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BackgroundRisk-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 ObjectiveTo 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 HypothesisRisk-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 DesignMulti-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 CriteriaInclusion 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; Primary EndpointSexual function measured by validated questionnaires.Sample Size1000 (333 per arm).Estimated Dates for Completing Accrual and Presenting ResultsIt is estimated recruitment will be completed by 2023 and results published by 2027.Trial Registration NumberISRCTN registry: 25 173 360 (https://doi.org/10.1186/ISRCTN25173360).

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

The number of ovarian cancer cases is predicted to rise by 14% in Europe and 55% worldwide over the next 2 decades. The current absence of a screening program, rising drug/treatment costs, and only marginal improvements in survival seen over the past 30 years suggest the need for maximizing primary surgical prevention to reduce the burden of ovarian cancer. Primary surgical prevention through risk-reducing salpingo-oophorectomy (RRSO) is well established as the most effective method for preventing ovarian cancer. In the UK, it has traditionally been offered to high-risk women (>10% lifetime risk of ovarian cancer) who have completed their family. The cost-effectiveness of RRSO in BRCA1/BRCA2 carriers older than 35 years is well established. Recently, RRSO has been shown to be cost-effective in postmenopausal women at lifetime ovarian cancer risks of 5% or greater and in premenopausal women at lifetime risks greater than 4%. The acceptability, uptake, and satisfaction with RRSO at these intermediate-risk levels remain to be established. Prospective outcome data on risk-reducing salpingectomy and delayed-oophorectomy for preventing ovarian cancer is lacking, and hence, this is best offered for primary prevention within the context and safe environment of a clinical trial. An estimated 63% of ovarian cancers occur in women with greater than 4% lifetime risk and 53% in those with 5% or greater lifetime-risk. Risk-reducing salpingo-oophorectomy can be offered for primary surgical prevention to women at intermediate risk levels (4%–5% to 10%). This includes unaffected women who have completed their family and have RAD51C, RAD51D, or BRIP1 gene mutations; first-degree relatives of women with invasive epithelial ovarian cancer; BRCA mutation–negative women from high-risk breast-and-ovarian cancer or ovarian-cancer-only families. In those with BRCA1, RAD51C/RAD51D/MMR mutations and the occasional families with a history of ovarian cancer in their 40s, surgery needs to be considered at younger than 45. In other moderate-risk gene mutation carriers and those with polygenic risk, RRSO needs be considered at 50. There is need for establishment/expansion of well-defined pathways to increase clinical access to RRSO. It is time to lower the risk threshold for RRSO to enable introduction of a targeted primary prevention approach, which could significantly impact the future burden of ovarian cancer.

ObjectiveDifferences in time intervals to diagnosis and treatment between jurisdictions may contribute to previously reported differences in stage at diagnosis and survival. The International Cancer Benchmarking Partnership Module 4 reports the first international comparison of routes to diagnosis and time intervals from symptom onset until treatment start for patients with lung cancer.DesignNewly diagnosed patients with lung cancer, their primary care physicians (PCPs) and cancer treatment specialists (CTSs) were surveyed in Victoria (Australia), Manitoba and Ontario (Canada), Northern Ireland, England, Scotland and Wales (UK), Denmark, Norway and Sweden. Using Wales as the reference jurisdiction, the 50th, 75th and 90th percentiles for intervals were compared using quantile regression adjusted for age, gender and comorbidity.ParticipantsConsecutive newly diagnosed patients with lung cancer, aged ≥40 years, diagnosed between October 2012 and March 2015 were identified through cancer registries. Of 10 203 eligible symptomatic patients contacted, 2631 (27.5%) responded and 2143 (21.0%) were included in the analysis. Data were also available from 1211 (56.6%) of their PCPs and 643 (37.0%) of their CTS.Primary and secondary outcome measuresInterval lengths (days; primary), routes to diagnosis and symptoms (secondary).ResultsWith the exception of Denmark (−49 days), in all other jurisdictions, the median adjusted total interval from symptom onset to treatment, for respondents diagnosed in 2012–2015, was similar to that of Wales (116 days). Denmark had shorter median adjusted primary care interval (−11 days) than Wales (20 days); Sweden had shorter (−20) and Manitoba longer (+40) median adjusted diagnostic intervals compared with Wales (45 days). Denmark (−13), Manitoba (−11), England (−9) and Northern Ireland (−4) had shorter median adjusted treatment intervals than Wales (43 days). The differences were greater for the 10% of patients who waited the longest. Based on overall trends, jurisdictions could be grouped into those with trends of reduced, longer and similar intervals to Wales. The proportion of patients diagnosed following presentation to the PCP ranged from 35% to 75%.ConclusionThere are differences between jurisdictions in interval to treatment, which are magnified in patients with lung cancer who wait the longest. The data could help jurisdictions develop more focused lung cancer policy and targeted clinical initiatives. Future analysis will explore if these differences in intervals impact on stage or survival.

