United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

This extension from University College London (UCL) is required for the entire period of extended follow-up of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and for as long as UKCTOCS Longitudinal Women’s Cohort (UKLWC) has samples and data that are of value to the research community.

UKCTOCS was a multicentre randomised control trial which aimed to assess the impact of screening on ovarian cancer mortality while comprehensively evaluating physical and psychological morbidity, compliance and resource implications of screening and performance characteristics of a serum CA125 (cancer antigen 125) versus ultrasound-based screening strategy. A key secondary objective was to create a bioresource of data and samples for ethically approved secondary studies with a focus on the early detection and treatment of disease.

Primary Purpose:

As part of the primary UKCTOCS analysis, diagnosis codes associated with an ovarian cancer and other gynaecological malignancies and corresponding operation codes are analysed. Where such codes are identified, UKCTOCS will request medical records from the GP or treating consultant for review and confirmation of diagnosis. As part of the UKCTOCS cost-effectiveness analysis, the project will need to consider hospital in-patient and out-patient resource use and costs relating to standard therapy and any follow-on costs associated with an ovarian cancer diagnosis as well as with false positive surgery/investigations in the screened population. A cost-effectiveness analysis compares the cost to the NHS of screening and treatment for ovarian cancer in the screen arms of the trial to costs of diagnosis and treatment in the control (no screening) arm of the trial. In- and out-patient Hospital Episode Statistics (HES) data is critical in identifying the procedures and treatments that both groups received. In addition, HES A&E and HES Critical Care data are required for the routes to diagnosis analysis as many ovarian cancers come through A&E. Some ovarian cancer patients are also likely to be admitted in critical care post-surgery or following a complication. All of this would need to be included in the cost-effectiveness analysis of treatment.

The processing of NHS England data has now concluded for the primary purpose above as the woman have been identified with ovarian cancer.

UCL requires access to NHS England data for the purpose of supporting secondary research studies.

The following is a summary of the aims of the secondary research project provided by UCL

The data will only be used to contribute to identification of cases for nested case control and cohort studies. The data contributes to disease identification and helps to establish the interval between sample collection and diagnosis date. In a proportion of studies, once potential cases are identified, the treating clinician is contacted for the details and confirmation of diagnosis followed by selection of the appropriate serum samples sets from the UKCTOCS biobank.

The above is the only processing activity carried out with NHS England data.

The following NHS England datasets will be accessed:

Hospital Episode Statistics - Admitted Patient Care, Accident & Emergency, Critical Care, Outpatients & Emergency Care Data Set (ECDS) - necessary because UCL need to identify women eligible for the case control or case-only secondary studies. This requires information about diagnosis, treatment, and comorbidity to ensure inclusion and exclusion criteria for individual study design. The information from this data set is combined with other NHS England data sets and information provided by the women in their follow-up questionnaires, data provided by clinicians and primary care physicians and UKCTOCS trial-generated data.

Civil Registration Mortality, Demographics & Cancer Registration necessary because UCL need to identify women diagnosed with the conditions that are being evaluated in the case control or case-only secondary studies.

The level of the data will be identifiable – necessary because UCL need to be able to identify individuals with particular diseases.

The data will be minimised as follows, limited to data for a study cohort identified by UCL who provided NHS number, name, and date of birth of 188,951 UKCTOCS participants. Limited to data received at last update (01-2021); Mortality, Cancers, and demographics – January 2021. Hospital Episode Statistics – February 2020 data (month 12 file). This is limited to 188,951 for NHS England the remaining data set is coming from NHS Northern Ireland. HES data is further limited to the English component of the 188,951.

UCL is the controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above.

There is intention in the future for NHS England data to be accessed by an individual with an honorary contract. If that materialises, UCL will inform NHS England.

The bioresource Data Access Committee members are all UCL substantive employees, the only exception being a UKCTOCS participant. However none of the Data Access Committee members have access to the data and their role is to approve projects.

No other organisations are involved in the management of the bioresource.

Amazon Web Services (AWS) is a processor acting under the instructions of UCL. AWS’ role is limited to secure back-up of data stored in UCL’s Data Safe Haven.

The lawful basis for processing personal data under the UK GDPR is: Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller.

The lawful basis for processing special category data under the UK GDPR is: Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. It is in the public interest because a cost-effectiveness analysis compares the cost to the NHS of screening and treatment for ovarian cancer in the screen arms of the trial to costs of diagnosis and treatment in the control (no screening) arm of the trial.

The funding is provided by UCL. The funding is specifically for the research study described. Funding is in place until end 2023 and is renewed annually.

A Public and Patient Information and Engagement group was consulted at the start of the trial in 2001 and throughout the trial regarding the collection of the data and samples for the purposes described above. Since the primary purpose has been completed this is now continued by having a participant in the Data Access Committee.

The core of the work (the trial) was academic and funded by MRC/CRUK/NIHR/ The Eve appeal.

With regards to secondary studies, this involves collaborations with both academic and industry partners in the areas outlined above.

Where a secondary study involves collaborations with industry partners there is no direct commercial benefit from using NHS England data to identify UKCTOCS participants with or without specific diseases. There may be indirect commercial benefits for the industry partners if the ensuing research supports or leads to the development of a product however these partners have no influence over how UCL (as controller) determine the purposes for this study. Products will either be used to improve detection or treatment of diseases and in doing so be of benefit to the general public.

The expected outputs of the processing will be: Presentations to scientific conferences, Publications are listed and published on the website, All outputs will be reported in Research FISH.

Data and samples from the trial will be a continuous resource for health research, especially early detection of disease. A database to be utilised as a resource for health research.

The outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The outputs will be communicated to relevant recipients through the following dissemination channels: Journals, Public events - conferences, Posters displayed at conferences and Press/media engagement.

The list of UKCTOCS publications are available on the website, UKCTOCS core publications and UKCTOCS secondary study publications. All outputs are also listed on Research Fish.

Outputs have been disseminated since the trial start in 2001 with the final results of the main trial published in 2021. With regards to secondary studies UCL expect outputs to continue, with those from current research slated to be published in the next 5 years.

Primary objective: The NHS England data contributed to the identification of ovarian cancer cases and deaths which were crucial to the core UKCTOCS publications for the main findings in the Lancet in 2016 and 2021. The results have shown that both at three and at nine and half years after end of screening, there was a significant increase in women with early-stage (stage I and II) and decrease in women with advanced-stage (stage III and IV) ovarian and tubal cancers in the multimodal screening group compared to the no screening group. However, there was no reduction in deaths from ovarian and tubal cancer in the screen groups compared to the no screening group. It suggests that general population screening cannot currently be recommended using the current tests. As a result there is an significant impetus both from charities such as Cancer Research UK (CRUK) and industry and academic groups to discover and validate new markers for ovarian cancer.

The results also illustrate the importance of specifying cancer deaths as the primary outcome in screening trials, as detecting less women with advanced stage disease did not translate into lives saved. This is a crucial finding given that there is a drive to shift from reduction in mortality to decrease in advanced stage as a primary end point for screening trials. In fact, the NHS Galleri trial (https://www.nhs-galleri.org/) that has just completed recruitment has already adopted the latter. The ongoing exploratory analyses for the disparity between decrease in advanced stage ovarian cancer and mortality, the modelling of ovarian cancer history and the exploration of surrogates for mortality in UKCTOCS will provide crucial information to the ongoing debate.

The UKCTOCS team have been invited to participate in discussions involving the NHS, CRUK and the National Institute for Health and Care Research (NIHR) on the implications of the UKCTOCS results, ways forward for early cancer detection, design and analysis strategies of new screening trials given the experience and conduct of UKCTOCS.

Secondary objective: There has been contribution to the field of knowledge in early detection cancer biomarkers through the research collaborations.

There are two distinct purposes for which the data are required.

Primary Purpose:

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a multicentre randomised control trial which aims to assess the impact of screening on ovarian cancer mortality while comprehensively evaluating physical and psychological morbidity, compliance and resource implications of screening and performance characteristics of a serum CA125 versus ultrasound based screening strategy.

The UKCTOCS team published the primary outcome on impact of screening for ovarian cancer on mortality in December 2015. The UKCTOCS team demonstrated for ovarian cancer a significant reduction in stage and a non-significant 15% mortality reduction in the multi-modal screening group compared to the control (no screening) group. When prevalent cancer cases were excluded, there was a significant reduction in mortality of 20%. The mortality rate was rising in the control arm at censorship while it seemed to be plateauing in the screen arms. On the basis of this evidence, the UKCTOCS team are undertaking extended follow-up of the UKCTOCS cohort through to end of 2019.

At the end of the extended follow-up there will be a further mortality and cost-effectiveness analysis. In addition, there will be continued detailed analysis of routes to diagnosis, investigations and treatment of the patients in the three arms of the trial.

The data will be processed only by the core UKCTOCS team for the purposes of:

• identification of episodes of ovarian and related cancers and details of management;

• identification of the treating physicians for the purposes of requesting medical documentation required for the review process;

• identification of resource costs involved in the diagnosis/treatment of ovarian cancer

• identification of treatment – surgery which may have resulted in removal of ovaries for the purpose of censorship

University College London is using the data to ensure that UKCTOCS have tracked individual patients for the cost-effectiveness analysis. The data will ensure that UKCTOCS capture ALL hospital events over the follow-up period. The analysis will be undertaken on an Intent to Treat basis from the perspective of the NHS provider and therefore, as there will be judgement used over which hospital events are directly related to ovarian cancer, particularly for the control arm patients, it will be valuable to include all hospital events for the individual patients enrolled in the trial.

GDPR:

The lawful basis for processing data under GDPR has been reviewed against the guidance provided by IGARD and been assessed as acceptable. The details are:

Article 6(1)(e)

"processing is necessary for the performance of a task in the public interest or in the exercise of official authority vested in the controller"

'Public Authority': University College London is a public authority. The Data Protection Act 2018 s7(1)(a) defines ‘public bodies’ for the purpose of the GDPR as “a public authority as defined by the Freedom of Information Act 2000”. The FOI Act 2000 Part 1, section 3 (1)(a)(i) specifies that a public authority means any body which is listed in Schedule 1. Schedule 1 of the FOI Act 2000 lists “Maintained schools and further and higher education institutions” as public authorities.

