Project to Help Improve Decision Aids for Predicting Outcomes in Early Breast Cancer: (ODR1718_390)

The University of Oxford requires access to NHS England data for the purpose of the following research programme: Project to Help Improve Decision Aids for Predicting Outcomes in Early Breast Cancer.

Female invasive breast cancer is the commonest cancer in England, with over 40,000 new cases diagnosed and nearly 10,000 deaths each year. Invasive breast cancer is a long drawn out disease, and the risk of recurrence or death from breast cancer continues for at least 20 years after diagnosis. Most patients have early stage disease and receive surgery as their first treatment. Outcomes following treatment for early invasive breast cancer differ substantially across different countries and across different patient characteristics within a country. Patients diagnosed with breast cancer and the clinicians who treat them need estimates of their likely prognosis to inform treatment decisions, follow-up, and prediction of event rates for groups of patients in clinical trials. They also need estimates of the risks of diseases other than breast cancer. These estimates require large-scale, population-based studies that consider the effects of multiple patient and tumour factors on the risks of recurrence of breast cancer, of death from breast cancer and of the incidence and mortality of other diseases. It is known that survival from breast cancer has improved and that incidence and mortality of other diseases has changed. However, detailed estimates based on patients treated recently are not currently available. These estimates are needed to enable clinicians to estimate prognosis for patients treated today using characteristics such as age, tumour size, nodal status, grade, receptor status and screening status.

The objectives of this project are as follows:

1. To describe the incidence of second cancers among women diagnosed with breast cancer according to the characteristics of both patients and their tumours, and to assess the extent to which this has changed with calendar year of diagnosis and how it varies with time since diagnosis.

2. To describe patterns of breast cancer mortality and of mortality from other causes according to the characteristics of both patients and their tumours, and to assess the extent to which this mortality has changed with calendar year of diagnosis and how it varies with time since diagnosis.

3. To describe the incidence of other diseases among women diagnosed with breast cancer according to the characteristics of both patients and their tumours, and to assess the extent to which this mortality has changed with calendar year of diagnosis and how it varies with time since diagnosis.

4. To provide predictions of the absolute magnitude of the likely benefits and risks of the various treatment options available for patients diagnosed recently, making them relevant to patients diagnosed today.

5. To provide estimate of the risk of developing a recurrence of breast cancer from routinely collected data, using methods derived in a separate project (ODR1718_364) which is being carried out in conjunction with NDRS staff.

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

The expected outputs of the processing will be:

• A series of peer-reviewed publications reporting the analyses of the data from the NDRS on outcomes in breast cancer patients, and on the development and validation of the prediction models. These are listed below with their current target dates:

• The first publication appeared in the journal Clinical Oncology in 2020 that provided estimates of the proportion of women receiving adjuvant breast cancer radiotherapy who would be eligible for partial breast radiotherapy according to both the NICE guidelines and the Royal College of Radiologists Consensus Statement. A second publication has been accepted by the British Medical Journal (BMJ) and will be published in June 2023.

• A paper describing a population based observational cohort study of breast cancer mortality in 500,000 women diagnosed with early invasive breast cancer in England, 1993-2015 has been accepted for publication in the British Medical Journal (BMJ). These findings:

• A manuscript describing the ability of Ki67 (a marker of cell proliferation which is available from routinely collected pathology reports) to improve prediction of mortality from breast cancer has been prepared and will be submitted for publication shortly. It is expected that this will be completed early in 2024.

• An analysis of the incidence of and mortality from other cancers in women diagnosed with breast cancer. It is expected that this will be completed in 2024

• An analysis of mortality from non-cancer diseases in women diagnosed with breast cancer. It is expected that this will be completed in 2024.

• An analysis of the incidence of non-cancer diseases in women diagnosed with breast cancer. It is expected that this will be completed in 2024.

• Finally, when the algorithm to identify recurrences in women with early breast cancer is ready, analyses of patterns of recurrence in women diagnosed with early breast cancer will be prepared and submitted to peer-reviewed journals. It is expected that this will be completed in 2025.

• Presentations will be made at conferences relating to breast cancer and other meetings to publicise the work.

• Periodic updates will be published to incorporate additional follow-up on women already diagnosed with breast cancer, information on women recently diagnosed with breast cancer, and appropriate improvements to the model.

