United Kingdom Collaborative Trial Of Ovarian Cancer Screening Research Articles

The Normal Risk Ovarian Screening Study (NROSS): Twenty-one year update.

5522 Background: The Normal Risk Ovarian Screening Study (NROSS) tested a two-stage screening strategy in post-menopausal women at conventional hereditary risk where significantly rising CA125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer. Methods: A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 women-years in a single arm study ( NCT00539162 ). Serum CA125 was analyzed with the Risk of Ovarian Cancer Algorithm (ROCA) each year. If risk was normal ( < 1:2000), women returned in a year. If risk was elevated ( > 1:500), TVS was undertaken immediately and if risk was intermediate, CA125 was repeated in 3 months, risk recalculated, and the participant re-triaged. An average of 2% of participants were referred to TVS annually. Results: Thirty-four patients were referred for operations detecting 15 ovarian cancers and 2 borderline tumors with 12 in early stage (I-II). In addition, 7 endometrial cancers were detected with 6 in early stage. Thus, the positive predictive value (PPV) of the NROSS trial was 50% (17/34) for detecting ovarian cancer and 74% (25/34) for any cancer, far exceeding the minimum acceptable study endpoint of 10% PPV. As 4 ovarian cancers and 2 borderline tumors were diagnosed within a year of each participant’s last normal risk, the sensitivity for detecting ovarian and borderline cancer was 74% (17/23) and 70% of ROCA-detected cases (12/17) were in stage I-II. NROSS screening reduced incidence of late stage (III-IV) disease by 34% compared to the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) control arm and by 30% compared to US SEER values. Results of our NROSS trial contrast dramatically with those of the recently reported UKCTOCS that showed only a modest 14% early-stage shift, underlying a lack of reduction in mortality. Across multiple randomized trials of mammography, those trials that demonstrated at least a 20% late-stage incidence reduction had a significant mortality reduction, whereas those with less of a stage shift did not. Conclusions: An elevated ROCA, characterized by a significantly rising CA125, prompted referral of 2% of participants to TVS each year and required only 2 operations to detect each case of ovarian cancer, indicating that CA125 used in this way is adequately specific for effective screening. While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV and marked stage shift support further development of this strategy. Clinical trial information: NCT00539162 .

Tracing the Evolution of Clonal Hematopoiesis to AML Using Longitudinal Pre-Diagnosis Blood Samples

▪The acquisition of somatic mutations in hematopoietic stem and progenitor cells (HSPCs) is increasingly common with age ('clonal hematopoiesis'). If sequential acquisition and clonal expansion of mutations occurs, progression to Acute Myeloid Leukemia (AML) can occur. While the mutational landscape of clonal hematopoiesis antecedent to AML development has been well-defined (Abelson et al. 2018, Desai et al. 2018), the timing of acquisition and growth dynamics of these high-risk mutations remain largely unknown. At what age are these mutations acquired? Are the fitness effects (growth rates) conferred by specific mutations predictable from person-to-person and how do fitness effects change with additive mutations? Are the clonal dynamics that precede AML development characterised by strong competition between clones (clonal interference)?To answer these questions, we identified 220 women from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) who were cancer-free at enrolment but subsequently developed AML during the >12 years follow-up. 50 of these women had annual blood samples collected at multiple time-points pre-AML diagnosis (mean: 5 time-points, range: 2-11). Deep error-corrected duplex sequencing, with a variant allele frequency (VAF) detection limit of 0.1%, was performed on peripheral blood DNA from these women, as well as from age- and timepoint-matched controls who remained blood cancer free. A custom designed next-generation sequencing (NGS) panel was used to enable detection of mutations in 34 clonal hematopoiesis/AML-associated genes, genome-wide mosaic chromosomal alterations (mCAs) and AML-associated translocations.Having samples from multiple timepoints enabled the fitness effects (growth rates) of mutations to be calculated, as well as the additive effect of further mutations. These growth rates, in combination with insights from evolutionary theory, allowed the acquisition time of many mutations to be estimated, with initiating driver mutations often arising in the first 2 decades of life in the pre-AML cases. Growth trajectory dynamics of co-occurring mutations enabled the clonal composition to be inferred in many instances and revealed linear evolution of successive mutations in some pre-AML cases, but a branching pattern with clear evidence of clonal interference in others. Specific variants, which we have previously identified as 'highly fit' in clonal hematopoiesis (Watson et al. 2020), were significantly enriched in pre-AML cases compared to controls and were often detectable at VAFs >10% more than 5 years pre-diagnosis. NPM1 mutations, which characteristically occur ‘late’ in AML development, could be detected as early as 2 years pre-diagnosis, highlighting the benefit afforded by error-corrected low VAF variant calling, particularly in high-risk individuals.Our findings, exploiting longitudinal blood samples collected pre-AML combined with an integrated assessment of multiple types of genetic changes, reveal key insights into the evolutionary dynamics of mutations in the years preceding AML development. Understanding which features distinguish pre-malignant from benign clonal evolution is key for risk stratification of individuals with clonal hematopoiesis to allow rational monitoring and identification of individuals that may benefit from early intervention studies. [Display omitted] DisclosuresWatson: Johnson & Johnson: Consultancy; Inivata: Consultancy. Menon: Abcodia Ltd: Current holder of individual stocks in a privately-held company. Blundell: Johnson & Johnson: Consultancy; Inivata: Consultancy.

