GENERATIONS study

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Datasets: + Hospital Episode Statistics Admitted Patient Care (HES APC); + Hospital Episode Statistics Outpatients (HES OP)

Objective for processing

The Institute of Cancer Research (ICR) requires mortality, civil registration of deaths, cancer incidence registrations, Hospital Episode statistics Admitted Patient Care (HES APC), Hospital Episode statistics Outpatients (HES OP) and demographic data for the purpose of a national cohort study of [5 words unchanged] for mortality and cancer incidence, with particular focus on breast cancer, in 113,735 113,766 volunteer participant women in the UK. The Generations Study has exceptional detail, size and power and will contribute to new information on the causes, survival and genetics of breast cancer and other major diseases of women. The objective is to enable preventive measures for these diseases and to give information for patients and their families, doctors and other health professionals advising patients, the public, and policy makers, and for health promotion campaigns, on risk factors, pathology, risk prediction, and survival for these diseases and potential measures to reduce the risks, including targeted measure based on genetic and other factors. The data requested are required for the scientific analyses. A Cohort cohort study is methodologically the most rigorous study design that can be undertaken of long-term cancer and mortality risks. The Generations Study cohort was set up in 2003, requesting volunteer participant women in the UK, with planned collection of exposure and follow-up data to continue for at least 40 years. This is the objective and why the by The Institute of Cancer Research in 2003, to investigate the causes of breast cancer with exceptional focus, size and comprehensiveness. The study is undertaking one of the study. largest and most comprehensive in the world to investigate the causes of breast cancer and provide risk prediction data to enable personalised screening and prophylaxis. The Generations Study is also investigating the causes of other cancers and diseases in women, survival, causes of death, and outcomes after breast and other cancers (including mortality, breast cancer recurrence, and other diseases). Finding the causes of cancer is important to enabling its prevention and identifying high risk groups for screening and early detection. Cancer now accounts for 26% of deaths in women in England, so is a major public health problem. Breast cancer is the most common cancer in women in the UK and worldwide. The Generations Cohort study was set up in 2003, to investigate the causes of breast cancer with exceptional focus, size and comprehensiveness, and also to investigate the causes of other cancers and causes of death in women. It is one of the leading such cohort studies in the world. The Generations Study recruited female volunteer participants in the UK with planned collection of exposure and follow-up data to continue for at least 40 years. The study has exceptional detail, size and power and has and will continue to contribute new information on the causes, survival and genetics of breast cancer and other major diseases of women. The objective is to enable preventive measures for these diseases and to give information for patients and their families, doctors and other health professionals advising patients, the public, and policy makers, and for health promotion campaigns, on risk factors, pathology, risk prediction, and survival for these diseases and potential measures to reduce the risks, including targeted measures based on genetic and other factors. This is the objective and why The Institute of Cancer Research is undertaking the study. Epidemiological evidence indicates that the aetiology of breast cancer involves genetic, behavioural and environmental factors, probably with interactions between these, and that the behavioural/environmental factors act at several different stages of life, probably starting before birth, and continuing to the menopause and beyond. Many of the likely causal factors are complex ones that are difficult or impossible to measure in retrospect – for instance serum concentrations of hormones at various ages – but more accurate investigation of these is crucial to understanding the causes of this cancer and hence its prevention. Women in the study may reside all over the country, therefore The Institute of Cancer Research is requesting information from NHS England for England. The only alternative way to gain full information on cancers, deaths, emigrations, and hospital episodes, on an ongoing basis for over 40 years would be to consult all of the medical case-notes of the women in the study on an on-going basis. This would be unacceptably intrusive and is not conceivably practicable, hence data are requested for the scientific analyses from NHS England for practicability reasons. To investigate these factors optimally needs a study in which information about them, and how they change through life, is collected prospectively in a large cohort