IBIS-II Prevention & DCIS (Observational)

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Datasets: + Emergency Care Data Set (ECDS); + HES-ID to MPS-ID HES Accident and Emergency; + HES-ID to MPS-ID HES Admitted Patient Care; + NDRS Cancer Consolidated Data Set

Objective for processing

Queen Mary University of London (QMUL) requires access to NHS England data for the purpose of the following research project: IBIS-II Prevention & DCIS (Observational) The following is a summary of the aims of the research project provided by QMUL: [2 paragraphs unchanged] On recruitment to the trial all participants were fully informed and consented by a principal investigator or fully trained and qualified research nurse. During this consenting process the Coordinating Central Office (CCO) at the Centre for Cancer Prevention (CCP) provided all participants with information on study withdrawal procedures. The withdrawal procedures detailed that the participant should contact the CCO at the CCP or their local trial hospital site/nurse. The IBIS-II CCO has documented procedures in place to ensure that participants’ wishes are implemented. The following NHS England Data will be accessed: In 2005 the REC approved a substantial amendment to the IBIS-II study that enabled the collection of personal information of UK IBIS-II participants. The purpose of this data collection was two-fold: to send participants the IBIS-II trial newsletter on trial progress and news, and to obtain follow-up information, including via NHS registries. The IBIS-II Informed Consent Form (ICF) was updated to version 10 and contained the additional sentence: “I understand that my name and contact details will be securely stored by the IBIS-II Coordinating Centre and used to send me news and information relating to the IBIS-II study and request additional follow-up information.” Re-consent procedures were not recommended by REC and Information Governance Manager at Queen Mary, University of London (QMUL) at the time, instead, everyone consented on all ICF versions (including <10.0) was notified of the change through a trial newsletter and given the opportunity to opt out of data collection and flagging. As the requirements have changed around the required ICF wording, a further Section 251 exemption was applied for in 2012 and granted on 27th September 2012. • Hospital Episode Statistics (HES) Admitted Patient Care (APC), HES Accident & Emergency (A&E), Emergency Care Data Set (ECDS), Cancer Registration, Civil Registration of Deaths and NDRS Cancer Consolidated Data Set– necessary because they are required to meet the study objectives, which include looking at the effect of tamoxifen and anastrozole on breast cancer, breast cancer mortality, other cancers, cardiovascular disease, fracture rates, and non-breast cancer deaths. The addition of the NDRS Cancer Consolidated Data Set will allow the applicant to meet the objectives relating to cancer types, such as the hormone receptor status, of future cancers. IBIS-II PREVENTION: The level of the Data will be: The IBIS-II Prevention cohort compares anastrozole 1mg vs placebo in 3864 women at risk of developing breast cancer. Participants were on treatment for a five-year period. • Identifiable – necessary because it will allow QMUL to confirm the accuracy and strength of each linkage for each IBIS-II participant in the cohort. Women included in the study would have been postmenopausal and between the ages of 40-70. Post-menopausal status is defined as: The Data will be minimised as follows: 1) Over the ages of 60 • Limited to a study cohort identified by QMUL: The cohort is made up of participants from IBIS-II Prevention and IBIS-II DCIS. The criteria included participants who were randomised to treatment in either study and were known to be alive and not to have withdrawn consent for follow up or data flagging. 2) Bilateral oophorectomy. • The cohort is made up of approximately 3000 UK participants. 3) Aged over 60 with a uterus and amenorrhea for at least 12 months. QMUL 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. 4) Aged over 60 without a uterus and with follicle-stimulating hormone (FSH) less than 30 IU/L (International Units per Litre). NB if participant is taking Hormone replacement therapy (HRT), an 8 week wash out period is required prior to FSH test being performed. The lawful basis for processing personal data under the UK GDPR is: Assessment of post-menopausal status is ultimately the responsibility of the Principal Investigator (PI)/clinician involved in the participant’s care. 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; IBIS II Prevention Inclusion Criteria: The lawful basis for processing special category data under the UK GDPR is: In addition to having been confirmed as post-menopausal, women must also satisfy at least one of the entry criteria listed below: 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. 1) A mammogram must have been taken in the last year and must not show any evidence of breast cancer. This study is in the interest of the public as it aims to inform the public and health professionals over chemo preventive strategies towards breast cancer and highlight the positivity and risks involved. 2) A baseline bone mineral density scan within the last two years (Dual-energy X-ray Absorptiometry of either of hip, lumbar spine, femoral neck or forearm) will be required for all women. Two spinal x rays in one lateral dimension will be required to assess low trauma vertebral fractures. The funding is provided by Cancer Research UK (CRUK). The funding is specifically for the project described. 3) Participants treated for Hodgkins disease are eligible if they develop the disease before the age of 30 and have been treated with mantle radiotherapy. 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 described above. The Patient and Public Involvement Group were last contacted in 2020, regarding the intention to conduct follow up via NHS registries, and there was strong support to continue collecting long term follow up data without further consent. 4) Participants who took part in IBIS I but have been off trial therapy for at least 5 years. The study entry criteria was also age dependant to reflect increasing baseline risk with age, and different criteria must be met for women ages 45-70, 60-70 and 40-44. IBIS II Prevention Exclusion Criteria: 1) Pre-menopausal women 2) Any previous diagnosis of breast cancer (including DCIS excised >6 months ago). 3) Any previous cancer in the past 5 years (except non-melanoma skin cancer or in situ cancer of the cervix). 4) Current or previous tamoxifen or raloxifene or other selective estrogen receptor modulators (SERMS) use for more than 6 months or participating in IBIS I. However, women who took part in IBIS I study and have been off trial therapy for at least 5 years are eligible. 5) Intention to continue to use oestrogen-based hormone replacement therapy. 6) Women who have had either a prophylactic mastectomy or are planning to have this procedure. 7) Evidence of osteoporosis or low trauma vertebral fractures within the spine 8) Any severe accompanying disease that would, in the opinion of the investigator, place the woman at unusual risk of confound the results of the study. 9) Life expectancy of less than 10 years, or other medical condition that would significantly interfere with the ability to accept the chemo preventive treatments. 10) Psychologically and physically unsuitable for 5 years anti-oestrogen therapy. 11) Treatment with non-approved or experimental drug during the 6 months before randomisation. 12) History of lactose or gluten intolerance. IBIS-II DCIS The IBIS-II DCIS cohort compares tamoxifen + anastrozole placebo with anastrozole + tamoxifen placebo in 2980 women with estrogen receptor (ER) or progesterone receptor (PgR) positive DCIS who previously received treatment for breast cancer. Participants were on treatment for a five-year period. IBS II DCIS Inclusion criteria: a) For a participant to be eligible, she must be post-menopausal and between the ages of 40-70. In certain circumstances, women who are within 24 months of this age may join the trial by obtaining prior approval from the IBIS II steering group. Assessment of post-menopausal status is ultimately the responsibility of the PI/clinician involved in the participant’s care. b) Participants’ who have had surgery to remove a DCIS (ductal carcinoma in situ) within the last 6 months (includes Paget’s disease with underlying DCIS). Oestrogen receptor and Progesterone receptor status of DCIS must be known. c) Participants who have been diagnosed with atypical hyperplasia or lobular carcinoma in situ at any time. d) A baseline bone mineral density scan within the last two years (DXA either of hip, lumbar spine or forearm) will be required for all women. Two spinal x rays in one lateral dimension will also be required to rule out low trauma vertebral fractures. e) Participants who took part in IBIS-I but have been off trial therapy for at least 5 years. The IBIS II DCIS trial is open to women who have had surgery to remove ER (oestrogen) or PgR (progesterone) positive DCIS within the last six months in which there are tumour free margins of at least 1mm. Patients with a single or multiple focus of micro invasion (<1mm) are eligible to join IBIS II. Radiotherapy may or may not be given. Depending on local practice, the hormone therapy can be started before, during or after the course of radiotherapy. Women treated with a mastectomy will not be eligible for this trial but can enter the parallel IBIS II (Prevention) trial. Women who have been diagnosed with atypical hyperplasia or lobular carcinoma in situ at any time will also be eligible. IBIS II DCIS Exclusion criteria: a) Premenopausal women. b) Any previous diagnosis of breast cancer (including DCIS excised >6months ago). c) Any other previous cancer in the past 5 years (except non melanoma skin cancer or in situ cancer of the cervix). d) Current treatment with anti-coagulants. e) Previous deep vein thrombosis or pulmonary embolus. f) Previous transient ischaemic attack (TIA) or cerebrovascular accident (CVA, stroke). g) Current or previous tamoxifen or raloxifene or other SERMS use for more than 6 months of participation in IBIS I. However, women who took part in IBIS-I and have been off trial therapy for at least 5 years are eligible. h) Intention to continue to use oestrogen-based hormone replacement therapy. i) Women who have either had a prophylactic mastectomy or are planning to have this procedure. j) Any woman with unexplained post-menopausal bleeding. k) Evidence of osteoporosis* or low trauma vertebral fractures within the spine. These women may still be eligible if their T score is greater than or equal to minus 4 and they have no more than two low trauma vertebral fractures. l) Any severe disease that would in the opinion of the investigator, place the woman at unusual risk or confound the results of the study. m) Psychologically and physically unsuitable for five years’ anti oestrogen therapy. n) Treatment with non-approved or experimental drug during the 6 months before randomisation. o) History of gluten and or lactose intolerance. The IBIS-II Central Coordinating Office (CCO) at the Centre for Cancer Prevention (CCP) has previously collected identifiable Medical Research Information Services (under NHS England) MRIS Members and Postings, Cause of Death, Flagging Current Status and Cohort Event Notification Reports (of which included Cancers), in regards to the IBIS-II Prevention and DCIS cohorts. In addition, identifiable Hospital Episodes Statistics (HES) Admitted Patient Care backdated from the 1997/98 year, and identifiable HES Accident & Emergency data backdated from the 2007/08 fiscal year were obtained under previous iterations of this Agreement. QMUL are now requesting to retain the data already received, and receive updated mortality and cancer registration data on cohort members in addition to up to date HES Admitted Patient Care. To address the GDPR Principle of Data Minimisation QMUL are only requesting data for a cohort limited to 2889 individuals and have only requested fields that they have deemed necessary for the purpose of this research. The CTIMP (IBIS II) element of this study is now closed and this Data Sharing Agreement is for the observational long term follow up, IBIS II-O. This agreement will allow QMUL to continue the assessment of the safety and efficacy of the long-term use of anastrozole in preventing ER positive breast cancer (Prevention cohort), as well as the safety and efficacy of tamoxifen/anastrozole in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours (DCIS cohort). The data provided by NHS England has enabled the IBIS-II CCO to examine the long-term safety and efficacy of cancer preventive treatments, research that is greatly supported by Cancer Research UK. In terms of intervention-related side effects, it should be noted in particular that research in the literature has shown that: - long-term use of anastrozole has been linked to increased fracture rates; - treatment by radiotherapy for DCIS is associated with an elevated risk of cardiovascular events. There is thus a need in the research community to determine the long-term side effects and safety of anastrozole and tamoxifen, in combination with other treatment interventions such as radiotherapy/local excision. Both IBIS-II cohorts have recruited participants who have received anastrozole and who may have had an intervention such as radiotherapy. Therefore, long-term follow-up of the cohorts via provision of data sets by NHS England would provide additional vital safety data on the interventions. QMUL will observe the number of fractures, cardiovascular and thromboembolic events occurring during the five-year treatment and follow-up periods in order to build a profile of possible side effects for each drug (tamoxifen and anastrozole), and in conjunction with local treatment. The lawful basis of processing falls under GDPR Article 6(1)(e) ‘Public Task’, because 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 processing of special category data (i.e. health data) falls under GDPR Article 9(2)(j) ‘Archiving, research and statistics’ processing is necessary for archiving purposes in the public interest, scientific or historical research 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 suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. This study is in the interest of the public as it aims to inform the public and health professionals over chemo preventive strategies towards breast cancer and highlight the positivity and risks involved. QMUL are the sole data controller, who also process NHS England Data for the purposes described within this Agreement. These serious adverse events are defined as a reaction or event experienced by the trial subject that is usually related to the study procedure/intervention. This was QMUL’s own safety data (not obtained via NHS England) which was collected by QMUL and held by QMUL only. This was an activity that occurred when the CTIMP study was open and was part of the study contract QMUL had with AstraZeneca at the time. As this part of the study has closed, this activity has now ceased. NHS England data have never been involved in this aspect of the previous study, as QMUL only ever sent AstraZeneca QMUL’s own data collected by QMUL when the study was open. For this current IBIS II O (Observational) study, the data QMUL from NHS England will only be used for follow up purposes and by QMUL only and will not be sent to any third party. Any decisions made are made solely by QMUL. The last public and patient involvement event took place at the Wolfson Institute on 15th January 2020 (prior to the COVID-19 pandemic) and was held as a way to meet the conditions set out by the CAG (Confidential Advisory Group) in the provisional approval letter received in April 2019. The event consisted of presentations from a handful of studies of which includes the IBIS studies. The findings were presented to the relevant patient population and participants also had the opportunity to ask questions. Additionally, this study also takes input from focus group sessions in relation to breast cancer. Participants who had taken part in breast cancer research were placed into a focus group where QMUL’s participants discussed how they felt about the trials team collecting long term follow up data without their consent. All of the attendees within the breast cancer focus group strongly agreed that it is acceptable to collect long term follow up data without consent. They were happy for QMUL to use the data so long as it was not being transferred to third parties. Participants also agreed that due to the age of the IBIS I study, it would not be appropriate to contact these participants and ask how they feel about the use of their patient identifiable data. Participants also suggested that rather than spending valuable time and resources on trying to update contact details for participants, it would be more worthwhile to track their status through their NHS number. QMUL also discussed on appropriate ways of being in touch with participants and the dissemination of results; the group felt it wasn’t wholly necessary to be in touch but that it would be a nice gesture to have contact. A suggestion was made to create an annual questionnaire and newsletter and send to these out to the current address details QMUL have on their records and to GP surgeries. The newsletter could also contain an “opt-out” clause if they did not want their details to be used in the long term follow up phase of the study. QMUL concluded that participants in general were very happy and forthcoming for QMUL to use their data for future analyses and felt that it could be used to look into different clinical specialities e.g. cardiovascular disease or dementia. Some of the highlighted quotes from those PPIE events include: “…it would be more appropriate to carry on collecting identifiable data from digital registries as opposed to attempting contact and requesting a re-consent with ex participants, which would be burdensome towards the participant…”. “…identifiable data could be used to conduct different analyses apart from assessing drug efficacy, such as how do chemopreventive agents such as tamoxifen affect women’s physical and emotional wellbeing in their marriage/relationships…” “…if researchers could look into the effects of tamoxifen on different clinical specialities such as cardiovascular disease or dementia…” [in women who had previously completed the IBIS studies.] Lastly, participants also talked about being in contact with the study team. They mentioned that “…it was not entirely necessary to be in touch but that it would be a nice gesture...” The group spoke about how the study team “…could send out an annual questionnaire or newsletter to their home addresses or GP surgeries to forward on to them. It would also be nice to have a newsletter sent which would include information on data opt out, in case women had decided they no longer wish for their data to be used by the study team…”. QMUL are currently considering implementing this suggestion.

