE-FIM protocol should be used for histopathological assessment following RRSO • Peritoneal washings should also be undertaken at RRSO

Narrative reviews
population-based genetic testing trials are being pioneered in the UK and Australia to identify individuals at increased cancer risk for targeted screening and prevention. 78The PROTECT-C study 79,80 is evaluating the impact of panel genetic testing for nine medically actionable (BRCA1, BRCA2, PALB2, RAD51C, RAD51D, BRIP1, MLH1, MSH2, MSH6) hereditary breast and ovarian cancer and Lynch syndrome genes, along with concurrent personalised breast cancer and ovarian cancer risk prediction using PRS and epidemiological and reproductive factors in unselected UK women aged over 18 years.The Australian DNA Screen study 81 is offering routine genetic testing for medically actionable hereditary breast and ovarian cancer, Lynch syndrome and familial hypercholesterolaemia genes (BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, LDLR, APOB, PCSK9) to 18-40-year-old individuals. 81Outcomes from these programs will help inform future policy and guidelines related to population genetic testing.

Risk-reducing salpingo-oophorectomy
Surgical prevention remains the gold standard and most effective ovarian cancer prevention strategy.The 2011 National Breast and Ovarian Cancer Centre and Cancer Australia guidelines currently recommend RRSO for women in Australia who are BRCA1 or BRCA2 carriers and/or have Lynch syndrome. 8,9,82RSO with peritoneal washings is undertaken through minimal access surgery and is associated with minimal surgical morbidity. 83RRSO can reduce ovarian cancer risk by 80-97% in BRCA carriers, 84 reduce ovarian cancer and all-cause mortality, 84 reduce ovarian cancer risk by 94% in women at the average population-level risk, 85 and systematic reviews show it is costeffective. 86A small residual risk (2-4%) of primary peritoneal cancer was reported in BRCA carriers, 84 but recent reports highlight negligible residual risk levels. 87RRSO is cost-effective at 4-5% or more lifetime ovarian cancer risk thresholds. 73,88This saves seven to ten years of a woman's life and has been found to be acceptable. 73,88,89This 4-5% lifetime ovarian cancer risk threshold has been supported by a Royal College of Obstetricians and Gynaecologists scientific impact paper 56 and a UK Cancer Genetics Group consensus statement. 55An American group suggested a lower 3-4% lifetime ovarian cancer risk threshold be considered. 90This approach broadens access to surgical prevention for more women at increased risk of ovarian cancer.
It is critical that a standardised histopathological Sectioning and Extensively Examining the Fimbria (SEE-FIM) protocol be used for histological examination after RRSO.Around 5.1% of cases (95% CI, 1.9-10.83%)may have occult STIC or invasive cancer at histology, 83 with most lesions (70%) being fimbrial or distal tubular and more likely to be missed without a SEE-FIM protocol. 91Surgeons should be aware that avoiding thermal injury to the tubal ends doubles the identification of occult tubal lesions. 92STIC and invasive cancers identified should be referred to a tertiary gynaecological oncology centre for multidisciplinary team management.RRSO in pre-menopausal women leads to early surgical menopause, which can detrimentally affect short and long term health outcomes.Pre-menopausal RRSO is associated with increased risks of osteoporosis, neurocognitive decline, heart disease, sexual dysfunction, drop in libido, and vaginal dryness. 93These can be minimised or ameliorated (but not necessarily eradicated) by HRT.Symptomatology, particularly sexual dysfunction, is poorer compared with women who have not undergone pre-menopausal oophorectomy.Although overall satisfaction levels remain high (88-95%), pre-menopausal RRSO is also associated with much higher (~9%) regret than post-menopausal (~1%) RRSO. 94HRT is recommended following pre-menopausal RRSO in women aged up to 51 years provided there is no other contraindication. 56Access to and compliance with HRT is therefore an important issue in the long term follow-up of these women.Poor access, with at times low and varying uptake rates have been reported in the past.Higher uptake rates are reported by women managed in specialist services and high risk clinics. 94,95For women who had RRSO alone (intact uterus), combined oestrogen and progestogen HRT is the standard recommendation.Women with Lynch syndrome may also undergo a hysterectomy due to increased endometrial cancer risk and they therefore need oestrogen-only HRT.HRT can be commenced immediately post-operatively and transdermal preparations have a better side-effect profile.More detailed descriptions on HRT and non-HRT management for early menopause can be found elsewhere. 56