of women, with long-term follow-up for breast cancer. For aspects such as the relationship of serum concentrations of Insulin-like growth factor (IGF1) and of sex hormones to risk of subsequent breast cancer, this is essentially the only design that can give valid data. Such a study design is also the optimal one to assess gene-environment interactions affecting the risk of breast cancer. The cohort design has similar strengths for investigation of other major cancers and causes of death. The level of the Data will be: The Generations cohort is one of the largest and most comprehensive in the world to investigate the causes of breast cancer, and provide risk prediction data to enable personalised screening and prophylaxis. It is also investigating breast cancer and ovarian cancer pathology and survival. • Identifiable Individual level data on cancer, deaths and emigrations is required. The information is for women who have joined the study and given their consent for ICR to receive such information. The ICR send identifiers they hold for the women in the cohort who have provided consent for this. NHS Digital link the flagging data and return this for these women the ICR have already identified. The following NHS England Data will be accessed: Information is requested for the years specified in the Agreement because this is an on-going cohort study: the scientific purpose of the study, agreed by the participants, is to analyse risk in the period since joining the study, for follow-up of 40 years or longer thereafter. Thus, it is intrinsic to it to update follow-up regularly. • Cancer Registrations Women in the study may reside all over the country Therefore the Institute of Cancer Research is requesting information from England and Wales from NHS Digital. • Demographics The only alternative way to gain full information on cancers, deaths, and emigrations, on an ongoing basis for over 40 years would be to consult all of the medical case-notes of the (over 100,000) women in the study on an on-going basis. This would be unacceptably intrusive and is not conceivably practicable, hence data are requested from NHS Digital for practicability reasons. • Civil Registration of deaths The Institute of Cancer Research has only requested the data required for the purposes outlined in this Agreement. These datasets will be used to link cancer to survival outcomes, provide details on cancer incidence and report on exits from registration with the NHS (e.g. if a participant emigrates). The data under this Data sharing agreement will be processed under Articles 6 and 9 of EU GDPR. The legal basis for the processing of personal data is that this is necessary to perform a task in the public interest and the exemption for the processing of special category personal data (Article 6(1)(e)) and under Article 9 of EU GDPR is that the processing is necessary for scientific research purposes (Article 9 (2)(j)). • HES APC The study is of cohort design, recruiting volunteer women from the general population of the UK aged 18 years and older, who have completed an extensive questionnaire about breast cancer risk factors, given a blood sample, and given informed consent for follow-up via national routine data systems. Over 110,000 women have been recruited since 2003 with active recruitment stopping in 2009. Participants still continue to join the study, however these are not in great numbers. A cohort study is methodologically the most rigorous study design that can be undertaken of long-term cancer and mortality risks. Appropriate analyses requires comprehensive information on occurrence of cancer and deaths, and emigrations. Without the data from NHS Digital the study results would be incomplete, inaccurate and biased. • HES OP Follow-up is primarily by 3-yearly questionnaires. It is planned that collection of exposure and follow-up data will continue for at least 40 years. In addition periodic newsletters are sent to participants with a reply slip for notification of changes in address and, with signed informed consent, the ICR also uses flagging at NHS Digital to provide follow-up data, including cancer registrations and causes of death. The value of HES records is that it will provide more detailed, accurate and unbiased information about non-cancer health conditions, common diseases, and serious medical conditions, such as obesity, diabetes, and cardiovascular disease, for a well-defined and characterised cohort. This data requested will only be used for purposes detailed in this Agreement. In combination with ongoing repeated questionnaire data collection from participants in the Generations Study the HES data will help ICR: The Institute of Cancer Research is the sole Data Controller who also process the data. • advance understanding of the need for, or effectiveness of, preventative health and care measures (e.g. physical activity); Breast Cancer Now is a funder for the study, however they do not make any decisions regarding the data requested for this study and are therefore not listed as a data controller under this Agreement. Only substantive employees at