Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers
University of Cambridge · Academic
In term In term in the September 2026 edition: the latest version runs to 16 June 2029.
- Reference
- DARS-NIC-302473-K6R0Z
- Current version
- v8.5
- Term of current version
- 17 June 2026 to 16 June 2029
- Start date
- Before 1 October 2018
- Data controller
- Sole Data Controller
- Commercial purposes
- No
- Sublicensing
- No
- Files released to date
- 36
Why the data was released
Objective for processing
BACKGROUND
Germline mutations (a gene change in a body's reproductive cell (egg or sperm) that can be passed down to offspring) in at least thirteen genes are now known to predispose to an increased susceptibility to breast or ovarian cancer. In the context of high-risk families the genes BRCA1 and BRCA2 are by far the most important. Germline BRCA1 mutations confer a high lifetime risk of breast cancer as well as a high risk of ovarian cancer. BRCA2 mutations confer a similarly high risk of breast cancer together with a smaller risk of ovarian cancer. BRCA2 mutation carriers also suffer significantly increased risks of pancreatic and prostate cancer. BRCA2 mutations (and, to a lesser extent, BRCA1 mutations) also cause a smaller increased risk of breast cancer in men. Since the identification of these genes in the mid-1990s, genetic testing for mutations in the genes has been become a major component of clinical cancer genetics.
Management of mutation carriers in families due to BRCA1 and BRCA2 is critically dependent on information derived from epidemiological studies: the age and site-specific risks of cancer for different mutations, the extent of risk modification available through lifestyle changes and/or chemo preventive action and the extent of cancer risk reduction associated with prophylactic surgery (removals of breasts/ovary to prevent risk of cancer). Other areas of major uncertainty are the efficacy of mammographic (breast) and ultrasound screening in gene 4 carriers and the prognosis of breast and ovarian cancer occurring in affected mutation carriers.
The EMBRACE study (http://ccge.medschl.cam.ac.uk/embrace/), led by the University of Cambridge, was established in 1998. It is the largest national prospective study of BRCA1/2 carriers and their relatives, having recruited more than 15,000 individuals, of whom ~5,000 are known female carriers.
The primary aims of this study are:
1. to define a cohort of breast/ovarian cancer gene mutation carriers, and their relatives, identified through clinical genetics centres in the UK, who can be followed prospectively to determine cancer risks and to examine the efficacy of different interventions;
2. to obtain simple epidemiological information, by questionnaire, on affected and unaffected mutation carriers in order to determine lifestyle factors which may modify risk;
3. To collect serial blood samples from participants to evaluate:
a. genetic variants that may modify the risk of cancer
b. blood markers that may be able to detect cancer earlier
A secondary aim is to establish the feasibility of serial cervical sampling to evaluate markers for early detection of ovarian cancer.
The University of Cambridge aims to: (1) continue its register of BRCA1 and BRCA2 families and (2) create a register of families who have a fault in other genes to find out more about their associated cancer type and risk. Participants will be asked to fill in a questionnaire and provide blood samples. Blood samples will be analysed in a laboratory as part of this research. Some of the recruits will be followed up through further questionnaires and for blood samples. Carriers and Non-Carrier members of these families can take part in this study as can those members affected or not affected with cancer.
DATA CONTROLLERSHIP/FUNDING
The University of Cambridge is the sole data controller that also processes the NHS England data disseminated under this Agreement.
EMBRACE is collaborating with the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) (https://cimba.ccge.medschl.cam.ac.uk/) and the International BRCA1/2 Carrier Cohort Study (IBCCS) (http://www.ibccs.nl/) consortia. CIMBA and IBCCS are international consortia of studies with similar designs to the EMBRACE study.
The EMBRACE study team at the University of Cambridge also collaborate in the CRUK funded BrOvEd (Breast and Ovarian Cancer Early Detection) project with the with the CRUK Cambridge Institute (CI) Rosenfeld Group (https://www.cruk.cam.ac.uk/research-groups/rosenfeld-group). This is an internal collaborative project within the University of Cambridge and involves analysis of tumour blood samples. The NHS England data disseminated under this Agreement will not be and has not been used for the purposes of the BrOvEd study.
Collaborating teams, funding organisations and sponsors have not and will not access or process the NHS England data received as part of the EMBRACE study and will not have decision-making responsibility regarding how NHS England data is processed.
The EMBRACE study is funded by Cancer Research UK (CRUK) And has been awarded another grant from Cancer Research UK to continue until at least January 2027. NHS Cambridge University Hospitals (CUH) and the University of Cambridge are joint sponsors.
