Adjuvant Tamoxifen Treatment - Offer -More? - ATTOM

This Data Sharing Agreement permits the retention nad processing 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 Institute of Cancer Research to complete the necessary actions to enable a subsequent application to amend and extend the Agreement meeting all applicable data sharing standards as published in NHS England's website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance).

Below is a summary of the Agreement detail from the previous version.

Breast cancer is the most common female cancer. In the 1990’s 5-years of tamoxifen treatment was the standard but there was uncertainty as to whether tamoxifen should be given for longer. The aTTom (Adjuvant Tamoxifen Treatment - Offer -More?) trial, which commenced in 1991, was designed to determine if giving tamoxifen for longer than 5 years was beneficial. aTTom is a clinical trial of an investigational medicinal product and falls under the clinical trials regulations for medicinal products.

A preliminary analysis of aTTom has been presented and also published and it has shown that extending taxoxifen beyond 5 years reduces breast cancer events, although the impact on survival was less clear. There was a small but significant increased risk of endometrial cancer with longer tamoxifen.

The original 10-year follow-up period for the aTTom trial patients was reached in October 2015. However, long-term toxicity remains a concern and continued follow-up of these patients is vital to determine the full impact of extended tamoxifen on breast cancer specific and overall survival. To this end (and following the recommendations of the Medicines and Healthcare products Regulatory Agency) approval, research ethics and CAG approval has been sought for a follow-on study called aTTom-Extended (Extended follow-up of patients enrolled in the aTTom trial). aTTom-Extended falls outside of the remit of clinical trials governing medicinal products. aTTom-Extended will continue to follow-up the aTTom patients for an additional 10 years (REC specified end date December 2027).

A sub-study within the aTTom-Extended trial, called Trans-aTTom, involves the collection and analysis of tissue samples. These tissue samples will be subjected to laboratory analyses to determine molecular characterisation of the tumours. More specifically the samples will be characterised using a validated multiparametric analysis “the breast cancer index” which is capable of predicting risk of late relapse from breast cancer. Data under this Agreement will be linked with data from analysis of participants’ tissue samples and from the linked data, data will be derived. Subsequent analyses will use the derived data only and will not involve any further processing of the data under this Agreement.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1). The University of Birmingham is a public authority, as defined in the Freedom of Information Act 2000, whose primary purpose is the advancement of education and research which are deemed to deliver a public benefit. All research is conducted in accordance with the University’s Code of Practice for Research. The results of the aTTom/aTTom-Extended study will advance the treatment of breast cancer patients internationally and is therefore considered to be in the public interest.

Organisations Involved:

The University of Birmingham is the Data Controller. The University of Birmingham requires mortality data and data on cancer registrations relating to the cohort for use in the aTTom/aTTom-Extended studies for the purpose described below.

aTTom and aTTom-Extended are sponsored (in accordance with the UK Policy Framework for Health and Social Care Research) by the University of Birmingham. The Chief Investigator is based at the University of Birmingham. The CRCTU is one of two trials units within the University of Birmingham the other being the Birmingham Clinical Trials Unit (BCTU) which is responsible for the analysis (processing) of aTTom (performed by the Trial Statistician). The statistical lead moved from the University of Birmingham to the University of Oxford in September 2010. The statistical lead retains an honorary contract with the University of Birmingham. The University of Birmingham has signed a formal contractual agreement with the University of Oxford to enable them to process data on behalf of the University of Birmingham. Under this Agreement, the University of Oxford will be authorised to process data on behalf of and for the purposes determined by the University of Birmingham.

Information about patients with breast cancer who took part in the aTTom trial was collected from NHS organisations (oncology hospitals and General Practitioners) in compliance with the clinical trials regulations, this included patient identifiers and medical information about the patients breast cancer diagnosis and treatment in addition to date and cause of death (where known). This data was collected on a Case Report Form (CRF) and supplied to the CRCTU, University of Birmingham, where it was entered onto the trial database. Data from NHS England is also supplied to the CRCTU, University of Birmingham, and date and cause of death entered into the same trial database.

Ethics and Office of National Statistics (ONS) approval was granted in January 2015 to send the date and cause of death to the NHS organisation treating the patient to clarify discrepancies in the data supplied by the NHS organisation and to request additional information about site and date of recurrence of the patients breast cancer. This practice will come to an end when the aTTom trial is closed with participating NHS organisations. Other than this exception, access to data supplied by NHS England will be restricted to individuals working under appropriate supervision on behalf of the University of Birmingham, who are subject to the same policies, procedures and sanctions as substantive employees of this organisation and to substantive employees of the University of Oxford under the terms of the contract between the University of Birmingham and the University of Oxford.

The University of Birmingham and the University of Oxford are undertaking this work to improve the care of patients with breast cancer, not only in the UK, but worldwide. Breast cancer is the most common female cancer, with over 45,000 new patients diagnosed in the UK per annum and 1.1 million worldwide. Five years of tamoxifen treatment remains the standard of care for many women worldwide with oestrogen receptor positive breast cancer, but there remains uncertainty as to whether tamoxifen should be given for longer. Ultimately, this work could save the lives of thousands of women per year. The continued provision of date and cause of death is vital to this goal.

A sub-study within the aTTom-Extended trial, called Trans-aTTom, involves the collection and analysis of tissue samples. This ethically approved work is being undertaken in collaboration with the Biomarkers and Companion Diagnostics Group, University of Edinburgh; bioTheranostics, Inc. and Massachusetts General Hospital. None of these organisations will have access to the data provided by NHS England or patient identifiable data from any other source. The roles of these collaborators are limited to the following functions:

- The hospital sites from which participants were recruited retrieve the participants' tissues samples from the NHS histopathology archives and anonymise these before sending them to the University of Edinburgh's Cancer Research Centre (ECRC).

- The ECRC Medical Laboratory Scientific Officer will ensure that the tissue blocks are robustly anonymised quoting a unique laboratory number only before sending on for analysis by researchers at either Massachusetts General Hospital and bioTheranostics Inc.

- Researchers (laboratory staff, pathologists or researchers) from Massachusetts General Hospital and bioTheranostics Inc. will be involved with the tissue analysis. No patient identifiable data will be provided to the researchers nor will they have access to the clinical data, therefore they will not be able to link tissue sample analysis data with the patient’s clinical outcome data. The tissues will not be permanently or irrevocably unlinked, but the unique laboratory number will be used to prevent identification of the samples to the researchers involved.

- The data from the analyses will be provided to the University of Birmingham for linkage and further analysis as part of the Trans-aTTom sub-study.

Aims of the Work:

The objective of the aTTom trial is to determine if treating women with oestrogen receptor positive breast cancer with adjuvant tamoxifen treatment for an additional 5 years above the current standard of care is better in terms of disease-free survival, overall survival and late toxicity. The original trial was funded to follow aTTom patients annually for at least 10 years after recruitment. This time point has now been met and preliminary analyses performed. However, it is clear that later events in terms of breast cancer outcome and toxicity will impact on the assessment of clinical utility and further follow up data is required. This will be addressed by continued collection of survival and cause of death data (from NHS England and the National Records of Scotland; NRS) as part of aTTom-Extended.

The aTTom-Extended protocol also includes a proposal to retrospectively collect tissue samples, collected for diagnostic purposes during the patients’ initial surgery for breast cancer, and stored in hospital pathology archives. These tissue samples will be subjected to laboratory analyses to determine molecular characterisation of the tumours. More specifically, the samples will be characterised using a validated multiparametic analysis “the breast cancer index” which is capable of predicting risk of late relapse from breast cancer. The researchers are also interested in determining if this biomarker which incorporates molecular characterisation (the so-called H/I index) is capable of providing predictive information in relation to prevention of late relapse after prior tamoxifen. If this is the case, the test could be used to help define who will and who will not benefit from extended tamoxifen therapy. This work forms a sub-study of the aTTom-Extended protocol and is called Trans-aTTom.

This Agreement requires use of the data for the purpose of Trans-aTTom (the tissue sample and collection analysis being undertaken as part of the aTTom-Extended study). This is in addition to the purposes described previously for aTTom and aTTom-Extended, which obtained approval under previous iterations of this Agreement. The use of the data will be limited to linkage with data from the tissue sample and collection analysis and manipulation of that dataset to produced derived data. All subsequent processing for the purpose of Trans-aTTom will use only the derived data and will not involve any further processing of the data under this Agreement.