the ICR are able to access NHS Digital data. No other organisations, including Breast Cancer Now, will have access to or process NHS Digital data. • contribute information to evidence-based decision-making for policy-makers, local decision-makers, and patients; • inform planning of health services and programmes, for example to improve equity of access; • provide a mechanism for checking the quality of care (identifying areas of good practice to learn from, or areas of poorer practice which need to be addressed); • support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work). The Data will be minimised as follows • Limited to a study cohort identified ICR – approximately 100,000 individuals. The total cohort is ~113,000 women however this includes women in Scottland, this agreement covers ~100,000 participants in England only. The study is of cohort design, recruiting volunteer women from the general population of the UK aged 16 years and older, who have completed an extensive questionnaire about breast cancer risk factors, given a blood sample, and given informed consent for participation in the study, access to medical records, and follow-up via national routine data systems (in the event of The Institute of Cancer Research having lost contact with the participant (for example, change of address), or the diagnosis of cancer or event of death.) Since 2003 the study recruited 113,766 women with active recruitment stopping in 2009. Follow-up is primarily by questionnaires with the fifth follow-up beginning in 2025. It was planned at onset that collection of exposure and follow-up data would continue for at least 40 years. In addition, periodic newsletters are sent (currently biannually) to participants to inform them about study progress and results and provide a link to a form where participants may inform The Institute of Cancer Research about changes in address and contact details. In addition to regular ‘flagging data’, The Institute of Cancer Research have under separate previous agreements (DARS-NIC-656751-H5K0Y-v1.2; DARS-NIC-656751-H5K0Y-v0.2; Public Health England ODR_2014_317) received for all cancer patients information from: • NDRS Cancer Pathway • NDRS Cancer Registrations • NDRS National Radiotherapy Dataset (RTDS) • NDRS Systemic Anti-Cancer Therapy Dataset (SACT) • NDRS Linked HES Admitted Patient Care • NDRS Linked HES Outpatients to enable us to evaluate outcomes after breast cancer (including mortality, breast cancer recurrence and other diseases) and to apply algorithms developed to ascertain breast cancer recurrence and non-cancer outcomes in the breast cancer patients. This amendment is to include data linkages on a regular basis to HES data for the whole cohort (who have provided consent for access to medical records.) 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. This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care. The processing is record linkage to NHS-England data systems for scientific analyses. The standard statistical analyses are those for cohort studies, but also nested case-control analyses for exposure variables (e.g. various biological assays from the collected blood samples) that can only practically be analysed on this basis. Results are presented as summary measures or regression coefficients from statistical models. No identifiable level data would be published, and results are reviewed for small number suppression to protect confidentiality. The funding comes from multiple sources. The funders include: • Breast Cancer Now • The Institute of Cancer Research Funding to continue the work described will be sought on an ongoing basis. Breast Cancer Now (formerly known as Breakthrough Breast Cancer) do not make any decisions regarding the data requested for this study and are therefore not listed as a data controller under this Agreement. The Institute of Cancer Research is the sole data controller and data processor. Only substantive employees at The Institute of Cancer Research are able to access NHS England data. No other organisations, including Breast Cancer Now, will have access to or process NHS England data. This data that are requested will only be used for purposes detailed in this Agreement. The Institute of Cancer Research will only store NHS England data in a folder on the Storage Area Network (SAN) marked “not for tape backup”. No data received from NHS England going forward will be backed up to tapes. The Institute of Cancer Research commits to find an appropriate solution for the NHS England data previously backed up to tapes. The Institute of Cancer Research Information Governance Committee acknowledges the risks associated with retaining NHS England data on backup tapes and are committed to addressing the issue. For clarity, study questionnaires (but not consent forms) were previously stored in a secure facility managed by Deepstore Ltd. In 2024 these paper questionnaires were securely destroyed and Deepstore no longer store any study documentation. (Electronic images of all questionnaires are stored securely in The Institute of Cancer Research’s data safe haven.)