Purpose:Accurate preoperative clinical assessment of adnexal masses can optimize outcomes by ensuring appropriate and timely surgery. This article addresses whether a new technology, ovarian HistoScanning, has an additional diagnostic value in mathematical models developed for the differential diagnosis of adnexal masses.Patients and Methods:Transvaginal sonography-based morphological variables were obtained through blinded analysis of archived images in 199 women enrolled in a prospective study to assess the performance of ovarian HistoScanning. Logistic regression (LR) and neural network (NN) models including these variables and clinical and patient data along with the HistoScanning score (HSS) (range, 0-125; based on mathematical algorithms) were developed in a learning set (60% patients). The remaining 40% patients (evaluation set) were used to assess model performance.Results:Of all morphological and clinical variables tested, serum CA-125, presence of a solid component, and HSS were most significant and used to develop the LR model. The NN model included all variables. The novel variable, HSS, offered significant improvement in the LR and NN models' performance. The LR and NN models in an independent evaluation set were found to have area under the receiver operating characteristic curve = 0.97 (95% confidence interval [CI], 94-99) and 0.93 (95% CI, 88-98), sensitivities = 83% (95% CI, 71%-91%) and 80% (95% CI, 67%-89%), and specificities = 98% (95% CI, 89%-99%) and 86% (95% CI, 72%-95%), respectively. In addition, these models showed an improved performance when compared with 3 other existing models (allP< 0.05).Conclusions:This initial report shows a clear benefit of including ovarian HistoScanning into mathematical models used for discriminating benign from malignant ovarian masses. These models may be specifically helpful to the less experienced examiner. Future research should assess performance of these models in prospective clinical trials in different populations.

The objective is to explore how clinical decisions are made in a cancer multidisciplinary team meeting (MDM). The study design is qualitative based on participant observation, in depth interviews, and questionnaires. The research setting was weekly cancer MDM which provides a forum for clinical debate for practitioners in the field of women's health, working within one Cancer Network in England. The participants were 53 practitioners attending a weekly MDM over a 4-month period. Analysis of nonparticipant observation data and practitioner interview narratives identified key influences on the work of the MDM, and in particular decision-making. The research identified three major influences on the conduct of the MDM. First, MDM discussions are dominated by those with surgical, medical, or diagnostic expertise with limited contributions from those with a nursing, palliative, or psychosocial background. Second, decision-making is shaped by an overriding need to comply with policy initiatives concerning the organization of diagnosis and treatment. The third influence is whether the patient is known or unknown to some degree by members of the MDM. Where there is preexisting knowledge of the patient, the discussion and decision is inclusive of a wider range of disciplines. Team working in these circumstances is an acknowledged source of satisfaction and motivation. Where the patient is not known, discussion concerns only the physical details necessary to make a diagnosis and contributions from the wider team (including those with knowledge of psychosocial care) are rare. Practitioners' sphere of expertise, Department of Health policy, and familiarity of the team with the patient are key factors in shaping decision-making in MDMs.

A variety of biomarkers have been developed to monitor growth of ovarian cancer and to detect disease at an early interval. CA125 (MUC16) has provided a useful serum tumor marker for monitoring response to chemotherapy, detecting disease recurrence, distinguishing malignant from benign pelvic masses, and potentially improving clinical trial design. A rapid fall in CA125 during chemotherapy predicts a favorable prognosis and could be used to redistribute patients on multiarmed randomized clinical trials. Several studies now document that CA125 can serve as a surrogate marker for response in phase II trials. Serial measurement of CA125 might also provide a useful marker for monitoring stabilization of disease with cytostatic targeted therapeutic agents. The greatest potential for serum markers may be in detecting ovarian cancer at an early stage. A rising CA125 can be used to trigger transvaginal sonography (TVS) in a small fraction of patients. An algorithm has been developed that calculates risk of ovarian cancer based on serial CA125 values and refers patients at highest risk for TVS. Use of the algorithm is currently being evaluated in a trial with 200,000 women in the UK that will test critically the ability of a two-stage screening strategy to improve survival in ovarian cancer. Whatever the outcome, as 20% of ovarian cancers have little or no expression of CA125, additional serum markers will be required to detect all patients in an initial phase of screening. More than 30 serum markers have been evaluated alone and in combination with CA125 by different investigators. Some of the most promising include: HE4, mesothelin, M-CSF, osteopontin, kallikrein(s), and soluble EGF receptor. Two proteomic approaches have been used: one examines the pattern of peaks on mass spectroscopy and the other uses proteomic analysis to identify a limited number of critical markers that can be assayed by more conventional methods. Both approaches are promising and require further development. Several groups are placing markers on multiplex platforms to permit simultaneous assay of multiple markers with very small volumes of serum. Mathematical techniques are being developed to analyze combinations of marker levels to improve sensitivity and specificity. In the future, serum markers should improve the sensitivity of detecting recurrent disease as well as facilitate earlier detection of ovarian cancer.

There has been concern about current ovarian cancer screening strategies after the publication showing a lack of benefit from screening in the ovarian part of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The ongoing United Kingdom Collaborative Trial of Ovarian Cancer Screening involves 202,638 low-risk postmenopausal women. The performance characteristics on prevalence screen in sensitivity, specificity, and stage distribution have been encouraging. Screening differs from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the use of algorithms to interpret CA125 and ultrasound imaging and well-defined, centrally coordinated management of screen-detected abnormalities with protocols for intervention based on screening findings. There is a possibility that these essential differences may be sufficient to alter the natural history of ovarian cancer and ultimately lead to demonstration of a mortality benefit from screening when the trial reports in 2014/2015.

Meeting abstracts Early stage detection of cancer is the key to provide a better outcome for therapeutic intervention. Proteomic technologies hold recently great promise in the search of new clinical biomarkers for the early detection and diagnosis of cancer or for the development of new vaccines

There has been considerable interest in the prospect of early detection of ovarian cancer through screening asymptomatic women from the general population. The results of recently published trials provide encouraging data on the possible impact on mortality. There are, however, concerns about compliance, cost, and morbidity from surgery for false positive screen results. The two ongoing randomized controlled trials in the US and UK aim to establish definitively the true impact of screening on ovarian cancer mortality while comprehensively tackling the issues of target population, compliance, health economics, and physical and psychological morbidity of screening.