Completeness and accuracy of national cancer and death registration for outcome ascertainment in trials\u2014an ovarian cancer exemplar

BackgroundThere is a trend to increasing use of routinely collected health data to ascertain outcome measures in trials. We report on the completeness and accuracy of national ovarian cancer and death registration in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).MethodsOf the 202,638 participants, 202,632 were successfully linked and followed through national cancer and death registries of Northern Ireland, Wales and England. Women with registrations of any of 19 pre-defined ICD-10 codes suggestive of tubo-ovarian cancer or notification of ovarian/tubal/peritoneal cancer from hospital episode statistics or trial sites were identified. Copies of hospital and primary care notes were retrieved and reviewed by an independent outcomes review committee. National registration of site and cause of death as ovarian/tubal/peritoneal cancer (C56/C57/C48) obtained up to 3 months after trial censorship was compared to that assigned by outcomes review (reference standard).ResultsOutcome review was undertaken in 3110 women on whom notification was received between 2001 and 2014. Ovarian cancer was confirmed in 1324 of whom 1125 had a relevant cancer registration. Sensitivity and specificity of ovarian/tubal/peritoneal cancer registration were 85.0% (1125/1324; 95% CI 83.7–86.2%) and 94.0% (1679/1786; 95% CI 93.2–94.8%), respectively. Of 2041 death registrations reviewed, 681 were confirmed to have a tubo-ovarian cancer of whom 605 had relevant death registration. Sensitivity and specificity were 88.8% (605/681; 95% CI 86.4–91.2%) and 96.7% (1482/1533, 95% CI 95.8–97.6%), respectively. When multiple electronic health record sources were considered, sensitivity for cancer site increased to 91.1% (1206/1324, 95% CI 89.4–92.5%) and for cause of death 94.0% (640/681, 95% CI 91.9–95.5%).Of 1232 with cancer registration, 8.7% (107/1232) were wrongly designated as ovarian/tubal/peritoneal cancers by the registry and 4.0% (47/1172) of confirmed tubo-ovarian cancers were mis-registered. In 656 with death registrations, 7.8% (51/656) were wrongly assigned as due to ovarian/tubal/peritoneal cancers while 6.2% (40/645) of confirmed tubo-ovarian cancer deaths were mis-registered.ConclusionFollow-up of trial participants for tubo-ovarian cancer using national registry data will result in incomplete ascertainment, particularly of the site due in part to the latency of registration. This can be reduced by using other routinely collected data such as hospital episode statistics. Central adjudication by experts though resource intensive adds value by improving the accuracy of diagnoses.Trial registrationISRCTN: ISRCTN22488978. Registered on 6 April 2000

Multi-Marker Longitudinal Algorithms Incorporating HE4 and CA125 in Ovarian Cancer Screening of Postmenopausal Women.

