PROSPECTIVE STUDY OF OUTCOMES IN SPORADIC VERSUS HEREDITARY BREAST CANCER (POSH)

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

Datasets: + Hospital Episode Statistics Admitted Patient Care (HES APC); + NDRS Cancer Consolidated Data Set

Objective for processing

The University of Southampton (UoS) requires access to NHS England data for the purpose of the following research project: The Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer (POSH). The Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer (POSH). [1 paragraph unchanged] The UoS is the Data Controller. University Hospital Southampton NHS FT is the trial sponsor. The POSH study began in 2001 and recruitment ended at the end of December 2008, since then follow up data has been collected from hospitals and by requesting data from NHS England. The study has a steering committee comprised of national experts in breast cancer, oncology and surgery. The committee members’ experience covers clinical cancer genetics, molecular genetics and genetic epidemiology, breast cancer treatment, trial design and statistical analysis and molecular pathology. Other collaborators will be clinicians treating breast cancer in breast units throughout the UK. The role of the committee is to advise on the direction of analysis and interpretation, review manuscripts and advise on scientific interpretation given to results. The committee does not have decision-making responsibilities relating to the data under this Agreement. The following is a summary of the aims of the research project: POSH was funded by Breast Cancer Campaign and Cancer Research UK and is now funded by AstraZeneca. • To investigate the prognosis of breast cancer patients with BRCA1 or BRCA2 mutations compared to non-carriers. POSH is a unique cohort because patients were consented for genotyping and were recruited before the widespread use of genetic testing for breast cancer but after the introduction of second generation chemotherapy. It is the only cohort in which the UoS can document the natural history for young breast cancer patients found to carry genetic susceptibility genes and the only way that the study will be able to fully evidence the true benefit or otherwise of extensive surgical intervention over and above the management needed for the presenting cancer. • Examine differences in recurrence patterns and tumor phenotypes in patients with inherited gene mutations. Study manuscripts and protocols and the Patient Information Sheet are all available on the study website https://www.southampton.ac.uk/medicine/research/posh.page. This is easily located using an internet search for “POSH study”. Main study outcomes are emailed to Primary Investigators in each of the participating oncology centres. • Evaluate whether there is a distinct tumor phenotype or host tissue response in patients with BRCA1 or BRCA2 mutations. The study began in 2001 and is a purely non-commercial study. The recruitment period ended at the end of December 2008 and since then follow up data has been collected from hospitals and subsequently by requesting data from NHS Digital. • To obtain longer-term follow-up data to assess the effectiveness of early risk-reducing surgery for gene carriers. The consent obtained from the participants covered follow-up for 20 years, referencing the intention to ‘request an update on [participants’] progress from time to time form the hospital or [their] GP. This was not considered to evidence sufficiently informed consent for the requisite data sharing in order to receive the relevant follow-up data from NHS Digital rather than directly from the hospital or GP and so in 2009 POSH obtained Section 251 support to receive mortality and Cancer flagging from NHS Digital (then known as the Health and Social Care Information Centre). CAG have approved a 20 year follow up. The study centre has no direct contact with study patients. Recruitment was via participating oncology centres. The study does not keep any patient addresses. The same centres who find it difficult to give POSH follow up data (and therefore the centres where MRIS tracing would be most useful) would probably have difficulty sending out letters asking for repeat consent and would have to check on NHS tracing to be sure the patient was still alive and the address still current. There may not be full coverage of this cohort and the study would be left with too many “unknown”. Failure to capture all study participants might unnecessarily compromise the successful completion of the study. • To determine the pattern of distant breast cancer recurrence between BRCA1/BRCA2 mutation carriers and non-carrier patients. The research team are examining inherited high-risk genes for breast cancer, such as BRCA1 and BRCA2, in this group, with a view to developing treatments for genetic breast cancer. The research team are looking at the DNA from younger breast cancer patients to find out whether clues in the BRCA genes could help predict their response to treatment and the risk of cancer coming back. There is some evidence that BRCA1 gene carriers may be more sensitive to certain types of chemotherapy. The primary aims of the POSH study are to determine whether: • Collect data on secondary endpoints, including new primary cancers, breast tumor recurrence, and other malignancies. • The prognosis of patients with breast cancer who harbour BRCA1 or BRCA2 gene mutations differs from non-carrier patients matched for age and other major prognostic indicators. • Facilitate additional exploratory analyses, such as the association of cancer phenotypes with non-BRCA cancer predisposing genes (CPGs). • Breast cancers occurring in patients with different predisposing inherited gene mutations have a consistent and distinct tumour phenotype? • To include anonymized biological samples in collaborative biological research studies. • There are differences in the pattern of distant breast cancer recurrence between patients with BRCA1 or BRCA2 gene mutations and matched non carrier patients? • To provide valuable data for clinicians and patients to aid in treatment decisions, particularly in regard to high-risk breast cancer genes. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) study is a unique cohort of 2888 (England - 2756 and Wales - 132) UK patients aged <41 with <37 years at first breast cancer diagnosis. The following NHS England data will be accessed The following NHS Digital data will be accessed: • Hospital Episode Statistics • Civil Registration Mortality – necessary because the study is interested in breast cancer mortality and distant metastasis free survival as primary end points; • Admitted Patient Care – necessary to identify specific surgery episodes including mastectomy and salpingo-oophorectomy, and relevant outcome measures including morbidity/complications, subsequent pregnancy following index breast cancer diagnosis (especially relevant in oestrogen-receptor positive breast cancer due to the effects of hormonal treatment); • NDRS Cancer Consolidated Data Set - necessary to obtain information on cancer recurrence and treatment modalities in order to fully complete our analyses. This includes data on new and/or relapsed cancers, specific surgery episodes including mastectomy and salpingo-oophorectomy, radiotherapy, and systemic therapy (e.g. chemotherapy, endocrine therapy, targeted and immunotherapy), and relevant outcome measures; • Civil Registration of Deaths – necessary because the study is interested in breast cancer mortality and distant metastasis free survival as primary end points. [2 paragraphs unchanged] The level of the data is: Data will be: • Identifiable – necessary in order to link enable the linkage of the data received from NHS Digital England with the data already held. held by UoS. Receipt of this data will allow UoS to achieve the above outcomes in the following ways: The data will be minimised as follows: • The prognosis of patients with breast cancer who harbour BRCA1 or BRCA2 gene mutations differs from non-carrier patients matched for age and other major prognostic indicators. • Limited to cohort of 2888 (England-2756 and Wales-132). The initial analysis of outcomes for this cohort of patients was published in Lancet oncology based on a median of 8 years of follow up time. The study observed no difference in overall survival for high-risk gene carriers compared to non-carriers. However in a sub-group analysis the study observed an initially better survival and a predicted worse survival over the time interval after 5 years which indicated that it would be very important that UoS had a longer follow up period to understand the potential benefits of early risk reducing surgery for gene carriers. This definitive estimate of benefit will not be possible to derive without bias from any other study and is information that will be very valuable for patients and clinicians in making treatment decisions. The University of Southampton 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. • Breast cancers occurring in patients with different predisposing inherited gene mutations have a consistent and distinct tumour phenotype? The lawful basis for processing personal data under the UK GDPR is: The observation that cancer phenotypes are driven by germline genetic variants has been captured over the last few years and the study has published in this area from the POSH cohort but there are additional analyses in progress that would benefit from longer term follow up capturing new primary cancers and cancer related mortality. 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. • There are differences in the pattern of distant breast cancer recurrence between patients with BRCA1 or BRCA2 gene mutations and matched non carrier patients? The lawful basis for processing special category data under the UK GDPR is: Capturing the site of distant metastatic disease was achieved through collecting relevant clinical records during the active phase of the study, continuing to collect information about the site of distant metastases is especially valuable in hormone receptor positive patients (typically a characteristic of BRCA2 and CHEK2 carriers) will be important to complete these analyses. 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. Further Objectives are: This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care. 1) To investigate long-term clinical outcomes of young breast cancer patients with and without BRCA1 or BRCA2 pathogenic mutations including onset of second malignancies, effectiveness and optimum timing of risk-reducing surgery. The funding is provided by AstraZeneca. The funding is specifically for the study described. 2) To enable additional exploratory analyses of clinically important endpoints using the POSH dataset: AstraZeneca have no control over the data, analyses planned or outputs from the study a) The association of (i) pathological breast cancer phenotypes and (ii) clinical outcomes with non-BRCA CPGs The data will only be accessed by substantive employees of the UoS and will not be accessed or processed by any other third party. b) Clinical and pathological characterisation of pregnancy associated breast cancer The study has a steering committee comprised of national experts in breast cancer, oncology and surgery. The committee members’ experience covers clinical cancer genetics, molecular genetics and genetic epidemiology, breast cancer treatment, trial design and statistical analysis and molecular pathology. Other collaborators are clinicians treating breast cancer in breast units throughout the UK. The role of the committee is to advise on the direction of analysis and interpretation, review manuscripts and advise on scientific interpretation given to results. The committee does not have decision-making responsibilities relating to the data under this Agreement. 3) To facilitate inclusion of anonymised POSH biological samples in national and international collaborative ethically approved biological research studies with the same broad aims as the POSH study. The justification of processing this data under the principles of GDPR, is Article 6(1)(e): ‘Processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller’ as this is a task within the public interest and as the research involves health data. Article 9(2)(j) is also applicable, as this details that processing is necessary for scientific and research purposes, subject to appropriate safeguards. The research team are examining inherited high-risk genes for breast cancer, such as BRCA1 and BRCA2, in this group, with a view to developing treatments for genetic breast cancer which is in the public interest.