LEGAL BASIS FOR PROCESSING PERSONAL DATA AND SPECIAL CATEGORIES OF PERSONAL DATA
The University of Cambridge has a legal basis to process personal data and special categories of personal data under the following provisions of the UK General Data Protection Regulation (UK GDPR):
- 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’.
- Article 9 (2)(j) – ‘processing is necessary for achieving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89 (1)’.
This research is in public interest given the large proportion of people who suffer from breast and ovarian cancer. To this end it meets the conditions outlined in Schedule 1 Part 1 (4) of the Data Protection Act 2018.
COHORT
The EMBRACE study is comprised of two cohorts – a retrospective and prospective cohort. The University of Cambridge received section 251 support under the NHS Act 2006 to permit access to NHS number, name, date of birth and address including postcode for the retrospective cohort (approximately 10,300 participants).
Informed patient consent to supply NHS England with individuals’ confidential patient information (NHS number, name, address and date of birth) for linkage with cancer registration and mortality date has been sought as the legal basis to meet the common law duty of confidentiality in respect of the prospective cohort (approximately 5,200 participants).
EMBRACE study participants are: (1) carriers of mutations in the breast and ovarian cancer susceptibility genes identified through clinical genetics centres in the UK; (2) family members from families with mutations who themselves do not carry the mutation (treated as “controls” in certain analyses).
Study participants are recruited via clinics across the UK that identify eligible patients based on the study’s criteria. As these clinics are involved in following up the participants for their own respective purposes, the EMBRACE study team will inform them if a participant has passed away to avoid causing upset to relatives when attempting to make contact. The EMBRACE study team do not pass on the cause of death or the actual date of death. However, the clinics will have access to these data themselves via the NHS tracking system, often before the EMBRACE study team does. When communicating a death, both parties use encrypted identifiers and date of birth.
Prospective Cohort specifically:
Information packs will be sent out by the clinics to those patients identified as eligible (meeting study criteria) by their Genetics Counsellor/Nurse. These potential recruits will also have had the study introduced to them in their clinic consultation. The pack will contain a cover invitation letter, detailed patient information sheet which contains information pertaining to the UK General Data Protection Regulation (UK GDPR) and a consent form.
The informed consent of participants follows Good Clinical Practice (GCP) guidelines (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/good-clinical-practice/).
Consent documentation is completed, signed and returned in the post to the EMBRACE study team. Patients are entitled to withdraw at any point if they no longer want to take part in the study without it affecting the care they receive through the NHS. The local coordinators at each site are responsible for checking the addresses and status of these recruits when the EMBRACE study team at the University of Cambridge want to approach them for follow up.
DATA SUMMARY
The University of Cambridge holds Demographics, Cancer Registration and Civil Registration mortality data. These datasets have been and will continue to be essential to the validity of the study.
The University of Cambridge require the data to be disseminated annually.
Data on cancer occurrence are collected by the EMBRACE study team, at the University of Cambridge, using questionnaires. However, the study design only allows for three follow up questionnaires. The data provided by NHS England allows the University of Cambridge to address the gaps between questionnaires and is the only source of data for the study once a participant has completed their final questionnaire or if a participant does not return follow-up questionnaires (for example if they move and cannot be traced). Without these data, the analysis of the study will be invalid as, for example, individuals may die before being able to return a follow-up questionnaire. In addition, the data from NHS England provides accurate confirmation of the cancer type and diagnosis date, which a participant may not know or remember exactly. Identifiable cancer data is required (cancer registry number) in order to check whether the data is consistent with cancers self-reported by a patient.
The mortality data is necessary in order to evaluate the survival after cancer in carriers, and mortality from other causes of death, both of which are important aims of the study. The University of Cambridge require both date and cause of death. The mortality data also, to a large extent, reduces the risk of the EMBRACE study team attempting to contact deceased participants, which could cause upset to family members. No identifiable fields are required from the Mortality dataset.
Although the main cancers of interest are breast and ovarian, analyses need to take account of other cancers (either prior to the start of the study or after recruitment). Other types of cancers have been shown to have a link with BRCA1/2 mutations, including prostate and pancreatic cancer. The increasing recruitment base combined with additional years of follow up may reveal more associations. As the project aims to evaluate the full spectrum of cancer risks in carriers, it is necessary to analyse the data on all cancers that occur in the cohort - a filter on a particular type of cancer would remove this valuable information.