Longitudinal CA125 algorithms are the current basis of ovarian cancer screening. We report on longitudinal algorithms incorporating multiple markers. In the multimodal arm of United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), 50,640 postmenopausal women underwent annual screening using a serum CA125 longitudinal algorithm. Women (cases) with invasive tubo-ovarian cancer (WHO 2014) following outcome review with stored annual serum samples donated in the 5 years preceding diagnosis were matched 1:1 to controls (no invasive tubo-ovarian cancer) in terms of the number of annual samples and age at randomisation. Blinded samples were assayed for serum human epididymis protein 4 (HE4), CA72-4 and anti-TP53 autoantibodies. Multimarker method of mean trends (MMT) longitudinal algorithms were developed using the assay results and trial CA125 values on the training set and evaluated in the blinded validation set. The study set comprised of 1363 (2–5 per woman) serial samples from 179 cases and 181 controls. In the validation set, area under the curve (AUC) and sensitivity of longitudinal CA125-MMT algorithm were 0.911 (0.871–0.952) and 90.5% (82.5–98.6%). None of the longitudinal multi-marker algorithms (CA125-HE4, CA125-HE4-CA72-4, CA125-HE4-CA72-4-anti-TP53) performed better or improved on lead-time. Our population study suggests that longitudinal HE4, CA72-4, anti-TP53 autoantibodies adds little value to longitudinal serum CA125 as a first-line test in ovarian cancer screening of postmenopausal women.

Socioeconomic Status and Ovarian Cancer Stage at Diagnosis: A Study Nested Within UKCTOCS.

Background: Tubo-ovarian cancer (OC) continues to be the most lethal of all gynaecological cancers. Over half of women are diagnosed with late stage (III/IV) disease, which has a five-year survival rate of 11%. Socioeconomic status (SES) has been shown to have an impact on outcomes of several cancer types, including OC. This study aims to investigate any potential association between SES and stage at diagnosis of OC. Methods: Women from the non-screening arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) with a confirmed diagnosis of OC prior to 01 January 2015 and an English index of multiple deprivation (IMD) score were eligible for the study. The association between IMD and OC stage (FIGO) was analysed using an ordinal logistic regression model adjusted for age at diagnosis and BMI. Results: Four-hundred and fifty seven women were eligible for inclusion in the primary analysis. The odds of being diagnosed with the higher dichotomization of stage (I vs. II/III/IV; I/II vs. III/IV; I/II/III vs. IV) was 1.29 (p = 0.017; 95% CI: 1.048–1.592) per unit SD (standard deviation) increase in IMD. This translates to a 29% increase in odds of being diagnosed at the higher stage per each unit SD increase in IMD. Conclusion: Increased deprivation is consistently associated with a higher probability of being diagnosed with later stage OC.

Ovarian Cancer - Current Status of Blood Biomarker and Imaging Screening Strategies

Ovarian cancer is most lethal of all the gynecologic malignancies and the fifth leading cause of cancer deaths in women overall, accounting for about 5% of female cancer deaths. To improve the outcomes, an efficient screening tool for early detection of the disease at an earlier, curable stage would be required. Since the vast majority of ovarian cancer cases are sporadic in nature with relatively low incidence, a screening test has to offer very high specificity to avoid unnecessary interventions in false-positive cases to be considered suitable for general population use. Another approach to screening would entail increasing the pretest likelihood by focusing on patients at increased risk only. Several larger scale, randomized controlled trials are working on establishing screening strategies for the general population with the most promising results so far shown by the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which revealed improvement in survival rates and reduction in mortality within screened patients. However, more data is required to establish the benefits, warranting further validation. Currently, research is ongoing on OC screening benefits and developing a suitable algorithm in order to have better patient outcomes. In this review article, we discuss current updates on OC screening strategies with special focus on novel development in biomarkers and sonography, as screening tools.