Processing activities

Under previous iterations of this Data Sharing Agreement, UoS has received Demographics, Cancer Registration and Mortality data covering the period from November 2010 to March 2016. The original downloaded data which UoS historically received from NHS England will be deleted and replaced with the updated download when received. The University of Southampton will transfer data to NHS England. The data will consist of identifying details of 2888 participants from across England and Wales (specifically NHS Number, Date of Birth, Name, Postcode, Gender and a unique person ID) for the cohort to be linked with NHS England data. The UoS will transfer data to NHS England. The data will consist of identifying details of 2888 participants from across England and Wales (specifically NHS Number, Date of Birth, Name, Postcode, Gender and a unique person ID) for the cohort to be linked with NHS England NHS England will provide the relevant records from the HES APC, NDRS Cancer Consolidated Data Set, Civil Registration of Deaths, Cancer Registration dataset and Demographics datasets to UoS. NHS England will provide the relevant records from the Demographics, Cancer Registration and Civil Registration Mortality datasets to UoS. The data will contain directly identifying data items - specifically NHS Number [8 words unchanged] validate linkage at patient level with data previously obtained, including from NHS England England. The UoS will retain and re-use Demographics, Cancer Registration and Mortality data covering the period from November 2010 to the latest available data in 2022. The Data will not be transferred to any other location. The data is held securely within Southampton Clinical Trials Unit at the UoS. The unit has controlled access to the building and to individual rooms within the building. Access is limited to substantive employees of UoS who have been vetted and approved. Computer access is password protected to limited individuals employed within the unit. Storage areas are securely maintained and all reasonable protection from floods, fire and physical damage are in place. Data is held securely within Southampton Clinical Trials Unit at the UoS. The unit has controlled access to the building and to individual rooms within the building. Access is limited to substantive employees of UoS who have been vetted and approved. Computer access is password protected to limited individuals employed within the unit. Storage areas are securely maintained and all reasonable protection from floods, fire and physical damage are in place. The Data will be accessed onsite at the premises of University of Southampton only. Data will only be accessed and processed by substantive employees of the UoS and will not be accessed or processed by any other third parties. The Data will not leave England/Wales at any time. No identifiable information will be included as part of any publication or presentation. Data will be processed and analysed solely by research personnel tasked with this particular activity. Appropriate care will be made to protect participants confidentiality at all times through the secure and limited handling of data. The data will be used for the specific purposes listed in the study protocol. Access is restricted to substantive employees of University of Southampton and will not be accessed or processed by any other third parties. All personnel accessing the Data have been appropriately trained in data protection and confidentiality. [1 paragraph unchanged]

