The EMBED Study: Early Markers for Breast Cancer Detection

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Objective for processing

BACKGROUND The University of Cambridge requires access to NHS England data for the purpose of the following research project: The EMBED Study: Early Markers for Breast Cancer Detection The following is a summary of the aims of the research project provided by the University of Cambridge: [3 paragraphs unchanged] The EMBED study (Early Markers for Breast Cancer Detection) (https://embed.phpc.cam.ac.uk/), which this [34 words unchanged] Breast Cancer) study (covered under a separate Data Sharing Agreement with NHS Digital - England- DARS-NIC-302473-K6R0Z) - a prospective cohort study which has recruited and followed individuals [20 words unchanged] a new cohort of women at an increased risk of breast cancer. The EMBED study team at the University of Cambridge also collaborate in [31 words unchanged] University of Cambridge and involves analysis of tumour blood samples. The NHS Digital England data requested under this DSA will not be used for the purposes of the EMBRACE or BrOvEd study. AIMS AND OBJECTIVES [4 paragraphs unchanged] DATA SUBJECTS The following NHS England Data will be accessed: The EMBED study team at the University of Cambridge are recruiting two cohorts of women: • Civil Registration Mortality – necessary to evaluate the survival rate after cancer diagnosis, and mortality from other causes of death, both of which are important aims of the study. The University of Cambridge require both the date and causes of death to be provided. The mortality data also, to a large extent, prevents the EMBED study team from attempting to contact deceased participants, which could cause upset to family members. • Cohort 1: The first cohort is expected to comprise approximately 2700 women at recruitment end (currently 1449). Participants are recruited because they have a strong family inherited history of breast cancer, have an increased lifetime risk of developing the disease and are hence undergoing more intensive (annual) screening (per National Institute for Health and Care Excellence (NICE) CG164 recommendations for screening women at an increased risk of breast cancer - https://www.nice.org.uk/guidance/cg164/chapter/recommendations). This may enable the University of Cambridge to establish a resource of serial blood and mammogram (breast) images over a number of years. The blood samples of women, who later go on to develop breast cancer, along with their tumour tissue, will be analysed for ctDNA. The University of Cambridge will also look at mammographic images for changes that could correlate with the stage of disease. The University of Cambridge will request mammographic images directly from the relevant hospitals (see here for the list of NHS Trusts the University of Cambridge are recruiting from - https://embed.phpc.cam.ac.uk/further-information/for-patients/). All identifiable information such as NHS number, name and date of birth will be removed by hospital staff before the images are sent to the EMBED study team at the University of Cambridge. • Cancer Registration – necessary because the data is expected to provide accurate confirmation of the cancer type and diagnosis date, which a participant may not remember exactly. In addition, some patients may develop cancer after the questionnaire has been completed (or may die or become lost to follow-up), so cancer data from NHS England could be very important in minimising the amount of missing cancer information and in avoiding biased results. • Cohort 2: The second cohort is expected to comprise 200 women at recruitment end (currently 43). Participants are recruited because they have been re-called to the Cambridge Breast Unit due to abnormal mammograms. These women will have attended mammographic screening as part of the NHS breast screening programme, but an abnormality in the image has been detected which requires further investigation. These women (aged 50-69) form an appropriate cohort for evaluating ctDNA assays as ctDNA is likely to be present at varying concentrations depending on the patient’s stage of cancer, and at greater concentrations than in the asymptomatic women recruited in cohort 1. This may enable the University of Cambridge to refine the assays that will be used to detect ctDNA in incident cancers. The level of the Data will be: NHS guidance states that mammographic screening will only be provided automatically for women between the ages of 50-53. Women will then be invited every 3 years until they turn 71. The NICE CG164 recommendations for screening women at an increased risk of breast cancer referenced above state that women under the age of 50, but over the age of 30, can be considered for mammographic screening if their risk of breast cancer is high. No women under the age of 30 will be offered mammographic screening. • Identifiable – necessary because identifiable cancer data is required (cancer registry number) to check the consistency with cancers self-reported by a patient; only pseudonymised mortality data is required. Women at an increased risk of cancer represent an appropriate cohort for initial evaluation of new early detection strategies. Since their cancer risks are higher, the statistical power of such studies is greater, and the positive predictive value of a test