Other Relevant Background:

The aTTom trial randomised 8,863 women from 178 UK hospitals between July 1991 and March 2005. Data has been received from NHS England since its conception in the mid-1990s. The overall objectives for aTTom (and latterly aTTom-Extended) have remained the same.

The aTTom trial has been funded by a number of organisations over the years including the Medical Research Council and more recently Cancer Research UK. The collection of tissue blocks for the Trans-aTTom sub-study has recently been funded by bioTheranostics Inc.

Date and cause of death are required from NHS England in order to perform Kaplan-Meier disease-free and overall survival analyses for the aTTom/aTTom-Extended trials and to determine other potential causes of death (e.g., endometrial cancer). For aTTom, this data was collected to provide missing data for patients taking part in the trial who were no longer seen by a medical practitioner or were lost to follow-up for the purposes of the trial. For aTTom-Extended, data provided by NHS England/NRS will be the only source of data for these analyses.

Patient and Public Involvement:

The aTTom clinical trial started in 1991 when there was no formal requirement to have patient involvement with a clinical trial. The process differs substantially today, and patient engagement is a key aspect of both the aTTom-Extended and Trans-aTTom sub-study. In both cases, patient representatives from Independent Cancer Patient Voice (ICPV) are integral members of the Trial Management Group and are involved in both the design and execution of the studies.

In addition, a patient consultation group was held at the Wellcome Trust Clinical Research facility on Thursday 14th June 2018. It was attended by the researchers and five patient advocates representing the patient groups ICPV, Breast Cancer Care and Challenge Breast Cancer Scotland. The meeting was chaired by an independent facilitator from the University of Edinburgh’s public engagement department. A short presentation was given covering the background of and the methodology of the project, with particular attention paid to the use of data. A lengthy discussion was had around the following points:

• The proposed access to and use of patient data

• The value of the research to future patients in relation to data risks

• The proposed funding of the collection of tissue blocks as part of the Trans-aTTom sub-study

• The international nature of the Trans-aTTom sub-study collaboration

The consensus from all the patient advocates was that the proposed research had significant value to patients and far outweighed the theoretical risk to patient data. They felt comfortable with the use of data and the restrictions in place by the applicants. Comments from the participants included it was a “no brainer that the benefit outweighed the data risks”. They felt the Breast Cancer Index incorporating the H/I ratio test would enable patients to have more involvement in their treatment decision making process with their oncologists. Some of the patients, having experienced the side effects from tamoxifen, felt that this project could help spare the next generation of breast cancer patients of having to undergo potentially unnecessary side effects from tamoxifen treatment.

The outputs produced for aTTom to date include presentation of the preliminary results of the trial at the American Society for Clinical Oncology (ASCO) (Journal of Clinical Oncology 31, No.18 Suppl: 5-5) and at the European Society for Medical Oncology (ESMO) (European Journal of Cancer 49, Suppl 2, S1-S1028) in 2013. The results were presented as plenary presentations at the auspicious oncology meeting. The results demonstrated a relapse-free survival benefit for extended tamoxifen treatment. However, an increase in endometrial cancer was also reported. This work has yet to be published as further follow up for overall and breast cancer specific survival was needed prior to publication and there have been subsequent delays caused by issues with ONS data access and subsequent data cleaning. However, the current findings are very widely known.

The intent is to publish this work in the Lancet Oncology as soon as possible. The data is currently being prepared for publication by the trial management group. Any resultant publication will be open access. It is anticipated that there would be a press release from Cancer Research UK and the University of Birmingham associated with the publication of this paper.

A lay version of the findings will be made available on the Cancer Research UK aTTom website and on the CRCTU aTTom/aTTom Extended website.

The first results from Trans-aTTom, in conjunction with the clinical outcome data from aTTom, has been published in the Annals of Oncology (Bartlett et al. Volume 30: 1776; 2019). As previously mentioned, this laboratory-based study evaluated the Breast Cancer Index (BCI) test. The results demonstrate that BCI was predictive of response to tamoxifen and identified a subset of patients who gained significant benefit from 10 versus 5 years of therapy. A second manuscript describing the findings across the whole aTTom cohort confirms the findings in the original publication (Bartlett et al. Clinical Cancer Research; Volume 28: 1871; 2022). The team have also presented analysis of each biomarker evaluated and report that only the BCI (H/I) results are predictive of tamoxifen benefit (Sgroi et al. Cancer Research 2021).

Further laboratory-based research using the samples from Trans-aTTom and the clinical data from aTTom are planned. All outputs will contain only data that is aggregated with small number suppression applied in line with the HES Analysis Guide.

Tamoxifen is still in widespread use and is saving thousands of lives world-wide. The aTTom trial has shown that taking tamoxifen for 10 years is more effective than taking tamoxifen for 5 years. Many women are now being advised to take tamoxifen for 10 years. Tamoxifen can often lead to side effects such as hot flushes. Putting up with these for 10 years can be quite a burden for some patients. Rare but serious side effects from tamoxifen include an increased risk of endometrial cancer (cancer of the womb lining). The aTTom-Extended study was recommended by the Medicines and Healthcare products Regulatory Agency to continue the long term follow up of patients enrolled into this study continued.

The first results from Trans-aTTom have now been published and have shown that the BCI test can be used to predict response to tamoxifen and to identify patients who gain a benefit from extended treatment. A recommendation to use this test has been included in International USA and European breast cancer treatment guidelines. The test has not yet been assessed by UK authorities (NICE and other bodies) so use within the NHS is not possible at present.

This Data Sharing Agreement permits the retention and processing 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 Institute of Cancer Research 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).

Breast cancer is the most common female cancer. In the 1990’s 5-years of tamoxifen treatment was the standard but there was uncertainty as to whether tamoxifen should be given for longer. The aTTom (Adjuvant Tamoxifen Treatment - Offer -More?) trial, which commenced in 1991, was designed to determine if giving tamoxifen for longer than 5 years was beneficial. aTTom is a clinical trial of an investigational medicinal product and falls under the clinical trials regulations for medicinal products.

A preliminary analysis of aTTom has been presented but not yet published and has shown that extending taxoxifen beyond 5 years reduces breast cancer events, although the impact on survival was less clear. There was a small but significant increased risk of endometrial cancer with longer tamoxifen.

The original 10-year follow-up period for the aTTom trial patients was reached in October 2015. However, long-term toxicity remains a concern and continued follow-up of these patients is vital to determine the full impact of extended tamoxifen on breast cancer specific and overall survival. To this end (and following the recommendations of the Medicines and Healthcare products Regulatory Agency) approval, research ethics and CAG approval has been sought for a follow-on study called aTTom-Extended (Extended follow-up of patients enrolled in the aTTom trial). aTTom-Extended falls outside of the remit of clinical trials governing medicinal products. aTTom-Extended will continue to follow-up the aTTom patients for an additional 10 years (REC specified end date December 2027).

A sub-study within the aTTom-Extended trial, called Trans-aTTom, involves the collection and analysis of tissue samples. These tissue samples will be subjected to laboratory analyses to determine molecular characterisation of the tumours. More specifically the samples will be characterised using a validated multiparametric analysis “the breast cancer index” which is capable of predicting risk of late relapse from breast cancer. Data under this Agreement will be linked with data from analysis of participants’ tissue samples and from the linked data, data will be derived. Subsequent analyses will use the derived data only and will not involve any further processing of the data under this Agreement.

In order to carry out these studies, the personal data (which includes special categories of data) will be processed, in accordance with the General Data Protection Act 2016 Article 6 (1) (e) processing is necessary for the performance of a task carried out in the public interest; and Article 9 (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). The University of Birmingham is a public authority, as defined in the Freedom of Information Act 2000, whose primary purpose is the advancement of education and research which are deemed to deliver a public benefit. All research is conducted in accordance with the University’s Code of Practice for Research. The results of the aTTom/aTTom-Extended study will advance the treatment of breast cancer patients internationally and is therefore considered to be in the public interest. There are no ethical issues or risk of harm to the public from the dissemination of these results.