‘Public Task’: Section 8 of the Data Protection Act 2018 clarifies that “In Article 6(1) of the GDPR (lawfulness of processing), the reference in point (e) to processing of personal data that is necessary for the performance of a task carried out in the public interest or in the exercise of the controller’s official authority includes processing of personal data that is necessary for… (d) the exercise of a function of the Crown, a Minister of the Crown or a government department”. University College London has a Royal Charter that includes the following statement “The objects of the College shall be to provide education and courses of study in the fields of Arts, Laws, Pure Sciences, Medicine and Medical Sciences, Social Sciences and Applied Sciences and in such other fields of learning as may from time to time be decided upon by the College and to encourage research in the said branches of knowledge and learning and to organise, encourage and stimulate postgraduate study in such branches.

‘Necessity’: Throughout the application process, the necessity of the processing for the performance of the task has been assessed. This included but was not limited to ensuring appropriate minimisation of the data to ensure that only the minimum amount of data required are processed. During the application process it has been considered whether the information that the processing aims to determine is already available from other sources or whether the task could be performed using publicly available data or data from alternative sources than NHS Digital. Consideration has been given to whether the volume of data being requested is proportionate to the expected benefit and, through examination of the expected benefits consideration has been given to whether the task is itself necessary. The applicants have been involved in this process and participated in teleconference with our data production team to agree which data products and fields were appropriate for use for the purpose of processing. Therefore, we are satisfied that this request is appropriate, necessary and proportionate for the performance of the task described in the Purpose statement and that there is no other reasonable means for the data processor to achieve their purpose that is less intrusive to the data subjects.

Article 9(2)(j)

"processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject"

The data are required for research purposes in the public interest – meeting the conditions in the DPA 2018 Schedule 1 Part 1 (4) - which GDPR Recital 52(2) determines is an appropriate derogation from the prohibition on processing special categories of personal data. The ways in which the processing of data will be of benefit to the public – thereby demonstrating that the processing is in the public interest – are described in section ‘5d. ii. Expected Measurable Benefits to Health and/or Social Care Including Target Date’.

- In accordance with GDPR Article 89(1) processing is subject to appropriate safeguards. These include:

i. The data will only be used in identifiable form for the specific purpose of data linkage and quality assurance of that linkage – for which purpose use of identifiable data is necessary – and measures are taken to ensure subsequent uses of the data will involve only data that has been appropriately pseudonymised

ii. The data recipient’s technical and organisational measures to safeguard the data have been assessed and meet NHS Digital’s acceptance criteria (see sections 2 and 5b of this application for further details);

iii. The requested data has been assessed as proportionate to the aim pursued (see section 5a of this application for further details);

iv. Controls, data retention and processing activities have been assessed to ensure respect to the essence of the right to data protection (see sections 5a, 5b and 8a of this application for further details);

v. Measures to protect the rights and freedoms of data subjects have been assessed including transparency (fair processing) publishing subject’s rights to withdraw consent and/or have their data erased or rectified, etc. (further information on fair processing is provided within this Abstract below and in section 4 of this application).

Supporting Secondary Research Studies:

At recruitment, which took place between 2001 and 2005, participants donated serum samples to be used along with their data in future ethically approved secondary studies. They provided written consent to allow access to their medical notes and to permit use of their data.

The team is committed to using the data collected during the long-term follow up of the cohort together with donated serum samples for identification and validation of novel risk prediction/screening/ early detection/diagnosis/treatment strategies including costs, disease biomarkers, insights into natural history of disease and wellbeing in older women and impact of lifestyle and screening on disease outcome.

Proposals for secondary studies have to be ethically approved and access to samples/data have to be approved by a Data Access Committee which includes a trial participant. Secondary studies in the field of cancer, cardio-vascular disease and increasingly other chronic diseases in older women are continuously being proposed, submitted for grant applications and being funded, with CRUK and European Union the largest funders so far. As it is not possible to predict exactly which cancer/disease will be investigated UKCTOCS requires HES data on the entire range of diagnoses rather than just the ovarian cancer episodes needed for the primary purpose.

To support the secondary studies detailed above, the UKCTOCS team will use the data supplied by NHS Digital solely for the purpose of

(1) identification of participants to be included in a specific secondary study. Examples include

a. for a case control study of myocardial infarction (MI), where the UKCTOCS team already have self-reported data on MI and data from MINAP, HES data will be used to confirm and validate the reported data, to identify episodes that occurred after the date of self-reporting as well as additional cases. This would be done by searching for the specific ICD codes in relevant HES fields such as outpatient/inpatient DIAG. The information will be used towards generating a new processed FINAL DIAG data field.

b. for a case control study of dementia, where the UKCTOCS team have not asked about the disease on postal surveys, HES data would be used to identify cases by searching for the specific ICD codes in relevant HES fields such as outpatient/inpatient DIAG. Information on dementia will also be obtained from death registration data. The information will be used to generate a new processed FINAL DIAG data field.

(2) enrichment of phenotypic data on a woman with regard to a specific disease. For example

a. in a cohort study of MI for a prognostic biomarker, the UKCTOCS team would classify the treatment patients underwent into a few major groups. This would be derived by searching the relevant HES field using OPCS codes. The information will be used to generate a final treatment category that will be stored in a new processed FINAL TREATMENT data field.

b. in phenotyping a cancer the UKCTOCS team might infer routes to diagnosis by the hospital department where the patient was seen in the episode that led to the diagnosis for e.g. an ovarian cancer patient being admitted through A&E or first seen in Gastroenterology outpatients instead of Gynaecological Oncology. The information will be used to generate a final routes to diagnosis category that will be stored in a new processed FINAL ROUTES DIAG data field.

(3) provide comparative cost-effectiveness data. For example:

a. The samples from over 45,000 women will be tested for a condition called MGUS. MGUS (monoclonal gammopathy of unknown significance) is a non-cancerous condition. People with MGUS make an abnormal protein, called a paraprotein or M-protein, which is found in the urine or blood. To estimate the cost-effectiveness of screening for MGUS in the UK and the prevention or early treatment of associated health conditions, HES data will be used to compare the health care resource use and disease incidence (for a set of pre-specified conditions) of the potentially 1000 participants who will be found to have undiagnosed MGUS and matched 5,000 (from the 170,000) controls. The UKCTOCS team will use existing unit cost resources (e.g. NHS Reference Costs) to cost secondary health care use in these group and disease incidence to model future survival and quality of life.

The use of samples/data in secondary studies, usually case control studies, requires not only identifying the disease but also further details of the individual/disease to ensure eligibility for the particular study. This additional data, required to make the case/control selection, include type of treatment, route to diagnosis, treatment date so that appropriate samples before or after diagnosis/treatment/recurrence of a cancer are identified and confounding information such as other diseases both in individuals with diseases (cases) and controls. The enriched phenotypic information is generated from the combination of HES data with information provided by the women in their follow-up questionnaires as well as information provided by clinicians and primary care physicians. HES data (in relation to secondary purposes) may only be used to identify and characterise individuals that could have their serum samples/data used within particular studies.

The raw NHS Digital data will only be accessed, analysed and processed by the UKCTOCS team within the Data Safe Haven at the University College London (UCL) and will not be shared with any third party. No dates will ever be shared. Where a diagnosis or event has been identified using HES data the age at which the diagnosis/event occurred will be generated from the HES date and the self-reported date of birth which the participants have shared with the UKCTOCS team.

The data that third parties will have access to is limited to generated fields. Only anonymous data will be released to third parties.

The secondary studies involve both academic and industry partners including Abcodia (a UCL spin-off) which has an exclusive commercial license to work on biomarker discovery and validation using serum samples from the UKCTOCS biobank. Women have given specific written consent as to whether their samples/data should be shared with commercial partners. Neither the storage facility nor any third party (including Abcodia) will have access to the NHS Digital data. Only the UKCTOCS team will have access to the patient level data and data will only be accessed at the approved locations.

Products are limited to publications in peer-reviewed Medical and Scientific Journals, oral and written presentations at national and international conferences and funding/governance reports. Personal data is not disclosed and published data contain only aggregate results where possible with small number suppression used for record level anonymous data, in line with the HES Analysis Guidelines. For some publications in keeping with the data sharing requirements for clinical trials/studies (http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html) the UKCTOCS team need to share individual data that underlie the results reported in the article after de-identification. Record level data would only be shared with researchers who had provided a methodologically sound proposal, which had been reviewed by a steering committee and where a signed data access agreement was in place.

Primary Objective:

The mortality results were published in December 2015. The results showed a significant increase in diagnosis of earlier stage ovarian cancer and a non-significant 15% reduction in disease-specific mortality in the Multi-modal screening group compared to the Control group. There was a significant reduction of 20% when prevalent cases were excluded from the analysis. On the basis of these results and the experience from other screening studies (where long term follow-up resulted in more accurate outcome results) further follow up of the UKCTOCS cohort till 2024 was approved by the ethics committee. A NIHR HTA / CRUK grant has been awarded for initial follow-up and a further mortality analysis when 231 new ovarian cancer deaths have occurred in the control arm (currently estimated to be June 2020). The primary analysis will continue to be a modified intention-to-screen comparison using the Cox proportional hazards model of multimodal screening versus unscreened and Trans-vaginal ultrasound screening versus unscreened separately. Additional analysis will include fitting Royston-Parmar models for a delayed effect and estimating the long term screening effect by excluding prevalent cases. A new cost-effectiveness analysis will involve both within study analysis and modelling of screening in the NHS over a longer time frame using the primary mortality endpoint.