Enhanced Liver Fibrosis Test Predicts Liver-Related Outcomes in Postmenopausal Women with Risk Factors - A Case Control Study Nested within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Background: Chronic liver disease (CLD) is usually asymptomatic but earlier detection is critical to permit life-saving interventions for those at risk due to high alcohol consumption and increased body mass index (BMI). We evaluated performance of the Enhanced Liver Fibrosis (ELF) test in predicting CLD in postmenopausal women with risk factors in a nested case control study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS). Methods: ELF was measured in blinded samples from 58 participants with selfreported high alcohol use and/or BMI ≥25kg/m2 who developed liver-related events (LRE) (cases), and in 115 controls matched for age, alcohol and BMI who did not develop LRE during median follow-up of 8*5 years. Findings: Using Cox regression at an ELF threshold of 9*8 hazard ratio (HR) for LRE was 2*21 (unadjusted model) and 2*18 (adjusted for deprivation and selfreported hypertension, heart disease, hypercholesterolaemia or diabetes). At a threshold of 10*51, HR was 4*88 (unadjusted) and 4*62 (adjusted). ELF was evaluated as a time dependent variable by generating timedependent Cox models; HRs at an ELF threshold of 9*8 were 1*85 (unadjusted) and 1*80 (adjusted), and at a threshold of 10*51 HRs were 1*94 (unadjusted) and 2*05 (adjusted). Interpretation: This study demonstrates that the ELF test predicts complications of CLD in postmenopausal women with risk factors, creating the opportunity to intervene to reduce liver-related mortality and morbidity. Although larger studies are required, these results demonstrate the possible role for ELF as a prognostic tool in health checks in primary care. Funding Statement: No external funding for this nested study. The trial, UKCTOCS, was funded by Medical Research Council (G9901012 and G0801228), Cancer Research UK (C1479/A2884), and the UK Department of Health, with additional support from The Eve Appeal. UM and WMR are supported by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre. SA was funded by Abcodia Pvt Ltd. Declaration of Interests: UM has stocks awarded to her by UCL in Abcodia Pvt. Ltd. WMR is an inventor of the ELF test and has received fees from Siemens Healthineers for lecturing, travel, and consulting and research support. All the other authors declare no conflict of interest. Ethics Approval Statement: The current study was approved by the National Research Ethics Service (NRES) Committee London - Bentham (Ref: 05/Q0505/57) on 10th August 2011.

Comparison of Longitudinal CA125 Algorithms as a First-Line Screen for Ovarian Cancer in the General Population.

Purpose: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), women in the multimodal (MMS) arm had a serum CA125 test (first-line), with those at increased risk, having repeat CA125/ultrasound (second-line test). CA125 was interpreted using the "Risk of Ovarian Cancer Algorithm" (ROCA). We report on performance of other serial algorithms and a single CA125 threshold as a first-line screen in the UKCTOCS dataset.Experimental Design: 50,083 post-menopausal women who attended 346,806 MMS screens were randomly split into training and validation sets, following stratification into cases (ovarian/tubal/peritoneal cancers) and controls. The two longitudinal algorithms, a new serial algorithm, method of mean trends (MMT) and the parametric empirical Bayes (PEB) were trained in the training set and tested in the blinded validation set and the performance characteristics, including that of a single CA125 threshold, were compared.Results: The area under receiver operator curve (AUC) was significantly higher (P = 0.01) for MMT (0.921) compared with CA125 single threshold (0.884). At a specificity of 89.5%, sensitivities for MMT [86.5%; 95% confidence interval (CI), 78.4-91.9] and PEB (88.5%; 95% CI, 80.6-93.4) were similar to that reported for ROCA (sensitivity 87.1%; specificity 87.6%; AUC 0.915) and significantly higher than the single CA125 threshold (73.1%; 95% CI, 63.6-80.8).Conclusions: These findings from the largest available serial CA125 dataset in the general population provide definitive evidence that longitudinal algorithms are significantly superior to simple cutoff values for ovarian cancer screening. Use of these newer algorithms requires incorporation into a multimodal strategy. The results highlight the importance of incorporating serial change in biomarker levels in cancer screening/early detection strategies. Clin Cancer Res; 24(19); 4726-33. ©2018 AACR.