Processing activities

Data sent by Queen Mary, University of London (QMUL) to NHS England: QMUL will transfer a cohort to NHS England. The data will consist of identifying details (specifically Name, NHS Number, Date of Birth, Postcode, Gender and a unique person ID) for the cohort to be linked with NHS England data. The Centre for Cancer Prevention (CCP) at QMUL have sent IBIS-II cohort data, i.e. a list of IBIS-II study participants, to NHS England for linkage. The following identifiers have been sent to NHS England by the CCP team at QMUL: NHS England will provide the relevant records from the HES APC, HES A&E, ECDS, Cancer Registration Data, Civil Registrations of Death and NDRS Cancer Consolidated datasets to QMUL. The Data will: - Full Name • contain directly identifying data items including Names, NHS Number, Date of Birth, Postcode and Gender which are required to link the Data at record level with data already held by the recipient - Study ID The Data will not be transferred to any other location. - Postcode The Data will be stored on servers at QMUL. - Sex QMUL uses offsite back-up services provided by Iron Mountain. - Date of Birth The Data will be accessed onsite at the premises of QMUL only. - NHS Number The Data will not leave England/Wales at any time. NHS England then linked these identifiers to Mortality, Cancers and HES Data, and securely transferred data back to QMUL. Access is restricted to individuals within The Centre for Cancer Prevention (CCP) of QMUL who have authorisation from the Principal Investigator. All such individuals are substantive employees of QMUL. The datasets returned by NHS England to QMUL contain identifiable data. This is so that QMUL can confirm the accuracy and strength of each linkage for each IBIS-II participant in the cohorts. This ensures that all side effects, survival and cancer incidence data are correctly attributed to each IBIS-II participant, thus avoiding any errors that would invalidate the study. All personnel accessing the Data have been appropriately trained in data protection and confidentiality. On receipt of the returned data set from NHS England, the CCP at QMUL link this data set to the data set contained in the IBIS-II study database via the full name, date of birth, NHS number, post code and study ID. As mentioned, the data linkage enables the correct identification of the IBIS-II participants from the data set sent by NHS England. 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. The data received by CCP at QMUL will not be used for any purpose other than to meet objectives as stated in the trial protocol and will not be shared with any other third party or organisation. Analysts from the CCP at QMUL will analyse the Data for the purposes described above. The data sets returned by NHS England will provide vital information, and using this data the IBIS-II Central Coordinating Office (CCO) will conduct research and analyses that will investigate: - The safety efficacy of the long-term use of anastrozole in preventing ER positive breast cancer; - The safety of tamoxifen in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours; - The efficacy of tamoxifen in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours is effective; - which drug (tamoxifen or anastrozole) is more effective and safer in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours is effective; - the type, duration and severity of side effects related to the interventions; - a thorough risk-benefit assessment of tamoxifen and anastrozole. Once the participants have been linked, accredited researchers substantively employed by QMUL updated the participant entries in the IBIS-II study database with date and cause of death, cancer recurrence, diagnosis, and coding as well as any HES data relevant to the study (fractures, cardiovascular and thrombo-embolic events). Following the linkage and participant identification, all identifiers except the study ID will be removed from the data set returned by NHS England and stored separately as a reference for analysis until study completion. Following receipt of the data sets by NHS England, if further information was required in addition to that provided from the HES/Mortality data sets the IBIS-II CCO requested supporting information from the participant’s general practitioner (GP) or IBIS-II local site team (local hospital database). The supporting information requested by the IBIS-II CCO would comprise cancer recurrence (i.e. grade, site, receptor status) and side effects (i.e. fractures, cardiovascular events, thrombo-embolic events). These are the secondary objectives to the trial protocol. Processed data sets with all identifiers removed except the Study ID will be retained for analysis until study completion, following which it will be archived for 20 years (subject to having appropriate permissions from NHS England). The original ‘raw’ data set returned by NHS England containing identifiable data will be stored on a separate server to meet security requirements. QMUL would like to emphasise that personal identifiable data are stored on the secure network and never on the local drives of unencrypted QMUL desktop PCs. QMUL creates back-ups of the data stored on its network. The encrypted backup tapes are stored offsite with Iron Mountain UK Ltd. The data is not accessible by any Iron Mountain employee. All personal identifiable data received at the CCP are stored electronically on a database, local to and administered by QMUL. Personal identifiers of study participants are encrypted in the database and stored separately to the clinical data, with access strictly restricted to only QMUL substantive members of staff who have accredited researcher status. Only these members of staff will have access to the personal identifiable data. Additionally, access to the personal identifiers on the database is controlled by separate username and password access and is controlled by the IT Department. The separate Mortality and HES servers are self-contained within the Barts Cancer Research Centre network, within the QMUL network. They are firewalled from external connections and the rest of the network. All traffic through the checkpoint firewall is logged. Access to data will be from within the network using workstations that have a currently supported operating system which includes security patches. No remote access (i.e. through a VPN/RDP connection) is permitted. No mobile devices will be used to access any data. The network is externally scanned via appropriate and reliable software on a regular basis. The ‘raw’ data sets will be stored until the data destruction date as per the Agreement with NHS England. The storage architecture is compliant with the NHS England contract and once QMUL is issued with a Data Destruction notice, the data from all storage including backups can be securely and permanently removed within 14 days. In this circumstance, data will be wiped to NHS England standards.