Organisations Involved:

The University of Birmingham is the Data Controller. The University of Birmingham requires mortality data and data on any new cancer registrations relating to the cohort for use in the aTTom/aTTom-Extended studies for the purpose described below.

aTTom and aTTom-Extended are sponsored (in accordance with the UK Policy Framework for Health and Social Care Research) by the University of Birmingham. The Chief Investigator is based at the University of Birmingham. The CRCTU is one of two trials units within the University of Birmingham the other being the Birmingham Clinical Trials Unit (BCTU) which is responsible for the analysis (processing) of aTTom (performed by the Trial Statistician). The statistical lead moved from the University of Birmingham to the University of Oxford in September 2010. The statistical lead retains an honorary contract with the University of Birmingham. The University of Birmingham has signed a formal contractual agreement with the University of Oxford to enable them to process data on behalf of the University of Birmingham. Under this Agreement, the University of Oxford will be authorised to process data on behalf of and for the purposes determined by the University of Birmingham.

Information about patients with breast cancer who took part in the aTTom trial was collected from NHS organisations (oncology hospitals and General Practitioners) in compliance with the clinical trials regulations, this included patient identifiers and medical information about the patients breast cancer diagnosis and treatment in addition to date and cause of death (where known). This data was collected on a Case Report Form (CRF) and supplied to the CRCTU, University of Birmingham, where it was entered onto the trial database. Data from NHS Digital is also supplied to the CRCTU, University of Birmingham, and date and cause of death entered into the same trial database.

Ethics and Office of National Statistics (ONS) approval was granted in January 2015 to send the date and cause of death to the NHS organisation treating the patient to clarify discrepancies in the data supplied by the NHS organisation and to request additional information about site and date of recurrence of the patients breast cancer. This practice will come to an end when the aTTom trial is closed with participating NHS organisations which is now planned for end-2019. Other than this exception, access to data supplied by NHS Digital will be restricted to individuals working under appropriate supervision on behalf of the University of Birmingham, who are subject to the same policies, procedures and sanctions as substantive employees of this organisation and to substantive employees of the University of Oxford under the terms of the contract between the University of Birmingham and the University of Oxford.

The University of Birmingham and the University of Oxford are undertaking this work to improve the care of patients with breast cancer, not only in the UK, but worldwide. Breast cancer is the most common female cancer, with over 45,000 new patients diagnosed in the UK per annum and 1.1 million worldwide. Five years of tamoxifen treatment remains the standard of care for many women worldwide with oestrogen receptor positive breast cancer, but there remains uncertainty as to whether tamoxifen should be given for longer. Ultimately, this work could save the lives of thousands of women per year. The continued provision of date and cause of death is vital to this goal.

A sub-study within the aTTom-Extended trial, called Trans-aTTom, involves the collection and analysis of tissue samples. This ethically approved work is being undertaken in collaboration with the Biomarkers and Companion Diagnostics Group, University of Edinburgh; bioTheranostics, Inc. and Massachusetts General Hospital. None of these organisations will have access to the data provided by NHS Digital or patient identifiable data from any other source. The roles of these collaborators are limited to the following functions:

- The hospital sites from which participants were recruited retrieve the participants' tissues samples from the NHS histopathology archives and anonymise these before sending them to the University of Edinburgh's Cancer Research Centre (ECRC).

- The ECRC Medical Laboratory Scientific Officer will ensure that the tissue blocks are robustly anonymised quoting a unique laboratory number only before sending on for analysis by researchers at either Massachusetts General Hospital and bioTheranostics Inc.

- Researchers (laboratory staff, pathologists or researchers) from Massachusetts General Hospital and bioTheranostics Inc. will be involved with the tissue analysis. No patient identifiable data will be provided to the researchers nor will they have access to the clinical data, therefore they will not be able to link tissue sample analysis data with the patient’s clinical outcome data. The tissues will not be permanently or irrevocably unlinked, but the unique laboratory number will be used to prevent identification of the samples to the researchers involved.

- The data from the analyses will be provided to the University of Birmingham for linkage and further analysis as part of the Trans-aTTom sub-study.

Aims of the Work:

The objective of the aTTom trial is to determine if treating women with oestrogen receptor positive breast cancer with adjuvant tamoxifen treatment for an additional 5 years above the current standard of care is better in terms of disease-free survival, overall survival and late toxicity. The original trial was funded to follow aTTom patients annually for at least 10 years after recruitment. This time point has now been met and preliminary analyses performed. However, it is clear that later events in terms of breast cancer outcome and toxicity will impact on the assessment of clinical utility and further follow up data is required. This will be addressed by continued collection of survival and cause of death data (from NHS Digital and the National Records of Scotland; NRS) as part of aTTom-Extended.

The aTTom-Extended protocol also includes a proposal to retrospectively collect tissue samples, collected for diagnostic purposes during the patients’ initial surgery for breast cancer, and stored in hospital pathology archives. These tissue samples will be subjected to laboratory analyses to determine molecular characterisation of the tumours. More specifically, the samples will be characterised using a validated multiparametic analysis “the breast cancer index” which is capable of predicting risk of late relapse from breast cancer. The researchers are also interested in determining if this biomarker which incorporates molecular characterisation (the so-called H/I index) is capable of providing predictive information in relation to prevention of late relapse after prior tamoxifen. If this is the case, the test could be used to help define who will and who will not benefit from extended tamoxifen therapy. This work forms a sub-study of the aTTom-Extended protocol and is called Trans-aTTom.

This Agreement requires use of the data for the purpose of Trans-aTTom (the tissue sample and collection analysis being undertaken as part of the aTTom-Extended study). This is in addition to the purposes described previously for aTTom and aTTom-Extended, which obtained approval under previous iterations of this Agreement. The use of the data will be limited to linkage with data from the tissue sample and collection analysis and manipulation of that dataset to produced derived data. All subsequent processing for the purpose of Trans-aTTom will use only the derived data and will not involve any further processing of the data under this Agreement.

Other Relevant Background:

Multicentre research ethical approval for the original aTTom trial was granted in February 1998. Ethical approval for the aTTom-Extended protocol, which includes the collection and analysis of tissue samples as part of the Trans-aTTom sub-study, was granted in July 2016.

The aTTom trial randomised 8,863 women from 178 UK hospitals between July 1991 and March 2005. Data has been received from NHS Digital since its conception in the mid-1990s. The overall objectives for aTTom (and latterly aTTom-Extended) have remained the same.

The aTTom trial has been funded by a number of organisations over the years including the Medical Research Council and more recently Cancer Research UK. The collection of tissue blocks for the Trans-aTTom sub-study has recently been funded by bioTheranostics Inc.

Date and cause of death are required from NHS Digital in order to perform Kaplan-Meier disease-free and overall survival analyses for the aTTom/aTTom-Extended trials and to determine other potential causes of death (e.g., endometrial cancer). For aTTom, this data was collected to provide missing data for patients taking part in the trial who were no longer seen by a medical practitioner or were lost to follow-up for the purposes of the trial. For aTTom-Extended, data provided by NHS Digital/NRS will be the only source of data for these analyses.

Patient and Public Involvement:

The aTTom clinical trial started in 1991 when there was no formal requirement to have patient involvement with a clinical trial. The process differs substantially today, and patient engagement is a key aspect of both the aTTom-Extended and Trans-aTTom sub-study. In both cases, patient representatives from Independent Cancer Patient Voice (ICPV) are integral members of the Trial Management Group and are involved in both the design and execution of the studies.

In addition, a patient consultation group was held at the Wellcome Trust Clinical Research facility on Thursday 14th June 2018. It was attended by the researchers and five patient advocates representing the patient groups ICPV, Breast Cancer Care and Challenge Breast Cancer Scotland. The meeting was chaired by an independent facilitator from the University of Edinburgh’s public engagement department. A short presentation was given covering the background of and the methodology of the project, with particular attention paid to the use of data. A lengthy discussion was had around the following points:

• The proposed access to and use of patient data

• The value of the research to future patients in relation to data risks

• The proposed funding of the collection of tissue blocks as part of the Trans-aTTom sub-study

• The international nature of the Trans-aTTom sub-study collaboration

The consensus from all the patient advocates was that the proposed research had significant value to patients and far outweighed the theoretical risk to patient data. They felt comfortable with the use of data and the restrictions in place by the applicants. Comments from the participants included it was a “no brainer that the benefit outweighed the data risks”. They felt the Breast Cancer Index incorporating the H/I ratio test would enable patients to have more involvement in their treatment decision making process with their oncologists. Some of the patients, having experienced the side effects from tamoxifen, felt that this project could help spare the next generation of breast cancer patients of having to undergo potentially unnecessary side effects from tamoxifen treatment.