Audit of transvaginal sonography of normal postmenopausal ovaries by sonographers from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Background: We report on a unique audit of seven sonographers self-reporting high visualization rates of normal postmenopausal ovaries in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). This audit was ordered by the trial’s Ultrasound Management Subcommittee after an initiative taken in 2008 to improve the quality of scanning and the subsequent increase in the number of sonographers claiming very high ovary visualisation rates. Methods: Seven sonographers reporting high rates (>89%) of visualizing normal postmenopausal ovaries in examinations performed between 1 st January and 31 st December 2008 were identified. Eight experts in gynaecological scanning reviewed a random selection of exams performed by these sonographers and assessed whether visualization of both ovaries could be confirmed (cVR-Both) in the examinations. A random effects bivariate probit model was fitted to analyse the results. Results: The eight experts reviewed images from 357 examinations performed on 349 postmenopausal women (mean age 60.0 years, range 50.2-73.3) by the seven sonographers. The mean cVR-Both obtained from the model for these sonographers was 67.2% with a range of 47.6-86.5% (95%CI 63.9-70.5%). The range of cVR-Both between the experts was 47.3-88.3% and the intra-class correlation coefficient (ICC) for left and right ovary confirmation was 0.39. Conclusions: The audit suggests that self-reported visualization of postmenopausal ovaries is unreliable, as visualisation of both ovaries could not be confirmed in almost a third of examinations. The agreement for visualization of both ovaries based on review of a static image between experts and sonographers and between expert reviewers alone was only moderate. Further research is needed to develop reliable Quality Control metrics for transvaginal ultrasound.

Audit of transvaginal sonography of normal postmenopausal ovaries by sonographers from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

Background: We report on a unique audit of seven sonographers self-reporting high visualization rates of normal postmenopausal ovaries in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). This audit was ordered by the trial's Ultrasound Management Subcommittee after an initiative taken in 2008 to improve the quality of scanning and the subsequent increase in the number of sonographers claiming very high ovary visualisation rates. Methods: Seven sonographers reporting high rates (>89%) of visualizing normal postmenopausal ovaries in examinations performed between 1 st January and 31 st December 2008 were identified. Eight experts in gynaecological scanning reviewed a random selection of exams performed by these sonographers and assessed whether visualization of both ovaries could be confirmed (cVR-Both) in the examinations. A random effects bivariate probit model was fitted to analyse the results. Results: The eight experts reviewed images from 357 examinations performed on 349 postmenopausal women (mean age 60.0 years, range 50.2-73.3) by the seven sonographers. The mean cVR-Both obtained from the model for these sonographers was 67.2% with a range of 47.6-86.5% (95%CI 63.9-70.5%). The range of cVR-Both between the experts was 47.3-88.3% and the intra-class correlation coefficient (ICC) for left and right ovary confirmation was 0.39. Conclusions: The audit suggests that self-reported visualization of postmenopausal ovaries is unreliable, as visualisation of both ovaries could not be confirmed in almost a third of examinations. The agreement for visualization of both ovaries based on review of a static image between experts and sonographers and between expert reviewers alone was only moderate. Further research is needed to develop reliable Quality Control metrics for transvaginal ultrasound.

Abstract IA15: Early detection of ovarian cancer: An update

Abstract IA15: Early detection of ovarian cancer: An update

Parenclitic networks for predicting ovarian cancer.

Prediction and diagnosis of complex disease may not always be possible with a small number of biomarkers. Modern ‘omics’ technologies make it possible to cheaply and quantitatively assay hundreds of molecules generating large amounts of data from individual samples. In this study, we describe a parenclitic network-based approach to disease classification using a synthetic data set modelled on data from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and serological assay data from a nested set of samples from the same study. This approach allows us to integrate quantitative proteomic and categorical metadata into a single network, and then use network topologies to construct logistic regression models for disease classification. In this study of ovarian cancer, comprising of 30 controls and cases with samples taken <14 months to diagnosis (n = 30) and/or >34 months to diagnosis (n = 29), we were able to classify cases with a sensitivity of 80.3% within 14 months of diagnosis and 18.9% in samples exceeding 34 months to diagnosis at a specificity of 98%. Furthermore, we use the networks to make observations about proteins within the cohort and identify GZMH and FGFBP1 as changing in cases (in relation to controls) at time points most distal to diagnosis. We conclude that network-based approaches may offer a solution to the problem of complex disease classification that can be used in personalised medicine and to describe the underlying biology of cancer progression at a system level.