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

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

• Journals

• Social media (e.g. press releases)

• Public reports (all journal publications are accessible by the public)

• Briefing documents provided to clinicians [details to be decided]

• Open source frameworks [it is planned that, when all are satisfied with its performance, the source code for identifying recurrences will be available within NCRAS for use by NCRAS staff and other researchers]

• Oral presentations and poster displays at conferences

• Patient Information leaflets [results will form the basis of revised patient information leaflets]

• Press/media engagement

• Public promotion of the research [e.g. via press/media engagement]

Data for this study has previously been shared when the data were controlled and managed by Public Health England (PHE). As such there are some yielded benefits to be observed from the access to the data for the study prior to NHS England becoming data controller. These yielded benefits are noted below:

The manuscripts cited in the outputs have proved helpful in planning resources needed for radiotherapy and are hoped will influence clinical practice and guidelines.

This research work has already changed clinical practice. In breast cancer where The University of Oxford have provided clinicians with information on the benefits and risks of various treatment options. This allows them to make informed choices about which treatments to recommend to individual patients.

Studies derived from this research have been primary references in each of the major international guidelines for the management of breast cancer including those produced by the National Institute for Health and Care Excellence (NICE)1,2 the Scottish Intercollegiate Guidelines Network (SIGN),32 the UK’s Royal College of Radiologists (RCR),4 the American National Comprehensive Cancer Network (NCCN),5 the Japan Breast Cancer Society,6 and the joint American Society of Clinical Oncology/American Society for Radiation Oncology/Society for Surgical Oncology (ASCO/ASTRO/SSO).7

The results of this research are essential in treatment decisions, so they are used in training oncologists and related health care professionals. For example, results have been presented annually at the European Society of Therapeutic Radiation Oncology teaching course since 2009 and at the 4-yearly National Cancer Institute Radiation Epidemiology Dosimetry course.

The University of Oxford requires access to NHS England data for the purpose of the following research programme: Project to Help Improve Decision Aids for Predicting Outcomes in Early Breast Cancer.

Female invasive breast cancer is the commonest cancer in England, with over 40,000 new cases diagnosed and nearly 10,000 deaths each year. Invasive breast cancer is a long drawn out disease, and the risk of recurrence or death from breast cancer continues for at least 20 years after diagnosis. Most patients have early stage disease and receive surgery as their first treatment. Outcomes following treatment for early invasive breast cancer differ substantially across different countries and across different patient characteristics within a country. Patients diagnosed with breast cancer and the clinicians who treat them need estimates of their likely prognosis to inform treatment decisions, follow-up, and prediction of event rates for groups of patients in clinical trials. They also need estimates of the risks of diseases other than breast cancer. These estimates require large-scale, population-based studies that consider the effects of multiple patient and tumour factors on the risks of recurrence of breast cancer, of death from breast cancer and of the incidence and mortality of other diseases. It is known that survival from breast cancer has improved and that incidence and mortality of other diseases has changed. However, detailed estimates based on patients treated recently are not currently available. These estimates are needed to enable clinicians to estimate prognosis for patients treated today using characteristics such as age, tumour size, nodal status, grade, receptor status and screening status.

The objectives of this project are as follows:

1. To describe the incidence of second cancers among women diagnosed with breast cancer according to the characteristics of both patients and their tumours, and to assess the extent to which this has changed with calendar year of diagnosis and how it varies with time since diagnosis.

2. To describe patterns of breast cancer mortality and of mortality from other causes according to the characteristics of both patients and their tumours, and to assess the extent to which this mortality has changed with calendar year of diagnosis and how it varies with time since diagnosis.

3. To describe the incidence of other diseases among women diagnosed with breast cancer according to the characteristics of both patients and their tumours, and to assess the extent to which this mortality has changed with calendar year of diagnosis and how it varies with time since diagnosis.

4. To provide predictions of the absolute magnitude of the likely benefits and risks of the various treatment options available for patients diagnosed recently, making them relevant to patients diagnosed today.

5. To provide estimate of the risk of developing a recurrence of breast cancer from routinely collected data, using methods derived in a separate project (ODR1718_364) which is being carried out in conjunction with NDRS staff.

To achieve objective 1 The University of Oxford would like to receive updated versions of two files previously disseminated under Public Health England (PHE). These involve providing data on cancer registrations up to the end of 2020 for patients already in the study. In addition, The University of Oxford received information on the potential prognostic factor Ki67.