The study is UK wide although NHS England data is only requested in relation to English and Welsh patients. The genetic mutations in these genes are uncommon and it is therefore necessary to recruit patients from the whole country to provide an adequately powered study. In addition, without using national data, it would not be possible to guarantee that the dataset would be accurately representative of the mutation carriers and hence the results may not be broadly applicable. The data are required for a long period as the project is monitoring cancers that may take many years to manifest.
PATIENT AND PUBLIC INVOLVEMENT
The EMBRACE study used National Institute for Health Research (NIHR) INVOLVE (https://www.invo.org.uk/) to identify people with a history of breast cancer who would be able to review patient leaflets for content, ease of understanding and sensitivity. In total 5 people came forward to read and review the documents; their comments have been incorporated into the EMBRACE study consent documentation. A patient representative has also been involved in the writing of the grant proposal. As the EMBRACE study is an experimental study, a patient delegate will also be invited for feedback on the outputs and outcomes for the study newsletters, once these are available. All participants are always able to communicate with the EMBRACE study team at any time by email and phone if they have any questions they would like to be answered - contact details are available on the EMBRACE study website.
Processing activities
In respect of the retrospective cohort, no additional confidential patient information will be supplied to NHS England under this iteration of the Agreement. In relation to the prospective cohort, as the EMBRACE study team are still recruiting participants to the study, the University of Cambridge will flow NHS number and date of birth plus a unique Study ID assigned to each participant to NHS England for linkage to cancer registration and mortality data. Approximately 5,200 participants have consented to participate in the study so far (for the prospective cohort) and a further ~750 participants are recruited to the EMBRACE study each year. Consent is ongoing and is expected to run until February 2027 inline with funding.
The University of Cambridge requires that NHS England provide an updated file of mortality and cancer registration data for the retrospective cohort of approximately 10,300 participants (for which identifying information has already been supplied) on an annual basis plus a file of linked cancer registration and mortality data on an annual basis for the approx. 5,200 participants already consented to the study and those participants recruited to the study over the previous year.
The linked data is supplied to the University of Cambridge via NHS England’s Secure Electronic File Transfer (SEFT) service and uploaded to the University of Cambridge Clinical School’s Secure Research Computing Platform (SRCP) (previous the Secure Data Hosting Site - SDHS). Using the unique Study ID the University of Cambridge then link the linked NHS England data to the information already stored there.
The SRCP is a distinct area set up to ensure the security of personal identifiable data for studies like the EMBRACE study. Only the EMBRACE study team at the University of Cambridge can access NHS England data and only when onsite, using their own two passwords and their physical ‘Signify’ key, which generates a unique third password every minute. Data is only accessed by individuals within the EMBRACE study team who have authorisation from the Data Manager and Study Principal Investigator to access the data for the purpose(s) described, all of whom are substantive employees of the University of Cambridge. Internet traffic to and from the SRCP is removed.
The downloaded data is stored in a separate folder to the main study database within the SRCP. Cancer data is linked and compared to the information already held using the Study ID supplied to NHS England if corresponding questionnaires are present. This will augment the data collected by the study and increase the number of people in the cancer group, hence reducing analysis bias caused by missing data. Mortality data will be linked periodically to ensure deceased patients are not contacted by the EMBRACE study team for follow up.
None of the collaborating teams or funders listed in this application will have access to or process the NHS England data disseminated. Identifiable cancer registration data can be only accessed by the study data manager. Pseudonymised study data will be available only to EMBRACE study researchers who are substantive employees of the University of Cambridge.
No data covered under this Data Sharing Agreement will be shared with any third parties outside of the University of Cambridge except in the form of aggregated data with small numbers suppressed in line with the HES Analysis Guide. No data will be used for any purpose other than for the EMBRACE study as described here.
Expected output
Results from the EMBRACE study have been and are anticipated to continue to be published in peer-reviewed journals such as the BMJ (British Medical Journal) or the Journal of Clinical Oncology, depending on each journal’s requirements. Multiple publications are expected over the next 1-5 years and beyond subject to funding.
The EMBRACE study has contributed data to 130 publications in high-impact journals, including publications developed through the study team’s collaboration with the IBCCS prospective cohort study and the CIMBA. Due to the continuous nature of the study there will be no final results paper: results will be published once sufficient data have been accrued to allow robust statistical analysis. These analyses include: (1) estimating cancer risks for mutation carriers; (2) estimating risks of second cancers; (3) evaluating the effects of different risk factors on cancer risk in carriers, including genetic modifiers and the role of lifestyle/hormonal risk factors; (4) evaluating the effects of risk-reducing surgery and other interventions on cancer risks and other outcomes; (5) evaluating the role of mammographic density of breast cancer risk; (6) assessing the associations between molecular tumour characteristics of BRCA1/2-associated tumours and prognosis.