Estimating Cost-effectiveness of a Multimodal Ovarian Cancer Screening Program in the United States

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is the largest randomized clinical trial to evaluate screening's impact on ovarian cancer mortality, assigning women to multimodal screening (MMS) with serum cancer antigen 125 (CA-125) interpreted using a risk algorithm. If the MMS screening method is eventually shown to reduce mortality and be cost-effective, then it may be accepted by the medical community as a feasible screening tool. To estimate the cost-effectiveness of an MMS screening program in the United States. A Markov simulation model was constructed using data from UKCTOCS to compare MMS with no screening in the United States. Screening would begin at the age of 50 years for women in the general population. Published estimates of the long-term effect of MMS screening on ovarian cancer mortality and the trial's published hazard ratios were used to simulate mortality estimates up to 40 years from start of screening. Base-case costs included CA-125, ultrasound, and false-positive work-up results, in addition to a risk algorithm cost estimate of $100. The utility and costs of ovarian cancer treatment were incorporated into the model. Screening strategies varied by costs of the algorithm and treatment for advanced ovarian cancer, rates of screening compliance, ovarian cancer incidence, and extrapolation of ovarian cancer mortality. Costs, quality-adjusted life-years (QALYs), and mortality reduction of ovarian cancer screening. Multimodal screening is both more expensive and more effective in reducing ovarian cancer mortality over a lifetime than no screening. After accounting for uncertainty in the underlying parameters, screening women starting at age 50 years with MMS is cost-effective 70% of the time, when decision makers are willing to pay $150 000 per QALY. Screening reduced mortality by 15%, with an incremental cost-effectiveness ratio (ICER) ranging from $106 187 (95% CI, $97 496-$127 793) to $155 256 (95% CI, $150 369-$198 567). Ovarian cancer screening is potentially cost-effective in the United States depending on final significance of mortality reduction and cost of the CA-125 risk algorithm. These results are limited by uncertainty around the effect of screening on ovarian cancer mortality beyond the 11 years of UKCTOCS.

P2.13-013 Determination of the Detection Lead Time for Autoantibody Biomarkers in Early Stage Lung Cancer Using the UKCTOCS Cohort

Tumor associated (TA) autoantibodies are present during early stage lung cancer and have been detected up to five years before diagnosis. However the detection lead time provided by their measurement has never been accurately determined due to a lack of suitable patient samples. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) recruited 202,638 postmenopausal women. Annual blood samples were collected for over 10 years during which time a number of lung cancer cases were diagnosed. The primary aim of this study was to determine the detection lead time of tumor associated autoantibody assays for a subset of the UKCTOCS cohort. A set of 142 primary lung cancer cases (NSCLC 83%, SCLC 12%) with 7 serial samples over a pre-diagnosis period of 10 years were randomly split into Training (n=100) and Validation (n=42) cohorts and matched to healthy controls by age-at-diagnosis, age-at-first sample and smoking history. TA autoantibody profiles were produced for each patient by measuring autoantibody levels against a panel of tumor associated antigens ( p53, SOX2, CAGE, NY-ESO-1, GBU4-5, MAGE A4, HuD, CK8, CK20, LMYC, SSX1, p53-95, p16 and p62) using ELISA. The profiles for each patient were compared to those for the preceding time point using a multivariate distance measure to determine if a statistically significant positive change had occurred. Comparison against a population based cut-off for the earliest time point sample for each patient was used to determine initial positivity. An optimized algorithm was developed on the Training cohort and then applied to the Validation cohort. There were 49 positive patients in the training cohort: 11 at the earliest time point and 38 during serial sampling. For the Validation cohort there were 14: 3 at the earliest and 11 during serial sampling. The median detection lead time for the Training cohort was 4.0 years (0.3 to 9.4 range) and for the Validation cohort 4.3 years (0.1 to 9.0 range) before clinical diagnosis. The median was 4.1 years (0.1 to 9.4 range) for the entire cohort. This is the first time statistically sound estimates of detection lead time have been reported for tumor associated autoantibody tests run on such a large cohort of pre-diagnostic serial samples. These cancer biomarkers can be detected on average 4 years before diagnosis. Monitoring autoantibody profiles could be hugely beneficial by enabling earlier detection and stratification of screening populations for cancer. This could lower mortality rates and reduce healthcare costs.

