Multicentre Study to determine Predictive and Prognostic Biomarkers and Therapeutic Targets for Oesophageal and Junctional Adenoarcinoma including whole genome sequencing (ODR1718_082)

Cambridge University Hospitals NHS Foundation Trust and University of Cambridge requires access to NHS England National Disease Registration Service (NDRS) data for the purpose of the following research project:

Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) study.

The Cancer data for this study was historically shared by Public Health England who were Data Controllers for the NDRS data until October 2021 when NHS Digital, now NHS England became the controllers

The OCCAMS study is a network of clinical centres across the UK recruiting patients with oesophageal and gastro oesophageal junction adenocarcinoma. Oesophageal adenocarcinoma patient data and clinical samples are used to identify clinical demographic and molecular factors affecting development and progression of this cancer. OCCAMS is a large multisite observational study that has involved 26 NHS hospital trusts in the UK and it has been adopted on the National Institute for Health Research’s (NIHR) portfolio of high-quality studies.

The aims of the OCCAMS study are to:

• Better characterise the clinico-demographic risk factors.

• Characterise the molecular genetic landscape (DNA, RNA, epigenome).

• Determine disease sub-types and develop new clinically relevant classification systems.

• Develop and validate improved clinical staging and prognostic algorithms.

• Ascertain new therapeutic targets for future research.

Under this iteration of this Data Sharing Agreement (DSA), the University of Cambridge ask that PhD students at the University are permitted to process the requested data in support of the aims stated above.

The main focus of the OCCAMS study is to develop a model that can be used to better assess therapeutic options for future patients with this specific condition. A key aim is identifying markers that indicate the likely pathway and rate of progression of the condition in individuals so that care plans can be appropriately tailored.

In support of this work, the following NDRS Datasets will be disseminated:

• Civil Registrations of Death.

• NDRS Cancer Registry (incl. Route to Diagnosis Information).

• NDRS Linked Hospital Episode Statistics (HES) Admitted Patient Care (APC).

• NDRS Systemic Anti-Cancer Therapy (SACT) Dataset.

•NDRS National Radiotherapy Dataset (RTDS).

The study already holds these datasets for cohort members diagnosed with an oesophagael-gastric tumour between 2010-2016, and who have consented to the collection of their health data by the study .

The level of data will be identifiable. Identifiers are required to ensure that the requested data can be linked to the Mortality data received by the study under DARS-NIC-38314-C3P0Z.

The requested data will be minimised as follows:

• Limited to a cohort of ~4600 individuals who consented to inclusion in this data collection. Recruitment is ongoing and additional cohort members may be added to the data collection under future iterations of this Agreement.

University of Cambridge (UoC) in collaboration with Cambridge University Hospitals NHS Foundation Trust (CUH) are the joint Data Controllers and study sponsors, responsible for ensuring that the Data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK General Data Protection Regulation (GDPR) is:

The processing necessary to perform this task is in the public interest (Article 6 (1)(e)) as the results of this study will provide information for future therapeutic options with this specific condition. Future alternative cancer treatments and diagnostics will benefit from the increased knowledge base that the research team expect to develop through the dataset to allow further research teams to develop new treatment trials.

Public interest is in line with Article 9 (2) (j) ‘processing is necessary for scientific or historical research purposes’. Processing these data is necessary for successfully fulfilling the aims of this study as listed above.

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

ii. The data recipient’s technical and organisational measures to safeguard the data have been assessed and meet NHS England'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.

Funding is provided by a grant from the Medical Research Council (MRC) awarded for the purposes of increasing knowledge of the processes and development of new clinical methods of treatment of oesophago-gastric cancer (expires in March 2026).

Standard statement:

The funder(s) will have no ability to suppress or otherwise limit the publication of findings.

The University of Cambridge is the controller who also processes the data.

Oxford University Hospitals NHS Foundation Trust whilst noted in some of the participant information sheets associated with this study are no longer part of the study and will not process or have access to any of the data flowing from NHS England. Oxford University Hospitals NHS Foundation Trust have not had any access to any data disseminated under any previous versions of this agreement.