Benefits reported

[4 paragraphs unchanged] Mortality data and targeted code searching of HES was used to strengthen secondary endpoint data. In an updated the 2010 long-term analysis of the IBIS-II data, researchers were able to show that [35 words unchanged] that patients and their health care practitioner have all the relevant information available available, and the inclusion of HES data has enabled QMUL to evaluate the long-lasting effects of anastrozole. A further benefit to the NHS from data available so far, has [12 words unchanged] one breast cancer during the first 12 years of follow-up. In the most recent analysis and publication from 2019 the number was 29 for anastrozole, which compares favourably with the 58 needed for tamoxifen at that time of the previous analysis and publication. Results published during the 2020 San Antonio Breast Cancer Symposium confirmed that an improved understanding of the [36 words unchanged] NICE to inform the prescribing utility of these drugs as chemopreventive agents. Data on long-term outcomes have also contributed to secondary analyses, including a nested case-control study from IBIS-II that found the benefit of anastrozole was likely limited to women with medium or high (quartiles 2–4) ratios of oestradiol to sex hormone binding globulin (SHBG). These findings suggest a potential role for measuring oestradiol, and SHBG more widely, both in determining which individuals are at high risk and the likely response to endocrine treatment. https://www.thelancet.com/article/S1470-2045(23)00578-8/fulltext Results from the IBIS-II Prevention trial have provided evidence to support a license variation for use of anastrozole in England as a preventive option as reported in the media (Nov 2023), for example https://www.bbc.co.uk/news/health-67337081. More recently, QMUL have supported development of agreement via NHS England to facilitate future licensing applications for use of Anastrozole in other countries therefore widening impact internationally in breast cancer prevention. [1 paragraph unchanged] Due to the COVID-19 pandemic, there hasn’t been consistent attention on this and QMUL are just starting to pick up but it is envisioned that the data generated could hugely contribute if QMUL are able to carry on accessing long term follow up data. Future plans are to continue analysis of the long term follow up for IBIS-II which could have importance both in the UK and internationally.

Unchanged: Expected output, Expected measurable benefits.

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

Datasets: + Cancer Registration Data; + Civil Registrations of Death; + Hospital Episode Statistics Accident and Emergency (HES A and E); + Hospital Episode Statistics Admitted Patient Care (HES APC)