Risk of chronic liver disease in post-menopausal women due to body mass index, alcohol and their interaction: a prospective nested cohort study within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

BackgroundWe investigated the risk of chronic liver disease (CLD) due to alcohol consumption and body mass index (BMI) and the effects of their interaction in a prospective cohort study of women recruited to the UKCTOCS trial.Methods95,126 post-menopausal women without documented CLD were stratified into 12 groups defined by combinations of BMI (normal, overweight, obese) and alcohol consumption (none, <1–15, 16–20 and ≥21 units/week), and followed for an average of 5.1 years. Hazard ratios (HR) were calculated for incident liver-related events (LRE).ResultsFirst LREs were reported in 325 (0.34%) participants. Compared to women with normal BMI, HR = 1.44 (95% CI; 1.10–1.87) in the overweight group and HR = 2.25 (95% CI; 1.70–2.97) in the obese group, adjusted for alcohol and potential confounders. Compared to those abstinent from alcohol, HR = 0.70 (95% CI; 0.55–0.88) for <1–15 units/week, 0.93 (95% CI; 0.50–1.73) for 16–20 units/week and 1.82 (95% CI; 0.97–3.39) for ≥21 units/week adjusted for BMI and potential confounders. Compared to women with normal BMI drinking no alcohol, HR for LRE in obese women consuming ≥21 units/week was 2.86 (95% CI; 0.67–12.42), 1.58 (95% CI; 0.96–2.61) for obese women drinking <1–15 units/week and 1.93 (95% CI; 0.66–5.62) in those with normal BMI consuming ≥21 units/week after adjustment for potential confounders. We found no significant interaction between BMI and alcohol.ConclusionHigh BMI and alcohol consumption and abstinence are risk factors for CLD in post-menopausal women. However, BMI and alcohol do not demonstrate significant interaction in this group.Trial registrationUKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978. Registered 06/04/2000.

Evidence of Stage Shift in Women Diagnosed With Ovarian Cancer During Phase II of the United Kingdom Familial Ovarian Cancer Screening Study

(Abstracted from J Clin Oncol 2017:35(13):1411–1420) For the randomized general population, the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) investigated a new multimodal screening test using the Risk of Ovarian Cancer Algorithm (ROCA), which interprets serial CA-125 results, and transvaginal sonography as a second-line test. High sensitivity and specificity were achieved with this test.

Abstract KP01: UNITED KINGDOM COLLABORATIVE TRIAL OF OVARIAN CANCER SCREENING – (UKCTOCS) – EXPLORING THE RESULTS

Abstract The continued high case fatality ratio in ovarian cancer has underpinned efforts to develop a screening strategy that could impact on mortality. In the general population randomised control trial - United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) two screening strategies (multimodal MMS and ultrasound USS) were compared to no screening (control C). Of 202,638 women randomised between April 2001-October 2005, 50,624 MMS; 50,623 USS; and 101,299 C were eligible for analysis. By the end of screening (December 2011) 345,570 MMS and 327,775 USS annual screens were performed. At censorship for the initial mortality analysis on 31st December 2014, there was an overall significant stage shift in invasive epithelial ovarian/tubal/peritoneal cancer in the MMS group compared to C in an ‘intention to screen’ analysis. More detailed analysis has shown this stage shift seen in the MMS group was limited to Type II (high grade serous) ovarian cancers. This was associated with a delayed but not yet statistically significant mortality reduction. Disease specific mortality rates in the C arm were continuing to rise while they appeared to have plateaued in the screen arms. Further follow-up is now underway to confirm the mortality reduction and determine its full extent. Meanwhile a focus on detecting low volume disease using cancer specific markers, novel biospecimens such as endocervical samples, targeted imaging and time series algorithms for interpreting marker profile suggest that a new era in ovarian cancer screening is underway. Citation Format: Usha Menon. UNITED KINGDOM COLLABORATIVE TRIAL OF OVARIAN CANCER SCREENING – (UKCTOCS) – EXPLORING THE RESULTS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr KP01.

Cost-effectiveness of screening for ovarian cancer amongst postmenopausal women: a model-based economic evaluation.