Processing activities

The ICR supplied cohort identifiers to NHS Digital consisting of: The institute of Cancer Research will transfer data to NHS England. The data will consist of identifying details NHS Number, DOB, Family name and Gender for the cohort to be linked with NHS England data. Forenames and Surnames NHS England will provide the relevant records from the HES APC, HES OP, Civil Registration of deaths, Cancer registration and Demographics data. Date of Birth The data will contain directly identifying data items including which are required to ensure accurate linkages of individual participants’ data. Sex The Data will be accessed by authorised personnel via remote access. Study ID The Controller(s) must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract. The participants’ entries are then flagged on NHS Digital’s computer system. Only identifiers of participants with whom the ICR has lost contact or who have self-reported cancers and/or who are believed to have died are supplied to NHS Digital for flagging. Otherwise, the ICR continues to collect information directly from the participants. For remote access: 41,695 participants had been flagged prior to September 2018. Approximately 800 additional participants who meet the above criteria will be flagged at fixed points each year. ICR will supply identifying details of these additional participants to NHS Digital for the purpose of flagging. Under this Agreement, the ICR is not permitted to flag new participants recruited during or since 2015 (at which point guidance NHS Digital issued new guidance on consent). - Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA: - Data supplied by NHS Digital are being processed on ICR machines within a data safe haven environment. Users must log into the system using their ICR credentials. Movement of any data or files into and out of the data safe haven is strictly controlled: a small number of authorised staff have the rights to move data, and this process is monitored and audited. - Access controls granting users the minimum level of access required are in place; - The data is being matched to the existing cohort data for the women themselves, which is not a publicly available data set. - Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data; - For flagged participants NHS Digital reports details of the cancer diagnoses and/or the details of deaths (date and cause) and also reports exits from registration with the NHS (e.g. if a participant emigrates). NHS Digital has supplied this data to the ICR on a regular basis since 2008. These data are used only for analyses for the approved medical research project identified above. - Multifactor authentication (MFA) is required for remote access; - Analyses are conducted of risk factors for breast cancer and other cancers and causes of death mainly by standard cohort analyses methods (Breslow & Day, 1987), but also in nested case-control analyses for exposure variables (e.g. various assays) that can only practically be obtained on this basis. - Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access; - Identifiable data are required to ensure accurate linkages of individual participants’ data. Access to the identifiable data is restricted to ICR researchers with authorisation from the Chief Investigator, or the Information Asset Administrator of the ICR’s Epidemiology Team. The data will be accessed and analysed solely at ICR for the analyses described above, which are the purpose of the study and the purpose of obtaining the data from NHS Digital. - All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy. All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract – i.e. employees, agents and contractors of the Data Recipient who may have access to the data). The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose). The Institute of Cancer Research confirm that data processing is only carried out by substantive employees of the data controllers who have been appropriately trained in data protection and confidentiality. Remote processing will be from secure locations within England/Wales, The data will not leave England/Wales at any time. Deepstore is a secure storage facility, which the ICR use to house study documents that are unable to be stored on ICR premises. Deepstore is not permitted any access to the data. All data stored at The Institutes of Cancer Research’s premises are held on servers owned and managed by The Institute of Cancer Research. For clarity, Breast Cancer Now, the study funders, are not able to access the data or servers holding the data. Additionally, these data are stored and processed in the secure data safe haven, a part of The Institute of Cancer Research computer network with additional security to meet Data Security and Protection (DSP) Toolkit requirements. Users must log into the system using their ICR credentials using ICR owned computers. Movement of any data or files into and out of the data safe haven is strictly controlled: a small number of authorised staff have the rights to move data, and this process is monitored and audited. Access to the identifiable data is restricted to ICR researchers with authorisation from the study Chief Investigators, or the Information Asset Administrator of the ICR’s Clinical Cancer Epidemiology Team and Integrative Cancer Epidemiology Team. Access will only be authorised for the purposes described and for individuals who are substantive employees of the ICR. The NHS data will be accessed and analysed solely at ICR for the analyses described above, which are the purpose of the study and the purpose of obtaining the data from NHS England. The Institute of Cancer Research confirm that data processing is only carried out by substantive employees of the data controllers who have been appropriately trained in data protection and confidentiality. The Institute of Cancer Research does not use agents or contractors to process this data. Data will be accessed by substantive employees of ICR and: • PhD students enrolled with The Institute of Cancer Research (part of University of London). The individuals have completed mandatory data protection and confidentiality training (as recommended and required by NHS) and are subject to ICR’s policies on data protection and confidentiality. The individual accessing the data will do so under the supervision of a substantive employee of ICR. ICR would be responsible and liable for any work carried out by the individual. The PhD students would only work on the data for the purposes described in this Data Sharing Agreement (DSA). • Individuals holding an honorary contract under the supervision of a substantive employee of ICR (a named controller or processor) for the purposes described in this DSA only. ICR must maintain records in a single location that cover the following details of each individual given access under an honorary contract: - Their substantive employer; - Their role in respect of the purpose for the processing specified in the DSA; - The start date and end date of the duration in which the Data will be accessed by the individual under an honorary contract; - The necessity for the Data to be accessed by the person(s) holding an honorary contract, instead of a substantive employee of an organisation named as controller or a processor in this DSA; - Confirmation that an appropriate contract is in place which follows the relevant guidance and is countersigned by the substantive employer of the honorary contract holder. - The individuals have completed mandatory data protection and confidentiality training (as recommended and required by NHS) and are subject to ICR’s policies on data protection and confidentiality. A Public and Patient Involvement and Engagement group helped refine the purpose of the research. The group strongly supported the collection of the data for the purposes of the general research. A Participant Panel currently meets twice a year to involve participants in ongoing proposed use of the data. The Institute of Cancer Research has only requested the data required for the purposes outlined in this Agreement. Information is requested for the years specified in the Agreement because this is an on-going cohort study: the scientific purpose of the study, agreed by the participants, is to analyse risk in the period since joining the study, for follow-up of 40 years or longer thereafter. Thus, it is intrinsic to study design and rationale to update follow-up regularly.