Benefits reported

[4 paragraphs unchanged] The POSH Study's most recent publication (February 2018) explored the impact of inherited genetic susceptibility on treatment [124 words unchanged] their families. This hypothesis is currently being examined in an implementation trial [2 paragraphs unchanged]

Changed only in punctuation, spacing or capitalisation: Expected output.

Unchanged: Expected measurable benefits.

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

Data controllers: − UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST

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

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 The University of Southampton and The University Hospital Southampton NHS Trust 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 University of Southampton (UoS) requires access to NHS England for the purpose of the following research project: The Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer (POSH). The following provides background information on the purpose of the original study: The study is looking at the prognosis for breast cancer patients with BRCA1 or BRCA2 gene mutations, at differences in patterns of recurrence and whether cancers in these patients have a distinct tumour phenotype or host tissue response. The Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer (POSH) study focuses on younger patients, who have a significantly reduced chance of survival. Breast cancer is the most common type of cancer in the UK, but thanks to international research efforts, over 80 per cent of women are alive five years after diagnosis and at least two-thirds survive for 20 years or more. However, it is known that women diagnosed under the age of 40 often have more aggressive cancers, with a significantly lower chance of survival, and some carry genetic factors predisposing them to the disease. The UoS is the Data Controller. University Hospital Southampton NHS FT is the trial sponsor. The study is a multicentre prospective observational cohort study of 3000 young women diagnosed with breast cancer in the UK between 2000 and 2008. It completed recruitment of just over 3000 cases by 31st December 2008. The study continues to follow up annually as funding allows. Oncologists at hospitals throughout the UK recruited patients. The study has a steering committee comprised of national experts in breast cancer, oncology and surgery. The committee members’ experience covers clinical cancer genetics, molecular genetics and genetic epidemiology, breast cancer treatment, trial design and statistical analysis and molecular pathology. Other collaborators will be clinicians treating breast cancer in breast units throughout the UK. The role of the committee is to advise on the direction of analysis and interpretation, review manuscripts and advise on scientific interpretation given to results. The committee does not have decision-making responsibilities relating to the data under this Agreement. The primary aims of the POSH study are to determine whether: POSH was funded by Breast Cancer Campaign and Cancer Research UK and is now funded by AstraZeneca. • The prognosis of patients with breast cancer who harbour BRCA1 or BRCA2 gene mutations differs from non carrier patients matched for age and other major prognostic indicators. POSH is a unique cohort because patients were consented for genotyping and were recruited before the widespread use of genetic testing for breast cancer but after the introduction of second generation chemotherapy. It is the only cohort in which the UoS can document the natural history for young breast cancer patients found to carry genetic susceptibility genes and the only way that the study will be able to fully evidence the true benefit or otherwise of extensive surgical intervention over and above the management needed for the presenting cancer. Study manuscripts and protocols and the Patient Information Sheet are all available on the study website https://www.southampton.ac.uk/medicine/research/posh.page. This is easily located using an internet search for “POSH study”. Main study outcomes are emailed to Primary Investigators in each of the participating oncology centres. The study began in 2001 and is a purely non-commercial study. The recruitment period ended at the end of December 2008 and since then follow up data has been collected from hospitals and subsequently by requesting data from NHS Digital. The consent obtained from the participants covered follow-up for 20 years, referencing the intention to ‘request an update on [participants’] progress from time to time form the hospital or [their] GP. This was not considered to evidence sufficiently informed consent for the requisite data sharing in order to receive the relevant follow-up data from NHS Digital rather than directly from the hospital or GP and so in 2009 POSH obtained Section 251 support to receive mortality and Cancer flagging from NHS Digital (then known as the Health and Social Care Information Centre). CAG have approved a 20 year follow up. The study centre has no direct contact with study patients. Recruitment was via participating oncology centres. The study does not keep any patient addresses. The same centres who find it difficult to give POSH follow up data (and therefore the centres where MRIS tracing would be most useful) would probably have difficulty sending out letters asking for repeat consent and would have to check on NHS tracing to be sure the patient was still alive and the address still current. There may not be full coverage of this cohort and the study would be left with too many “unknown”. Failure to capture all study participants might unnecessarily compromise the successful completion of the study. The research team are examining inherited high-risk genes for breast cancer, such as BRCA1 and BRCA2, in this group, with a view to developing treatments for genetic breast cancer. The research team are looking at the DNA from younger breast cancer patients to find out whether clues in the BRCA genes could help predict their response to treatment and the risk of cancer coming back. There is some evidence that BRCA1 gene carriers may be more sensitive to certain types of chemotherapy. The primary aims of the POSH study are to determine whether: • The prognosis of patients with breast cancer who harbour BRCA1 or BRCA2 gene mutations differs from non-carrier patients matched for age and other major prognostic indicators. [2 paragraphs unchanged] This study is funded by Breast Cancer Campaign and Cancer Research UK. The study began in 2001 and is a purely non-commercial study. The recruitment period ended at the end of December 2008 and since then follow up data has been collected from hospitals, and when not known by the original recruiting hospital, by requesting data from NHS Digital. NHS Digital has previously provided cohort data. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) study is a unique cohort of 2888 (England - 2756 and Wales - 132) UK patients aged <41 with <37 years at first breast cancer diagnosis. The sponsor of the study is University Hospital Southampton NHS Foundation Trust and it is being managed on their behalf by University of Southampton's Southampton Clinical Trials Unit (SCTU). The following NHS Digital data will be accessed: N.B. A Sponsor is an individual, company, institution, organisation or group of organisations that takes on responsibility for initiation, management and financing (or arranging the financing) of the research. A sponsor can delegate specific responsibilities to any other individual or organisation that is willing and able to accept them. All research falling under the remit of the Secretary of State for Health must have a formal sponsor. This includes all research in health and social care that involve NHS patients, their tissue or information. • Civil Registration Mortality – necessary because the study is interested in breast cancer mortality and distant metastasis free survival as primary end points; More than 3,000 women diagnosed with breast cancer under the age of 40 took part in the study. Only about five per cent of all breast cancers are diagnosed in women under 40 years of age, so over the eight years that patients joined the study, this makes up around a quarter of all women with breast cancer in this age group in the UK. Participants contributed a blood sample and tumour tissue for genetic research. The progress of study participants is followed annually, including using data received from NHS Digital for women who are no longer in contact with their treating hospital centre. • Cancer Registration – necessary because the study is interested in secondary end points of: 1) ipsilateral breast tumour recurrence, 2) new primary breast cancer, 3) new primary cancer not in the breast; Data supplied by NHS Digital is being used for long-term follow up of patients to assess their primary and secondary endpoints. SCTU Statistics Team analyse the data and alongside the chief investigator (Professor of Genetics) write a number of papers which will be published in medical journals. All outputs will be aggregated with small numbers suppressed in line with the HES Analysis Guide. • Demographics – necessary to track which cohort members continue to be registered with the NHS and who becomes lost to follow (e.g. due to immigration, etc.). N.B. An endpoint in clinical trials, is an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives. Some examples of endpoints are survival, improvements in quality of life, relief of symptoms, and disappearance of the tumor. The level of the data is: The research team are examining inherited high-risk genes for breast cancer, such as BRCA1 and BRCA2, in this group, with a view to developing treatments for genetic breast cancer. They are looking at the DNA from younger breast cancer patients to find out whether clues in the BRCA genes could help predict their response to treatment and the risk of cancer coming back. There is some evidence that BRCA1 gene carriers may be more sensitive to certain types of chemotherapy. • Identifiable – necessary in order to link data received from NHS Digital with data already held. Receipt of this data will allow UoS to achieve the above outcomes in the following ways: • The prognosis of patients with breast cancer who harbour BRCA1 or BRCA2 gene mutations differs from non-carrier patients matched for age and other major prognostic indicators. The initial analysis of outcomes for this cohort of patients was published in Lancet oncology based on a median of 8 years of follow up time. The study observed no difference in overall survival for high-risk gene carriers compared to non-carriers. However in a sub-group analysis the study observed an initially better survival and a predicted worse survival over the time interval after 5 years which indicated that it would be very important that UoS had a longer follow up period to understand the potential benefits of early risk reducing surgery for gene carriers. This definitive estimate of benefit will not be possible to derive without bias from any other study and is information that will be very valuable for patients and clinicians in making treatment decisions. • Breast cancers occurring in patients with different predisposing inherited gene mutations have a consistent and distinct tumour phenotype? The observation that cancer phenotypes are driven by germline genetic variants has been captured over the last few years and the study has published in this area from the POSH cohort but there are additional analyses in progress that would benefit from longer term follow up capturing new primary cancers and cancer related mortality. • There are differences in the pattern of distant breast cancer recurrence between patients with BRCA1 or BRCA2 gene mutations and matched non carrier patients? Capturing the site of distant metastatic disease was achieved through collecting relevant clinical records during the active phase of the study, continuing to collect information about the site of distant metastases is especially valuable in hormone receptor positive patients (typically a characteristic of BRCA2 and CHEK2 carriers) will be important to complete these analyses. Further Objectives are: 1) To investigate long-term clinical outcomes of young breast cancer patients with and without BRCA1 or BRCA2 pathogenic mutations including onset of second malignancies, effectiveness and optimum timing of risk-reducing surgery. 2) To enable additional exploratory analyses of clinically important endpoints using the POSH dataset: a) The association of (i) pathological breast cancer phenotypes and (ii) clinical outcomes with non-BRCA CPGs b) Clinical and pathological characterisation of pregnancy associated breast cancer 3) To facilitate inclusion of anonymised POSH biological samples in national and international collaborative ethically approved biological research studies with the same broad aims as the POSH study. The justification of processing this data under the principles of GDPR, is Article 6(1)(e): ‘Processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller’ as this is a task within the public interest and as the research involves health data. Article 9(2)(j) is also applicable, as this details that processing is necessary for scientific and research purposes, subject to appropriate safeguards. The research team are examining inherited high-risk genes for breast cancer, such as BRCA1 and BRCA2, in this group, with a view to developing treatments for genetic breast cancer which is in the public interest.