will be greater (i.e. there will be fewer false negative and false positive results - therefore it is more likely that the University of Cambridge will be able to predict the diagnostic values with greater certainty). Moreover, they are often in regular surveillance programmes, providing opportunities to compare new screening approaches with existing surveillance. Finally, individuals with a family history of cancer are generally highly concerned by virtue of their personal experience of the disease. Strategies developed in a high-risk population, however, may become applicable in the general population if they are sufficiently cost-effective. The Data will be minimised as follows: The University of Cambridge use a layered approach to provide study information to participants. A brief study flyer is either included in appointment letters or sent separately from participating Breast Units. These flyers signpost where further information can be obtained: (i) through the study website (https://embed.phpc.cam.ac.uk/) and/or (ii) by emailing or telephoning the study office and/or (iii) at participating Breast Units. Information packs, which contain a cover letter, detailed patient information sheet and a consent form, are also sent to all potential participants. • Limited to a study cohort identified by the University of Cambridge – This is split into two cohort groups meeting the following inclusion criteria: The informed consent of participants follows Good Clinical Practice (GCP) guidelines (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/good-clinical-practice/). - Cohort 1: 3768 participants (so far) who have been recruited because they have a strong family inherited history of breast cancer, have an increased lifetime risk of developing the disease and are hence undergoing more intensive (annual) screening. Consent documentation for women in cohort 1 may be completed online or returned in the post. Potential participants therefore have a sufficient amount of time to read the information sheet, ask questions and return the consent form. - Cohort 2: 200 participants (expected to end at 500 participants), who have been recruited because they have been re-called to the Cambridge Breast Unit due to abnormal mammograms. Consent documentation for women in Cohort 2 are completed and signed face-to-face with a research nurse present during the patient’s hospital appointment at the Breast Unit. As well as having the opportunity to access further study information before their appointment, patients also have the opportunity to ask for further information before deciding on whether to take part. The University of Cambridge is the research sponsor and the controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above. Patients are entitled to withdraw at any point if they no longer want to take part without it affecting the care they receive through the NHS. The lawful basis for processing personal data under the UK GDPR is: The consent forms and patient information sheets participants signed up to are almost the same across versions. The only difference being references to Public Health England (PHE) in v3 of the consent form and v4 of the patient information sheet for cohort 1. The University of Cambridge were planning to apply for the cancer and mortality data from PHE, but since PHE has now been dissolved and these data are now under the controllership of NHS Digital, the University of Cambridge has had to update the wording in the consent forms and patient information sheets to reflect this change. Following discussions with NHS Digital, the University of Cambridge sent a newsletter to all participants notifying them of the change from PHE to NHS Digital. The newsletter has also been uploaded to the EMBED study website, and a copy supplied to NHS Digital. In addition, the EMBED study team at the University of Cambridge will contacted 15 participants via email clarifying whether it was within their reasonable expectations for their confidential patient information to flow to NHS Digital for linkage to cancer registration and mortality data in light of the dissolution of PHE. No participants replied with any concerns. 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 Cohort 1 The lawful basis for processing special category data under the UK GDPR is: • Consent Form v2 (16.03.2020) and PIS v3 (22.07.2020) all consented to NHS Digital n=272. (No participants recruited before 22/07/2020) 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. • Consent Form v3 (24.03.2021) and PIS v4 (24.03.2021) all consented to PHE n=987. The funding is provided by Cancer Research UK. The funding is specifically for the study described. • Consent Form v4 (04.012022) and PIS v5 (04.01.2022) all consented to NHS digital n=190 The funder will have no ability to suppress or otherwise limit the publication of findings. Cohort 2 • Consent Form v4 (04.01.2022) and PIS v4 (07.01.2022), all consented to NHS Digital n=43 (No Cohort 2 participants recruited before 04/01/2022) DATA REQUEST The University of Cambridge are requesting access to annual drops of record-level, latest available Cancer Registration and Civil Registration (Deaths) data. Identifiable cancer data is required (cancer registry number) to check the consistency with cancers self-reported by a patient; only pseudonymised mortality data is required. The