Expected output

The planned outputs will include several hundred published papers in peer-reviewed scientific journals, submitted over the next 40 years, on the causes and risks of cancer incidence and cause-specific mortality, and on cancer pathology and survival, in women (see below for examples). The research is funded primarily by Breast Cancer Now, as the major part of a programme of breast cancer-related peer-reviewed research funded by them, and has produced many high-profile publications listed below, so PHE can be assured that it will continue to do so with longer follow-up and hence more valuable results. The extended follow-up will enable analyses on a growing spectrum of less-common conditions as greater numbers of cancers and deaths accumulate, and enable increasingly long-term risks to be assessed. The ICR will publicise the results to patients and society more widely by press releases and blogs, to professional standard, from the Institute’s and Breast Cancer Now’s very active communications departments, information sent to Breast Cancer Now (the major UK breast cancer charity) supporters and patient groups and put on the Study website, and by talks given to patient and lay groups as well as to appropriate medical and scientific conferences, meetings and seminars. SPECIFIC OUTPUTS EXPECTED The study has now produced >100 papers in peer-reviewed journals, many in the leading research journals for their specialities, on aetiology and genetics and hence prevention and patient counselling of cancer and its risk factors. Planned research activities for 2025 are: development and validation of breast cancer risk models for the UK general population; impact of mammography density and tumour characteristic on risk assessment for screen-detected and interval breast cancers; to identify tissue-based predictors of progression from benign breast disease to breast cancer using Artificial Intelligence (AI) analyses of digital pathology images; modifiable lifestyle factors before and after diagnosis and the risk of breast cancer recurrence and mortality. Over the next 40 years the study is expected to produce several hundred more papers in peer reviewed journals, on aetiology and genetics, and hence patient counselling, on cancer and its risk factors and on other diseases. During 2019 papers were published on, among other topics, the relation of breast cancer risk to weight change (important for preventive messages on losing weight); the relation of breast cancer risk to shift work (an important public health issue given the large number of female shift workers and whether their shift work is affecting their cancer risk); breast cancer risks in relation to recent pregnancies (important because these temporarily raise risk, but it needs to be discovered how much and for how long after the pregnancy) and several papers on the genetic risks of female reproductive related cancer risks (important to genetic counselling of patients and their families). Longer term the planned outputs will include several hundred published papers in peer-reviewed scientific journals, submitted over the next 20+ years, on the causes and risks of cancer incidence and cause-specific mortality, and on cancer pathology and survival, in women, which may be expected to have clinical utility in cancer prevention programs, and for patient counselling of cancer and its risk factors and on other diseases. Outputs will be in the form of scientific papers and reports. No individual level data will be presented. Data will be presented as aggregated summary data in tables or as parameter estimates from statistical analyses, which give no opportunity for individual identification. Where necessary, small numbers would be supressed. The research is funded primarily by the charity Breast Cancer Now and has produced many high-profile publications so NHS-England can be assured that the study will continue to do so with longer follow-up and hence more valuable results. The extended follow-up will enable analyses on a growing spectrum of less-common conditions as greater numbers of cancers and deaths accumulate and enable increasingly long-term risks to be assessed. A number of papers have now been published using the Generations Study data, in journals including the International Journal of Cancer and the International Journal of Epidemiology. No individual level data is published. Data is presented as aggregated summary data in tables or as parameter estimates from statistical analyses, which give no opportunity for individual identification. Where necessary, small numbers are supressed. DISSEMINATION AND COMMUNICATION In addition to publication in scientific journals The ICR will disseminate the results by press releases, talks given to patient and lay groups as well as to appropriate medical and scientific conferences, meetings and seminars. The ICR will communicate the results to patients and society more widely by official blogs from the Institute’s and Breast Cancer Now’s very active communications departments, information sent to Breast Cancer Now (the major UK breast cancer charity) supporters and patient groups and put on the study website.

Expected measurable benefits

Finding the causes of cancer is important to enabling its prevention and identifying high risk groups for screening and early detection. Cancer now accounts for 26% of deaths in women in England, so is a major public health problem. Breast cancer is the most common cancer in women in the UK and worldwide. The Generations Cohort study was set up in 2003, to investigate the causes of breast cancer with exceptional focus, size and comprehensiveness, and also to investigate the causes of other cancers and causes of death in women. (i) BENEFIT TYPES Over the next 20+ years the study is expected to produce several hundred more papers in peer reviewed journals, which may be expected to have clinical utility in cancer prevention programs, and for patient counselling of cancer and its risk factors and on other diseases, for the benefit of the general public, cancer patients and their families. (ii) EXPECTED MEASURABLE BENEFITS TO HEALTH AND SOCIAL CARE Finding the causes of cancer is important to enabling its prevention and identifying high risk groups for screening and early detection. Cancer now accounts for 26% of deaths in women in England, so is a major public health problem. Breast cancer is the most common cancer in women in the UK and worldwide. The Generations Study cohort was set up in 2003, to investigate the causes of breast cancer with exceptional focus, size and comprehensiveness, and also to investigate the causes of other cancers and causes of death in women. [1 paragraph unchanged] To investigate these factors optimally needs a study in which information about them, these factors, and how they change through life, is collected prospectively in a large [8 words unchanged] breast cancer. For aspects such as the relationship of serum concentrations of IGF1 insulin-like growth factor 1 (IGF1) and of sex hormones to risk of subsequent breast cancer, this is [32 words unchanged] similar strengths for investigation of other major cancers and causes of death. The Generations Study cohort is one of the largest and most comprehensive in the world to investigate the causes of breast cancer, and to provide risk prediction data to enable personalised screening and prophylaxis. It is also investigating breast cancer and ovarian cancer pathology and survival. The study has exceptional detail, size and power to provide new information [83 words unchanged] personalised risk prediction, and on pathology and survival from cancer to aid diagnosis diagnosis, treatment, and treatment/ follow-up.