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. Under previous iterations of this Data Sharing Agreement, UoS has received Demographics, Cancer Registration and Mortality data covering the period from November 2010 to March 2016. The original downloaded data which UoS historically received from NHS England will be deleted and replaced with the updated download when received. The study data, including data provided by NHS Digital under previous agreements, are currently held by University Hospital Southampton NHS Foundation Trust. The UoS will transfer data to NHS England. The data will consist of identifying details of 2888 participants from across England and Wales (specifically NHS Number, Date of Birth, Name, Postcode, Gender and a unique person ID) for the cohort to be linked with NHS England The following provides background on the processing activities undertaken prior to this Agreement: NHS England will provide the relevant records from the Demographics, Cancer Registration and Civil Registration Mortality datasets to UoS. The data will contain directly identifying data items - specifically NHS Number and Date of Birth which are required to validate linkage at patient level with data previously obtained, including from NHS England Identifiable data was shared with ONS to carry out the linkage between the study data and civil registration data. Participants records were ‘flagged’ with the Office for National Statistics (ONS). ONS notified the study team at University Hospital Southampton NHS Foundation Trust of participants’ deaths (date and cause) and cancer events when they occurred. The ‘flagging for long-term follow up’ service transferred from ONS to the HSCIC in 2008. Data was last supplied in March 2016. The UoS will retain and re-use Demographics, Cancer Registration and Mortality data covering the period from November 2010 to the latest available data in 2022. Data is held securely within Southampton Clinical Trials Unit at the UoS. The unit has controlled access to the building and to individual rooms within the building. Access is limited to substantive employees of UoS who have been vetted and approved. Computer access is password protected to limited individuals employed within the unit. Storage areas are securely maintained and all reasonable protection from floods, fire and physical damage are in place. Data will only be accessed and processed by substantive employees of the UoS and will not be accessed or processed by any other third parties. No identifiable information will be included as part of any publication or presentation. Data will be processed and analysed solely by research personnel tasked with this particular activity. Appropriate care will be made to protect participants confidentiality at all times through the secure and limited handling of data. The data will be used for the specific purposes listed in the study protocol. Data received will be linked with the long term follow up data currently held.