Cancer Registration data from NHS Digital will augment the data the University of Cambridge collects for both cohorts (through the use of questionnaires). The data is expected to provide accurate confirmation of the cancer type and diagnosis date, which a participant may not remember exactly. In addition, some patients may develop cancer after the questionnaire has been completed (or may die or become lost to follow-up), so cancer data from NHS Digital could be very important in minimising the amount of missing cancer information and in avoiding biased results. For samples in which cancer/tumour are identified, the University of Cambridge will then use the longitudinal data to analyse the change in the levels and sensitivity of ctDNA over time prior to diagnosis. The serial mammograms will be retrieved from the breast cancer cases and matched controls. Data will be used to examine whether tumours were observable on earlier images, and whether the presence of such microscopic lesions were related to ctDNA detection. The University of Cambridge will also relate the sensitivity to gene, Single-nucleotide polymorphism (SNP) profiles, overall predicted breast cancer risk and prognostic features of the tumour. SNP profiles act as tags to specific regions of DNA, and these regions can be scanned for variations that may be involved in a human disease or disorder. The project aims to evaluate early detection of cancer and is applicable to any tumour type. It is therefore necessary to analyse the data on all cancers that occur in the cohort. Without cancer data from NHS Digital, the above analysis would be difficult. The mortality data is required to evaluate the survival rate after cancer diagnosis, and mortality from other causes of death, both of which are important aims of the study. The University of Cambridge require both the date and causes of death to be provided. The mortality data also, to a large extent, prevents the EMBED study team from attempting to contact deceased participants, which could cause upset to family members. The study aims to analyse the long-term survival from cancer and other diseases, and requires continued access to mortality data. Receiving cancer and mortality data annually from NHS Digital will update the University of Cambridge with the latest numbers on cancer cases and facilitate the planning of future work. For example, the University of Cambridge may need to make arrangements to collect tumour blocks from hospitals for those diagnosed with cancer. The study is composed of patients treated in English hospitals only - approx. 20 centres have been involved in recruitment and new sites are continually being added to the study. It is necessary to recruit patients from the whole country in order to provide an adequately powered study – i.e. in order to recruit a sufficient number of women into the study the University of Cambridge need to recruit from NHS sites across England (see here for the list of NHS Trusts the University of Cambridge are recruiting from - https://embed.phpc.cam.ac.uk/further-information/for-patients/). The aim is to recruit 2700 women with a moderate to high lifetime risk of developing breast cancer. In addition, without using national data, it would not be possible to guarantee that the dataset would be accurately representative of the entire population and hence the results may not be broadly applicable. CONTROLLERSHIP AND FUNDING The sole data controller is the University of Cambridge who will also process the NHS Digital data requested. The EMBED study is funded through Cancer Research UK. Cambridge University Hospitals (CUH) NHS Foundation Trust and the University of Cambridge are joint sponsors. CUH NHS Foundation Trust are the lead research and development site. The National Institute for Health and Care Research (NIHR) Clinical Research Network (CRN) Eastern – Cancer Division supports the study and has been actively involved in recruiting sites. CUH NHS Foundation Trust and NIHR CRN Eastern – Cancer Division, as well as the funding organisation Cancer Research UK, will not have to access to or process the NHS Digital data required, nor do they determine the means and purposes of the processing of NHS Digital data. To this end, per the definitions provided under article 4 of the GDPR, they are not considered data controllers or data processors for the purposes of this Data Sharing Agreement. LEGAL BASIS FOR PROCESSING The University of Cambridge have a legal basis to process the personal data and special categories of personal data requested under this Data Sharing Agreement per the following provisions of the General Data Protection Regulation (GDPR): - 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 controller͟”. - Article 9 (2)(j) – “processing is necessary for achieving purposes in the public interest, scientific or historical research purposes or statistical purposes.” The University of Cambridge are considered a public authority under Schedule 1 of the Freedom of Information Act 2000. The research study is in the public interest given the large proportion of people who suffer from breast cancer and because it may enable earlier, more cost-effective detection of cancer. To this end it meets the conditions outlined in Schedule 1 Part 1 (4) of the Data Protection Act 2018. PATIENT AND PUBLIC INVOLVEMENT (PPI) [1 paragraph unchanged]