Objective for processing

Established in 2002, the International Breast Cancer Intervention Study (IBIS-II) Prevention and DCIS (Ductal Carcinoma InSitu) In Situ) studies are designed to continue the work started by the IBIS-I trial [27 words unchanged] 40–70 years. The study is now in a phase of extended follow-up. [2 paragraphs unchanged] In 2005 the REC approved a substantial amendment to the IBIS-II study [44 words unchanged] Form (ICF) was updated to version 10 and contained the additional sentence: "I “I understand that my name and contact details will be securely stored by [9 words unchanged] news and information relating to the IBIS-II study and request additional follow-up information." information.” Re-consent procedures were not recommended by REC and Information Governance Manager at [5 words unchanged] (QMUL) at the time, instead, everyone consented on all ICF versions (including <v10.0) <10.0) was notified of the change through a trial newsletter and given the [23 words unchanged] exemption was applied for in 2012 and granted on 27th September 2012. [6 paragraphs unchanged] 4) Aged over 60 without a uterus and with FSH follicle-stimulating hormone (FSH) less than 30 IU/L. IU/L (International Units per Litre). NB if participant is taking HRT, Hormone replacement therapy (HRT), an 8 week wash out period is required prior to FSH test being performed. Assessment of post-menopausal status is ultimately the responsibility of the PI/clinician Principal Investigator (PI)/clinician involved in the participant’s care. [6 paragraphs unchanged] The study entry criteria are was also age dependant to reflect increasing baseline risk with age. age, and different criteria must be met for women ages 45-70, 60-70 and 40-44. Women ages 45-70; at least one of the following must be satisfied: 1) First degree relative who developed breast cancer at age 50 or less. 2) First degree relative who developed bilateral breast cancer. 3) Two or more first or second-degree relatives who developed breast or ovarian cancer. If both relatives are second degree and opposites side of the family then at least one must have been diagnosed at age 50 or less. 4) Nulliparous (or first birth at age 30 or above) and a first degree relative who developed breast cancer. 5) Benign biopsy with proliferative disease and a first degree relative who developed breast cancer. Mammographic opacity covering at least 50% of the breast in absence of HRT use within the last 3 months. Films or digitised images must be verified by either a designated national radiologist or by someone that has undertaken the mammographic density training for confirmation of eligibility prior to randomisation Women aged 60-70: Because of the high baseline risk, women aged 60-70 can enter the study with a smaller relative risk. This corresponds to a similar 5-year absolute risk as that for a 50-year-old woman in the above group (approx. 3% at 5 years). These women need only have one or more of the following risk factors: 1) First degree relative with breast cancer at any age. 2) Age at menopause >/ 55 years. 3) Nulliparous or age at first birth 30 years or above. Women aged 40-44 Women between ages of 40-44 and are post-menopausal (usually because of a bilateral oophorectomy) are eligible if they satisfy one or more of the following criteria (approx. 4-fold risk or greater). 1) Two or more first or second-degree relatives who developed breast or ovarian cancer at age 50 or less. 2) First degree relative with bilateral breast cancer who developed the first breast cancer at age 50 or less. 3) Has never given birth (or first birth at age 30 or above) and a first degree relative who developed breast cancer at age 40 or less. 4) Benign biopsy with proliferative disease and a first degree relative who developed breast cancer at age 40 or less. All age groups (40-70): 1) Lobular carcinoma insitu (LCIS).LCIS is a common condition in which abnormal cells form in the milk glands (lobules) in the breast. LCIS isn't cancer. But being diagnosed with LCIS indicates that you have an increased risk of developing breast cancer. 2) Atypical ductal or lobular hyperplasia in a benign lesion. Atypical hyperplasia is when cells lining the ducts or lobules increase in number and also develop an unusual pattern or shape. 3) Ductal carcinoma in situ (DCIS), an early form of breast cancer, treated by a mastectomy within the last 6 months. 4) Women with a ten-year risk greater than 5%, who do not fit into the above categories. All risk equivalent women must be approved by the Steering Committee. These women must have clearly apparent family history and/or other risk factors including appropriate risk of breast cancer for their age. Particularly careful assessment of the risk-benefit for these women should be undertaken before a woman from this group is entered. [4 paragraphs unchanged] 4) Current or previous tamoxifen or raloxifene or other SERMS selective estrogen receptor modulators (SERMS) use for more than 6 months or participating in IBIS I. However, [9 words unchanged] have been off trial therapy for at least 5 years are eligible. [9 paragraphs unchanged] The IBIS-II DCIS cohort compares tamoxifen+anastrozole tamoxifen + anastrozole placebo with anastrozole+tamoxifen anastrozole + tamoxifen placebo in 2980 women with estrogen receptor (ER) or progesterone receptor (PgR) [5 words unchanged] treatment for breast cancer. Participants were on treatment for a five-year period. [15 paragraphs unchanged] g) Current or previous tamoxifen or raloxifene or other selective estrogen receptor modulators (SERMS) SERMS use for more than 6 months of participation in IBIS I. However, [7 words unchanged] have been off trial therapy for at least 5 years are eligible. [8 paragraphs unchanged] The IBIS-II Central Coordinating Office (CCO) at the Centre for Cancer Prevention (CCP) has previously collected identifiable Medical Research Information Services (under NHS England) MRIS Members and Postings, Cause of Death, Flagging Current Status and Cohort Event Notification Reports, Reports (of which included Cancers), in addition regards to for the IBIS-II Prevention and DCIS cohorts. In addition to this, addition, identifiable HES APC Hospital Episodes Statistics (HES) Admitted Patient Care backdated from the 1997/98 year, and identifiable HES A&E Accident & Emergency data backdated from the 2007/08 fiscal year were obtained under previous iterations [11 words unchanged] already received, and receive updated mortality and cancer registration data on cohort members. members in addition to up to date HES Admitted Patient Care. [1 paragraph unchanged] This extension will allow QMUL to continue assess the safety and efficacy of the long-term use of anastrozole in preventing ER positive breast cancer (Prevention cohort), as well as the safety and efficacy of tamoxifen/anastrozole in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours (DCIS cohort). The data provided by NHS Digital has enabled the IBIS-II CCO to examine the long-term safety and efficacy of cancer preventive treatments, research that is greatly supported by Cancer Research UK. The CTIMP (IBIS II) element of this study is now closed and this Data Sharing Agreement is for the observational long term follow up, IBIS II-O. This agreement will allow QMUL to continue the assessment of the safety and efficacy of the long-term use of anastrozole in preventing ER positive breast cancer (Prevention cohort), as well as the safety and efficacy of tamoxifen/anastrozole in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours (DCIS cohort). The data provided by NHS England has enabled the IBIS-II CCO to examine the long-term safety and efficacy of cancer preventive treatments, research that is greatly supported by Cancer Research UK. [3 paragraphs unchanged] There is thus a need in the research community to determine the [40 words unchanged] long-term follow-up of the cohorts via provision of data sets by NHS Digital England would provide additional vital safety data on the interventions. QMUL will observe [26 words unchanged] for each drug (tamoxifen and anastrozole), and in conjunction with local treatment. [1 paragraph unchanged] The processing of special category data (i.e. health data) falls under GDPR [56 words unchanged] to safeguard the fundamental rights and the interests of the data subject. This study is in the interest of the public as it aims to inform the public and health professionals over chemo preventive strategies towards breast cancer and highlight the positivity and risks involved. QMUL are the sole data controller, who also process NHS Digital England Data for the purposes described within this Agreement. This work is funded by AstraZeneca but the study team is responsible to submit pharmacovigilance reports, and this is processed by their PV team, such as serious adverse events and suspected unexpected serious adverse reactions. An annual report is provided to them in their capacity as funder but there is no follow up from them. These serious adverse events are defined as a reaction or event experienced by the trial subject that is usually related to the study procedure/intervention. This was QMUL’s own safety data (not obtained via NHS England) which was collected by QMUL and held by QMUL only. This was an activity that occurred when the CTIMP study was open and was part of the study contract QMUL had with AstraZeneca at the time. As this part of the study has closed, this activity has now ceased. NHS England data have never been involved in this aspect of the previous study, as QMUL only ever sent AstraZeneca QMUL’s own data collected by QMUL when the study was open. For this current IBIS II O (Observational) study, the data QMUL from NHS England will only be used for follow up purposes and by QMUL only and will not be sent to any third party. Any decisions made are made solely by QMUL. The last public and patient involvement event took place at the Wolfson Institute on 15th January 2020 (prior to the COVID-19 pandemic) and was held as a way to meet the conditions set out by the CAG (Confidential Advisory Group) in the provisional approval letter received in April 2019. The event consisted of presentations from a handful of studies of which includes the IBIS studies. The findings were presented to the relevant patient population and participants also had the opportunity to ask questions. Additionally, this study also takes input from focus group sessions in relation to breast cancer. Participants who had taken part in breast cancer research were placed into a focus group where QMUL’s participants discussed how they felt about the trials team collecting long term follow up data without their consent. All of the attendees within the breast cancer focus group strongly agreed that it is acceptable to collect long term follow up data without consent. They were happy for QMUL to use the data so long as it was not being transferred to third parties. Participants also agreed that due to the age of the IBIS I study, it would not be appropriate to contact these participants and ask how they feel about the use of their patient identifiable data. Participants also suggested that rather than spending valuable time and resources on trying to update contact details for participants, it would be more worthwhile to track their status through their NHS number. QMUL also discussed on appropriate ways of being in touch with participants and the dissemination of results; the group felt it wasn’t wholly necessary to be in touch but that it would be a nice gesture to have contact. A suggestion was made to create an annual questionnaire and newsletter and send to these out to the current address details QMUL have on their records and to GP surgeries. The newsletter could also contain an “opt-out” clause if they did not want their details to be used in the long term follow up phase of the study. QMUL concluded that participants in general were very happy and forthcoming for QMUL to use their data for future analyses and felt that it could be used to look into different clinical specialities e.g. cardiovascular disease or dementia. Some of the highlighted quotes from those PPIE events include: “…it would be more appropriate to carry on collecting identifiable data from digital registries as opposed to attempting contact and requesting a re-consent with ex participants, which would be burdensome towards the participant…”. “…identifiable data could be used to conduct different analyses apart from assessing drug efficacy, such as how do chemopreventive agents such as tamoxifen affect women’s physical and emotional wellbeing in their marriage/relationships…” “…if researchers could look into the effects of tamoxifen on different clinical specialities such as cardiovascular disease or dementia…” [in women who had previously completed the IBIS studies.] Lastly, participants also talked about being in contact with the study team. They mentioned that “…it was not entirely necessary to be in touch but that it would be a nice gesture...” The group spoke about how the study team “…could send out an annual questionnaire or newsletter to their home addresses or GP surgeries to forward on to them. It would also be nice to have a newsletter sent which would include information on data opt out, in case women had decided they no longer wish for their data to be used by the study team…”. QMUL are currently considering implementing this suggestion.

Processing activities

All organisations party to this agreement will comply with the Data Sharing Framework Contract, including requirements on 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 that data). Data sent by Queen Mary, University of London (QMUL) to NHS England: Data sent by Queen Mary, University of London (QMUL) to NHS Digital: The Centre for Cancer Prevention (CCP) at QMUL have sent IBIS-II cohort data, i.e. a list of IBIS-II study participants, to NHS England for linkage. The following identifiers have been sent to NHS England by the CCP team at QMUL: The Centre for Cancer Prevention (CCP) at QMUL have sent IBIS-II cohort data, i.e. a list of IBIS-II study participants, to NHS Digital for linkage. The following identifiers have been sent to NHS Digital by the CCP team at QMUL: [6 paragraphs unchanged] NHS Digital England then linked these identifiers to Mortality Mortality, Cancers and HES Data, and securely transferred data back to QMUL. The datasets returned by NHS Digital England to QMUL contain identifiable data. This is so that QMUL can confirm [29 words unchanged] each IBIS-II participant, thus avoiding any errors that would invalidate the study. On receipt of the returned data set from NHS Digital, England, the CCP at QMUL link this data set to the data set [28 words unchanged] identification of the IBIS-II participants from the data set sent by NHS Digital. England. [1 paragraph unchanged] The data sets returned by NHS Digital England will provide vital information, and using this data the IBIS-II Central Coordinating Office (CCO) will conduct research and analyses that will investigate: [4 paragraphs unchanged] Once the participants have been linked, accredited researchers substantively employed by QMUL [45 words unchanged] study ID will be removed from the data set returned by NHS Digital England and stored separately as a reference for analysis until study completion. Following receipt of the data sets by NHS Digital, England, if further information was required in addition to that provided from the HES/Mortality data sites, sets the IBIS-II CCO requested supporting information from the participant's participant’s general practitioner (GP) or IBIS-II local site team (local hospital database). The [22 words unchanged] events, thrombo-embolic events). These are the secondary objectives to the trial protocol. Processed data sets with all identifiers removed except the Study ID will [11 words unchanged] be archived for 20 years (subject to having appropriate permissions from NHS Digital). England). The original 'raw' ‘raw’ data set returned by NHS Digital England containing identifiable data will be stored on a separate server to meet [16 words unchanged] network and never on the local drives of unencrypted QMUL desktop PCs. [5 paragraphs unchanged] The network is externally scanned via AlienVault Network Vulnerability Scanner appropriate and reliable software on a regular basis. The 'raw' ‘raw’ data sets will be stored until the data destruction date as per the Agreement with NHS Digital. England. The storage architecture is compliant with the NHS Digital England contract and once QMUL is issued with a Data Destruction notice, the data from all storage including backups can be securely and permanently removed within 14 days. Data can In this circumstance, data will be securely wiped to NHS Digital England standards.