Risk-reducing early salpingectomy and delayed oophorectomy
The broad acceptance of the role of the fallopian tube in the aetiopathogenesis of HGSOC, coupled with the detrimental consequences of early menopause, has enabled the attractive proposition of an alternative two-stage surgical prevention option, with pre-menopausal early salpingectomy (first step) followed by delayed oophorectomy nearer or at menopause.This enables women who may not have undergone RRSO to retain ovarian function for longer while obtaining a level of ovarian cancer risk reduction.The precise level of ovarian cancer risk reduction is not yet established and the long term impact on ovarian function is unknown.RRESDO is currently being offered within research trials in the UK, the US and the Netherlands.These studies have evaluated acceptability, safety, quality of life, impact on menopause, and cost-effectiveness of this approach.The PROTECTOR trial compares RRESDO, RRSO and no surgery (controls) across 42 UK centres. 96Preliminary results from the Dutch multicentre TUBA trial show RRESDO is an acceptable alternative for patients and clinicians, 94,95 and is associated with better sexual function and fewer menopause symptoms than RRSO. 97RRESDO should currently only be offered within a research study setting.

Surgical prevention options for average risk individuals
Widespread recognition of the contribution of the fallopian tube to ovarian cancer aetiology has led to an increasing uptake of OBS as a method of ovarian cancer prevention among women undergoing routine benign gynaecological surgery, such as hysterectomy and sterilisation.Available data confirm OBS is safe, takes minimal additional time, does not increase complication rate, and has acceptable morbidity, albeit a potentially increased need for analgesia. 98A higher risk of haemorrhage (odds ratio [OR], 1.24; 95% CI, 1.15-1.33)and blood transfusion may occur in women undergoing salpingectomy during a caesarean delivery, although the absolute effect size (3.8% v 3.1%) is small. 99OBS is frequently discussed or offered in Australia, usually at the time of hysterectomy. 100itial evidence for ovarian cancer risk reduction with salpingectomy comes from large Scandinavian populationbased case-control studies from Denmark (ovarian cancer cases, Narrative reviews 13 241; 1:15 age-matched controls) 101 and Sweden (salpingectomy cases, 34 433; controls, 5 449 919). 102These studies suggested bilateral salpingectomy was associated with a 42% (OR, 0.58; 95% CI, 0.36-0.95) 101and 65% (hazard ratio [HR], 0.35; 95% CI, 0.17-0.73) 102reduction in ovarian cancer risk.These studies have been criticised for being retrospective, not correcting for all confounders, having indication and detection biases, having a small number of events, the intervention not being an opportunistic salpingectomy, and the comparator not being the routine gynaecological surgical procedure.Systematic reviews suggest poor quality of evidence from these studies.A lower level of ovarian cancer risk reduction (HR, 0.72; 95% CI, 0.56-0.93)was found from bilateral salpingectomy in a follow-up study after correcting for pelvic inflammatory disease. 103Recent emerging prospective data confirm reduction in serous ovarian cancer risk in particular. 104Although short term follow-up data for up to a couple of years are reassuring, these are not predictive of onset of menopause, and the impact on long term endocrine function and menopause remains to be elucidated.
Hence, initial published data from OBS are helpful and reassuring.However, there is a need for prospective long term high quality studies to inform outcomes of ovarian cancer risk reduction and endocrine function for informed counselling and recommendations for clinical practice.