The outputs produced for aTTom to date include presentation of the preliminary results of the trial at the American Society for Clinical Oncology (ASCO) (Journal of Clinical Oncology 31, No.18 Suppl: 5-5) and at the European Society for Medical Oncology (ESMO) (European Journal of Cancer 49, Suppl 2, S1-S1028) in 2103. The results were presented as plenary presentations at these auspicious oncology meeting. The results demonstrated a relapse-free survival benefit for extended tamoxifen treatment. However an increase in endometrial cancer was also reported. This work has yet to be published as further follow up for overall and breast cancer specific survival was needed prior to publication and there have been subsequent delays caused by issues with ONS data access.

The intent is to publish this work in the Lancet Oncology (a high impact peer review journal) as soon as possible. A draft publication has been written but further analysis is on hold pending the approval of the University of Oxford as a processing organisation. Any resultant publication will be open access. It is anticipated that there would be a press release from Cancer Research UK and the University of Birmingham associated with the publication of this paper.

aTTom is a high-profile study which has been presented in provisional format at an ASCO and ESMO plenary sessions. The current findings are very widely known, and the peer reviewed manuscript will be submitted to the Lancet, thus information will be very well publicised and readily available to guideline groups and individual breast cancer clinicians making patient level recommendations.

Further publications in peer reviewed journals are also planned on long term toxicity and survival from the aTTom-Extended protocol.

A lay version of the findings from aTTom and aTTom-Extended will be made available on the Cancer Research UK aTTom website and on the CRCTU aTTom/aTTom Extended website.

The output from the analysis of the translational work (Trans-aTTom) in conjunction with the clinical outcome data will be presented and published separately. These results are of great clinical interest and irrespective of the findings are likely to be accepted for publication in a high impact oncology journal. The University of Birmingham would be targeting a presentation at the American Society of Clinical Oncology and publication in the Journal of Clinical Oncology or Lancet Oncology. Positive results from this study will be practice changing and generate a high level of interest Internationally.

The findings from these studies are expected to be practice changing.

All outputs will contain only data that is aggregated in line with the HES Analysis Guide.

Tamoxifen is still in widespread use and is saving thousands of lives world-wide. The aTTom trial has shown that taking tamoxifen for 10 years is more effective than taking tamoxifen for 5 years. Many women are now being advised to take tamoxifen for 10 years. Tamoxifen can often lead to side effects such as hot flushes. Putting up with these for 10 years can be quite a burden for some patients. Rare but serious side effects from tamoxifen include an increased risk of endometrial cancer (cancer of the womb lining). The aTTom-Extended study was recommended by the Medicines and Healthcare products Regulatory Agency to continue the long term follow up of patients enrolled into this study.

Yielded benefits will be updated in the subsequent version of this Agreement.

Background Information:

Breast cancer is the most common female cancer. In the 1990’s 5-years of tamoxifen treatment was the standard but there was uncertainty as to whether tamoxifen should be given for longer. The aTTom (Adjuvant Tamoxifen Treatment - Offer -More?) trial, which commenced in 1991, was designed to determine if giving tamoxifen for longer than 5 years was beneficial. aTTom is a clinical trial of an investigational medicinal product and falls under the clinical trials regulations for medicinal products.

A preliminary analysis of aTTom has been presented but not yet published this has shown that extending taxoxifen beyond 5 years reduces breast cancer events the impact on survival was less clear. There was a small but significant increased risk of endometrial cancer with longer tamoxifen.

The original 10-year follow-up period for the aTTom trial patients was reached in October 2015. However long-term toxicity remains a concern and continued follow-up of these patients is vital to determine the full impact of extended tamoxifen on breast cancer specific and overall survival. To this end (and following the recommendations of the Medicines and Healthcare products Regulatory Agency) approval (research ethics and CAG approval) has been sought for a follow-on study called aTTom-Extended (Extended follow-up of patients enrolled in the aTTom trial). aTTom-Extended falls outside of the remit of clinical trials governing medicinal products. aTTom-Extended will continue to follow-up the aTTom patients for an additional 10 years (REC specified end date December 2027).

A sub-study within the aTTom-Extended trial, called Trans-aTTom, involves the collection and analysis of tissue samples. These tissue samples will be subjected to laboratory analyses to determine molecular characterisation of the tumours. More specifically the samples will be characterised using a validated multiparametric analysis “the breast cancer index” which is capable of predicting risk of late relapse from breast cancer. Data under this Agreement will be linked with data from analysis of participants’ tissue samples and from the linked data, data will be derived. Subsequent analyses will use the derived data only and will not involve any further processing of the data under this Agreement.

Data Controller:

The University of Birmingham is the Data Controller. The University of Birmingham requires mortality data and data on any new cancer registrations relating to the cohort for use in the aTTom/aTTom-Extended studies for the purpose described below.

In order to carry these studies, the personal data (which includes special categories of data) will be processed, in accordance with the General Data Protection Act 2016 Article 6 (1) (e) processing is necessary for the performance of a task carried out in the public interest; and Article 9 (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) The University of Birmingham is a public authority, as defined in the Freedom of Information Act 2000, whose primary purpose is the advancement of education and research which are deemed to deliver a public benefit. All research is conducted in accordance with the University’s Code of Practice for Research. The results of the aTTom/aTTom-Extended study will advance the treatment of breast cancer patients internationally and is therefore considered to be in the public interest. There are no ethical issues or risk of harm to the public from the dissemination of these results.

Organisations Involved:

aTTom and aTTom-Extended are sponsored (in accordance with the UK Policy Framework for Health and Social Care Research) by the University of Birmingham which is also the Data Controller. The Chief Investigator is based at the University of Birmingham. The CRCTU is one of two trials units within the University of Birmingham the other being the Birmingham Clinical Trials Unit (BCTU) which is responsible for the analysis (processing) of aTTom (performed by the Trial Statistician). The statistical lead moved from the University of Birmingham to the University of Oxford in September 2010. The statistical lead retains an honorary contract with the University of Birmingham. The University of Birmingham has signed a formal contractual agreement with the University of Oxford to enable them to process data on behalf of the University of Birmingham. Under this Agreement, the University of Oxford will be authorised to process data on behalf of and for the purposes determined by the University of Birmingham.

Information about patients with breast cancer who took part in the aTTom trial was collected from NHS organisations (oncology hospitals and General Practitioners) in compliance with the clinical trials regulations, this included patient identifiers and medical information about the patients breast cancer diagnosis and treatment in addition to date and cause of death (where known). This data was collected on a Case Report Form (CRF) and supplied to the CRCTU, University of Birmingham where it was entered onto the trial database. Data from NHS Digital is also supplied to the CRCTU, University of Birmingham and date and cause of death entered into the same trial database.

Ethics and Office of National Statistics (ONS) approval was granted in January 2015 to send the date and cause of death to the NHS organisation treating the patient to clarify discrepancies in the data supplied by the NHS organisation and to request additional information about site and date of recurrence of the patients breast cancer. This practice will come to an end when the aTTom trial is closed with participating NHS organisations which is now planned for end-2019. Other than this exception, access to data supplied by NHS Digital will be restricted to individuals, working under appropriate supervision on behalf of the University of Birmingham, who are subject to the same policies, procedures and sanctions as substantive employees of this organisation and to substantive employees of the University of Oxford under the terms of the contract between the University of Birmingham and the University of Oxford.

The University of Birmingham, and the University of Oxford, are undertaking this work to improve the care of patients with breast cancer not only in the UK but worldwide. Breast cancer is the most common female cancer, with over 45,000 new patients diagnosed in the UK per annum and 1.1 million worldwide. Five years of tamoxifen treatment remains the standard of care for many women worldwide with oestrogen receptor positive breast cancer but there remains uncertainty as to whether tamoxifen should be given for longer. Ultimately this work could save the lives of thousands of women per annum. The continued provision of date and cause of death is vital to this goal.