Benefits reported

The study is one of the major cohort studies worldwide focussed on cancer, and has produced over 100 scientific peer-reviewed publications (see section 5.c), many of them heavily used and cited (thousands of citations). These include contributions to discovery of the majority of the single nucleotide polymorphisms (SNPs) that are known to affect the risk of breast cancer, and many affecting risks of endometrial cancer, ovarian cancer and melanoma. These are the major discoveries in cancer genetics of the last 5-10 years that enable improved risk prediction and counselling for patients in clinics and their families. The ICR has published data showing that the previous literature has generally underestimated the risks of breast cancer from hormone replacement therapy (HRT), used by very large numbers of women around the menopause: this is vital in giving more accurate estimation of risks for patients and their doctors weighing the risks and benefits of taking HRT – a major public health issue. The ICR has developed, using the study data, a new, improved measure of family history of breast cancer incidence, to enable improved advice to women in clinics about their risk of breast cancer if members of their close family have had the disease, with greater precision and power than previously used measures. These outputs and uses demonstrate clearly the feasibility and public benefit. The study is one of the major cohort studies worldwide focused on breast cancer and has produced over 190 scientific peer-reviewed publications, many in the leading research journals for their specialties, on disease aetiology, genetics, and risk prediction and many of them heavily used and cited (thousands of citations). In 2024, Generations Study data contributed to six new scientific peer reviewed publications, on: identifying credible causal risk variants associated with different histotypes of epithelial ovarian cancer; disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density; plasma prolactin and postmenopausal breast cancer risk: long-term survival in tubo-ovarian high-grade serous carcinoma; body mass index and breast cancer risk around age at menopause; leisure-time physical activity and risk of premenopausal breast cancer. The study data have been used to develop improved models of risk prediction for breast cancer incidence, to enable improved advice to women about their risk of breast cancer, with greater explanatory power than previously used measures. These outputs and uses clearly demonstrate the feasibility and public benefit. Since July 2020, a further 20 scientific peer-reviewed papers have been published in leading journals. More generally the study has contributed to discovery of the majority of the single nucleotide polymorphisms (SNPs) that are known to affect the risk of breast cancer, and many affecting risks of endometrial cancer, ovarian cancer, and melanoma. These are major discoveries in cancer genetics of the last 10 years that enable improved risk prediction and counselling for patients in clinics and their families. The Institute of Cancer Research has published data showing that the previous literature has generally underestimated the risks of breast cancer from hormone replacement therapy (HRT), used by very large numbers of women around the menopause: this is vital in giving more accurate estimation of risks for patients and their doctors weighing the risks and benefits of taking HRT — a major public health issue. The Institute of Cancer Research has published on the risk of breast cancer in relation to night shift work, and our data (reassuringly) does not support an increased risk — which is important because a substantial proportion of women in the general population undertake night shift work at some time in their lives. The Institute of Cancer Research has developed, using the study data, a new, improved measure of family history of breast cancer incidence, to enable improved advice to women in clinics about their risk of breast cancer if members of their close family have had the disease, with greater precision and power than previously used measures. The study data have also been used to develop improved models of risk prediction for breast cancer incidence, to enable improved advice to women about their risk of breast cancer, with greater explanatory power than previously used measures.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Datasets: + Cancer Registration Data; + Civil Registrations of Death; + Demographics