Conclusions
Some important practice points are listed in Box 4. Ovarian cancer screening is not currently recommended for women at population-level risk in Australia or elsewhere, and a survival benefit has not yet been demonstrated in women at high risk.Surrogate markers such as stage shift seen in the UKCTOCS trial are not reliable endpoints for ovarian cancer screening trials.RRSO is the most clinically effective method for preventing ovarian cancer.There is broadening access to RRSO with it also being recommended for intermediate risk ovarian cancer CSGs and individuals with more than 4-5% lifetime risk of ovarian cancer.Early salpingectomy is associated with fewer menopause symptoms and better sexual function, but the impact on the level of ovarian cancer risk reduction and long term menopause remains to be established.RRESDO should currently only be offered in research studies.Greater unselected testing at cancer diagnosis and upcoming population-based testing strategies can provide a pivotal change to optimise identification of individuals at increased risk of ovarian cancer who can benefit from preventive strategies.

••
Two-centre, case-control, cross sectional trial • Target population: 3600 women aged 45-70 years • MCED biomarker: uterine Pap smear (DOvEEgene) to detect cfDNA using somatic cancer-related mutations, in combination with an established machine learning algorithm • Trial is ongoing • Primary outcome: performance of detection of ovarian and endometrial cancer NHS Galleri trial ‡ (UK; ClinicalTrials.govIdentifier NCT05611632) Pragmatic randomised controlled trial with 1:1 randomisation • Participants: 140 000 individuals, aged 50-77years, who have not received previous cancer treatment for the past 3 years.• MCED biomarker: blood test (Galleri) using DNA methylation patterns to measure cfDNA and assign tissue of origin • Recruitment is complete (31 August 2021 -16 July 2022) • Primary outcome: incidence rate of stage III-IV cancers adjusted by the follow-up time (up to 3-4 years following randomisation) -comparison of incidence in intervention v the control arm cfDNA = cell-free DNA; CSO = cancer signal origin; NHS = National Health Service; PET-C T = positron emission tomography-computed tomography; UK = United Kingdom; US = United States.* All cancers.† Ovarian and endometrial cancers.‡ Fifty types of cancer, including breast, colorectal and ovarian cancer.◆ Ca125 = cancer antigen 125; HRT = hormone replacement therapy; NICE = National Institute for Health and Care Excellence; UK = United Kingdom; RRSO = risk-reducing salpingooophorectomy; SEE-FIM = Sectioning and Extensively Examining the Fimbria.◆ 21 10 12 13 14 15 17

2 Screening average and populations at high risk for ovarian cancer (evidence from key trials) Trial design/arms Key findings and conclusion Populations at average risk
Participants: 202 638 post-menopausal women (median age, 63 years; range, 50-74 years) • Screening strategy: multimodal (longitudinal serum Ca125 interpreted using the ROCA calculation with transvaginal ultrasound and repeat Ca125 as a second line test) and transvaginal ultrasound as first and second line tests • Follow-up: median, 16.3 years (IQR, 15.1-17.3years) • Ovarian cancers: 522/50 625 in the multimodal screening arm; 517/50 623 in the ultrasound scan arm; 1016/101 314 in the control arm • Multicentre, multi-arm RC T with 1:1:2 randomisation to the two screening and the no screening arms respectively • 32 27 Screening strategy: annual serum Ca125 interpreted using single cut-off and transvaginal ultrasound • Follow-up: mean, 3.2 years per woman • WSYs: 11 366 • Ovarian cancers: 26 cases during 11 233 screen-years, additional 10 ovarian cancers beyond censoring 365 days after last screen • Single-arm interventional trial • Participants: 3563 women with ≥ 10% lifetime risk of ovarian cancer • 29 28 31

3 Summary of multicancer early detection (MCED) trials and cohort studies
45 44 PPV for MCED-E and MCED-Scr: 38% and 43.1% respectively; > 1% false positive rates for both versions • Accuracy of cancer signal prediction (CSO): 97% • MCED biomarker: blood test focused on targeted methylation plasma cfDNA-based named "Galleri" (early version MCED-E and later version MCED-Scr) • Primary outcome: number and types of subsequent diagnostic tests, as well as time needed for diagnostic resolution after a signal is identified by the test • Cancer signal was detected in 92 participants • MCED detected 35 cancers; 48% of them were stage I or II • 71% of detected cancers are types of cancers that do not qualify for routine screening •