Expected output

[1 paragraph unchanged] The most recent major outcome analysis for IBIS-II Prevention and for IBIS-II [30 words unchanged] tamoxifen. These results have also been published in the Lancet in December 2020. 2020 (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32955-1/fulltext https://oncology.medicinematters.com/sabcs-2020/breast-cancer/ibis-ii-update-dcis/18680894). Results were also published on the BBC around the same time. time (https://www.bbc.co.uk/news/health-50757993). [3 paragraphs unchanged] Any data, which is used for publication, will be fully anonymised and [5 words unchanged] level. Data will be aggregated with small numbers suppressed in line with the HES analysis guide. NHS England guidelines. Additionally, any comparisons between findings from other studies or countries will be made at an aggregated level with suppression rules applied and under no circumstances will identifiable patient level data be used for this. [2 paragraphs unchanged] Annual reports are to be provided AstraZeneca, as the funder of this study. All data provided will be aggregated with small numbers supressed in line with HES Analysis Guidance.

Expected measurable benefits

The It is hoped the data sets returned disseminated by NHS Digital England will provide vital information on side effects, survival and breast cancer incidence. Using data, these data sets, the IBIS-II Central Coordinating Office (CCO) will conduct research and analyses that will could help provide further information on: [1 paragraph unchanged] - The safety of tamoxifen in local control and prevention of contralateral disease with locally excised ER estrogen receptor (ER) or PgR progesterone receptor (PgR) positive breast cancer tumours; [2 paragraphs unchanged] These analyses will could enable the research community and medical practitioners to make more informed decisions on tamoxifen and anastrozole vis-a-vis patient safety and both their short- and long-term effectiveness. These analyses will could enable patients and including women at identified as having a higher risk of developing breast cancer to make a more informed decision on the treatment options available to them. Events reported through registry data provide us QMUL with a platform to investigate further by initially informing us QMUL of the event, which we QMUL will then follow up in primary and secondary care records to collect highly relevant outcome data such as cancer grade, size and receptor status. This information informs our QMUL’s secondary and exploratory objectives which are breast cancer and all-cause mortality, cancers other than breast, cardiovascular/cerebrovascular events, and fractures. The next outcome analysis for IBIS-II Prevention and for IBIS-II DCIS is in 2023. The long-term follow-up protocol should be active by late spring and will run side by side until the Clinical Trial of an Investigational Medicinal Product (CTIMP) protocol is closed. It is hoped the findings from any future research carried out from being able to collect long term follow up data will hugely benefit the medical profession, women at high risk from breast cancer and women who have been newly diagnosed. Currently, the data collected has been of huge importance but in order to properly inform and predict a prognosis for women with breast cancer QMUL are still missing vital long term data that will potentially enable the study to form a wealth of information allowing health professionals and women with breast cancer a choice of treatments and access to more information. Access to follow up data also massively contributes to understanding and predicting any current testing on biomarkers by going back and carrying out this testing on samples (with consent in place) held from these cohorts. The next outcome analysis for IBIS-II Prevention and for IBIS-II DCIS is in 2023. The long-term follow-up protocol is now active. The Clinical Trial of an Investigational Medicinal Product (CTIMP) protocol is closed.

Benefits reported

[2 paragraphs unchanged] The data received so far has identified multiple breast cancer and ductal carcinoma in situ (DCIS) events in participants who were lost to follow up, up*, and whose diagnoses were not known to the trial team. As these [16 words unchanged] the current research findings, contributing to the high significance of the results. Mortality data and targeted code searching of HES was used to strengthen secondary endpoint data. In an updated long-term analysis of the IBIS-II data, researchers were able to show that adverse events, such as fractures, were not increased once women stopped with the active drug (anastrozole). This information is important for clinicians to communicate with women at increased risk of breast cancer. It is crucial that patients and their health care practitioner have all the relevant information available and the inclusion of HES data has enabled us to evaluate the long-lasting effects of anastrozole. * To clarify, the statement means that they consented to having their data collected and therefore QMUL have been able to find out long term outcomes for these women via NHS Digital but these same women were lost to being contacted towards the end of the trial and were not contactable via patient questionnaires which would have allowed QMUL and sites to create the data entry first hand. Mortality data and targeted code searching of HES was used to strengthen secondary endpoint data. In an updated long-term analysis of the IBIS-II data, researchers were able to show that adverse events, such as fractures, were not increased once women stopped with the active drug (anastrozole). This information is important for clinicians to communicate with women at increased risk of breast cancer. It is crucial that patients and their health care practitioner have all the relevant information available and the inclusion of HES data has enabled QMUL to evaluate the long-lasting effects of anastrozole. [1 paragraph unchanged] Results published during the San Antonio Breast Cancer Symposium confirmed that an improved understanding of the adverse event profile would help patients with hormone receptor (HR) positive DCIS to make an informed decision regarding their treatment. Results [15 words unchanged] NICE to inform the prescribing utility of these drugs as chemopreventive agents. [1 paragraph unchanged] Due to the COVID-19 pandemic, there hasn’t been consistent attention on this and QMUL are just starting to pick up but it is envisioned that the data generated could hugely contribute if QMUL are able to carry on accessing long term follow up data.

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

Datasets: − Hospital Episode Statistics Accident and Emergency (HES A and E); − Hospital Episode Statistics Admitted Patient Care (HES APC)