To achieve objectives 2-5 The University of Oxford would like to receive the information summarised below and additionally, would like to receive information on the prognostic factor Ki67. This information will be supplied using new pseudo_ids. However, The University of Oxford would like to receive a file linking the old pseudo_ids with the new pseudo_ids for those patients who are in the existing cohort. It is important for the fulfilment of objectives 2-5 that The university of Oxford receive information on patients diagnosed since 2017. As recently shown (BMJ2023;381:e074684), the breast cancer mortality rate increases rapidly during the first two years after initial diagnosis and reaches a peak during the third year. The study team have also shown that mortality rates at any given time after diagnosis have been changing rapidly in recent years. Therefore additional patients diagnosed since 2017 is required in order to be able to provide estimates that are relevant for patients who are being diagnosed now. The study team also need information on patients diagnosed recently to estimate the risk of developing a recurrence, partly in order to provide up-to-date estimates but also in order to make use of recent developments in data capture and storage by NDRS.

To achieve objectives 2-5, the following NHS England data will be accessed:

• National Disease Registration Service (NDRS) Cancer Registration

• National Disease Registration Service (NDRS) Hospital Episode Statistics

- Admitted Patient Care

- Outpatients

- Accident & Emergency

• National Disease Registration Service (NDRS) National Radiotherapy (RTDS)

• National Disease Registration Service (NDRS) Systemic Anti Cancer (SACT)

• National Disease Registration Service (NDRS) Cancer Wait Times (CWT)

• National Disease Registration Service (NDRS) Diagnostic Imaging Dataset (DIDs)

• National Disease Registration Service (NDRS) Cancer Pathway (CWT)

The quantum of Data requested is necessary to achieve the objectives of this project.

The level of the data will be Pseudonymised and will be minimised as follows

• Limited to data for a study cohort identified by NHS England

• Limited to data between 1 Jan 1971 – latest available

• Limited to conditions relevant to the study identified by specific ICD codes for invasive breast cancer ICD10:

C50x, ICD9: 174X, ICD8: 174X;

• Limited to the following geographic areas [England]

• Women only

The University of Oxford is the research sponsor and the data controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above. Additionally, the study team have taken all steps necessary to ensure that they have all the appropriate institutional ethical support in place from University of Oxford.

The University of Oxford rely on Article 6(1)(e) - the processing is necessary for you to perform a task in the public interest or for your official functions, and the task or function has a clear basis in law. The public interest in this circumstance is research to increase medical knowledge for the benefit of all and to improve public health.

The University of Oxford rely on Article 9(2)(j) - processing is necessary for archiving purposes in public interest, scientific or historical research purposes. The legitimate need for processing special category data under 9(2)(j) is that it adheres to the UK Policy Framework for Health and Social Care Research and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care".

The funding is provided by The University of Oxford and Cancer Research UK via a Programme Grant. Funding is in place until 2027. Cancer Research UK will have no ability to suppress or otherwise limit the publication of findings of this research.

The University of Oxford is the sole data controller and sole data processor.

There are no other organisation(s) involved or accessing the NHS England data, including organisations acting in an advisory capacity or as part of an oversight or steering committee.

Before starting the project, the opinions of oncologists, surgeons, breast cancer groups (e.g. the National Cancer Research Institute Breast Clinical Studies Group and the National Cancer Intelligence Network Breast Site Specific Clinical Reference Group) and consumer representatives (Independent Cancer Patients Voices) were sought in an advisory capacity using questionnaires and at meetings to help inform the objectives of the work.

In line with the National data opt-out policy, opt-outs are not applied because the data is not Confidential Patient Information as defined in section 251(10) and (11) of the National Health Service Act 2006

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

The expected outputs of the processing will be:

• A series of peer-reviewed publications reporting the analyses of the data from the NDRS on outcomes in breast cancer patients, and on the development and validation of the prediction models. These are listed below with their current target dates:

• The first publication appeared in the journal Clinical Oncology in 2020 that provided estimates of the proportion of women receiving adjuvant breast cancer radiotherapy who would be eligible for partial breast radiotherapy according to both the NICE guidelines and the Royal College of Radiologists Consensus Statement. A second publication has been accepted by the British Medical Journal (BMJ) and will be published in June 2023.

A paper describing a population based observational cohort study of breast cancer mortality in 500,000 women diagnosed with early invasive breast cancer in England, 1993-2015 has been accepted for publication in the British Medical Journal (BMJ). These findings:

- A manuscript describing the ability of Ki67 (a marker of cell proliferation which is available from routinely collected pathology reports) to improve prediction of mortality from breast cancer has been prepared and will be submitted for publication shortly. It is expected that this will be completed early in 2024.