Genomics England whilst noted in some of the participant information sheets and consent forms associated with this study will not process or have access to any of the data flowing from NHS England. Genomics England have not had any access to any data disseminated under any previous versions of this agreement.

Natera whilst noted in some of the participant information sheets and consent forms will not process or have access to any of the data flowing from NHS England. Natera have not had any access to any data disseminated under any previous versions of this agreement.

The Cambridge PPI panel have contributed several times with the study design and document reviews. Between the period of 2017 till 2022 they have reviewed documents which include patient information sheets and consent form content and design of patient facing instruction leaflet for collection of blood samples using blood spot cards to ensure all are patient friendly. They also had input with design of a 13 page lifestyle and exposures questionnaire which provides valuable study data.

No Cancer Data will be stored or processed at Cambridge University Hospitals NHS Foundation Trust or Telefonica Tech Northern Ireland Limited. Telefonica Tech is being added to the Mortality agreement as a data processor.

Where individuals have opted out of disease registration by the National Disease Registration Service (NDRS), their data has been permanently removed from the registry and therefore will not be disseminated under this Data Sharing Agreement (DSA). https://digital.nhs.uk/ndrs/patients/opting-out

The University of Cambridge will transfer data to NHS England. The data will consist of identifying details, including NHS Number, Date of Birth and OCCAMS Study ID.

NHS England will provide the relevant records from:

• Civil Registrations of Death.

• NDRS Cancer Registry.

• NDRS Linked Hospital Episode Statistics (HES) Admitted Patient Care (APC).

• NDRS Route to Diagnosis.

• NDRS Systemic Anti-Cancer Therapy (SACT) Dataset.

This data will contain identifying data items to link the data at a record level with the Mortality data the study previously received under DARS-NIC-38314-C3P0Z.

NDRS Data:

Personal data (of any level, derived or otherwise) will not be transferred to any other organisation once the University of Cambridge has received the requested data.

The NDRS data will be stored on servers supporting the Secure Data Hosting Service (SDHS) at the School of Clinical Medicine, University of Cambridge.

No Cancer Data will be stored or processed at Cambridge University Hospitals NHS Foundation Trust or Telefonica Tech Northern Ireland Limited. Telefonica Tech is data processor for the Mortality data only.

Employees of Cambridge University Hospitals NHS Trust, under honorary contract or otherwise, are not permitted to access the data.

The data will be accessed onsite at the University of Cambridge; therefore, the data covered under this Agreement will not leave England and Wales at any time.

Mortality Data:

NHS England will match and flag the cohort and will return identifiable mortality data (including date and cause of death) linked to the study ID. This data will be stored on the CUH secure server, and analysed by substantive employees of UoC, who also hold honorary contracts or letters of access with CUH all of whom have been appropriately trained in data protection and confidentiality.

Cambridge University Hospitals NHS Foundation Trust data backups are stored within CUH as well as with Amito, a secondary data centre. Amito, previously known as Everest Data Centre, provide backup storage to the CUH servers. Amito will not access the data held under this Agreement.

Telefonica are outsourced infrastructure providers who manage CUH IT systems including backups. Telefonica are considered data processors as they supply support to the system, and have access to the backup data files in order to manage them.

Access is restricted to substantive employees of the University of Cambridge who are part of the OCCAMS study team, all of whom have been appropriately trained in data protection and confidentiality. The study team have confirmed that the PhD student referenced in the ‘Objectives for Processing’ is a substantive employee of the University of Cambridge.

The NHS England data will be stored on a restricted access network drive, with access restricted by password to the authorised user of the data only. Both the PC and the network drive are part of the CUH secure network. The local network and PCs are operated under the CUH information security and information governance policies.

Once the data has been linked, the identifying details will be stored separately from the pseudonymised asset used for analysis. There will be no requirement or attempt to re-identify individuals when using pseudonymised data.

The data flows differ between the mortality/ NDRS cancer data, largely due to the technical arrangements which were in place with the different providing organisations. Now that data will all be provided by NHSE the applicant will look to consolidate this for future data flows. For this flow the data processing locations and arrangements will remain as historically agreed under both DARS-NIC-38314 (mortality) & DARS-NIC-659284 (NDRS).