Objective for processing

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling Queen Mary University of London to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance). Established in 2002, the International Breast Cancer Intervention Study (IBIS-II) Prevention and DCIS (Ductal Carcinoma InSitu) studies are designed to continue the work started by the IBIS-I trial in determining whether a chemo preventive strategy towards breast cancer is beneficial. IBIS-II Prevention and DCIS are double-blinded, placebo controlled, randomised trials which recruited post-menopausal women aged 40–70 years. The study is now in a phase of extended follow-up. The following provides background information on the purpose of the original study: Established in 2002, the International Breast Cancer Intervention Study (IBIS-II) Prevention and DCIS (Ductal Carcinoma In-Situ) studies are designed to continue the work started by the IBIS-I trial (MR710) in determining whether a chemopreventive strategy towards breast cancer is beneficial. IBIS-II Prevention and DCIS are double-blinded, placebo controlled, randomised trials which recruited post-menopausal women aged 40–70 years. [1 paragraph unchanged] On recruitment to the trial all participants were fully informed and consented [29 words unchanged] participants with information on study withdrawal procedures. The withdrawal procedures detailed that participants the participant should contact the CCO at the CCP or their local trial hospital site/nurse. The IBIS-II CCO has documented procedures in place to ensure that participants' wishes are implemented. [1 paragraph unchanged] IBIS-II PREVENTION: [1 paragraph unchanged] Women included in the study would have been postmenopausal and between the ages of 40-70. Post-menopausal status is defined as: 1) Over the ages of 60 2) Bilateral oophorectomy. 3) Aged over 60 with a uterus and amenorrhea for at least 12 months. 4) Aged over 60 without a uterus and with FSH less than 30 IU/L. NB if participant is taking HRT, an 8 week wash out period is required prior to FSH test being performed. Assessment of post-menopausal status is ultimately the responsibility of the PI/clinician involved in the participant’s care. IBIS II Prevention Inclusion Criteria: In addition to having been confirmed as post-menopausal, women must also satisfy at least one of the entry criteria listed below: 1) A mammogram must have been taken in the last year and must not show any evidence of breast cancer. 2) A baseline bone mineral density scan within the last two years (Dual-energy X-ray Absorptiometry of either of hip, lumbar spine, femoral neck or forearm) will be required for all women. Two spinal x rays in one lateral dimension will be required to assess low trauma vertebral fractures. 3) Participants treated for Hodgkins disease are eligible if they develop the disease before the age of 30 and have been treated with mantle radiotherapy. 4) Participants who took part in IBIS I but have been off trial therapy for at least 5 years. The study entry criteria are age dependant to reflect increasing baseline risk with age. Women ages 45-70; at least one of the following must be satisfied: 1) First degree relative who developed breast cancer at age 50 or less. 2) First degree relative who developed bilateral breast cancer. 3) Two or more first or second-degree relatives who developed breast or ovarian cancer. If both relatives are second degree and opposites side of the family then at least one must have been diagnosed at age 50 or less. 4) Nulliparous (or first birth at age 30 or above) and a first degree relative who developed breast cancer. 5) Benign biopsy with proliferative disease and a first degree relative who developed breast cancer. Mammographic opacity covering at least 50% of the breast in absence of HRT use within the last 3 months. Films or digitised images must be verified by either a designated national radiologist or by someone that has undertaken the mammographic density training for confirmation of eligibility prior to randomisation Women aged 60-70: Because of the high baseline risk, women aged 60-70 can enter the study with a smaller relative risk. This corresponds to a similar 5-year absolute risk as that for a 50-year-old woman in the above group (approx. 3% at 5 years). These women need only have one or more of the following risk factors: 1) First degree relative with breast cancer at any age. 2) Age at menopause >/ 55 years. 3) Nulliparous or age at first birth 30 years or above. Women aged 40-44 Women between ages of 40-44 and are post-menopausal (usually because of a bilateral oophorectomy) are eligible if they satisfy one or more of the following criteria (approx. 4-fold risk or greater). 1) Two or more first or second-degree relatives who developed breast or ovarian cancer at age 50 or less. 2) First degree relative with bilateral breast cancer who developed the first breast cancer at age 50 or less. 3) Has never given birth (or first birth at age 30 or above) and a first degree relative who developed breast cancer at age 40 or less. 4) Benign biopsy with proliferative disease and a first degree relative who developed breast cancer at age 40 or less. All age groups (40-70): 1) Lobular carcinoma insitu (LCIS).LCIS is a common condition in which abnormal cells form in the milk glands (lobules) in the breast. LCIS isn't cancer. But being diagnosed with LCIS indicates that you have an increased risk of developing breast cancer. 2) Atypical ductal or lobular hyperplasia in a benign lesion. Atypical hyperplasia is when cells lining the ducts or lobules increase in number and also develop an unusual pattern or shape. 3) Ductal carcinoma in situ (DCIS), an early form of breast cancer, treated by a mastectomy within the last 6 months. 4) Women with a ten-year risk greater than 5%, who do not fit into the above categories. All risk equivalent women must be approved by the Steering Committee. These women must have clearly apparent family history and/or other risk factors including appropriate risk of breast cancer for their age. Particularly careful assessment of the risk-benefit for these women should be undertaken before a woman from this group is entered. IBIS II Prevention Exclusion Criteria: 1) Pre-menopausal women 2) Any previous diagnosis of breast cancer (including DCIS excised >6 months ago). 3) Any previous cancer in the past 5 years (except non-melanoma skin cancer or in situ cancer of the cervix). 4) Current or previous tamoxifen or raloxifene or other SERMS use for more than 6 months or participating in IBIS I. However, women who took part in IBIS I study and have been off trial therapy for at least 5 years are eligible. 5) Intention to continue to use oestrogen-based hormone replacement therapy. 6) Women who have had either a prophylactic mastectomy or are planning to have this procedure. 7) Evidence of osteoporosis or low trauma vertebral fractures within the spine 8) Any severe accompanying disease that would, in the opinion of the investigator, place the woman at unusual risk of confound the results of the study. 9) Life expectancy of less than 10 years, or other medical condition that would significantly interfere with the ability to accept the chemo preventive treatments. 10) Psychologically and physically unsuitable for 5 years anti-oestrogen therapy. 11) Treatment with non-approved or experimental drug during the 6 months before randomisation. 12) History of lactose or gluten intolerance. IBIS-II DCIS [1 paragraph unchanged] The IBIS-II Central Coordinating Office (CCO) at the Centre for Cancer Prevention (CCP) wishes to collect breast cancer, other cancers, mortality and side effects data for the IBIS-II Prevention and DCIS cohorts. This is in order to assess the safety and efficacy of the long-term use of anastrozole in preventing ER positive breast cancer (Prevention cohort) as well as the safety and efficacy of tamoxifen/anastrozole in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours (DCIS cohort). The data provided by NHS Digital would enable the IBIS-II CCO to examine the long-term safety and efficacy of cancer preventive treatments, research that is greatly supported by Cancer Research UK. IBS II DCIS Inclusion criteria: a) For a participant to be eligible, she must be post-menopausal and between the ages of 40-70. In certain circumstances, women who are within 24 months of this age may join the trial by obtaining prior approval from the IBIS II steering group. Assessment of post-menopausal status is ultimately the responsibility of the PI/clinician involved in the participant’s care. b) Participants’ who have had surgery to remove a DCIS (ductal carcinoma in situ) within the last 6 months (includes Paget’s disease with underlying DCIS). Oestrogen receptor and Progesterone receptor status of DCIS must be known. c) Participants who have been diagnosed with atypical hyperplasia or lobular carcinoma in situ at any time. d) A baseline bone mineral density scan within the last two years (DXA either of hip, lumbar spine or forearm) will be required for all women. Two spinal x rays in one lateral dimension will also be required to rule out low trauma vertebral fractures. e) Participants who took part in IBIS-I but have been off trial therapy for at least 5 years. The IBIS II DCIS trial is open to women who have had surgery to remove ER (oestrogen) or PgR (progesterone) positive DCIS within the last six months in which there are tumour free margins of at least 1mm. Patients with a single or multiple focus of micro invasion (<1mm) are eligible to join IBIS II. Radiotherapy may or may not be given. Depending on local practice, the hormone therapy can be started before, during or after the course of radiotherapy. Women treated with a mastectomy will not be eligible for this trial but can enter the parallel IBIS II (Prevention) trial. Women who have been diagnosed with atypical hyperplasia or lobular carcinoma in situ at any time will also be eligible. IBIS II DCIS Exclusion criteria: a) Premenopausal women. b) Any previous diagnosis of breast cancer (including DCIS excised >6months ago). c) Any other previous cancer in the past 5 years (except non melanoma skin cancer or in situ cancer of the cervix). d) Current treatment with anti-coagulants. e) Previous deep vein thrombosis or pulmonary embolus. f) Previous transient ischaemic attack (TIA) or cerebrovascular accident (CVA, stroke). g) Current or previous tamoxifen or raloxifene or other selective estrogen receptor modulators (SERMS) use for more than 6 months of participation in IBIS I. However, women who took part in IBIS-I and have been off trial therapy for at least 5 years are eligible. h) Intention to continue to use oestrogen-based hormone replacement therapy. i) Women who have either had a prophylactic mastectomy or are planning to have this procedure. j) Any woman with unexplained post-menopausal bleeding. k) Evidence of osteoporosis* or low trauma vertebral fractures within the spine. These women may still be eligible if their T score is greater than or equal to minus 4 and they have no more than two low trauma vertebral fractures. l) Any severe disease that would in the opinion of the investigator, place the woman at unusual risk or confound the results of the study. m) Psychologically and physically unsuitable for five years’ anti oestrogen therapy. n) Treatment with non-approved or experimental drug during the 6 months before randomisation. o) History of gluten and or lactose intolerance. The IBIS-II Central Coordinating Office (CCO) at the Centre for Cancer Prevention (CCP) has previously collected identifiable MRIS Members and Postings, Cause of Death, Flagging Current Status and Cohort Event Notification Reports, in addition to for the IBIS-II Prevention and DCIS cohorts. In addition to this, identifiable HES APC backdated from the 1997/98 year, and identifiable HES A&E data backdated from the 2007/08 fiscal year were obtained under previous iterations of this Agreement. QMUL are now requesting to retain the data already received, and receive updated mortality and cancer registration data on cohort members. To address the GDPR Principle of Data Minimisation QMUL are only requesting data for a cohort limited to 2889 individuals and have only requested fields that they have deemed necessary for the purpose of this research. This extension will allow QMUL to continue assess the safety and efficacy of the long-term use of anastrozole in preventing ER positive breast cancer (Prevention cohort), as well as the safety and efficacy of tamoxifen/anastrozole in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours (DCIS cohort). The data provided by NHS Digital has enabled the IBIS-II CCO to examine the long-term safety and efficacy of cancer preventive treatments, research that is greatly supported by Cancer Research UK. [3 paragraphs unchanged] There is thus a need in the research community to determine the [27 words unchanged] received anastrozole and who may have had an intervention such as radiotherapy. Therefore Therefore, long-term follow-up of the cohorts via provision of data sets by NHS Digital would provide additional vital safety data on the interventions. The applicant QMUL will observe in particular the number of fractures, cardiovascular and thrombo-embolic thromboembolic events occurring during the five-year treatment and follow-up periods in order to [7 words unchanged] for each drug (tamoxifen and anastrozole), and in conjunction with local treatment. The lawful basis of processing falls under GDPR Article 6(1)(e) ‘Public Task’, because 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 processing of special category data (i.e. health data) falls under GDPR Article 9(2)(j) ‘Archiving, research and statistics’ processing is necessary for archiving purposes in the public interest, scientific or historical research 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 suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. QMUL are the sole data controller, who also process NHS Digital Data for the purposes described within this Agreement. This work is funded by AstraZeneca but the study team is responsible to submit pharmacovigilance reports, and this is processed by their PV team, such as serious adverse events and suspected unexpected serious adverse reactions. An annual report is provided to them in their capacity as funder but there is no follow up from them.