A sub-study within the aTTom-Extended trial, called Trans-aTTom, involves the collection and analysis of tissue samples. This ethically approved work is being undertaken in collaboration with the Biomarkers and Companion Diagnostics Group, University of Edinburgh; bioTheranostics, Inc. and Massachusetts General Hospital. None of these organisations will have access to the data provided by NHS Digital or patient identifiable data from any other source. The roles of these collaborators are limited to the following functions:

- The hospital sites from which participants were recruited retrieve the participants' tissues samples from the NHS histopathology archives and anonymise these before sending them to the University of Edinburgh's Cancer Research Centre (ECRC).

- The ECRC Medical Laboratory Scientific Officer will ensure that the tissue blocks are robustly anonymised quoting a unique laboratory number only before sending on for analysis by researchers at either Massachusetts General Hospital and bioTheranostics Inc.

- Researchers (laboratory staff, pathologists or researchers) from Massachusetts General Hospital and bioTheranostics Inc. will be involved with the tissue analysis. No patient identifiable data will be provided to the researchers nor will they have access to the clinical data, therefore they will not be able to link tissue sample analysis data with the patient’s clinical outcome data. The tissues will not be permanently or irrevocably unlinked, but the unique laboratory number will be used to prevent identification of the samples to the researchers involved.

- The data from the analyses will be provided to the University of Birmingham for linkage and further analysis as part of the Trans-aTTom sub-study.

Aims of the Work:

The objective of the aTTom trial is to determine if treating women with oestrogen receptor positive breast cancer with adjuvant tamoxifen treatment for an additional 5 years above the current standard of care is better in terms of disease-free survival, overall survival and late toxicity. The original trial was funded to follow aTTom patients annually for at least 10 years after recruitment. This time point has now been met and preliminary analyses performed. However, it is clear that later events in terms of breast cancer outcome and toxicity will impact on the assessment of clinical utility and further follow up data is required. This will be addressed by continued collection of survival and cause of death data (from NHS Digital and the National Records of Scotland; NRS) as part of aTTom-Extended.

The aTTom-Extended protocol also includes a proposal to retrospectively collect tissue samples, collected for diagnostic purposes during the patients’ initial surgery for breast cancer, and stored in hospital pathology archives. These tissue samples will be subjected to laboratory analyses to determine molecular characterisation of the tumours. More specifically the samples will be characterised using a validated multiparametic analysis “the breast cancer index” which is capable of predicting risk of late relapse from breast cancer. The researchers are also interested in determining if this biomarker which incorporates molecular characterisation (the so-called H/I index) is capable of providing predictive information in relation to prevention of late relapse after prior tamoxifen. If this is the case the test could be used to help define who will and who will not benefit from extended tamoxifen therapy. This work forms a sub-study of the aTTom-Extended protocol and is called Trans-aTTom.

This Agreement requires use of the data for the purpose of Trans-aTTom (the tissue sample and collection analysis being undertaken as part of the aTTom-Extended study). This is in addition to the purposes described previously for aTTom and aTTom-Extended which obtained approval under previous iterations of this Agreement. The use of the data will be limited to linkage with data from the tissue sample and collection analysis and manipulation of that dataset to produced derived data. All subsequent processing for the purpose of Trans-aTTom will use only the derived data and will not involve any further processing of the data under this Agreement.

Other Relevant Background:

Multicentre research ethical approval for the original aTTom trial was granted in February 1998. Ethical approval for the aTTom-Extended protocol, which includes the collection and analysis of tissue samples as part of the Trans-aTTom sub-study, was granted in July 2016.

The aTTom trial randomised 8,863 women from 178 UK hospitals between July 1991 and March 2005. Data has been received from NHS Digital since its conception in the mid-1990s. The overall objectives for aTTom (and latterly aTTom-Extended) have remained the same.

The aTTom trial has been funded by a number of organisations over the years including the Medical Research Council and more recently Cancer Research UK. The collection of tissue blocks for the Trans-aTTom sub-study has recently been funded by bioTheranostics Inc.

Date and cause of death are required from NHS Digital in order to perform Kaplan-Meier disease-free and overall survival analyses for the aTTom/aTTom-Extended trials and to determine other potential causes of death (e.g. endometrial cancer). For aTTom this data was collected to provide missing data for patients taking part in the trial who were no longer seen by a medical practitioner or were lost to follow-up for the purposes of the trial. For aTTom-Extended data provided by NHS Digital/NRS will be the only source of data for these analyses.

Patient and Public Involvement:

The aTTom clinical trial started in 1991 when there was no formal requirement to have patient involvement with a clinical trial. The process differs substantially today and patient engagement is a key aspect of both the aTTom-Extended and Trans-aTTom sub-study. In both cases patient representatives from Independent Cancer Patient Voice (ICPV) are integral members of the Trial Management Group and are involved in both the design and execution of the studies.

In addition, a patient consultation group was held at the Wellcome Trust Clinical Research facility on Thursday 14th June 2018. It was attended by the researchers and five patient advocates representing the patient groups ICPV, Breast Cancer Care and Challenge Breast Cancer Scotland. The meeting was chaired by an independent facilitator from the University of Edinburgh’s public engagement department. A short presentation was given covering the background of and the methodology of the project, with particular attention paid to the use of data. A lengthy discussion was had around the following points:

• The proposed access to and use of patient data

• The value of the research to future patients in relation to data risks

• The proposed funding of the collection of tissue blocks as part of the Trans-aTTom sub-study

• The international nature of the Trans-aTTom sub-study collaboration

The consensus from all the patient advocates was that the proposed research had significant value to patients and far outweighed the theoretical risk to patient data. They felt comfortable with the use of data and the restrictions in place by the applicants. Comments from the participants included it was a “no brainer that the benefit outweighed the data risks”. They felt the Breast Cancer Index incorporating the H/I ratio test would enable patients to have more involvement in their treatment decision making process with their oncologists. Some of the patients, having experienced the side effects from tamoxifen, felt that this project could help spare the next generation of breast cancer patients of having to undergo potentially unnecessary side effects from tamoxifen treatment.

The outputs produced for aTTom to date include presentation of the preliminary results of the trial at the American Society for Clinical Oncology (ASCO) (Journal of Clinical Oncology 31, No.18 Suppl: 5-5) and at the European Society for Medical Oncology (ESMO) (European Journal of Cancer 49, Suppl 2, S1-S1028) in 2103. The results were presented as plenary presentations at these auspicious oncology meeting. The results demonstrated a relapse-free survival benefit for extended tamoxifen treatment. However an increase in endometrial cancer was also reported. This work has yet to be published as further follow up for overall and breast cancer specific survival was needed prior to publication and there have been subsequent delays caused by issues with ONS data access.

The intent is to publish this work in the Lancet Oncology (a high impact peer review journal) as soon as possible. A draft publication has been written but further analysis is on hold pending the approval of the University of Oxford as a processing organisation. Any resultant publication will be open access. It is anticipated that there would be a press release from Cancer Research UK and the University of Birmingham associated with the publication of this paper.

Further publications in peer reviewed journals are also planned on long term toxicity and survival from the aTTom-Extended protocol.

A lay version of the findings from aTTom and aTTom-Extended will be made available on the Cancer Research UK aTTom website and on the CRCTU aTTom/aTTom Extended website.

The output from the analysis of the translational work (Trans-aTTom) in conjunction with the clinical outcome data will be presented and published separately. These results are of great clinical interest and irrespective of the findings are likely to be accepted for publication in a high impact oncology journal. The University of Birmingham would be targeting a presentation at the American Society of Clinical Oncology and publication in the Journal of Clinical Oncology or Lancet Oncology. Positive results from this study will be practice changing and generate a high level of interest Internationally.

The findings from these studies are expected to be practice changing.

All outputs will contain only data that is aggregated in line with the HES Analysis Guide.

Tamoxifen is still in widespread use and is saving thousands of lives world-wide. The aTTom trial has shown that taking tamoxifen for 10 years is more effective than taking tamoxifen for 5 years. Many women are now being advised to take tamoxifen for 10 years. Tamoxifen can often lead to side effects such as hot flushes. Putting up with these for 10 years can be quite a burden for some patients. Rare but serious side effects from tamoxifen include an increased risk of endometrial cancer (cancer of the womb lining). The aTTom-Extended study was recommended by the Medicines and Healthcare products Regulatory Agency to continue the long term follow up of patients enrolled into this study.