• An analysis of the incidence of and mortality from other cancers in women diagnosed with breast cancer. It is expected that this will be completed in 2024

• An analysis of mortality from non-cancer diseases in women diagnosed with breast cancer. It is expected that this will be completed in 2024.

• An analysis of the incidence of non-cancer diseases in women diagnosed with breast cancer. It is expected that this will be completed in 2024.

• Finally, when the algorithm to identify recurrences in women with early breast cancer is ready, analyses of patterns of recurrence in women diagnosed with early breast cancer will be prepared and submitted to peer-reviewed journals. It is expected that this will be completed in 2025.

In addition to the above:

• Presentations will be made at conferences relating to breast cancer and other meetings to publicise the work.

• Periodic updates will be published to incorporate additional follow-up on women already diagnosed with breast cancer, information on women recently diagnosed with breast cancer, and appropriate improvements to the model.

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

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

• Journals

• Social media (e.g. press releases)

• Public reports (all journal publications are accessible by the public)

• Briefing documents provided to clinicians [details to be decided]

• Open source frameworks [it is planned that, when all are satisfied with its performance, the source code for identifying recurrences will be available within NCRAS for use by NCRAS staff and other researchers]

• Oral presentations and poster displays at conferences

• Patient Information leaflets [results will form the basis of revised patient information leaflets]

• Press/media engagement

• Public promotion of the research [e.g. via press/media engagement]

Data for this study has previously been shared when the data were controlled and managed by Public Health England (PHE). As such there are some yielded benefits to be observed from the access to the data for the study prior to NHS England becoming data controller. These yielded benefits are noted below:

The manuscripts cited in the outputs have proved helpful in planning resources needed for radiotherapy and are hoped will influence clinical practice and guidelines.

This research work has already changed clinical practice. In breast cancer where The University of Oxford have provided clinicians with information on the benefits and risks of various treatment options. This allows them to make informed choices about which treatments to recommend to individual patients.

Studies derived from this research have been primary references in each of the major international guidelines for the management of breast cancer including those produced by the National Institute for Health and Care Excellence (NICE)1,2 the Scottish Intercollegiate Guidelines Network (SIGN),32 the UK’s Royal College of Radiologists (RCR),4 the American National Comprehensive Cancer Network (NCCN),5 the Japan Breast Cancer Society,6 and the joint American Society of Clinical Oncology/American Society for Radiation Oncology/Society for Surgical Oncology (ASCO/ASTRO/SSO).7

The results of this research are essential in treatment decisions, so they are used in training oncologists and related health care professionals. For example, results have been presented annually at the European Society of Therapeutic Radiation Oncology teaching course since 2009 and at the 4-yearly National Cancer Institute Radiation Epidemiology Dosimetry course.

References:

1: Early and locally advanced breast cancer: diagnosis and management. [I] Evidence reviews for postmastectomy Radiotherapy. NICE guideline NG101, Evidence reviews. July 2018; https://www.nice.org.uk/guidance/ng101/evidence/evidence-review-i-postmastectomy-radiotherapy-pdf-176567997780

2: Early and locally advanced breast cancer: diagnosis and management. [H] Evidence reviews for breast radiotherapy. NICE guideline NG101, Evidence reviews. July 2018; https://www.nice.org.uk/guidance/ng101/evidence/evidence-review-h-breast-radiotherapy-pdf-4904666613

3: SIGN 134. Treatment of primary breast cancer. A national clinical guideline. September 2013; https://www.sign.ac.uk/assets/sign134.pdf

4: Postoperative radiotherapy for breast cancer: UK consensus statements. November 2016; https://www.rcr.ac.uk/system/files/publication/field_publication_files/bfco2016_breast-consensus-guidelines.pdf

5: National Comprehensive Cancer Network Clinical Practice Guideline in Oncology: Breast cancer Version 5.2020. https://www2.tri-kobe.org/nccn/guideline/breast/english/breast.pdf

6: Komoike Y, Inokuchi M, Toshikazu T, Kaouru K, Goro K, Takehiko S, Hiromitsu J, Noriaki W, Shozo O, Hirofumi M. Japan Breast Cancer Society clinical practice guideline for surgical treatment of breast cancer. Breast Cancer 2015; 22(1): 37-48.

7: Recht A, Comen EA, Fine RE, Fleming GF, Hardenbergh PH, Ho AY, Hudis CA, Hwang ES, Kirshner JJ, Morrow M, Saleron KE, Sledge Jr GW, Solin LJ, Spears PA, Whelan TJ, Somerfield MR, Edge SB. Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update. Practical Radiation Oncology 2016; 6(6): e219-34