The UKCTOCS team will also continue to undertake data analysis to explore in this unbiased population cohort OC management in the UK, trends with time, novel epidemiological risk factors and symptoms/ routes to diagnosis (in the unscreened arm), stage and socioeconomic status. To achieve this, data received from NHS Digital will continue to be used to identify/trace women diagnosed with ovarian cancer so that the study team can retrieve the patient notes on which analysis is based and to contribute to the analyses. These include:

1) Is Adjudication necessary in ovarian cancer screening trials? A view from United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) - Submitted to BJOG

2) Ovarian cancer symptoms, routes to diagnosis and survival - population cohort study in the ‘no screen’ arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) – Submitted to International Journal of Cancer.

3) Endometrial Thickness and Risk of Cancer: A cohort study nested in the ultrasound arm of the United Kingdom Collaborative Trial for Ovarian Cancer Screening (UKCTOCS) – submitted - JAMA Oncology

4) Association of hysterectomy and primary ovarian cancer risk in post-menopausal women: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) - circulated to authors, feedback received, for submission to Lancet Oncology in Jan 2019

Supporting Secondary Research Studies:

The output of using the data is typically the identification of other cancers/diseases (in the same way as for ovarian cancer) to select cases for inclusion in nested case control studies. Data provided by NHS Digital is used alone or in combination with other data sources and/or new data generated from donated serum samples for identification and validation of novel risk prediction/screening/ early detection/diagnosis/treatment strategies including costs, disease biomarkers, insights into natural history of disease and wellbeing in older women and impact of lifestyle and screening on disease outcome. To date, in addition to the reporting of the primary outcome of UKCTOCS, there have been over 60 published UKCTOCS papers and significantly more oral presentations.

Funding/Governance reports:

Progress reports are also submitted to Ethics committees, Sponsors (UCL) and funders (the NIHR and the Eve Appeal). These do not contain any patient data.

With regards to the primary objective, the mortality results reported in 202 1indicate that currently ovarian cancer screening cannot be recommended in the general population. The results also illustrate the importance of specifying cancer deaths as the primary outcome in screening trials, given that detecting more women earlier with Stage I and II disease did not translate into lives saved.

Below are a number of recent publications that have been prepared using NHS Digital provided data, either in the identification of Ovarian cancer cases or in the identification of case/control nested sample sets. No record-level data supplied by NHS Digital has been published.

Taylor JA, Burnell M, Ryan A, Karpinskyj C, Kalsi JK, Taylor H, Apostolidou S, Sharma A, Manchanda R, Woolas R, Campbell S, Parmar M, Singh N, Jacobs IJ, Menon U, Gentry-Maharaj A. Association of hysterectomy and invasive epithelial ovarian and tubal cancer: a cohort study within UKCTOCS. BJOG. 2021 Sep 23. doi: 10.1111/1471-0528.16943. Online ahead of print. PMID: 34555263

Menon U, Gentry-Maharaj A, Burnell M, Singh N, Ryan A, Karpinskyj C, Carlino G, Taylor J, Massingham SK, Raikou M, Kalsi JK, Woolas R, Manchanda R, Arora R, Casey L, Dawnay A, Dobbs S, Leeson S, Mould T, Seif MW, Sharma A, Williamson K, Liu Y, Fallowfield L, McGuire AJ, Campbell S, Skates SJ, Jacobs IJ, Parmar M. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2021 Jun 5;397(10290):2182-2193. doi: 10.1016/S0140-6736(21)00731-5. Epub 2021 May 12. PMID: 33991479.

Kalsi JK, Ryan A, Gentry-Maharaj A, Margolin-Crump D, Singh N, Burnell M, Benjamin E, Apostolidou S, Habib M, Massingham S, Karpinskyj C, Woolas R, Widschwendter M, Fallowfield L, Campbell S, Skates S, McGuire A, Parmar M, Jacobs I, Menon U. Completeness and accuracy of national cancer and death registration for outcome ascertainment in trials-an ovarian cancer exemplar. Trials. 2021 Jan 25;22(1):88. doi: 10.1186/s13063-020-04968-x. PMID: 33494753; PMCID: PMC7831170.

Borges MC, Schmidt AF, Jefferis B, Wannamethee SG, Lawlor DA, Kivimaki M, Kumari M, Gaunt TR, Ben-Shlomo Y, Tillin T, Menon U, Providencia R, Dale C, Gentry-Maharaj A, Hughes A, Chaturvedi N, Casas JP, Hingorani AD; UCLEB Consortium**. Circulating Fatty Acids and Risk of Coronary Heart Disease and Stroke: Individual Participant Data Meta-Analysis in Up to 16 126 Participants. J Am Heart Assoc. 2020 Mar 3;9(5):e013131. doi: 10.1161/JAHA.119.013131. Epub 2020 Mar 2. PMID: 32114887; PMCID: PMC7335585.

Geary B, Walker MJ, Snow JT, Lee DCH, Pernemalm M, Maleki-Dizaji S, Azadbakht N, Apostolidou S, Barnes J, Krysiak P, Shah R, Booton R, Dive C, Crosbie PA, Whetton AD. Identification of a Biomarker Panel for Early Detection of Lung Cancer Patients. J Proteome Res. 2019 Sep 6;18(9):3369-3382. doi: 10.1021/acs.jproteome.9b00287. Epub 2019 Aug 21.PMID: 31408348

Jin, Z., Collier, T. S., Dai, D. L. Y., Chen, V., Hollander, Z., Ng, R. T, McManus BM, Balshaw R, Apostolidou, S, Penny, MS, Bystrom, C. Development and Validation of Apolipoprotein AI-Associated Lipoprotein Proteome Panel for the Prediction of Cholesterol Efflux Capacity and Coronary Artery Disease. Clin Chem. 2019 Feb; 65(2):282-290. doi: 10.1373/clinchem.2018.291922. Epub 2018 Nov 21.

Methylation patterns in serum DNA for early identification of disseminated breast cancer. Widschwendter M, Evans I, Jones A, Ghazali S, Reisel D, Ryan A, Gentry-Maharaj A, Zikan M, Cibula D, Eichner J, Genome Med. 2017 Dec 22;9(1):115. doi: 10.1186/s13073-017-0499-9.

There are two distinct purposes for which the data are required.

Primary Purpose:

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a multicentre randomised control trial which aims to assess the impact of screening on ovarian cancer mortality while comprehensively evaluating physical and psychological morbidity, compliance and resource implications of screening and performance characteristics of a serum CA125 versus ultrasound based screening strategy.

The UKCTOCS team published the primary outcome on impact of screening for ovarian cancer on mortality in December 2015. The UKCTOCS team demonstrated for ovarian cancer a significant reduction in stage and a non-significant 15% mortality reduction in the multi-modal screening group compared to the control (no screening) group. When prevalent cancer cases were excluded, there was a significant reduction in mortality of 20%. The mortality rate was rising in the control arm at censorship while it seemed to be plateauing in the screen arms. On the basis of this evidence, the UKCTOCS team are undertaking extended follow-up of the UKCTOCS cohort through to end of 2019.

At the end of the extended follow-up there will be a further mortality and cost-effectiveness analysis. In addition, there will be continued detailed analysis of routes to diagnosis, investigations and treatment of the patients in the three arms of the trial.

The data will be processed only by the core UKCTOCS team for the purposes of:

• identification of episodes of ovarian and related cancers and details of management;

• identification of the treating physicians for the purposes of requesting medical documentation required for the review process;

• identification of resource costs involved in the diagnosis/treatment of ovarian cancer

• identification of treatment – surgery which may have resulted in removal of ovaries for the purpose of censorship

University College London is using the data to ensure that UKCTOCS have tracked individual patients for the cost-effectiveness analysis. The data will ensure that UKCTOCS capture ALL hospital events over the follow-up period. The analysis will be undertaken on an Intent to Treat basis from the perspective of the NHS provider and therefore, as there will be judgement used over which hospital events are directly related to ovarian cancer, particularly for the control arm patients, it will be valuable to include all hospital events for the individual patients enrolled in the trial.

Supporting Secondary Research Studies:

At recruitment, which took place between 2001 and 2005, participants donated serum samples to be used along with their data in future ethically approved secondary studies. They provided written consent to allow access to their medical notes and to permit use of their data.

The team is committed to using the data collected during the long-term follow up of the cohort together with donated serum samples for identification and validation of novel risk prediction/screening/ early detection/diagnosis/treatment strategies including costs, disease biomarkers, insights into natural history of disease and wellbeing in older women and impact of lifestyle and screening on disease outcome.

Proposals for secondary studies have to be ethically approved and access to samples/data have to be approved by a Data Access Committee which includes a trial participant. Secondary studies in the field of cancer, cardio-vascular disease and increasingly other chronic diseases in older women are continuously being proposed, submitted for grant applications and being funded, with CRUK and European Union the largest funders so far. As it is not possible to predict exactly which cancer/disease will be investigated UKCTOCS requires HES data on the entire range of diagnoses rather than just the ovarian cancer episodes needed for the primary purpose.

To support the secondary studies detailed above, the UKCTOCS team will use the data supplied by NHS Digital solely for the purpose of

(1) identification of participants to be included in a specific secondary study. Examples include

a. for a case control study of myocardial infarction (MI), where the UKCTOCS team already have self-reported data on MI and data from MINAP, HES data will be used to confirm and validate the reported data, to identify episodes that occurred after the date of self-reporting as well as additional cases. This would be done by searching for the specific ICD codes in relevant HES fields such as outpatient/inpatient DIAG. The information will be used towards generating a new processed FINAL DIAG data field.

b. for a case control study of dementia, where the UKCTOCS team have not asked about the disease on postal surveys, HES data would be used to identify cases by searching for the specific ICD codes in relevant HES fields such as outpatient/inpatient DIAG. Information on dementia will also be obtained from death registration data. The information will be used to generate a new processed FINAL DIAG data field.

(2) enrichment of phenotypic data on a woman with regard to a specific disease. For example

a. in a cohort study of MI for a prognostic biomarker, the UKCTOCS team would classify the treatment patients underwent into a few major groups. This would be derived by searching the relevant HES field using OPCS codes. The information will be used to generate a final treatment category that will be stored in a new processed FINAL TREATMENT data field.

b. in phenotyping a cancer the UKCTOCS team might infer routes to diagnosis by the hospital department where the patient was seen in the episode that led to the diagnosis for e.g. an ovarian cancer patient being admitted through A&E or first seen in Gastroenterology outpatients instead of Gynaecological Oncology. The information will be used to generate a final routes to diagnosis category that will be stored in a new processed FINAL ROUTES DIAG data field.