No benefits have yet been yielded as a result of the aTTom-Extended study.

Background Information:

Breast cancer is the most common female cancer. In the 1990’s 5-years of tamoxifen treatment was the standard but there was uncertainty as to whether tamoxifen should be given for longer. The aTTom (Adjuvant Tamoxifen Treatment - Offer -More?) trial, which commenced in 1991, was designed to determine if giving tamoxifen for longer than 5 years was beneficial. aTTom is a clinical trial of an investigational medicinal product and falls under the clinical trials regulations for medicinal products.

A preliminary analysis of aTTom has been presented but not yet published this has shown that extending taxoxifen beyond 5 years reduces breast cancer events the impact on survival was less clear. There was a small but significant increased risk of endometrial cancer with longer tamoxifen.

The original 10-year follow-up period for the aTTom trial patients was reached in October 2015. However long-term toxicity remains a concern and continued follow-up of these patients is vital to determine the full impact of extended tamoxifen on breast cancer specific and overall survival. To this end (and following the recommendations of the Medicines and Healthcare products Regulatory Agency) approval (research ethics and CAG approval) has been sought for a follow-on study called aTTom-Extended (Extended follow-up of patients enrolled in the aTTom trial). aTTom-Extended falls outside of the remit of clinical trials governing medicinal products. aTTom-Extended will continue to follow-up the aTTom patients for an additional 10 years (REC specified end date December 2027).

A sub-study within the aTTom-Extended trial, called Trans-aTTom, involves the collection and analysis of tissue samples. These tissue samples will be subjected to laboratory analyses to determine molecular characterisation of the tumours. More specifically the samples will be characterised using a validated multiparametric analysis “the breast cancer index” which is capable of predicting risk of late relapse from breast cancer. Data under this Agreement will be linked with data from analysis of participants’ tissue samples and from the linked data, data will be derived. Subsequent analyses will use the derived data only and will not involve any further processing of the data under this Agreement.

Data Controller:

The University of Birmingham is the Data Controller. The University of Birmingham requires mortality data and data on any new cancer registrations relating to the cohort for use in the aTTom/aTTom-Extended studies for the purpose described below.

In order to carry these studies, the personal data (which includes special categories of data) will be processed, in accordance with the General Data Protection Act 2016 Article 6 (1) (e) processing is necessary for the performance of a task carried out in the public interest; and Article 9 (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) The University of Birmingham is a public authority, as defined in the Freedom of Information Act 2000, whose primary purpose is the advancement of education and research which are deemed to deliver a public benefit. All research is conducted in accordance with the University’s Code of Practice for Research. The results of the aTTom/aTTom-Extended study will advance the treatment of breast cancer patients internationally and is therefore considered to be in the public interest. There are no ethical issues or risk of harm to the public from the dissemination of these results.

Organisations Involved:

aTTom and aTTom-Extended are sponsored (in accordance with the UK Policy Framework for Health and Social Care Research) by the University of Birmingham which is also the Data Controller. The Chief Investigator is based at the University of Birmingham. The CRCTU is one of two trials units within the University of Birmingham the other being the Birmingham Clinical Trials Unit (BCTU) which is responsible for the analysis (processing) of aTTom (performed by the Trial Statistician). The statistical lead moved from the University of Birmingham to the University of Oxford in September 2010. The statistical lead retains an honorary contract with the University of Birmingham. The University of Birmingham has signed a formal contractual agreement with the University of Oxford to enable them to process data on behalf of the University of Birmingham. Under this Agreement, the University of Oxford will be authorised to process data on behalf of and for the purposes determined by the University of Birmingham.

Information about patients with breast cancer who took part in the aTTom trial was collected from NHS organisations (oncology hospitals and General Practitioners) in compliance with the clinical trials regulations, this included patient identifiers and medical information about the patients breast cancer diagnosis and treatment in addition to date and cause of death (where known). This data was collected on a Case Report Form (CRF) and supplied to the CRCTU, University of Birmingham where it was entered onto the trial database. Data from NHS Digital is also supplied to the CRCTU, University of Birmingham and date and cause of death entered into the same trial database.

Ethics and Office of National Statistics (ONS) approval was granted in January 2015 to send the date and cause of death to the NHS organisation treating the patient to clarify discrepancies in the data supplied by the NHS organisation and to request additional information about site and date of recurrence of the patients breast cancer. This practice will come to an end when the aTTom trial is closed with participating NHS organisations which is now planned for end-2019. Other than this exception, access to data supplied by NHS Digital will be restricted to individuals, working under appropriate supervision on behalf of the University of Birmingham, who are subject to the same policies, procedures and sanctions as substantive employees of this organisation and to substantive employees of the University of Oxford under the terms of the contract between the University of Birmingham and the University of Oxford.

The University of Birmingham, and the University of Oxford, are undertaking this work to improve the care of patients with breast cancer not only in the UK but worldwide. Breast cancer is the most common female cancer, with over 45,000 new patients diagnosed in the UK per annum and 1.1 million worldwide. Five years of tamoxifen treatment remains the standard of care for many women worldwide with oestrogen receptor positive breast cancer but there remains uncertainty as to whether tamoxifen should be given for longer. Ultimately this work could save the lives of thousands of women per annum. The continued provision of date and cause of death is vital to this goal.

A sub-study within the aTTom-Extended trial, called Trans-aTTom, involves the collection and analysis of tissue samples. This ethically approved work is being undertaken in collaboration with the Biomarkers and Companion Diagnostics Group, University of Edinburgh; bioTheranostics, Inc. and Massachusetts General Hospital. None of these organisations will have access to the data provided by NHS Digital or patient identifiable data from any other source. The roles of these collaborators are limited to the following functions:

- The hospital sites from which participants were recruited retrieve the participants' tissues samples from the NHS histopathology archives and anonymise these before sending them to the University of Edinburgh's Cancer Research Centre (ECRC).

- The ECRC Medical Laboratory Scientific Officer will ensure that the tissue blocks are robustly anonymised quoting a unique laboratory number only before sending on for analysis by researchers at either Massachusetts General Hospital and bioTheranostics Inc.

- Researchers (laboratory staff, pathologists or researchers) from Massachusetts General Hospital and bioTheranostics Inc. will be involved with the tissue analysis. No patient identifiable data will be provided to the researchers nor will they have access to the clinical data, therefore they will not be able to link tissue sample analysis data with the patient’s clinical outcome data. The tissues will not be permanently or irrevocably unlinked, but the unique laboratory number will be used to prevent identification of the samples to the researchers involved.

- The data from the analyses will be provided to the University of Birmingham for linkage and further analysis as part of the Trans-aTTom sub-study.

Aims of the Work:

The objective of the aTTom trial is to determine if treating women with oestrogen receptor positive breast cancer with adjuvant tamoxifen treatment for an additional 5 years above the current standard of care is better in terms of disease-free survival, overall survival and late toxicity. The original trial was funded to follow aTTom patients annually for at least 10 years after recruitment. This time point has now been met and preliminary analyses performed. However, it is clear that later events in terms of breast cancer outcome and toxicity will impact on the assessment of clinical utility and further follow up data is required. This will be addressed by continued collection of survival and cause of death data (from NHS Digital and the National Records of Scotland; NRS) as part of aTTom-Extended.

The aTTom-Extended protocol also includes a proposal to retrospectively collect tissue samples, collected for diagnostic purposes during the patients’ initial surgery for breast cancer, and stored in hospital pathology archives. These tissue samples will be subjected to laboratory analyses to determine molecular characterisation of the tumours. More specifically the samples will be characterised using a validated multiparametic analysis “the breast cancer index” which is capable of predicting risk of late relapse from breast cancer. The researchers are also interested in determining if this biomarker which incorporates molecular characterisation (the so-called H/I index) is capable of providing predictive information in relation to prevention of late relapse after prior tamoxifen. If this is the case the test could be used to help define who will and who will not benefit from extended tamoxifen therapy. This work forms a sub-study of the aTTom-Extended protocol and is called Trans-aTTom.