Processing activities

Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement. All organisations party to this agreement will comply with the Data Sharing Framework Contract, including requirements on 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 that data). The study data, including data provided by NHS Digital under previous agreements, are currently held by Queen Mary University of London. The following provides background on the processing activities undertaken prior to this Agreement: [1 paragraph unchanged] The Centre for Cancer Prevention (CCP) at QMUL will send have sent IBIS-II cohort data, i.e. a list of IBIS-II study participants, to NHS Digital for linkage. The following identifiers will be have been sent to NHS Digital by the CCP team at QMUL: [6 paragraphs unchanged] NHS Digital then linked these identifiers to Mortality and HES Data, and Mortality products to send securely transferred data back to the CCP at QMUL. The data sets datasets returned by NHS Digital to QMUL contained contain identifiable data. This is was so that QMUL could can confirm the accuracy and strength of each linkage for each IBIS-II participant [18 words unchanged] each IBIS-II participant, thus avoiding any errors that would invalidate the study. On receipt of the returned data set from NHS Digital, the CCP at QMUL linked link this data set to the data set contained in the IBIS-II study [24 words unchanged] of the IBIS-II participants from the data set sent by NHS Digital. [1 paragraph unchanged] Once the participants are linked, accredited researchers at QMUL then updated the participant entries in the IBIS-II study database with date and cause of death, cancer recurrence, diagnosis and coding as well as any HES data relevant to the study (fractures, cardiovascular and thrombo-embolic events). Following the linkage and participant identification, all identifiers except the study ID will be removed from the data set returned by NHS Digital and stored as a reference for analysis until study completion. The data sets returned by NHS Digital will provide vital information, and using this data the IBIS-II Central Coordinating Office (CCO) will conduct research and analyses that will investigate: Following reception of the data sets by NHS Digital, if further information is required in addition to that provided from the HES/Mortality data sites, the IBIS-II CCO will request supporting information from the participant's general practitioner (GP) or IBIS-II local site team (local hospital database). The supporting information requested by the IBIS-II CCO would comprise cancer recurrence (i.e. grade, site, receptor status) and side effects (i.e. fractures, cardiovascular events, thrombo-embolic events). These are the secondary objectives to the trial protocol. - The safety efficacy of the long-term use of anastrozole in preventing ER positive breast cancer; Processed data sets with all identifiers removed except the Study ID will be retained for analysis until study completion, following which it will be archived for 20 years. The original 'raw' data set returned by NHS Digital containing identifiable data will be stored on a separate server to meet security requirements. QMUL would like to emphasise that personal identifiable data are stored on the secure network and never on the local drives of unencrypted QMUL desktop PCs. - The safety of tamoxifen in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours; - The efficacy of tamoxifen in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours is effective; - which drug (tamoxifen or anastrozole) is more effective and safer in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours is effective; - the type, duration and severity of side effects related to the interventions; - a thorough risk-benefit assessment of tamoxifen and anastrozole. Once the participants have been linked, accredited researchers substantively employed by QMUL updated the participant entries in the IBIS-II study database with date and cause of death, cancer recurrence, diagnosis, and coding as well as any HES data relevant to the study (fractures, cardiovascular and thrombo-embolic events). Following the linkage and participant identification, all identifiers except the study ID will be removed from the data set returned by NHS Digital and stored separately as a reference for analysis until study completion. Following receipt of the data sets by NHS Digital, if further information was required in addition to that provided from the HES/Mortality data sites, the IBIS-II CCO requested supporting information from the participant's general practitioner (GP) or IBIS-II local site team (local hospital database). The supporting information requested by the IBIS-II CCO would comprise cancer recurrence (i.e. grade, site, receptor status) and side effects (i.e. fractures, cardiovascular events, thrombo-embolic events). These are the secondary objectives to the trial protocol. Processed data sets with all identifiers removed except the Study ID will be retained for analysis until study completion, following which it will be archived for 20 years (subject to having appropriate permissions from NHS Digital). The original 'raw' data set returned by NHS Digital containing identifiable data will be stored on a separate server to meet security requirements. QMUL would like to emphasise that personal identifiable data are stored on the secure network and never on the local drives of unencrypted QMUL desktop PCs. [1 paragraph unchanged] All personal identifiable data received at the CCP are stored electronically on a database, local to and administered by QMUL (no third parties). QMUL. Personal identifiers of study participants are encrypted in the database and stored [46 words unchanged] separate username and password access and is controlled by the IT Department. [1 paragraph unchanged] The 'raw' data sets will be stored until the data destruction date as per the Agreement with NHS Digital. The storage architecture is compliant with the NHS Digital contract and once QMUL is issued with a Data Destruction notice, the data from all storage including backups can be securely and permanently removed within 14 days. Data can be securely wiped to NHS Digital standards (multi pass pattern wiped to at least HMG S5 Enhanced on site and if end of life, degaussed and physically destroyed). Access to data will be from within the network using workstations that have a currently supported operating system which includes security patches. No remote access (i.e. through a VPN/RDP connection) is permitted. No mobile devices will be used to access any data. The network is externally scanned via AlienVault Network Vulnerability Scanner on a regular basis. The 'raw' data sets will be stored until the data destruction date as per the Agreement with NHS Digital. The storage architecture is compliant with the NHS Digital contract and once QMUL is issued with a Data Destruction notice, the data from all storage including backups can be securely and permanently removed within 14 days. Data can be securely wiped to NHS Digital standards.

Expected output

This Agreement permits the secure retention of the data only and no other processing. Cancer Research UK (CRUK) is considerably interested in the results from the IBIS-II trials and first results have already been published (Cuzick J, Lancet 2014; 383: 1041–48; Spagnolo F, J Clin Oncol 2015 34:139-143; Forbes F, The Lancet 2015; 387:10021, 866–873.) No new outputs will be produced under this Data Sharing Agreement. The most recent major outcome analysis for IBIS-II Prevention and for IBIS-II DCIS occurred at the San Antonio Symposium (SABCS). The presentation focused on the data which had been analysed to show the comparable outcomes and difference in toxicities between anastrozole and tamoxifen. These results have also been published in the Lancet in December 2020. Results were also published on the BBC around the same time. Results will continue to be delivered in line with the strategic aims of primary funder Cancer Research UK to ‘beat cancer sooner’ by improving treatment data with a potential reach of 55,200 people diagnosed with breast cancer per year. The next major outcome analysis for IBIS-II DCIS is planned for the end of 2023 where the results are expected to be published in The Lancet, as with previous publications. Results will continue to be delivered in line with the strategic aims of primary funder Cancer Research UK to ‘beat cancer sooner’ by improving treatment data with a potential reach of 55,200 people diagnosed with breast cancer per year. Further outputs and analyses of the IBIS-II trials will be published in peer-reviewed medical journals such as The Lancet, The Lancet Oncology, Breast Cancer Research and Treatment and the British Journal of Cancer. The data will not be used for any purpose other than to meet objectives as stated in the trial protocol and will not be shared with any other organisation. Participants are kept informed of new and any significant updates via a newsletter sent by the study team. Any data, which is used for publication, will be fully anonymised and not presented at an individual level. Data will be aggregated with small numbers suppressed in line with the HES analysis guide. Additionally, any comparisons between findings from other studies or countries will be made at an aggregated level and under no circumstances will identifiable data be used for this. This research may be presented to advisory bodies such as NICE to aid in the development of clinical guidelines. Regular updates are published on the study’s website, with the aim of communicating findings in lay-friendly terms. Annual reports are to be provided AstraZeneca, as the funder of this study. All data provided will be aggregated with small numbers supressed in line with HES Analysis Guidance.

Expected measurable benefits

This Agreement permits the secure retention of the data only and no other processing. The data sets returned by NHS Digital will provide vital information Using data, the IBIS-II Central Coordinating Office (CCO) will conduct research and analyses that will on: - The safety efficacy of the long-term use of anastrozole in preventing ER positive breast cancer; - The safety of tamoxifen in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours; - The efficacy of tamoxifen in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours is effective; - which drug (tamoxifen or anastrozole) is more effective and safer in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours is effective; - the type, duration and severity of side effects related to the interventions; - a thorough risk-benefit assessment of tamoxifen and anastrozole. These analyses will enable the research community and medical practitioners to make more informed decisions on tamoxifen and anastrozole vis-a-vis patient safety and both their short- and long-term effectiveness. These analyses will enable patients and women at risk of developing breast cancer to make a more informed decision on the treatment options available to them. Events reported through registry data provide us with a platform to investigate further by initially informing us of the event, which we will then follow up in primary and secondary care records to collect highly relevant outcome data such as cancer grade, size and receptor status. This information informs our secondary and exploratory objectives which are breast cancer and all-cause mortality, cancers other than breast, cardiovascular/cerebrovascular events, and fractures. The next outcome analysis for IBIS-II Prevention and for IBIS-II DCIS is in 2023. The long-term follow-up protocol should be active by late spring and will run side by side until the Clinical Trial of an Investigational Medicinal Product (CTIMP) protocol is closed.