(3) provide comparative cost-effectiveness data. For example:

a. The samples from over 45,000 women will be tested for a condition called MGUS. MGUS (monoclonal gammopathy of unknown significance) is a non-cancerous condition. People with MGUS make an abnormal protein, called a paraprotein or M-protein, which is found in the urine or blood. To estimate the cost-effectiveness of screening for MGUS in the UK and the prevention or early treatment of associated health conditions, HES data will be used to compare the health care resource use and disease incidence (for a set of pre-specified conditions) of the potentially 1000 participants who will be found to have undiagnosed MGUS and matched 5,000 (from the 170,000) controls. The UKCTOCS team will use existing unit cost resources (e.g. NHS Reference Costs) to cost secondary health care use in these group and disease incidence to model future survival and quality of life.

The use of samples/data in secondary studies, usually case control studies, requires not only identifying the disease but also further details of the individual/disease to ensure eligibility for the particular study. This additional data, required to make the case/control selection, include type of treatment, route to diagnosis, treatment date so that appropriate samples before or after diagnosis/treatment/recurrence of a cancer are identified and confounding information such as other diseases both in individuals with diseases (cases) and controls. The enriched phenotypic information is generated from the combination of HES data with information provided by the women in their follow-up questionnaires as well as information provided by clinicians and primary care physicians. HES data (in relation to secondary purposes) may only be used to identify and characterise individuals that could have their serum samples/data used within particular studies.

The raw NHS Digital data will only be accessed, analysed and processed by the UKCTOCS team within the Data Safe Haven at the University College London (UCL) and will not be shared with any third party. No dates will ever be shared. Where a diagnosis or event has been identified using HES data the age at which the diagnosis/event occurred will be generated from the HES date and the self-reported date of birth which the participants have shared with the UKCTOCS team.

The data that third parties will have access to is limited to generated fields. Only anonymous data will be released to third parties.

The secondary studies involve both academic and industry partners including Abcodia (a UCL spin-off) which has an exclusive commercial license to work on biomarker discovery and validation using serum samples from the UKCTOCS biobank. Women have given specific written consent as to whether their samples/data should be shared with commercial partners. Neither the storage facility nor any third party (including Abcodia) will have access to the NHS Digital data. Only the UKCTOCS team will have access to the patient level data and data will only be accessed at the approved locations.

Products are limited to publications in peer-reviewed Medical and Scientific Journals, oral and written presentations at national and international conferences and funding/governance reports. Personal data is not disclosed and published data contain only aggregate results where possible with small number suppression used for record level anonymous data, in line with the HES Analysis Guidelines. For some publications in keeping with the data sharing requirements for clinical trials/studies (http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html) the UKCTOCS team need to share individual data that underlie the results reported in the article after de-identification. Record level data would only be shared with researchers who had provided a methodologically sound proposal, which had been reviewed by a steering committee and where a signed data access agreement was in place.

Primary Objective:

The mortality results were published in December 2015. The results showed a significant increase in diagnosis of earlier stage ovarian cancer and a non-significant 15% reduction in disease-specific mortality in the Multi-modal screening group compared to the Control group. There was a significant reduction of 20% when prevalent cases were excluded from the analysis. On the basis of these results and the experience from other screening studies (where long term follow-up resulted in more accurate outcome results) further follow up of the UKCTOCS cohort till 2024 was approved by the ethics committee. A NIHR HTA / CRUK grant has been awarded for initial follow-up and a further mortality analysis when 231 new ovarian cancer deaths have occurred in the control arm (currently estimated to be June 2020). The primary analysis will continue to be a modified intention-to-screen comparison using the Cox proportional hazards model of multimodal screening versus unscreened and Trans-vaginal ultrasound screening versus unscreened separately. Additional analysis will include fitting Royston-Parmar models for a delayed effect and estimating the long term screening effect by excluding prevalent cases. A new cost-effectiveness analysis will involve both within study analysis and modelling of screening in the NHS over a longer time frame using the primary mortality endpoint.

The UKCTOCS team will also continue to undertake data analysis to explore in this unbiased population cohort OC management in the UK, trends with time, novel epidemiological risk factors and symptoms/ routes to diagnosis (in the unscreened arm), stage and socioeconomic status. To achieve this, data received from NHS Digital will continue to be used to identify/trace women diagnosed with ovarian cancer so that the study team can retrieve the patient notes on which analysis is based and to contribute to the analyses. These include:

1) Is Adjudication necessary in ovarian cancer screening trials? A view from United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) - Submitted to BJOG

2) Ovarian cancer symptoms, routes to diagnosis and survival - population cohort study in the ‘no screen’ arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) – Submitted to International Journal of Cancer.

3) Endometrial Thickness and Risk of Cancer: A cohort study nested in the ultrasound arm of the United Kingdom Collaborative Trial for Ovarian Cancer Screening (UKCTOCS) – submitted - JAMA Oncology

4) Association of hysterectomy and primary ovarian cancer risk in post-menopausal women: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) - circulated to authors, feedback received, for submission to Lancet Oncology in Jan 2019

Supporting Secondary Research Studies:

The output of using the data is typically the identification of other cancers/diseases (in the same way as for ovarian cancer) to select cases for inclusion in nested case control studies. Data provided by NHS Digital is used alone or in combination with other data sources and/or new data generated from donated serum samples for identification and validation of novel risk prediction/screening/ early detection/diagnosis/treatment strategies including costs, disease biomarkers, insights into natural history of disease and wellbeing in older women and impact of lifestyle and screening on disease outcome. To date, in addition to the reporting of the primary outcome of UKCTOCS, there have been over 60 published UKCTOCS papers and significantly more oral presentations.

Funding/Governance reports:

Progress reports are also submitted to Ethics committees, Sponsors (UCL) and funders (the NIHR and the Eve Appeal). These do not contain any patient data.

Primary benefits and anticipated yields remain unchanged from the previous DSA: The initial results on the impact of screening for ovarian cancer in the general population on disease-specific mortality were published in December 2015. The results showed a significant increase in diagnosis of earlier stage ovarian cancer and a non-significant 15% reduction in disease-specific mortality in the Multi-modal screening group compared to the Control group. There was a significant reduction of 20% when prevalent cases were excluded from the analysis. On the basis of these results and the experience from other screening studies (where long term follow-up resulted in more accurate outcome results) further follow up of the UKCTOCS cohort till 2024 was approved by the ethics committee. A NIHR HTA / CRUK grant has been awarded for initial follow-up and a further mortality analysis when 231 new ovarian cancer deaths have occurred in the control arm (currently estimated to be June 2020). If mortality reduction is confirmed and is cost-effective on extended follow-up, this would support introduction of a national screening service for ovarian cancer in the UK and improve OC outcomes worldwide.

The cost-effectiveness analysis performed by the UKCTOCS group concluded that the Multimodal screening strategy quickly approaches the current NICE thresholds for cost-effectiveness. Similarly, a publication based on UKCTOCS summary data suggests that a multimodal screening programme for ovarian cancer in the United States could be potentially cost-effective depending upon final significance of mortality reduction and the cost of the CA-125 risk algorithm.

Below are a number of recent publications that have been prepared using NHS Digital provided data, either in the identification of Ovarian cancer cases or in the identification of case/control nested sample sets. No record-level data supplied by NHS Digital has been published.

1. A quantitative performance study of two automatic methods for the diagnosis of ovarian cancer. Biomed Signal Process Control. Vázquez MA, Mariño IP, Blyuss O, Ryan A, Gentry-Maharaj A, Kalsi J, Manchanda R, Jacobs I, Menon U, Zaikin A. 2018 Sep;46:86-93

2. Comparison of Longitudinal CA125 Algorithms as a First-Line Screen for Ovarian Cancer in the General Population. Jacobs I, Zaikin A, Menon U. Clin Cancer Res. 2018 Oct 1;24(19):4726-4733. doi: 10.1158/1078-0432.CCR-18-0208. Epub 2018 Jul 3.

3. Parenclitic networks for predicting ovarian cancer. Whitwell HJ, Blyuss O, Menon U, Timms JF, Zaikin A. Oncotarget. 2018 Apr 27;9(32):22717-22726. doi: 10.18632/oncotarget.25216. eCollection 2018 Apr 27.

4. Association between skirt size and chronic liver disease in post-menopausal women: a prospective cohort study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS). Trembling PM, Apostolidou S, Gentry-Maharaj A, Parkes J, Ryan A, Tanwar S, Burnell M, Menon U, Rosenberg WM. BMC Public Health. 2018 Mar 27;18(1):409. doi: 10.1186/s12889-018-5308-x.

5. The potential of circulating tumor DNA methylation analysis for the early detection and management of ovarian cancer. T, Yang Z, Teschendorff AE, Ryan A, Cibula D, Menon U, Wittenberger T. Genome Med. 2017 Dec 22;9(1):116. doi: 10.1186/s13073-017-0500-7.

6. Methylation patterns in serum DNA for early identification of disseminated breast cancer. Widschwendter M, Evans I, Jones A, Ghazali S, Reisel D, Ryan A, Gentry-Maharaj A, Zikan M, Cibula D, Eichner J, Genome Med. 2017 Dec 22;9(1):115. doi: 10.1186/s13073-017-0499-9.

7. Evidence of Altered Glycosylation of Serum Proteins Prior to Pancreatic Cancer Diagnosis. Krishnan S, Whitwell HJ, Cuenco J, Gentry-Maharaj A, Menon U, Pereira SP, Gaspari M, Timms JF. Int J Mol Sci. 2017 Dec 9;18(12). pii: E2670. doi: 10.3390/ijms18122670.