This Agreement requires use of the data for the purpose of Trans-aTTom (the tissue sample and collection analysis being undertaken as part of the aTTom-Extended study). This is in addition to the purposes described previously for aTTom and aTTom-Extended which obtained approval under previous iterations of this Agreement. The use of the data will be limited to linkage with data from the tissue sample and collection analysis and manipulation of that dataset to produced derived data. All subsequent processing for the purpose of Trans-aTTom will use only the derived data and will not involve any further processing of the data under this Agreement.

Other Relevant Background:

Multicentre research ethical approval for the original aTTom trial was granted in February 1998. Ethical approval for the aTTom-Extended protocol, which includes the collection and analysis of tissue samples as part of the Trans-aTTom sub-study, was granted in July 2016.

The aTTom trial randomised 8,863 women from 178 UK hospitals between July 1991 and March 2005. Data has been received from NHS Digital since its conception in the mid-1990s. The overall objectives for aTTom (and latterly aTTom-Extended) have remained the same.

The aTTom trial has been funded by a number of organisations over the years including the Medical Research Council and more recently Cancer Research UK. The collection of tissue blocks for the Trans-aTTom sub-study has recently been funded by bioTheranostics Inc.

Date and cause of death are required from NHS Digital in order to perform Kaplan-Meier disease-free and overall survival analyses for the aTTom/aTTom-Extended trials and to determine other potential causes of death (e.g. endometrial cancer). For aTTom this data was collected to provide missing data for patients taking part in the trial who were no longer seen by a medical practitioner or were lost to follow-up for the purposes of the trial. For aTTom-Extended data provided by NHS Digital/NRS will be the only source of data for these analyses.

Patient and Public Involvement:

The aTTom clinical trial started in 1991 when there was no formal requirement to have patient involvement with a clinical trial. The process differs substantially today and patient engagement is a key aspect of both the aTTom-Extended and Trans-aTTom sub-study. In both cases patient representatives from Independent Cancer Patient Voice (ICPV) are integral members of the Trial Management Group and are involved in both the design and execution of the studies.

In addition, a patient consultation group was held at the Wellcome Trust Clinical Research facility on Thursday 14th June 2018. It was attended by the researchers and five patient advocates representing the patient groups ICPV, Breast Cancer Care and Challenge Breast Cancer Scotland. The meeting was chaired by an independent facilitator from the University of Edinburgh’s public engagement department. A short presentation was given covering the background of and the methodology of the project, with particular attention paid to the use of data. A lengthy discussion was had around the following points:

• The proposed access to and use of patient data

• The value of the research to future patients in relation to data risks

• The proposed funding of the collection of tissue blocks as part of the Trans-aTTom sub-study

• The international nature of the Trans-aTTom sub-study collaboration

The consensus from all the patient advocates was that the proposed research had significant value to patients and far outweighed the theoretical risk to patient data. They felt comfortable with the use of data and the restrictions in place by the applicants. Comments from the participants included it was a “no brainer that the benefit outweighed the data risks”. They felt the Breast Cancer Index incorporating the H/I ratio test would enable patients to have more involvement in their treatment decision making process with their oncologists. Some of the patients, having experienced the side effects from tamoxifen, felt that this project could help spare the next generation of breast cancer patients of having to undergo potentially unnecessary side effects from tamoxifen treatment.

The outputs produced for aTTom to date include presentation of the preliminary results of the trial at the American Society for Clinical Oncology (ASCO) (Journal of Clinical Oncology 31, No.18 Suppl: 5-5) and at the European Society for Medical Oncology (ESMO) (European Journal of Cancer 49, Suppl 2, S1-S1028) in 2103. The results were presented as plenary presentations at these auspicious oncology meeting. The results demonstrated a relapse-free survival benefit for extended tamoxifen treatment. However an increase in endometrial cancer was also reported. This work has yet to be published as further follow up for overall and breast cancer specific survival was needed prior to publication and there have been subsequent delays caused by issues with ONS data access.

The intent is to publish this work in the Lancet Oncology (a high impact peer review journal) as soon as possible. A draft publication has been written but further analysis is on hold pending the approval of the University of Oxford as a processing organisation. Any resultant publication will be open access. It is anticipated that there would be a press release from Cancer Research UK and the University of Birmingham associated with the publication of this paper.

Further publications in peer reviewed journals are also planned on long term toxicity and survival from the aTTom-Extended protocol.

A lay version of the findings from aTTom and aTTom-Extended will be made available on the Cancer Research UK aTTom website and on the CRCTU aTTom/aTTom Extended website.

The output from the analysis of the translational work (Trans-aTTom) in conjunction with the clinical outcome data will be presented and published separately. These results are of great clinical interest and irrespective of the findings are likely to be accepted for publication in a high impact oncology journal. The University of Birmingham would be targeting a presentation at the American Society of Clinical Oncology and publication in the Journal of Clinical Oncology or Lancet Oncology. Positive results from this study will be practice changing and generate a high level of interest Internationally.

The findings from these studies are expected to be practice changing.

All outputs will contain only data that is aggregated in line with the HES Analysis Guide.

Tamoxifen is still in widespread use and is saving thousands of lives world-wide. The aTTom trial has shown that taking tamoxifen for 10 years is more effective than taking tamoxifen for 5 years. Many women are now being advised to take tamoxifen for 10 years. Tamoxifen can often lead to side effects such as hot flushes. Putting up with these for 10 years can be quite a burden for some patients. Rare but serious side effects from tamoxifen include an increased risk of endometrial cancer (cancer of the womb lining). The aTTom-Extended study was recommended by the Medicines and Healthcare products Regulatory Agency to continue the long term follow up of patients enrolled into this study.

No benefits have yet been yielded as a result of the aTTom-Extended study.

Background Information:

Breast cancer is the most common female cancer. In the 1990’s 5-years of tamoxifen treatment was the standard but there was uncertainty as to whether tamoxifen should be given for longer. The aTTom (Adjuvant Tamoxifen Treatment - Offer -More?) trial, which commenced in 1991, was designed to determine if giving tamoxifen for longer than 5 years was beneficial. aTTom is a clinical trial of an investigational medicinal product and falls under the clinical trials regulations for medicinal products.

A preliminary analysis of aTTom has been presented but not yet published this has shown that extending taxoxifen beyond 5 years reduces breast cancer events the impact on survival was less clear. There was a small but significant increased risk of endometrial cancer with longer tamoxifen.

The original 10-year follow-up period for the aTTom trial patients was reached in October 2015. However long-term toxicity remains a concern and continued follow-up of these patients is vital to determine the full impact of extended tamoxifen on breast cancer specific and overall survival. To this end (and following the recommendations of the Medicines and Healthcare products Regulatory Agency) approval (research ethics and CAG approval) has been sought for a follow-on study called aTTom-Extended (Extended follow-up of patients enrolled in the aTTom trial). aTTom-Extended falls outside of the remit of clinical trials governing medicinal products. aTTom-Extended will continue to follow-up the aTTom patients for an additional 10 years (REC specified end date December 2027).

Data Controller:

The University of Birmingham is the Data Controller. The University of Birmingham requires mortality data and data on any new cancer registrations relating to the cohort for use in the aTTom/aTTom-Extended studies for the purpose described below.

Organisations Involved:

aTTom and aTTom-Extended are sponsored (in accordance with the UK Policy Framework for Health and Social Care Research) by the University of Birmingham which is also the Data Controller. The Chief Investigator is based at the University of Birmingham. The CRCTU is one of two trials units within the University of Birmingham the other being the Birmingham Clinical Trials Unit (BCTU) which is responsible for the analysis (processing) of aTTom (performed by the Trial Statistician). The statistical lead moved from the University of Birmingham to the University of Oxford in September 2010. The statistical lead retains an honorary contract with the University of Birmingham. The University of Birmingham has signed a formal contractual agreement with the University of Oxford to enable them to process data on behalf of the University of Birmingham. Under this Agreement, the University of Oxford will be authorised to process data on behalf of and for the purposes determined by the University of Birmingham.

Information about patients with breast cancer who took part in the aTTom trial was collected from NHS organisations (oncology hospitals and General Practitioners) in compliance with the clinical trials regulations, this included patient identifiers and medical information about the patients breast cancer diagnosis and treatment in addition to date and cause of death (where known). This data was collected on a Case Report Form (CRF) and supplied to the CRCTU, University of Birmingham where it was entered onto the trial database. Data from NHS Digital is also supplied to the CRCTU, University of Birmingham and date and cause of death entered into the same trial database.