Objective for processing

[1 paragraph unchanged] Finding the causes of cancer is important to enabling its prevention and identifying high risk groups for screening and early detection. Cancer now accounts for 26% of deaths in women in England, so is a major public health problem. Breast cancer is the most common cancer in women in the UK and worldwide. The Generations Cohort study was set up in 2003, to investigate the causes of breast cancer with exceptional focus, size and comprehensiveness, and also to investigate the causes of other cancers and causes of death in women. The Generations Study has exceptional detail, size and power and will contribute to new information on the causes, survival and genetics of breast cancer and other major diseases of women. The objective is to enable preventive measures for these diseases and to give information for patients and their families, doctors and other health professionals advising patients, the public, and policy makers, and for health promotion campaigns, on risk factors, pathology, risk prediction, and survival for these diseases and potential measures to reduce the risks, including targeted measure based on genetic and other factors. The data requested are required for the scientific analyses. A Cohort study is methodologically the most rigorous study design that can be undertaken of long-term cancer and mortality risks. The Generations Study was set up in 2003, requesting volunteer participant women in the UK, with planned collection of exposure and follow-up data to continue for at least 40 years. This is the objective and why the Institute of Cancer Research is undertaking the study. Finding the causes of cancer is important to enabling its prevention and identifying high risk groups for screening and early detection. Cancer now accounts for 26% of deaths in women in England, so is a major public health problem. Breast cancer is the most common cancer in women in the UK and worldwide. The Generations Cohort study was set up in 2003, to investigate the causes of breast cancer with exceptional focus, size and comprehensiveness, and also to investigate the causes of other cancers and causes of death in women. It is one of the leading such cohort studies in the world. [1 paragraph unchanged] To investigate these factors optimally needs a study in which information about [5 words unchanged] through life, is collected prospectively in a large cohort of women, with long term long-term follow-up for breast cancer. For aspects such as the relationship of serum concentrations of IGF1 Insulin-like growth factor (IGF1) and of sex hormones to risk of subsequent breast cancer, this is [32 words unchanged] similar strengths for investigation of other major cancers and causes of death. [1 paragraph unchanged] The study has exceptional detail, size and power to contribute to new information on the causes, survival and genetics of breast cancer and other major diseases of women. The objective is to enable preventive measures for these diseases and to give information for patients and their families, doctors and other health professionals advising patients, the public, and policy makers, and for health promotion campaigns, on risk factors, pathology, risk prediction, and survival for these diseases and potential measures to reduce the risks, including targeted measures based on genetic and other factors. Individual level data on cancer, deaths and emigrations is required. The information is for women who have joined the study and given their consent for ICR to receive such information. The ICR send identifiers they hold for the women in the cohort who have provided consent for this. NHS Digital link the flagging data and return this for these women the ICR have already identified. Information is requested for the years specified in the Agreement because this is an on-going cohort study: the scientific purpose of the study, agreed by the participants, is to analyse risk in the period since joining the study, for follow-up of 40 years or longer thereafter. Thus, it is intrinsic to it to update follow-up regularly. Women in the study may reside all over the country Therefore the Institute of Cancer Research is requesting information from England and Wales from NHS Digital. The only alternative way to gain full information on cancers, deaths, and emigrations, on an ongoing basis for over 40 years would be to consult all of the medical case-notes of the (over 100,000) women in the study on an on-going basis. This would be unacceptably intrusive and is not conceivably practicable, hence data are requested from NHS Digital for practicability reasons. The Institute of Cancer Research has only requested the data required for the purposes outlined in this Agreement. The data under this Data sharing agreement will be processed under Articles 6 and 9 of EU GDPR. The legal basis for the processing of personal data is that this is necessary to perform a task in the public interest and the exemption for the processing of special category personal data (Article 6(1)(e)) and under Article 9 of EU GDPR is that the processing is necessary for scientific research purposes (Article 9 (2)(j)). The study is of cohort design, recruiting volunteer women from the general population of the UK aged 18 years and older, who have completed an extensive questionnaire about breast cancer risk factors, given a blood sample, and given informed consent for follow-up via national routine data systems. Over 110,000 women have been recruited since 2003 with active recruitment stopping in 2009. Participants still continue to join the study, however these are not in great numbers. A cohort study is methodologically the most rigorous study design that can be undertaken of long-term cancer and mortality risks. Appropriate analyses requires comprehensive information on occurrence of cancer and deaths, and emigrations. Without the data from NHS Digital the study results would be incomplete, inaccurate and biased. Follow-up is primarily by 3-yearly questionnaires. It is planned that collection of exposure and follow-up data will continue for at least 40 years. In addition periodic newsletters are sent to participants with a reply slip for notification of changes in address and, with signed informed consent, the ICR also uses flagging at NHS Digital to provide follow-up data, including cancer registrations and causes of death. This data requested will only be used for purposes detailed in this Agreement. The Institute of Cancer Research is the sole Data Controller who also process the data. Breast Cancer Now is a funder for the study, however they do not make any decisions regarding the data requested for this study and are therefore not listed as a data controller under this Agreement. Only substantive employees at the ICR are able to access NHS Digital data. No other organisations, including Breast Cancer Now, will have access to or process NHS Digital data.