8. The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Menon U, McGuire AJ, Raikou M, Ryan A, Davies SK, Burnell M, Gentry-Maharaj A, Kalsi JK, Singh N, Amso NN, Cruickshank D, Dobbs S, Godfrey K, Herod J, Leeson S, Mould T, Murdoch J, Oram D, Scott I, Seif MW, Williamson K, Woolas R, Fallowfield L, Campbell S, Skates SJ, Parmar M, Jacobs IJ. Br J Cancer. 2017 Aug 22;117(5):619-627. doi: 10.1038/bjc.2017.222. Epub 2017 Jul 25.

9. 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). Trembling PM, Apostolidou S, Gentry-Maharaj A, Parkes J, Ryan A, Tanwar S, Burnell M, Jacobs I, Menon U, Rosenberg WM. BMC Public Health. 2017 Jun 28;17(1):603. doi: 10.1186/s12889-017-4518-y.

10. Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer. Yang WL, Gentry-Maharaj A, Simmons A, Ryan A, Fourkala EO, Lu Z, Baggerly KA, Zhao Y, Lu KH, Bowtell D, Jacobs I, Skates SJ, He WW, Menon U, Bast RC Jr; AOCS Study Group. Clin Cancer Res. 2017 Oct 1;23(19):5912-5922. doi: 10.1158/1078-0432.CCR-17-0284. Epub 2017 Jun 21.

11. Testing breast cancer serum biomarkers for early detection and prognosis in pre-diagnosis samples. Kazarian A, Blyuss O, Metodieva G, Gentry-Maharaj A, Ryan A, Kiseleva EM, Prytomanova OM, Jacobs IJ, Widschwendter M, Menon U, Timms JF. Br J Cancer. 2017 Feb 14;116(4):501-508. doi: 10.1038/bjc.2016.433. Epub 2017 Jan 12.

12. Novel risk models for early detection and screening of ovarian cancer. Russell MR, D'Amato A, Graham C, Crosbie EJ, Gentry-Maharaj A, Ryan A, Kalsi JK, Fourkala EO, Dive C, Walker M, Whetton AD, Menon U, Jacobs I, Graham RL. Oncotarget. 2017 Jan 3;8(1):785-797. doi: 10.18632/oncotarget.13648.

13. Long-Term Secondary Care Costs of Endometrial Cancer: A Prospective Cohort Study Nested within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Pennington M, Gentry-Maharaj A, Karpinskyj C, Miners A, Taylor J, Manchanda R, Iyer R, Griffin M, Ryan A, Jacobs I, Menon U, Legood R. PLoS One. 2016 Nov 9;11(11):e0165539. doi: 10.1371/journal.pone.0165539. eCollection 2016.

14. Sex hormone measurements using mass spectrometry and sensitive extraction radioimmunoassay and risk of estrogen receptor negative and positive breast cancer: Case control study in UK Collaborative Cancer Trial of Ovarian Cancer Screening (UKCTOCS). Fourkala EO, Blyuss O, Field H, Gunu R, Ryan A, Barth J, Jacobs I, Zaikin A, Dawnay A, Menon U. Steroids. 2016 Jun;110:62-69. doi: 10.1016/j.steroids.2016.04.003. Epub 2016 Apr 16. PMID: 27091764

15. Serial Patterns of Ovarian Cancer Biomarkers in a Prediagnosis Longitudinal Dataset. Blyuss O, Gentry-Maharaj A, Fourkala EO, Ryan A, Zaikin A, Menon U, Jacobs I, Timms JF. Biomed Res Int. 2015;2015:681416. doi: 10.1155/2015/681416. Epub 2015 Dec 24. PMID: 26819954

16. Protein Z: A putative novel biomarker for early detection of ovarian cancer. Russell MR, Walker MJ, Williamson AJ, Gentry-Maharaj A, Ryan A, Kalsi J, Skates S, D'Amato A, Dive C, Pernemalm M, Humphryes PC, Fourkala EO, Whetton AD, Menon U, Jacobs I, Graham RL. Int J Cancer. 2016 Jun 15;138(12):2984-92. doi: 10.1002/ijc.30020. Epub 2016 Feb 19. PMID: 26815306

There are two distinct purposes for which the data are required.

Primary Purpose:

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a multicentre randomised control trial which aims to assess the impact of screening on ovarian cancer mortality while comprehensively evaluating physical and psychological morbidity, compliance and resource implications of screening and performance characteristics of a serum CA125 versus ultrasound based screening strategy.

The UKCTOCS team published the primary outcome on impact of screening for ovarian cancer on mortality in December 2015. The UKCTOCS team demonstrated for ovarian cancer a significant reduction in stage and a non-significant 15% mortality reduction in the multi-modal screening group compared to the control (no screening) group. When prevalent cancer cases were excluded, there was a significant reduction in mortality of 20%. The mortality rate was rising in the control arm at censorship while it seemed to be plateauing in the screen arms. On the basis of this evidence, the UKCTOCS team are undertaking extended follow-up of the UKCTOCS cohort through to end of 2019.

At the end of the extended follow-up there will be a further mortality and cost-effectiveness analysis. In addition, there will be continued detailed analysis of routes to diagnosis, investigations and treatment of the patients in the three arms of the trial.

The data will be processed only by the core UKCTOCS team for the purposes of:

• identification of episodes of ovarian and related cancers and details of management;

• identification of the treating physicians for the purposes of requesting medical documentation required for the review process;

• identification of resource costs involved in the diagnosis/treatment of ovarian cancer

• identification of treatment – surgery which may have resulted in removal of ovaries for the purpose of censorship

University College London is using the data to ensure that UKCTOCS have tracked individual patients for the cost-effectiveness analysis. The data will ensure that UKCTOCS capture ALL hospital events over the follow-up period. The analysis will be undertaken on an Intent to Treat basis from the perspective of the NHS provider and therefore, as there will be judgement used over which hospital events are directly related to ovarian cancer, particularly for the control arm patients, it will be valuable to include all hospital events for the individual patients enrolled in the trial.

Supporting Secondary Research Studies:

At recruitment, which took place between 2001 and 2005, participants donated serum samples to be used along with their data in future ethically approved secondary studies. They provided written consent to allow access to their medical notes and to permit use of their data.

The team is committed to using the data collected during the long-term follow up of the cohort together with donated serum samples for identification and validation of novel risk prediction/screening/ early detection/diagnosis/treatment strategies including costs, disease biomarkers, insights into natural history of disease and wellbeing in older women and impact of lifestyle and screening on disease outcome.

Proposals for secondary studies have to be ethically approved and access to samples/data have to be approved by a Data Access Committee which includes a trial participant. Secondary studies in the field of cancer, cardio-vascular disease and increasingly other chronic diseases in older women are continuously being proposed, submitted for grant applications and being funded, with CRUK and European Union the largest funders so far. As it is not possible to predict exactly which cancer/disease will be investigated UKCTOCS requires HES data on the entire range of diagnoses rather than just the ovarian cancer episodes needed for the primary purpose.

To support the secondary studies detailed above, the UKCTOCS team will use the data supplied by NHS Digital solely for the purpose of

(1) identification of participants to be included in a specific secondary study. Examples include

a. for a case control study of myocardial infarction (MI), where the UKCTOCS team already have self-reported data on MI and data from MINAP, HES data will be used to confirm and validate the reported data, to identify episodes that occurred after the date of self-reporting as well as additional cases. This would be done by searching for the specific ICD codes in relevant HES fields such as outpatient/inpatient DIAG. The information will be used towards generating a new processed FINAL DIAG data field.

b. for a case control study of dementia, where the UKCTOCS team have not asked about the disease on postal surveys, HES data would be used to identify cases by searching for the specific ICD codes in relevant HES fields such as outpatient/inpatient DIAG. Information on dementia will also be obtained from death registration data. The information will be used to generate a new processed FINAL DIAG data field.

(2) enrichment of phenotypic data on a woman with regard to a specific disease. For example

a. in a cohort study of MI for a prognostic biomarker, the UKCTOCS team would classify the treatment patients underwent into a few major groups. This would be derived by searching the relevant HES field using OPCS codes. The information will be used to generate a final treatment category that will be stored in a new processed FINAL TREATMENT data field.

b. in phenotyping a cancer the UKCTOCS team might infer routes to diagnosis by the hospital department where the patient was seen in the episode that led to the diagnosis for e.g. an ovarian cancer patient being admitted through A&E or first seen in Gastroenterology outpatients instead of Gynaecological Oncology. The information will be used to generate a final routes to diagnosis category that will be stored in a new processed FINAL ROUTES DIAG data field.

(3) provide comparative cost-effectiveness data. For example:

a. The samples from over 45,000 women will be tested for a condition called MGUS. MGUS (monoclonal gammopathy of unknown significance) is a non-cancerous condition. People with MGUS make an abnormal protein, called a paraprotein or M-protein, which is found in the urine or blood. To estimate the cost-effectiveness of screening for MGUS in the UK and the prevention or early treatment of associated health conditions, HES data will be used to compare the health care resource use and disease incidence (for a set of pre-specified conditions) of the potentially 1000 participants who will be found to have undiagnosed MGUS and matched 5,000 (from the 170,000) controls. The UKCTOCS team will use existing unit cost resources (e.g. NHS Reference Costs) to cost secondary health care use in these group and disease incidence to model future survival and quality of life.

The use of samples/data in secondary studies, usually case control studies, requires not only identifying the disease but also further details of the individual/disease to ensure eligibility for the particular study. This additional data, required to make the case/control selection, include type of treatment, route to diagnosis, treatment date so that appropriate samples before or after diagnosis/treatment/recurrence of a cancer are identified and confounding information such as other diseases both in individuals with diseases (cases) and controls. The enriched phenotypic information is generated from the combination of HES data with information provided by the women in their follow-up questionnaires as well as information provided by clinicians and primary care physicians. HES data (in relation to secondary purposes) may only be used to identify and characterise individuals that could have their serum samples/data used within particular studies.

The raw NHS Digital data will only be accessed, analysed and processed by the UKCTOCS team within the Data Safe Haven at the University College London (UCL) and will not be shared with any third party. No dates will ever be shared. Where a diagnosis or event has been identified using HES data the age at which the diagnosis/event occurred will be generated from the HES date and the self-reported date of birth which the participants have shared with the UKCTOCS team.