The expected outputs of the processing will be:

• Submission to peer-reviewed journals (i.e. Nature Genetics and the British Medical Journal)

• A report of findings to participating hospitals

• Presentations

• Conferences

The Principal Investigator is actively working on using evidence from the study to make recommendations on how treatments are planned and delivered based on specific indicators. Specifically:

- Developing algorithms to reduce diagnostic delay.

- Developing trials to evaluate precision treatment based on the molecular makeup of the tumour matched with treatment response and outcome.

- Developing standardised reporting tools in oesophageal cancer for endoscopy, surgery and pathology through evaluation of geographical variation in data collected in this UK-wide study.

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

The outputs will be communicated to the relevant recipient through the following dissemination channels:

• Journals

• The study’s webpage (https://www.occams.org.uk/index.html)

• Social media

• Public reports

• Direct bilateral engagement

• Industry newsletters

• Briefing documents

• Co-hosted events

• Open source frameworks

• Public events

• Posters displayed at [give details]

• Patient Information leaflets

• Press/media engagement

Outputs for the study will be regular until the end of the study in 2026.

The findings of this research study are expected to contribute to evidence-based decision-making for policymakers, local decision-makers (i.e. doctors), and patients to inform best practices to improve the care, treatment and experience of healthcare users relevant to the subject matter of the study.

The study has the potential to benefit patients by improving the understanding of oesophago-gastric cancer to enable earlier detection and determination of the likely severity and rates of progression so that more appropriately personalised medicines and treatment plans can be prescribed.

The study may allow researchers to understand better how an individual’s genetic profile determines whether they will respond to a particular treatment or which sub-category of cancer type (and prognosis) they fall into. Understanding how long a participant has lived with the disease and the specific nature of their condition will further the scientific communities understanding of the progression of the disease.

It is hoped that through the publication of findings in appropriate media, the results of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for, or within the NHS or treatment decisions in relation to specific patients.

The annual OCCAMS symposium is attended by approximately 60-80 investigators from the UK and overseas. Members of the OCCAMS consortium present their data from projects which accessed OCCAMS samples and data.

This study has been adopted to the NIHR portfolio. The NIHR portfolio consists of clinical research studies that are eligible for support from the National Institute for Health and Care Research Clinical Research Network (NIHR CRN) in England. All high-quality research studies, eligible for NIHR CRN support in England, are included on the NIHR CRN Portfolio. For a study to be eligible to be adopted to the NIHR portfolio, it must satisfy the requirements of the Department of Health and Social Care established Eligibility Criteria (https://www.nihr.ac.uk/documents/researchers/collaborations-services-and-support-for-your-research/run-your-study/Eligibility%20Criteria%20for%20NIHR%20Clinical%20Research%20Network%20Support.pdf)

The OCCAMS study conveys information to current patients in follow-up, meeting up with patients regularly at clinics and giving feedback about study progress and recruitment. A yielded benefit of OCCAMS is allowing patients to have a better understanding of their disease. This keeps the patients motivated and also lets them know how valuable their contribution is. New patients are also very keen to know details of how current samples and data are progressing the study towards improving knowledge and treatment options and developing new trials. At no point in this process would specific information about another patient be given to anyone else, and no information from NHS England be shared with anyone else.

The findings from the OCCAMS study have already led to the establishment of a revised Output Area Classification (OAC) classification method (https://pubmed.ncbi.nlm.nih.gov/19526624/)

This revised classification based on the number and location of involved lymph nodes provides improved prognostic power and incorporates features that may be useful before surgery in clinical management decisions. This allows for the provision of more accurate tumour staging and prognosis information to be available for patients so that they may be better informed about future possible treatments and their prognosis.

The study has led to multiple publications. Papers continue to be written and published and the study disseminates findings regularly through conferences, presentations in the UK and internationally where experts in the field meet to discuss the latest developments in classification of cancer through genomics and treatment/diagnosis innovations.

Publications, listed in the outputs section, focussing on treatment outcomes and detection and analysis of ctDNA (circulating tumour DNA) collections in detecting disease recurrence showed that ctDNA levels post-surgery could act as a predictor for patient relapse and assessment of treatment response following chemotherapy. The data available and the publications were enhanced by the extensive clinical data available.