All outputs have included and will continue to only include tables in the form of aggregated data with small numbers suppressed in line with the HES Analysis Guide. No record-level data has been or will be disclosed.
Interim reports have been and will continue to be made available to the main funding body (CRUK) on an annual basis. CRUK has a clear interest in the outputs of the study and is able to assist in promoting key papers in the media. Important publications are also highlighted on social media. CRUK cannot influence the outputs of the research or restrict their dissemination.
Results from the EMBRACE study are regularly presented at the UK Cancer Genetics Group (CGG) meetings, which is the national forum to assess and implement new findings of clinical relevance - http://www.ukcgg.org. These meetings have a membership of 350 individuals who comprise clinicians, counsellors and scientists, including all the clinics already involved in the study. The purpose of the CGG is to improve the quality of care patients and their families receive in respect of any condition resulting in hereditary tumours. Having frontline clinicians involved in the study and discussing progress with them directly in this fashion helps ensure findings are communicated effectively within the relevant groups - i.e. the genetic counsellors and by extension their patients. The EMBRACE study results are also presented in other national and international meetings e.g. the biannual BRCA symposium (https://brcasymposium.ca), the key international meeting in the field of hereditary breast and ovarian cancer, which attracts clinicians, researchers, policy makers and public and patient representatives.
The University of Cambridge lists publications on the EMBRACE study website (https://ccge.medschl.cam.ac.uk/embrace/embrace-study-news/) and produce simplified summaries of the findings for key papers. The University of Cambridge is committed to open access publications and to this end publications are available free of charge. No restrictions are placed on publications and the dissemination of results. The investigators also present the latest findings from the EMBRACE study at open days, held by regional clinical genetics centres across the UK, for BRCA1/2 carriers. The investigators will also work with the EMBRACE study patient and public partners to provide regular updates to EMBRACE study participants through newsletters, and the PPI delegates will be invited for comments and suggestions on the outputs and outcomes once these are available. All participants are always welcome to communicate with the EMBRACE study team by email and phone - details are available on the EMBRACE study website.
The University of Cambridge also disseminate the study at the Cambridge Science Festival, which is a celebration showcasing the leading edge in science, and can attract huge amount visitors every year.
Expected measurable benefits
1. Benefit to the people who have inherited faulty cancer genes
A small number of men and women have inherited faulty genes which means they are at an increased risk of developing certain cancers. Two of these genes are called BRCA1 and BRCA2 and when someone has a fault in these genes they are more likely to develop cancers of the breast, ovary or prostate. Testing for mutations in these genes has been part of clinical genetics practice for a number of years and as such National Institute for Health and Care Excellence (NICE) guidelines include specific screening programmes and some interventional procedures to lower risks for those that have these mutations. The EMBRACE study collects information about people who have inherited faulty cancer genes and the findings may help these people to understand the cancer and disease risk so they can make informed medical decisions about living a healthier lifestyle. The EMBRACE study may also help people to educate other family members about the potential risk.
2. Impact on wider society
The impact of knowing cancer risk at an earlier stage and subsequently making proper risk reduction decisions could filter down to the wider family. Spouses and partners would be reassured, minimising the disruption to family life caused by lengthy treatments and operations. Potentially, it could reduce the strain on the family's finances and the time out for rehabilitation.
Many women choose to continue to work through cancer treatment due to financial reasons or the need to continue with as normal a life as possible. Employers must be flexible and adaptable in accommodating the needs of these employees. However, this does not come without a cost for employers. Productivity may be down due to the need to attend hospital for treatment or for monitoring the disease. Side effects of treatment may also result in a reduction in the number of hours/days worked each week.
Most patients with cancer will also take with them a family member, friend or carer to hospital appointments thus doubling productive workdays lost.
3. Service implications for the NHS and other healthcare providers
The EMBRACE study may help to identify the role of genetic factors in disease occurrence in populations and families and evaluate the effectiveness of health programs and services in improving the population's health generally.
The results from this study may underpin counselling and the management of women with a family history of cancer. The management of individuals with a family history of cancer is a major part of the workload for NHS clinical genetics services. The cancer risk estimates generated by the EMBRACE study may be incorporated into the genetic testing and counselling protocols or recommendations for prevention in the UK and other countries.
The study results hope to guide clinical geneticists and other health professionals in determining the appropriate provision of cancer screening (for example using mammography or MRI), prophylactic surgery or risk reducing medication. For example, the evidence from the study shows that risk reducing surgeries may not be appropriate in women who are relatives of BRCA1/BRCA2 mutation carriers, which conflicts with the approaches in the clinical management of these women. Paper details are available in section 5.d.iii.