Processing activities

EMBED has recruited approx. 1,500 participants, and recruitment is still ongoing at approx. 800 new participants each year. The data linkage process is as follows: The University of Cambridge will transfer data to NHS England. The data will consist of identifying details (specifically NHS Number, Date of Birth, Postcode, Name and a unique person ID) for the cohort to be linked with NHS England data. 1. Study participants’ NHS numbers and dates of birth, plus a unique study ID, will be supplied to NHS Digital via Secure Electronic File Transfer (SEFT). NHS England will provide the relevant records from the Cancer Registrations and Civil Registration Deaths datasets to [the University of Cambridge. The Data will 2. NHS Digital will link the patient identifiers provided by the University of Cambridge to the Cancer Registration and Civil Registration (deaths) data. • contain no direct identifying data items but will contain a unique person ID which can be used to link the Data with other record level data already held by the recipient. 3. NHS Digital will remove all patient identifiable information (NHS number and date of birth) from the data extract with the unique study ID for each participant remaining only and send, via SEFT, the linked Cancer Registration and Civil Registration (Deaths) data to the University of Cambridge Clinical School’s Secure Data Hosting Site (SDHS). The Data will not be transferred to any other location. 4. University of Cambridge will then link the unique study ID supplied by NHS Digital to the study data already stored on the SDHS (cancer data collected via participant questionnaires). The Data will be stored on servers at the University of Cambridge Secure Research Computing Platform (SRCP). The SDHS is a distinct area set up to ensure the security of personal identifiable data for studies like the EMBED study. Only the EMBED study team at the University of Cambridge can access the EMBED study data, and only when onsite, using their own two passwords and their physical ‘Signify’ key, which generates a unique third password every minute. Data will only be accessed by individuals within the EMBED study team who have authorisation from the Data Manager and Study Principal Investigator to access the data for the purpose(s) described, all of whom are substantive employees of the University of Cambridge. Internet traffic to and from the SDHS is restricted. The research team will not have access to any identifiable data. NHS Digital data will always be kept within the SDHS system. No NHS Digital will be shared with any third parties outside of the University of Cambridge except in the form of aggregated data with small numbers suppressed. The data will only be used for the purposes outlined within this Data Sharing Agreement. The Data will not leave: England/Wales at any time. The downloaded data will be stored in a separate folder to the main study database within the SDHS. Cancer data is linked and compared to the data the University of Cambridge already hold using the unique study ID. This will augment the data collected by the EMBED study team and increase the number of people in the cancer patient cohort, hence reducing analysis bias caused by missing data. Mortality data will be linked periodically to ensure deceased patients are not contacted for follow-up. Access is restricted to employees or agents of the University of Cambridge who have authorisation from the study manager and principal investigator. All personnel accessing the Data have been appropriately trained in data protection and confidentiality. The Data will be linked at person record level with data held by the University of Cambridge stored on the SRCP (cancer data collected via participant questionnaires). The identifying details will be stored in a separate database to the linked dataset used for analysis. All analyses will use the pseudonymised dataset. There will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset. Researchers from the University of Cambridge will process the Data for the purposes described above.

Expected measurable benefits

The initial results for EMBED study are expected within 1-3 years of download of NHS Digital England data. EMBED study hope to provide information which may have an impact on the following areas: [16 paragraphs unchanged]

Benefits reported

Yielded Benefits is not a requirement for new applications. The University of Cambridge have been awarded further funding by Cancer Research UK for the next 5 years which will enable EMBED to continue the analysis that has already begun. Because the analysis work is still ongoing, the University of Cambridge don’t have results the team can share at the moment.

Unchanged: Expected output.