The data that third parties will have access to is limited to generated fields. Only anonymous data will be released to third parties.

The secondary studies involve both academic and industry partners including Abcodia (a UCL spin-off) which has an exclusive commercial license to work on biomarker discovery and validation using serum samples from the UKCTOCS biobank. Women have given specific written consent as to whether their samples/data should be shared with commercial partners. Neither the storage facility nor any third party (including Abcodia) will have access to the NHS Digital data. Only the UKCTOCS team will have access to the patient level data and data will only be accessed at the approved locations.

Products are limited to publications in peer-reviewed Medical and Scientific Journals, oral and written presentations at national and international conferences and funding/governance reports. Personal data is not disclosed and published data contain only aggregate results where possible with small number suppression used for record level anonymous data, in line with the HES Analysis Guidelines. For some publications in keeping with the data sharing requirements for clinical trials/studies (http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html) the UKCTOCS team need to share individual data that underlie the results reported in the article after de-identification. Record level data would only be shared with researchers who had provided a methodologically sound proposal, which had been reviewed by a steering committee and where a signed data access agreement was in place.

Primary Objective:

The mortality results were published in December 2015. The results showed a significant increase in diagnosis of earlier stage ovarian cancer and a non-significant 15% reduction in disease-specific mortality in the Multi-modal screening group compared to the Control group. There was a significant reduction of 20% when prevalent cases were excluded from the analysis. On the basis of these results and the experience from other screening studies (where long term follow-up resulted in more accurate outcome results) further follow up of the UKCTOCS cohort till 2024 was approved by the ethics committee. A NIHR HTA / CRUK grant has been awarded for initial follow-up and a further mortality analysis when 231 new ovarian cancer deaths have occurred in the control arm (currently estimated to be June 2020). The primary analysis will continue to be a modified intention-to-screen comparison using the Cox proportional hazards model of multimodal screening versus unscreened and Trans-vaginal ultrasound screening versus unscreened separately. Additional analysis will include fitting Royston-Parmar models for a delayed effect and estimating the long term screening effect by excluding prevalent cases. A new cost-effectiveness analysis will involve both within study analysis and modelling of screening in the NHS over a longer time frame using the primary mortality endpoint.

The UKCTOCS team will also continue to undertake data analysis to explore in this unbiased population cohort OC management in the UK, trends with time, novel epidemiological risk factors and symptoms/ routes to diagnosis (in the unscreened arm), stage and socioeconomic status. To achieve this, data received from NHS Digital will continue to be used to identify/trace women diagnosed with ovarian cancer so that the study team can retrieve the patient notes on which analysis is based and to contribute to the analyses. These include:

1) Is Adjudication necessary in ovarian cancer screening trials? A view from United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) - Submitted to BJOG

2) Ovarian cancer symptoms, routes to diagnosis and survival - population cohort study in the ‘no screen’ arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) – Submitted to International Journal of Cancer.

3) Endometrial Thickness and Risk of Cancer: A cohort study nested in the ultrasound arm of the United Kingdom Collaborative Trial for Ovarian Cancer Screening (UKCTOCS) – submitted - JAMA Oncology

4) Association of hysterectomy and primary ovarian cancer risk in post-menopausal women: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) - circulated to authors, feedback received, for submission to Lancet Oncology in Jan 2019

Supporting Secondary Research Studies:

The output of using the data is typically the identification of other cancers/diseases (in the same way as for ovarian cancer) to select cases for inclusion in nested case control studies. Data provided by NHS Digital is used alone or in combination with other data sources and/or new data generated from donated serum samples for identification and validation of novel risk prediction/screening/ early detection/diagnosis/treatment strategies including costs, disease biomarkers, insights into natural history of disease and wellbeing in older women and impact of lifestyle and screening on disease outcome. To date, in addition to the reporting of the primary outcome of UKCTOCS, there have been over 60 published UKCTOCS papers and significantly more oral presentations.

Funding/Governance reports:

Progress reports are also submitted to Ethics committees, Sponsors (UCL) and funders (the NIHR and the Eve Appeal). These do not contain any patient data.

Primary benefits and anticipated yields remain unchanged from the previous DSA: The initial results on the impact of screening for ovarian cancer in the general population on disease-specific mortality were published in December 2015. The results showed a significant increase in diagnosis of earlier stage ovarian cancer and a non-significant 15% reduction in disease-specific mortality in the Multi-modal screening group compared to the Control group. There was a significant reduction of 20% when prevalent cases were excluded from the analysis. On the basis of these results and the experience from other screening studies (where long term follow-up resulted in more accurate outcome results) further follow up of the UKCTOCS cohort till 2024 was approved by the ethics committee. A NIHR HTA / CRUK grant has been awarded for initial follow-up and a further mortality analysis when 231 new ovarian cancer deaths have occurred in the control arm (currently estimated to be June 2020). If mortality reduction is confirmed and is cost-effective on extended follow-up, this would support introduction of a national screening service for ovarian cancer in the UK and improve OC outcomes worldwide.

The cost-effectiveness analysis performed by the UKCTOCS group concluded that the Multimodal screening strategy quickly approaches the current NICE thresholds for cost-effectiveness. Similarly, a publication based on UKCTOCS summary data suggests that a multimodal screening programme for ovarian cancer in the United States could be potentially cost-effective depending upon final significance of mortality reduction and the cost of the CA-125 risk algorithm.

Below are a number of recent publications that have been prepared using NHS Digital provided data, either in the identification of Ovarian cancer cases or in the identification of case/control nested sample sets. No record-level data supplied by NHS Digital has been published.

1. A quantitative performance study of two automatic methods for the diagnosis of ovarian cancer. Biomed Signal Process Control. Vázquez MA, Mariño IP, Blyuss O, Ryan A, Gentry-Maharaj A, Kalsi J, Manchanda R, Jacobs I, Menon U, Zaikin A. 2018 Sep;46:86-93

2. Comparison of Longitudinal CA125 Algorithms as a First-Line Screen for Ovarian Cancer in the General Population. Jacobs I, Zaikin A, Menon U. Clin Cancer Res. 2018 Oct 1;24(19):4726-4733. doi: 10.1158/1078-0432.CCR-18-0208. Epub 2018 Jul 3.

3. Parenclitic networks for predicting ovarian cancer. Whitwell HJ, Blyuss O, Menon U, Timms JF, Zaikin A. Oncotarget. 2018 Apr 27;9(32):22717-22726. doi: 10.18632/oncotarget.25216. eCollection 2018 Apr 27.

4. Association between skirt size and chronic liver disease in post-menopausal women: a prospective cohort study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS). Trembling PM, Apostolidou S, Gentry-Maharaj A, Parkes J, Ryan A, Tanwar S, Burnell M, Menon U, Rosenberg WM. BMC Public Health. 2018 Mar 27;18(1):409. doi: 10.1186/s12889-018-5308-x.

5. The potential of circulating tumor DNA methylation analysis for the early detection and management of ovarian cancer. T, Yang Z, Teschendorff AE, Ryan A, Cibula D, Menon U, Wittenberger T. Genome Med. 2017 Dec 22;9(1):116. doi: 10.1186/s13073-017-0500-7.

6. Methylation patterns in serum DNA for early identification of disseminated breast cancer. Widschwendter M, Evans I, Jones A, Ghazali S, Reisel D, Ryan A, Gentry-Maharaj A, Zikan M, Cibula D, Eichner J, Genome Med. 2017 Dec 22;9(1):115. doi: 10.1186/s13073-017-0499-9.

7. Evidence of Altered Glycosylation of Serum Proteins Prior to Pancreatic Cancer Diagnosis. Krishnan S, Whitwell HJ, Cuenco J, Gentry-Maharaj A, Menon U, Pereira SP, Gaspari M, Timms JF. Int J Mol Sci. 2017 Dec 9;18(12). pii: E2670. doi: 10.3390/ijms18122670.

8. The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Menon U, McGuire AJ, Raikou M, Ryan A, Davies SK, Burnell M, Gentry-Maharaj A, Kalsi JK, Singh N, Amso NN, Cruickshank D, Dobbs S, Godfrey K, Herod J, Leeson S, Mould T, Murdoch J, Oram D, Scott I, Seif MW, Williamson K, Woolas R, Fallowfield L, Campbell S, Skates SJ, Parmar M, Jacobs IJ. Br J Cancer. 2017 Aug 22;117(5):619-627. doi: 10.1038/bjc.2017.222. Epub 2017 Jul 25.

9. 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). Trembling PM, Apostolidou S, Gentry-Maharaj A, Parkes J, Ryan A, Tanwar S, Burnell M, Jacobs I, Menon U, Rosenberg WM. BMC Public Health. 2017 Jun 28;17(1):603. doi: 10.1186/s12889-017-4518-y.

10. Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer. Yang WL, Gentry-Maharaj A, Simmons A, Ryan A, Fourkala EO, Lu Z, Baggerly KA, Zhao Y, Lu KH, Bowtell D, Jacobs I, Skates SJ, He WW, Menon U, Bast RC Jr; AOCS Study Group. Clin Cancer Res. 2017 Oct 1;23(19):5912-5922. doi: 10.1158/1078-0432.CCR-17-0284. Epub 2017 Jun 21.

11. Testing breast cancer serum biomarkers for early detection and prognosis in pre-diagnosis samples. Kazarian A, Blyuss O, Metodieva G, Gentry-Maharaj A, Ryan A, Kiseleva EM, Prytomanova OM, Jacobs IJ, Widschwendter M, Menon U, Timms JF. Br J Cancer. 2017 Feb 14;116(4):501-508. doi: 10.1038/bjc.2016.433. Epub 2017 Jan 12.

12. Novel risk models for early detection and screening of ovarian cancer. Russell MR, D'Amato A, Graham C, Crosbie EJ, Gentry-Maharaj A, Ryan A, Kalsi JK, Fourkala EO, Dive C, Walker M, Whetton AD, Menon U, Jacobs I, Graham RL. Oncotarget. 2017 Jan 3;8(1):785-797. doi: 10.18632/oncotarget.13648.