Expected output

This Agreement permits the secure retention of the data only and no other processing. Data supplied by NHS England is being used for long-term follow up of patients to assess their primary and secondary endpoints. The study investigators under the supervision of the chief investigator, will submit the findings as abstracts and academic papers to appropriate medical scientific conferences. With previous outputs, Cancer Research UK chose to press release the findings so newspaper reports and media interviews (including the BBC national news) covered the POSH Study findings. No new outputs will be produced under this Data Sharing Agreement. Resulting publications will be flagged to NICE as they may change existing national guidance on management of breast cancer patients. It is hoped the data will be used to further develop patient facing decision aids to support genetic testing after breast cancer diagnosis. It is hoped data will be incorporated, where appropriate, into presentations to BRCA family support days regionally and nationally. The plan is that data will be used to support professional training programmes for healthcare professionals responsible for discussing genetic testing with cancer patients. Publication records are maintained on the POSH trial web page. To date, 57 peer-reviewed publications have included POSH data and/ or biological samples. Highlights include: • Analysis of outcome data for BRCA1/2 gene carriers with breast cancer compared with sporadic breast cancer patients indicated no significant difference in OS or DDFI. This was published in Lancet Oncology, January 2018 (1), (Appendix 4). The paper made national news throughout publication day and received global media coverage (10). Our findings challenged the tendency for breast cancer specialists to recommend rapid bilateral mastectomy in newly diagnosed breast cancer patients with an underlying BRCA1/2 mutation. This benefits patients by providing rationale for women to choose to consider risk-reducing surgery at a later date after their primary diagnosis allowing time to recover physically and mentally whilst undergoing enhanced breast surveillance. • POSH study patients contributed to an international collaboration demonstrating the incidence of BRCA1/2 mutations in women with triple negative breast cancer (1), resulting in updated NICE clinical guidelines for BRCA testing 11). • A comparison of survival outcomes of the POSH cohort with predicted outcomes from the PREDICT algorithm (http://www.predict.nhs.uk), identified inaccuracies in short-term predictions for young women (12). Inclusion of POSH data has improved the calibration of this tool which is widely used by oncologists to inform management decisions (13). • We published the effects of body mass index, ethnicity and family history as independent prognostic factors, significantly expanding young patient data in these areas (14-16). • POSH cases have contributed to many genome wide association studies (GWAS), identifying novel breast cancer susceptibility loci associated with risk, pathological subtypes and survival (appendix 2)