Ethics and Office of National Statistics (ONS) approval was granted in January 2015 to send the date and cause of death to the NHS organisation treating the patient to clarify discrepancies in the data supplied by the NHS organisation and to request additional information about site and date of recurrence of the patients breast cancer. This practice will come to an end when the aTTom trial is closed with participating NHS organisations which is now planned for end-2019. Other than this exception, access to data supplied by NHS Digital will be restricted to individuals, working under appropriate supervision on behalf of the University of Birmingham, who are subject to the same policies, procedures and sanctions as substantive employees of this organisation and to substantive employees of the University of Oxford under the terms of the contract between the University of Birmingham and the University of Oxford.

A sub-study within the aTTom-Extended trial, called Trans-aTTom, involves the collection and analysis of tissue samples. This ethically approved work is being undertaken in collaboration with the Biomarkers and Companion Diagnostics Group, University of Edinburgh (tissue sample collection and preparation of digital images and micro-arrays); Biotheranostics, Inc. (diagnostic assay, quality assurance, analysis of anonymise data); and Massachusetts General Hospital (conventional biomarker and pathology quality assurance assessment). For the avoidance of doubt none of these organisations will have access to the data provided by NHS Digital or patient identifiable data from any other source.

The University of Birmingham, and the University of Oxford, are undertaking this work to improve the care of patients with breast cancer not only in the UK but worldwide. Breast cancer is the most common female cancer, with over 45,000 new patients diagnosed in the UK per annum and 1.1 million worldwide. Five years of tamoxifen treatment remains the standard of care for many women worldwide with oestrogen receptor positive breast cancer but there remains uncertainty as to whether tamoxifen should be given for longer. Ultimately this work could save the lives of thousands of women per annum. The continued provision of date and cause of death is vital to this goal.

Aims of the Work:

The objective of the aTTom trial is to determine if treating women with oestrogen receptor positive breast cancer with adjuvant tamoxifen treatment for an additional 5 years above the current standard of care is better in terms of disease-free survival, overall survival and late toxicity. The original trial was funded to follow aTTom patients annually for at least 10 years after recruitment. This time point has now been met and preliminary analyses performed. However, it is clear that later events in terms of breast cancer outcome and toxicity will impact on the assessment of clinical utility and further follow up data is required. This will be addressed by continued collection of survival and cause of death data (from NHS Digital and the National Records of Scotland; NRS) as part of aTTom-Extended.

The aTTom-Extended protocol also includes a proposal to retrospectively collect tissue samples, collected for diagnostic purposes during the patients’ initial surgery for breast cancer, and stored in hospital pathology archives. These tissue samples will be subjected to laboratory analyses to determine molecular characterisation of the tumours. More specifically the samples will be characterised using a validated multiparametic analysis “the breast cancer index” which is capable of predicting risk of late relapse from breast cancer. The researchers are also interested in determining if this biomarker which incorporates molecular characterisation (the so-called H/I index) is capable of providing predictive information in relation to prevention of late relapse after prior tamoxifen. If this is the case the test could be used to help define who will and who will not benefit from extended tamoxifen therapy. This work forms a sub-study of the aTTom-Extended protocol and is called Trans-aTTom.

Under this Agreement, use of the data for the purpose of Trans-aTTom is not permitted. If there is a requirement to use the data covered under this Agreement for the purpose of Trans-aTTom, the University of Birmingham must apply to amend this Agreement and enter into a formal Agreement permitting the relevant processing activities before the data can be used for such purposes.

Other Relevant Background:

Multicentre research ethical approval for the original aTTom trial was granted in February 1998. Ethical approval for the aTTom-Extended protocol, which includes the collection and analysis of tissue samples as part of the Trans-aTTom sub-study, was granted in July 2016.

The aTTom trial randomised 8863 women from 178 UK hospitals between July 1991 and March 2005. Data has been received from NHS Digital since its conception in the mid-1990s. The overall objectives for aTTom (and latterly aTTom-Extended) have remained the same.

The aTTom trial has been funded by a number of organisations over the years including the Medical Research Council and more recently Cancer Research UK. The collection of tissue blocks for the Trans-aTTom sub-study has recently been funded by Biotheranostics Inc.

Date and cause of death are required from NHS Digital in order to perform Kaplan-Meier disease-free and overall survival analyses for the aTTom/aTTom-Extended trials and to determine other potential causes of death (e.g. endometrial cancer). For aTTom this data was collected to provide missing data for patients taking part in the trial who were no longer seen by a medical practitioner or were lost to follow-up for the purposes of the trial. For aTTom-Extended data provided by NHS Digital/NRS will be the only source of data for these analyses.

Patient and Public Involvement:

The aTTom clinical trial started in 1991 when there was no formal requirement to have patient involvement with a clinical trial. The process differs substantially today and patient engagement is a key aspect of both the aTTom-Extended and Trans-aTTom sub-study. In both cases patient representatives from Independent Cancer Patient Voice (ICPV) are integral members of the Trial Management Group and are involved in both the design and execution of the studies.

In addition, a patient consultation group was held at the Wellcome Trust Clinical Research facility on Thursday 14th June 2018. It was attended by the researchers and five patient advocates representing the patient groups ICPV, Breast Cancer Care and Challenge Breast Cancer Scotland. The meeting was chaired by an independent facilitator from the University of Edinburgh’s public engagement department. A short presentation was given covering the background of and the methodology of the project, with particular attention paid to the use of data. A lengthy discussion was had around the following points:

• The proposed access to and use of patient data

• The value of the research to future patients in relation to data risks

• The proposed funding of the collection of tissue blocks as part of the Trans-aTTom sub-study

• The international nature of the Trans-aTTom sub-study collaboration

The consensus from all the patient advocates was that the proposed research had significant value to patients and far outweighed the theoretical risk to patient data. They felt comfortable with the use of data and the restrictions in place by the applicants. Comments from the participants included it was a “no brainer that the benefit outweighed the data risks”. They felt the Breast Cancer Index incorporating the H/I ratio test would enable patients to have more involvement in their treatment decision making process with their oncologists. Some of the patients, having experienced the side effects from tamoxifen, felt that this project could help spare the next generation of breast cancer patients of having to undergo potentially unnecessary side effects from tamoxifen treatment.

The outputs produced for aTTom to date include presentation of the preliminary results of the trial at the American Society for Clinical Oncology (ASCO) (Journal of Clinical Oncology 31, No.18 Suppl: 5-5) and at the European Society for Medical Oncology (ESMO) (European Journal of Cancer 49, Suppl 2, S1-S1028) in 2103. The results were presented as plenary presentations at these auspicious oncology meeting. The results demonstrated a relapse-free survival benefit for extended tamoxifen treatment. However an increase in endometrial cancer was also reported. This work has yet to be published as further follow up for overall and breast cancer specific survival was needed prior to publication and there have been subsequent delays caused by issues with ONS data access.

The intent is to publish this work in the Lancet Oncology (a high impact peer review journal) as soon as possible. A draft publication has been written but further analysis is on hold pending the approval of the University of Oxford as a processing organisation. Any resultant publication will be open access. It is anticipated that there would be a press release from Cancer Research UK and the University of Birmingham associated with the publication of this paper.

Further publications in peer reviewed journals are also planned on long term toxicity and survival from the aTTom-Extended protocol.

A lay version of the findings from aTTom and aTTom-Extended will be made available on the Cancer Research UK aTTom website and on the CRCTU aTTom/aTTom Extended website.

The findings from these studies are expected to be practice changing.

All outputs will contain only data that is aggregated in line with the HES Analysis Guide.

Tamoxifen is still in widespread use and is saving thousands of lives world-wide. The aTTom trial has shown that taking tamoxifen for 10 years is more effective than taking tamoxifen for 5 years. Many women are now being advised to take tamoxifen for 10 years. Tamoxifen can often lead to side effects such as hot flushes. Putting up with these for 10 years can be quite a burden for some patients. Rare but serious side effects from tamoxifen include an increased risk of endometrial cancer (cancer of the womb lining). The aTTom-Extended study was recommended by the Medicines and Healthcare products Regulatory Agency to continue the long term follow up of patients enrolled into this study.

No benefits have yet been yielded as a result of the aTTom-Extended study.