13. Long-Term Secondary Care Costs of Endometrial Cancer: A Prospective Cohort Study Nested within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Pennington M, Gentry-Maharaj A, Karpinskyj C, Miners A, Taylor J, Manchanda R, Iyer R, Griffin M, Ryan A, Jacobs I, Menon U, Legood R. PLoS One. 2016 Nov 9;11(11):e0165539. doi: 10.1371/journal.pone.0165539. eCollection 2016.

14. Sex hormone measurements using mass spectrometry and sensitive extraction radioimmunoassay and risk of estrogen receptor negative and positive breast cancer: Case control study in UK Collaborative Cancer Trial of Ovarian Cancer Screening (UKCTOCS). Fourkala EO, Blyuss O, Field H, Gunu R, Ryan A, Barth J, Jacobs I, Zaikin A, Dawnay A, Menon U. Steroids. 2016 Jun;110:62-69. doi: 10.1016/j.steroids.2016.04.003. Epub 2016 Apr 16. PMID: 27091764

15. Serial Patterns of Ovarian Cancer Biomarkers in a Prediagnosis Longitudinal Dataset. Blyuss O, Gentry-Maharaj A, Fourkala EO, Ryan A, Zaikin A, Menon U, Jacobs I, Timms JF. Biomed Res Int. 2015;2015:681416. doi: 10.1155/2015/681416. Epub 2015 Dec 24. PMID: 26819954

16. Protein Z: A putative novel biomarker for early detection of ovarian cancer. Russell MR, Walker MJ, Williamson AJ, Gentry-Maharaj A, Ryan A, Kalsi J, Skates S, D'Amato A, Dive C, Pernemalm M, Humphryes PC, Fourkala EO, Whetton AD, Menon U, Jacobs I, Graham RL. Int J Cancer. 2016 Jun 15;138(12):2984-92. doi: 10.1002/ijc.30020. Epub 2016 Feb 19. PMID: 26815306

There are two distinct purposes for which the data are required.

Primary Purpose:

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a multicentre randomised control trial which aims to assess the impact of screening on ovarian cancer mortality while comprehensively evaluating physical and psychological morbidity, compliance and resource implications of screening and performance characteristics of a serum CA125 versus ultrasound based screening strategy.

The UKCTOCS team published the primary outcome on impact of screening for ovarian cancer on mortality in December 2015. The UKCTOCS team demonstrated for ovarian cancer a significant reduction in stage and a non-significant 15% mortality reduction in the multi-modal screening group compared to the control (no screening) group. When prevalent cancer cases were excluded, there was a significant reduction in mortality of 20%. The mortality rate was rising in the control arm at censorship while it seemed to be plateauing in the screen arms. On the basis of this evidence, the UKCTOCS team are undertaking extended follow-up of the UKCTOCS cohort through to end of 2019.

At the end of the extended follow-up there will be a further mortality and cost-effectiveness analysis. In addition, there will be continued detailed analysis of routes to diagnosis, investigations and treatment of the patients in the three arms of the trial.

The data will be processed only by the core UKCTOCS team for the purposes of:

• identification of episodes of ovarian and related cancers and details of management;

• identification of the treating physicians for the purposes of requesting medical documentation required for the review process;

• identification of resource costs involved in the diagnosis/treatment of ovarian cancer

• identification of treatment – surgery which may have resulted in removal of ovaries for the purpose of censorship

University College London is using the data to ensure that UKCTOCS have tracked individual patients for the cost-effectiveness analysis. The data will ensure that UKCTOCS capture ALL hospital events over the follow-up period. The analysis will be undertaken on an Intent to Treat basis from the perspective of the NHS provider and therefore, as there will be judgement used over which hospital events are directly related to ovarian cancer, particularly for the control arm patients, it will be valuable to include all hospital events for the individual patients enrolled in the trial.

Supporting Secondary Research Studies:

At recruitment, which took place between 2001 and 2005, participants donated serum samples to be used along with their data in future ethically approved secondary studies. They provided written consent to allow access to their medical notes and to permit use of their data.

The team is committed to using the data collected during the long-term follow up of the cohort together with donated serum samples for identification and validation of novel risk prediction/screening/ early detection/diagnosis/treatment strategies including costs, disease biomarkers, insights into natural history of disease and wellbeing in older women and impact of lifestyle and screening on disease outcome.

Proposals for secondary studies have to be ethically approved and access to samples/data have to be approved by a Data Access Committee which includes a trial participant. Secondary studies in the field of cancer, cardio-vascular disease and increasingly other chronic diseases in older women are continuously being proposed, submitted for grant applications and being funded, with CRUK and European Union the largest funders so far. As it is not possible to predict exactly which cancer/disease will be investigated UKCTOCS requires HES data on the entire range of diagnoses rather than just the ovarian cancer episodes needed for the primary purpose.

To support the secondary studies detailed above, the UKCTOCS team will use the data supplied by NHS Digital solely for the purpose of

(1) identification of participants to be included in a specific secondary study. Examples include

a. for a case control study of myocardial infarction (MI), where the UKCTOCS team already have self-reported data on MI and data from MINAP, HES data will be used to confirm and validate the reported data, to identify episodes that occurred after the date of self-reporting as well as additional cases. This would be done by searching for the specific ICD codes in relevant HES fields such as outpatient/inpatient DIAG. The information will be used towards generating a new processed FINAL DIAG data field.

b. for a case control study of dementia, where the UKCTOCS team have not asked about the disease on postal surveys, HES data would be used to identify cases by searching for the specific ICD codes in relevant HES fields such as outpatient/inpatient DIAG. Information on dementia will also be obtained from death registration data. The information will be used to generate a new processed FINAL DIAG data field.

(2) enrichment of phenotypic data on a woman with regard to a specific disease. For example

a. in a cohort study of MI for a prognostic biomarker, the UKCTOCS team would classify the treatment patients underwent into a few major groups. This would be derived by searching the relevant HES field using OPCS codes. The information will be used to generate a final treatment category that will be stored in a new processed FINAL TREATMENT data field.

b. in phenotyping a cancer the UKCTOCS team might infer routes to diagnosis by the hospital department where the patient was seen in the episode that led to the diagnosis for e.g. an ovarian cancer patient being admitted through A&E or first seen in Gastroenterology outpatients instead of Gynaecological Oncology. The information will be used to generate a final routes to diagnosis category that will be stored in a new processed FINAL ROUTES DIAG data field.

(3) provide comparative cost-effectiveness data. For example:

a. The samples from over 45,000 women will be tested for a condition called MGUS. MGUS (monoclonal gammopathy of unknown significance) is a non-cancerous condition. People with MGUS make an abnormal protein, called a paraprotein or M-protein, which is found in the urine or blood. To estimate the cost-effectiveness of screening for MGUS in the UK and the prevention or early treatment of associated health conditions, HES data will be used to compare the health care resource use and disease incidence (for a set of pre-specified conditions) of the potentially 1000 participants who will be found to have undiagnosed MGUS and matched 5,000 (from the 170,000) controls. The UKCTOCS team will use existing unit cost resources (e.g. NHS Reference Costs) to cost secondary health care use in these group and disease incidence to model future survival and quality of life.

The use of samples/data in secondary studies, usually case control studies, requires not only identifying the disease but also further details of the individual/disease to ensure eligibility for the particular study. This additional data, required to make the case/control selection, include type of treatment, route to diagnosis, treatment date so that appropriate samples before or after diagnosis/treatment/recurrence of a cancer are identified and confounding information such as other diseases both in individuals with diseases (cases) and controls. The enriched phenotypic information is generated from the combination of HES data with information provided by the women in their follow-up questionnaires as well as information provided by clinicians and primary care physicians. HES data (in relation to secondary purposes) may only be used to identify and characterise individuals that could have their serum samples/data used within particular studies.

The raw NHS Digital data will only be accessed, analysed and processed by the UKCTOCS team within the Data Safe Haven at the University College London (UCL) and will not be shared with any third party. No dates will ever be shared. Where a diagnosis or event has been identified using HES data the age at which the diagnosis/event occurred will be generated from the HES date and the self-reported date of birth which the participants have shared with the UKCTOCS team.

The data that third parties will have access to is limited to generated fields. Only anonymous data will be released to third parties.

The secondary studies involve both academic and industry partners including Abcodia (a UCL spin-off) which has an exclusive commercial license to work on biomarker discovery and validation using serum samples from the UKCTOCS biobank. Women have given specific written consent as to whether their samples/data should be shared with commercial partners. Neither the storage facility nor any third party (including Abcodia) will have access to the NHS Digital data. Only the UKCTOCS team will have access to the patient level data and data will only be accessed at the approved locations.

Products are limited to publications in peer-reviewed Medical and Scientific Journals, oral and written presentations at national and international conferences and funding/governance reports. Personal data is not disclosed and published data contain only aggregate results where possible with small number suppression used for record level anonymous data, in line with the HES Analysis Guidelines. For some publications in keeping with the data sharing requirements for clinical trials/studies (http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html) the UKCTOCS team need to share individual data that underlie the results reported in the article after de-identification. Record level data would only be shared with researchers who had provided a methodologically sound proposal, which had been reviewed by a steering committee and where a signed data access agreement was in place.

Primary Objective:

The mortality results were published in December 2015. The results showed a significant increase in diagnosis of earlier stage ovarian cancer and a non-significant 15% reduction in disease-specific mortality in the Multi-modal screening group compared to the Control group. There was a significant reduction of 20% when prevalent cases were excluded from the analysis. On the basis of these results and the experience from other screening studies (where long term follow-up resulted in more accurate outcome results) further follow up of the UKCTOCS cohort till 2024 was approved by the ethics committee. A NIHR HTA / CRUK grant has been awarded for initial follow-up and a further mortality analysis when 231 new ovarian cancer deaths have occurred in the control arm (currently estimated to be June 2020). The primary analysis will continue to be a modified intention-to-screen comparison using the Cox proportional hazards model of multimodal screening versus unscreened and Trans-vaginal ultrasound screening versus unscreened separately. Additional analysis will include fitting Royston-Parmar models for a delayed effect and estimating the long term screening effect by excluding prevalent cases. A new cost-effectiveness analysis will involve both within study analysis and modelling of screening in the NHS over a longer time frame using the primary mortality endpoint.