BackgroundThe United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) was the biggest ovarian cancer screening trial to date. A non-significant effect of screening on ovarian cancer was reported, but the authors noted a potential delayed effect of screening, and suggested the need for four years further follow-up. There are no UK-based cost-effectiveness analyses of ovarian cancer screening. Hence we assessed the lifetime outcomes associated with, and the cost-effectiveness of, screening for ovarian cancer in the UK, along with the value of further research.MethodsWe performed a model-based economic evaluation. Effectiveness data were taken from UKCTOCS, which considered strategies of multimodal screening (MMS), ultrasound screening (USS) and no screening. We conducted systematic reviews to identify the remaining model inputs, and performed a rigorous and transparent prospective evaluation of different methods for extrapolating the effect of screening on ovarian cancer mortality. We considered costs to the UK healthcare system and measured effectiveness using quality-adjusted life years (QALYs). We used value of information methods to estimate the value of further research.ResultsOver a lifetime, MMS and USS were estimated to be both more expensive and more effective than no screening. USS was dominated by MMS, being both more expensive and less effective. Compared with no screening, MMS cost on average £419 more (95% confidence interval £255 to £578), and generated 0.047 more QALYs (0.002 to 0.088). The incremental cost-effectiveness ratio (ICER) comparing MMS with no screening was £8864 per QALY (£2600 to £51,576). Alternative extrapolation methods increased the ICER, with the highest value being £36,769 (£13,888 to dominated by no screening). Using the UKCTOCS trial horizon, both MMS and USS were dominated by no screening, as they produced fewer QALYs at a greater cost. The value of research into eliminating all uncertainty in long-term effectiveness was estimated to be worth up to £20 million, or approximately £5 million for four years follow-up.ConclusionsScreening for ovarian cancer with MMS is both more effective and more expensive than not screening. Compared to national willingness to pay thresholds, lifetime cost-effectiveness is promising, but there remains considerable uncertainty regarding extrapolated long-term effectiveness.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0743-y) contains supplementary material, which is available to authorized users.

Novel risk models for early detection and screening of ovarian cancer.

PurposeOvarian cancer (OC) is the most lethal gynaecological cancer. Early detection is required to improve patient survival. Risk estimation models were constructed for Type I (Model I) and Type II (Model II) OC from analysis of Protein Z, Fibronectin, C-reactive protein and CA125 levels in prospectively collected samples from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).ResultsModel I identifies cancers earlier than CA125 alone, with a potential lead time of 3-4 years. Model II detects a number of high grade serous cancers at an earlier stage (Stage I/II) than CA125 alone, with a potential lead time of 2-3 years and assigns high risk to patients that the ROCA Algorithm classified as normal.Materials and MethodsThis nested case control study included 418 individual serum samples serially collected from 49 OC cases and 31 controls up to six years pre-diagnosis. Discriminatory logit models were built combining the ELISA results for candidate proteins with CA125 levels.ConclusionsThese models have encouraging sensitivities for detecting pre-clinical ovarian cancer, demonstrating improved sensitivity compared to CA125 alone. In addition we demonstrate how the models improve on ROCA for some cases and outline their potential future use as clinical tools.

Long-Term Secondary Care Costs of Endometrial Cancer: A Prospective Cohort Study Nested within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

BackgroundThere is limited evidence on the costs of Endometrial Cancer (EC) by stage of disease. We estimated the long-term secondary care costs of EC according to stage at diagnosis in an English population-based cohort.MethodsWomen participating in UKCTOCS and diagnosed with EC following enrolment (2001–2005) and prior to 31st Dec 2009 were identified to have EC through multiple sources. Survival was calculated through data linkage to death registry. Costs estimates were derived from hospital records accessed from Hospital Episode Statistics (HES) with additional patient level covariates derived from case notes and patient questionnaires. Missing and censored data was imputed using Multiple Imputation. Regression analysis of cost and survival was undertaken.Results491 of 641 women with EC were included. Five year total costs were strongly dependent on stage, ranging from £9,475 (diagnosis at stage IA/IB) to £26,080 (diagnosis at stage III). Stage, grade and BMI were the strongest predictors of costs. The majority of costs for stage I/II EC were incurred in the first six months after diagnosis while for stage III / IV considerable costs accrued after the first six months.ConclusionsIn addition to survival advantages, there are significant cost savings if patients with EC are detected earlier.