Benefits reported

[1 paragraph unchanged] Findings from this data have led to updates in treatment recommendations from The National Institute for Health and Care Excellence (NICE) in the initial IBIS-II publication (1), publication, which built on the practice-changing findings from the IBIS-I trial (3) which showed that tamoxifen reduced the incidence of breast cancer by one third in these high risk high-risk women. Clinicians now have better guidance with which to make informed decisions when prescribing chemopreventive chemo preventive agents. There is no doubt of the benefit the data in this trial has had on patients, clinicians and healthcare provision in general. [1 paragraph unchanged] Events reported through registry data provide us with a platform to investigate further by initially informing us of the event, which we will then follow up in primary and secondary care records to collect highly relevant outcome data such as cancer grade, size and receptor status. This information informs our secondary and exploratory objectives which are breast cancer and all-cause mortality, cancers other than breast, cardiovascular/cerebrovascular events, and fractures. Mortality data and targeted code searching of HES was used to strengthen secondary endpoint data. In an updated long-term analysis of the IBIS-II data, researchers were able to show that adverse events, such as fractures, were not increased once women stopped with the active drug (anastrozole). This information is important for clinicians to communicate with women at increased risk of breast cancer. It is crucial that patients and their health care practitioner have all the relevant information available and the inclusion of HES data has enabled us to evaluate the long-lasting effects of anastrozole. Mortality data and targeted code searching of HES was used to strengthen secondary endpoint data. In an updated long-term analysis of the IBIS-II data, we were able to show that adverse events, such as fractures, were not increased once women stopped with the active drug (anastrozole). This information is important for clinicians to communicate with women at increased risk of breast cancer. It is crucial that patients and their health care practitioner have all the relevant information available and the inclusion of HES data has enabled us to evaluate the long-lasting effects of anastrozole. [1 paragraph unchanged] Results published during the San Antonio Breast Cancer Symposium confirmed that an improved understanding of the adverse event profile would help patients with (HR) positive DCIS to make an informed decision regarding their treatment. Results obtained from the ongoing long term data analysis is essential for informing bodies such as NICE to inform the prescribing utility of these drugs as chemopreventive agents. [1 paragraph unchanged] (3) Cuzick, J., Sestak, I. and Cawthorn, S. (2015). Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. The Lancet Oncology, [online] 16(1), pp.67-75. Available at: https://doi.org/10.1016/S1470-2045(14)71171-4 [Accessed 21 Feb. 2020]

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

Objective for processing

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling Queen Mary University of London to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance). The following provides background information on the purpose of the original study: [11 paragraphs unchanged]

Processing activities

All organisations party to this agreement will comply with the Data Sharing Framework Contract, including requirements on 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 that data). Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement. The study data, including data provided by NHS Digital under previous agreements, are currently held by Queen Mary University of London. The following provides background on the processing activities undertaken prior to this Agreement: [8 paragraphs unchanged] NHS Digital will then link to linked HES and Mortality products to send back to the CCP at QMUL. The data sets returned by NHS Digital to QMUL will contain contained identifiable data. This is was so that QMUL can could confirm the accuracy and strength of each linkage for each IBIS-II participant [18 words unchanged] each IBIS-II participant, thus avoiding any errors that would invalidate the study. On receipt of the returned data set from NHS Digital, the CCP at QMUL will link linked this data set to the data set contained in the IBIS-II study [24 words unchanged] of the IBIS-II participants from the data set sent by NHS Digital. [1 paragraph unchanged] Once the participants are linked, accredited researchers at QMUL will then update updated the participant entries in the IBIS-II study database with date and cause [43 words unchanged] NHS Digital and stored as a reference for analysis until study completion. [5 paragraphs unchanged] Access to data will be from within the network using workstations that have a currently supported operating system which includes security patches. No remote access (i.e. through a VPN/RDP connection) is permitted. No mobile devices will be used to access any data. The network is externally scanned via AlienVault Network Vulnerability Scanner on a regular basis. [1 paragraph unchanged]

Expected output

Cancer Research UK (CRUK) is considerably interested in the results from the IBIS-II trials and first results have already been published (Cuzick J, Lancet 2014; 383: 1041–48; Spagnolo F, J Clin Oncol 2015 34:139-143; Forbes F, The Lancet 2015; 387: 10021, 866–873.) This Agreement permits the secure retention of the data only and no other processing. Further outputs and analyses of the IBIS-II trials will be published in peer-reviewed medical journals such as The Lancet, The Lancet Oncology, Breast Cancer Research and Treatment and the British Journal of Cancer. No new outputs will be produced under this Data Sharing Agreement. Any data which is used for publication will be fully anonymised and not presented at an individual level. Data will be aggregated with small numbers suppressed in line with the HES analysis guide. Additionally, any comparisons between findings from other studies or countries will be made at an aggregated level and under no circumstances will identifiable data be used for this. The next outcome analysis for IBIS-II Prevention is Q3 2019 and for IBIS-II DCIS this is in 2020. The study on the current protocol should be closed by 2019. The long-term follow-up protocol should be active by late spring and will run side by side until the Clinical Trial of an Investigational Medicinal Product (CTIMP) protocol is closed.

Expected measurable benefits

The data sets returned by NHS Digital will provide vital information on side effects, survival and breast cancer incidence. This Agreement permits the secure retention of the data only and no other processing. Using these data sets, the IBIS-II Central Coordinating Office (CCO) will conduct research and analyses that will help provide further information on: - The safety of the long-term use of anastrozole in preventing ER positive breast cancer; - The efficacy of the long-term use of anastrozole in preventing ER positive breast cancer; - The safety of tamoxifen in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours; - The efficacy of tamoxifen in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours is effective; - which drug (tamoxifen or anastrozole) is more effective and safer in local control and prevention of contralateral disease with locally excised ER or PgR positive breast cancer tumours is effective; - the type, duration and severity of side effects related to the interventions; - a thorough risk-benefit assessment of tamoxifen and anastrozole. These analyses will enable the research community and medical practitioners to make more informed decisions on tamoxifen and anastrozole vis-a-vis patient safety and both their short- and long-term effectiveness. These analyses will enable patients and women at risk of developing breast cancer to make a more informed decision on the treatment options available to them. This long term data is essential for informing bodies such as NICE to inform the prescribing utility of these drugs as chemopreventive agents. The next outcome analysis for IBIS-II Prevention is Q3 2019 and for IBIS-II DCIS this is in 2020. The study on the current protocol should be closed by 2019. The long-term follow-up protocol should be active by late spring and will run side by side until the Clinical Trial of an Investigational Medicinal Product (CTIMP) protocol is closed.

Benefits reported

Registry data provided to date has identified multiple cases of breast cancers and DCIS events in participants that were lost to follow up and therefore not already known by the trial team. Collection of this data has contributed directly to the primary endpoints of the trial and will continue to provide valuable information on the long term risk/benefit status of the trial interventions. This long term data is essential for informing bodies such as NICE to inform the prescribing utility of these drugs as chemopreventive agents. QMUL have also used mortality data and the targeted code searching of HES to contribute directly to secondary endpoint data. QMUL use registry reported events as a prompt for further investigation by asking participating IBIS-II sites or the participant’s current GP practice to confirm the event and also provide any further information e.g. cancer grade, size, receptor status that is required to meet wider secondary and exploratory objectives. Registry data has thus far provided many benefits to healthcare provision in this field. Furthermore, it is anticipated that over the next 18 months that active site follow up could be replaced by registry follow up only. In 2017, an IBIS-II participating site that would have otherwise had to close due to lack of staff resource to deliver the trial was piloted as a ‘registry only’ follow up site. The preliminary data from years 2003-2015 has shown that a higher degree of correlation between the clinical events of interest reported via active follow up methods (questionnaires) and those reported via the registry data. Therefore, active follow up methods (annual questionnaires) have been concluded at the site and instead data collection using registry only data plus verification from the participant’s GP is being used. QMUL hope that this may be rolled out across all sites in England and Wales over the next 18 months so that QMUL can continue to collect essential primary and secondary endpoint data in the most appropriate way given the resource available at participating NHS sites (the trial has now been active for 14 years) and the burden of active follow up procedures on the ageing participant group. Findings from this data have led to updates in treatment recommendations from The National Institute for Health and Care Excellence (NICE) in the initial IBIS-II publication (1), which built on the practice-changing findings from the IBIS-I trial (3) which showed that tamoxifen reduced the incidence of breast cancer by one third in these high risk women. Clinicians now have better guidance with which to make informed decisions when prescribing chemopreventive agents. There is no doubt of the benefit the data in this trial has had on patients, clinicians and healthcare provision in general. The data received so far has identified multiple breast cancer and ductal carcinoma in situ (DCIS) events in participants who were lost to follow up, and whose diagnoses were not known to the trial team. As these are primary outcomes for the trial, the data provided has strengthened the accuracy and effectiveness of the current research findings, contributing to the high significance of the results. Events reported through registry data provide us with a platform to investigate further by initially informing us of the event, which we will then follow up in primary and secondary care records to collect highly relevant outcome data such as cancer grade, size and receptor status. This information informs our secondary and exploratory objectives which are breast cancer and all-cause mortality, cancers other than breast, cardiovascular/cerebrovascular events, and fractures. Mortality data and targeted code searching of HES was used to strengthen secondary endpoint data. In an updated long-term analysis of the IBIS-II data, we were able to show that adverse events, such as fractures, were not increased once women stopped with the active drug (anastrozole). This information is important for clinicians to communicate with women at increased risk of breast cancer. It is crucial that patients and their health care practitioner have all the relevant information available and the inclusion of HES data has enabled us to evaluate the long-lasting effects of anastrozole. A further benefit to the NHS from data available so far, has been a dramatic reduction in the number needed to treat to prevent one breast cancer during the first 12 years of follow-up. In the most recent analysis and publication the number was 29 for anastrozole, which compares favourably with the 58 needed for tamoxifen at that time of the previous analysis and publication. Overall, study data combined with registry data has substantially strengthened the already significant findings from previous IBIS analyses from 2014 to present. (3) Cuzick, J., Sestak, I. and Cawthorn, S. (2015). Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. The Lancet Oncology, [online] 16(1), pp.67-75. Available at: https://doi.org/10.1016/S1470-2045(14)71171-4 [Accessed 21 Feb. 2020]

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

Unchanged: Objective for processing, Processing activities, Expected output, Expected measurable benefits, Benefits reported.