The UKCTOCS team will also continue to undertake data analysis to explore in this unbiased population cohort OC management in the UK, trends with time, novel epidemiological risk factors and symptoms/ routes to diagnosis (in the unscreened arm), stage and socioeconomic status. To achieve this, data received from NHS Digital will continue to be used to identify/trace women diagnosed with ovarian cancer so that the study team can retrieve the patient notes on which analysis is based and to contribute to the analyses. These include:

1) Is Adjudication necessary in ovarian cancer screening trials? A view from United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) - Submitted to BJOG

2) Ovarian cancer symptoms, routes to diagnosis and survival - population cohort study in the ‘no screen’ arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) – Submitted to International Journal of Cancer.

3) Endometrial Thickness and Risk of Cancer: A cohort study nested in the ultrasound arm of the United Kingdom Collaborative Trial for Ovarian Cancer Screening (UKCTOCS) – submitted - JAMA Oncology

4) Association of hysterectomy and primary ovarian cancer risk in post-menopausal women: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) - circulated to authors, feedback received, for submission to Lancet Oncology in Jan 2019

Supporting Secondary Research Studies:

The output of using the data is typically the identification of other cancers/diseases (in the same way as for ovarian cancer) to select cases for inclusion in nested case control studies. Data provided by NHS Digital is used alone or in combination with other data sources and/or new data generated from donated serum samples for identification and validation of novel risk prediction/screening/ early detection/diagnosis/treatment strategies including costs, disease biomarkers, insights into natural history of disease and wellbeing in older women and impact of lifestyle and screening on disease outcome. To date, in addition to the reporting of the primary outcome of UKCTOCS, there have been over 60 published UKCTOCS papers and significantly more oral presentations.

Funding/Governance reports:

Progress reports are also submitted to Ethics committees, Sponsors (UCL) and funders (the NIHR and the Eve Appeal). These do not contain any patient data.

Primary benefits and anticipated yields remain unchanged from the previous DSA: The initial results on the impact of screening for ovarian cancer in the general population on disease-specific mortality were published in December 2015. The results showed a significant increase in diagnosis of earlier stage ovarian cancer and a non-significant 15% reduction in disease-specific mortality in the Multi-modal screening group compared to the Control group. There was a significant reduction of 20% when prevalent cases were excluded from the analysis. On the basis of these results and the experience from other screening studies (where long term follow-up resulted in more accurate outcome results) further follow up of the UKCTOCS cohort till 2024 was approved by the ethics committee. A NIHR HTA / CRUK grant has been awarded for initial follow-up and a further mortality analysis when 231 new ovarian cancer deaths have occurred in the control arm (currently estimated to be June 2020). If mortality reduction is confirmed and is cost-effective on extended follow-up, this would support introduction of a national screening service for ovarian cancer in the UK and improve OC outcomes worldwide.

The cost-effectiveness analysis performed by the UKCTOCS group concluded that the Multimodal screening strategy quickly approaches the current NICE thresholds for cost-effectiveness. Similarly, a publication based on UKCTOCS summary data suggests that a multimodal screening programme for ovarian cancer in the United States could be potentially cost-effective depending upon final significance of mortality reduction and the cost of the CA-125 risk algorithm.

Below are a number of recent publications that have been prepared using NHS Digital provided data, either in the identification of Ovarian cancer cases or in the identification of case/control nested sample sets. No record-level data supplied by NHS Digital has been published.

1. A quantitative performance study of two automatic methods for the diagnosis of ovarian cancer. Biomed Signal Process Control. Vázquez MA, Mariño IP, Blyuss O, Ryan A, Gentry-Maharaj A, Kalsi J, Manchanda R, Jacobs I, Menon U, Zaikin A. 2018 Sep;46:86-93

2. Comparison of Longitudinal CA125 Algorithms as a First-Line Screen for Ovarian Cancer in the General Population. Jacobs I, Zaikin A, Menon U. Clin Cancer Res. 2018 Oct 1;24(19):4726-4733. doi: 10.1158/1078-0432.CCR-18-0208. Epub 2018 Jul 3.

3. Parenclitic networks for predicting ovarian cancer. Whitwell HJ, Blyuss O, Menon U, Timms JF, Zaikin A. Oncotarget. 2018 Apr 27;9(32):22717-22726. doi: 10.18632/oncotarget.25216. eCollection 2018 Apr 27.

4. Association between skirt size and chronic liver disease in post-menopausal women: a prospective cohort study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS). Trembling PM, Apostolidou S, Gentry-Maharaj A, Parkes J, Ryan A, Tanwar S, Burnell M, Menon U, Rosenberg WM. BMC Public Health. 2018 Mar 27;18(1):409. doi: 10.1186/s12889-018-5308-x.

5. The potential of circulating tumor DNA methylation analysis for the early detection and management of ovarian cancer. T, Yang Z, Teschendorff AE, Ryan A, Cibula D, Menon U, Wittenberger T. Genome Med. 2017 Dec 22;9(1):116. doi: 10.1186/s13073-017-0500-7.

6. Methylation patterns in serum DNA for early identification of disseminated breast cancer. Widschwendter M, Evans I, Jones A, Ghazali S, Reisel D, Ryan A, Gentry-Maharaj A, Zikan M, Cibula D, Eichner J, Genome Med. 2017 Dec 22;9(1):115. doi: 10.1186/s13073-017-0499-9.

7. Evidence of Altered Glycosylation of Serum Proteins Prior to Pancreatic Cancer Diagnosis. Krishnan S, Whitwell HJ, Cuenco J, Gentry-Maharaj A, Menon U, Pereira SP, Gaspari M, Timms JF. Int J Mol Sci. 2017 Dec 9;18(12). pii: E2670. doi: 10.3390/ijms18122670.

8. The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Menon U, McGuire AJ, Raikou M, Ryan A, Davies SK, Burnell M, Gentry-Maharaj A, Kalsi JK, Singh N, Amso NN, Cruickshank D, Dobbs S, Godfrey K, Herod J, Leeson S, Mould T, Murdoch J, Oram D, Scott I, Seif MW, Williamson K, Woolas R, Fallowfield L, Campbell S, Skates SJ, Parmar M, Jacobs IJ. Br J Cancer. 2017 Aug 22;117(5):619-627. doi: 10.1038/bjc.2017.222. Epub 2017 Jul 25.

9. 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). Trembling PM, Apostolidou S, Gentry-Maharaj A, Parkes J, Ryan A, Tanwar S, Burnell M, Jacobs I, Menon U, Rosenberg WM. BMC Public Health. 2017 Jun 28;17(1):603. doi: 10.1186/s12889-017-4518-y.

10. Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer. Yang WL, Gentry-Maharaj A, Simmons A, Ryan A, Fourkala EO, Lu Z, Baggerly KA, Zhao Y, Lu KH, Bowtell D, Jacobs I, Skates SJ, He WW, Menon U, Bast RC Jr; AOCS Study Group. Clin Cancer Res. 2017 Oct 1;23(19):5912-5922. doi: 10.1158/1078-0432.CCR-17-0284. Epub 2017 Jun 21.

11. Testing breast cancer serum biomarkers for early detection and prognosis in pre-diagnosis samples. Kazarian A, Blyuss O, Metodieva G, Gentry-Maharaj A, Ryan A, Kiseleva EM, Prytomanova OM, Jacobs IJ, Widschwendter M, Menon U, Timms JF. Br J Cancer. 2017 Feb 14;116(4):501-508. doi: 10.1038/bjc.2016.433. Epub 2017 Jan 12.

12. Novel risk models for early detection and screening of ovarian cancer. Russell MR, D'Amato A, Graham C, Crosbie EJ, Gentry-Maharaj A, Ryan A, Kalsi JK, Fourkala EO, Dive C, Walker M, Whetton AD, Menon U, Jacobs I, Graham RL. Oncotarget. 2017 Jan 3;8(1):785-797. doi: 10.18632/oncotarget.13648.

13. Long-Term Secondary Care Costs of Endometrial Cancer: A Prospective Cohort Study Nested within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Pennington M, Gentry-Maharaj A, Karpinskyj C, Miners A, Taylor J, Manchanda R, Iyer R, Griffin M, Ryan A, Jacobs I, Menon U, Legood R. PLoS One. 2016 Nov 9;11(11):e0165539. doi: 10.1371/journal.pone.0165539. eCollection 2016.

14. Sex hormone measurements using mass spectrometry and sensitive extraction radioimmunoassay and risk of estrogen receptor negative and positive breast cancer: Case control study in UK Collaborative Cancer Trial of Ovarian Cancer Screening (UKCTOCS). Fourkala EO, Blyuss O, Field H, Gunu R, Ryan A, Barth J, Jacobs I, Zaikin A, Dawnay A, Menon U. Steroids. 2016 Jun;110:62-69. doi: 10.1016/j.steroids.2016.04.003. Epub 2016 Apr 16. PMID: 27091764

15. Serial Patterns of Ovarian Cancer Biomarkers in a Prediagnosis Longitudinal Dataset. Blyuss O, Gentry-Maharaj A, Fourkala EO, Ryan A, Zaikin A, Menon U, Jacobs I, Timms JF. Biomed Res Int. 2015;2015:681416. doi: 10.1155/2015/681416. Epub 2015 Dec 24. PMID: 26819954

16. Protein Z: A putative novel biomarker for early detection of ovarian cancer. Russell MR, Walker MJ, Williamson AJ, Gentry-Maharaj A, Ryan A, Kalsi J, Skates S, D'Amato A, Dive C, Pernemalm M, Humphryes PC, Fourkala EO, Whetton AD, Menon U, Jacobs I, Graham RL. Int J Cancer. 2016 Jun 15;138(12):2984-92. doi: 10.1002/ijc.30020. Epub 2016 Feb 19. PMID: 26815306