Processing activities

The study is of cohort design, recruiting volunteer women from the general population of the UK aged 18 years and older, who have completed an extensive questionnaire about breast cancer risk factors, given a blood sample, and given informed consent for follow-up via national routine data systems. Over 110,000 women have been recruited since 2003 with active recruitment stopping in 2009. Participants still continue to join the study, however these are not in great numbers. A cohort study is methodologically the most rigorous study design that can be undertaken of long-term cancer and mortality risks. Follow-up is primarily by 3-yearly questionnaires. It is planned that collection of exposure and follow-up data will continue for at least 40 years. In addition periodic newsletters are sent to participants with a reply slip for notification of changes in address and, with signed informed consent, the ICR also uses flagging at NHS Digital to provide follow-up data, including cancer registrations and causes of death. The ICR supplied cohort identifiers to NHS Digital consisting of: The ICR supplies cohort identifiers to NHS Digital and the participants’ entries are then flagged on NHS Digital’s computer system. Only identifiers of participants with whom the ICR has lost contact or who have self-reported cancers and/or who are believed to have died are supplied to NHS Digital for flagging. Otherwise, the ICR continues to collect information directly from the participants. 41,695 participants had been flagged prior to September 2018. Approximately 800 additional participants who meet the above criteria will be flagged at fixed points each year. ICR will supply identifying details of these additional participants to NHS Digital for the purpose of flagging. Under this Agreement, the ICR is not permitted to flag new participants recruited during or since 2015 (at which point guidance NHS Digital issued new guidance on consent). Forenames and Surnames For flagged participants NHS Digital reports details of the cancer diagnoses and/or the details of deaths (date and cause) and also reports exits from registration with the NHS (e.g. if a participant emigrates). NHS Digital has supplied this data to the ICR on a regular basis over many years. These data are used only for analyses for the approved medical research project identified above. Date of Birth Analyses are conducted of risk factors for breast cancer and other cancers and causes of death mainly by standard cohort analyses methods (Breslow & Day, 1987), but also in nested case-control analyses for exposure variables (e.g. various assays) that can only practically be obtained on this basis. Sex Identifiable data are required to ensure accurate linkages of individual participants’ data. Access to the identifiable data is restricted to ICR researchers with authorisation from the Chief Investigator, who is the Head of the ICR’s Epidemiology Team. The data will be accessed and analysed solely at ICR for the analyses described above, which are the purpose of the study and the purpose of obtaining the data from NHS Digital. Study ID The participants’ entries are then flagged on NHS Digital’s computer system. Only identifiers of participants with whom the ICR has lost contact or who have self-reported cancers and/or who are believed to have died are supplied to NHS Digital for flagging. Otherwise, the ICR continues to collect information directly from the participants. 41,695 participants had been flagged prior to September 2018. Approximately 800 additional participants who meet the above criteria will be flagged at fixed points each year. ICR will supply identifying details of these additional participants to NHS Digital for the purpose of flagging. Under this Agreement, the ICR is not permitted to flag new participants recruited during or since 2015 (at which point guidance NHS Digital issued new guidance on consent). - Data supplied by NHS Digital are being processed on ICR machines within a data safe haven environment. Users must log into the system using their ICR credentials. Movement of any data or files into and out of the data safe haven is strictly controlled: a small number of authorised staff have the rights to move data, and this process is monitored and audited. - The data is being matched to the existing cohort data for the women themselves, which is not a publicly available data set. - For flagged participants NHS Digital reports details of the cancer diagnoses and/or the details of deaths (date and cause) and also reports exits from registration with the NHS (e.g. if a participant emigrates). NHS Digital has supplied this data to the ICR on a regular basis since 2008. These data are used only for analyses for the approved medical research project identified above. - Analyses are conducted of risk factors for breast cancer and other cancers and causes of death mainly by standard cohort analyses methods (Breslow & Day, 1987), but also in nested case-control analyses for exposure variables (e.g. various assays) that can only practically be obtained on this basis. - Identifiable data are required to ensure accurate linkages of individual participants’ data. Access to the identifiable data is restricted to ICR researchers with authorisation from the Chief Investigator, or the Information Asset Administrator of the ICR’s Epidemiology Team. The data will be accessed and analysed solely at ICR for the analyses described above, which are the purpose of the study and the purpose of obtaining the data from NHS Digital. [1 paragraph unchanged] The Institute of Cancer Research confirm that data processing is only carried out by substantive employees of the data controllers who have been appropriately trained in data protection and confidentiality. Deepstore is a secure storage facility, which the ICR use to house study documents that are unable to be stored on ICR premises. Deepstore is not permitted any access to the data.

Expected output

[2 paragraphs unchanged] Over the next 40 years the study is expected to produce several [13 words unchanged] patient counselling, on cancer and its risk factors and on other diseases. It is planned that during During 2019 papers will be were published on, among other topics, the relation of breast cancer risk to [80 words unchanged] related cancer risks (important to genetic counselling of patients and their families). Outputs will be in the form of scientific papers and reports. No individual level data will be presented. Data will be presented as aggregated summary data in tables or as parameter estimates from statistical analyses, which give no opportunity for individual identification. Where necessary, small numbers would be supressed. A number of papers have now been published using the Generations Study data, in journals including the International Journal of Cancer and the International Journal of Epidemiology.

Benefits reported

[1 paragraph unchanged] The study data have been used to develop improved models of risk prediction for breast cancer incidence, to enable improved advice to women about their risk of breast cancer, with greater explanatory power than previously used measures. These outputs and uses clearly demonstrate the feasibility and public benefit. Since July 2020, a further 20 scientific peer-reviewed papers have been published in leading journals.

Unchanged: Expected measurable benefits.