Expected measurable benefits

This Agreement permits the secure retention of the data only and no other processing. [2 paragraphs unchanged] The latest data is beginning to suggest a survival advantage across the cohort for patients with a genetic predisposition who are offered more extensive surgery after their initial cancer treatment – again the data must have longer follow up to be certain of how beneficial this might be over time. These longer term analyses are essential to provide accurate information for patient care in the current era where early genetic testing in young onset breast cancer is becoming routine These longer term analyses are essential to provide accurate information for patient care in the current era where early genetic testing in young onset breast cancer is becoming routine – no other study will be able to provide this detailed evidence. Improved accuracy of information given to gene carriers where a genetic diagnosis is coincident with a cancer diagnosis. It is hoped this improved information will help inform better decision making for both clinicians and patients particularly around mitigation or prevention of future cancer risks. The study is looking at the prognosis for breast cancer patients with BRCA1 or BRCA2 gene mutations, at differences in patterns of recurrence and whether cancers in these patients have a distinct tumour phenotype or host tissue response. Germline genotyping of breast cancer predisposition genes (CPGs), detailed pathology and clinical outcome data have been collected. Output has been substantial with high impact publications and contributions to clinical guidelines. Longer-term follow-up and interrogation of other germline genetic data is required to generate further clinical recommendations. If the outlook for BRCA carrier patients is more optimistic than previously thought, preventive surgical options could be more confidently planned at the same time as breast cancer treatment. Ultimately the team want to empower women who carry this faulty gene to make informed decisions about their treatment options. The research could also lead to targeted ways to treat young women with breast cancer and improve their chances of beating the disease. Results published January 2018 show that young onset breast cancer patients have a high mortality and those who carry a BRCA gene mutation have similar survival to non-carriers. BRCA carriers presenting with triple negative breast cancer may have a survival advantage during the first few years after diagnosis compared to non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary cancer risks should take into account prognosis associated with the first malignancy and patient preference. A final outcome analysis is planned when the study follow up reaches a minimum duration of 15 years (2023).

Benefits reported

The study is looking at the prognosis for breast cancer patients with BRCA1 or BRCA2 gene mutations, at differences in patterns of recurrence and whether cancers in these patients have a distinct tumour phenotype or host tissue response. [1 paragraph unchanged] The study has already found that women diagnosed with breast cancer with [5 words unchanged] disease face a similar prognosis after treatment to other women with breast cancer. cancer to the median follow up time of 8 years but the study will need to follow over a longer period of time as it has observed a rising hazard for death towards the longer duration of follow up and this will need to be quantified with higher numbers. The study observation of the proportion of all young cases with BRCA1 and BRCA2 gene pathogenic variants has altered guidance for testing. NICE guidelines CG164 revised the guidelines age for testing women with triple negative breast cancer specifically but most genetic centres test all patients with invasive breast cancer below 40 for at least BRCA1 and BRCA2 pathogenic variants. The POSH Study's most recent publication (February 2018) explored the impact of inherited genetic susceptibility on treatment outcomes and has been cited 24 times in the 9 months since publication. It detailed the observation that immediate bilateral mastectomy for BRCA carriers was not an essential part of initial cancer treatment. This means that patients need to make an informed choice about whether or not they wish to pursue the option of risk reducing surgery. The study has worked with patients using qualitative and quantitative research methods to developed a prototype online Decision Aid for young women being diagnosed with cancer who are offered genetic testing. The study expects that this will give patients and their families the best opportunity to make a well informed choice about the timing of genetic testing and what implications the result may have for them and their families. This hypothesis is currently being examined in an implementation trial The assumption that a breast cancer patient with a BRCA1 or BRCA2 pathogenic variant must have immediate bilateral mastectomy was challenged by the 2018 Lancet Oncology paper and has become a more nuanced decision in most centres where overall prognosis from primary breast cancer is taken into account and decisions about contralateral mastectomy may be delayed to allow patients to fully adjust and future genetic risk to be more formally assessed. The POSH study believes, particularly for those choosing not to have risk reducing surgery at diagnosis, this longer term follow up data is important in order to fully inform those discussions with patients about additional surgery over and above that required to treat a presenting cancer.