As noted in section 5.d.iii, the study results may influence management guidelines such as the NICE guidelines and clinical practice through the counselling offered to carriers. For many areas of interest however (for example providing reliable prospective estimates on the risk of cancers other than breast and ovarian cancer, second cancer risks, the survival from cancer in carriers, long-term health outcomes), longer term follow-up of carriers to study incidence and mortality will be required. Individuals are identified and recruited at a relatively young age but cancer cases and deaths accrue over many years and it is only with long term follow-up that reliable estimates can be obtained.
In some cases the effects on healthcare are likely to be rapid (as indicated in section 5.d.iii) where dissemination of the findings to clinical practitioners will have an immediate effect on practice, though surveys would be required to monitor the extent of the change in behaviour. In the case of SNPs and Polygenic Risk Score (PRS) modifiers, ongoing studies are evaluating the acceptability and impact of SNP testing in carriers, so the impact on healthcare is likely to take longer. SNPs are the most common type of genetic variation among people, most commonly they can act as biological markers, helping to locate genes that are associated with disease.
In other cases, for example considering the risks of other cancers, any impact is likely to be long term and will require consideration of data from multiple studies. Similarly, the effect of lifestyle or genetic factors on cancer or non-cancer and mortality in carriers will take many years to evaluate. Examples of this are the long-term effects of risk-reducing oophorectomy (surgical procedure to remove one or both ovaries) and risk reducing medication such as tamoxifen. The outcomes of these analyses could have major implications to health provision in this population.
Benefits reported so far
It is hoped the results from the following papers published in accessible journals will guide clinical geneticists and other health professionals in determining the appropriate provision of cancer screening (for example using mammography or MRI), prophylactic surgery or risk reducing medication.
The EMBRACE study team at the University of Cambridge has made major contributions to several published papers with implications for the clinical management of BRCA1/2 carriers:
A JAMA paper (https://jamanetwork.com/journals/jama/fullarticle/2632503) provides the most reliable estimates on cancer risks to women with BRCA1/2 mutations to date.
Two manuscripts in European Urology provided the first prospective estimates of prostate cancer risk for men with mutations (https://pubmed.ncbi.nlm.nih.gov/31495749/; https://www.europeanurology.com/article/S0302-2838(20)30345-6/fulltext) -
A recent retrospective family-based study in the Journal of Clinical Oncology has evaluated the associations of BRCA1/2 mutations with 22 different cancers (other than breast and ovarian) and provided evidence that BRCA1/2 mutations are associated also with male breast cancer, pancreatic cancer and possibly stomach cancers. No evidence of association was found with the other cancers (https://pubmed.ncbi.nlm.nih.gov/35077220/). These cancer risk estimates have been incorporated into the genetic testing and counselling protocols or recommendations for prevention in several countries.
Another paper evaluated the effect of oophorectomy on breast cancer risk in carriers of BRCA1/2 mutations which has impacted clinical practice by altering the advice to women on the uptake and timing of risk reducing oophorectomy (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966793/).
Two parallel papers examined the effect of oral contraceptive use on breast and ovarian cancer risks in carriers (https://pubmed.ncbi.nlm.nih.gov/33493488/; https://pubmed.ncbi.nlm.nih.gov/31360853/). Based on these results a separate paper assessed that the risks and benefits of Oral Contraceptive use in carriers may impact the advice given to women with mutations (https://pubmed.ncbi.nlm.nih.gov/35048954/).
Another important piece of recent work looked at the effect of Single nucleotide polymorphisms (SNPs) (or polygenic risk scores) on the risk of cancer in BRCA1/2 carriers (https://pubmed.ncbi.nlm.nih.gov/28376175/; https://pubmed.ncbi.nlm.nih.gov/32665703/; https://pubmed.ncbi.nlm.nih.gov/34320204/). These may also influence clinical practice as clinicians incorporate SNP testing into genetic counselling. Based on these results, two randomised controlled trials assessing the impact of incorporating SNP testing for carriers on patient and clinical decision making have been set up and are currently ongoing (in the UK, USA and Australia). Results from these trials will allow risk reducing surgery or other interventions to be targeted more effectively at those women at the highest risk.
Finally, the EMBRACE study examined breast and ovarian cancer risks for BRCA1/BRCA2 predictive test negatives (proven non-carriers of the BRCA mutation segregating in their family) and found that they are not at an elevated risk of breast or ovarian cancer (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033314/). There have been conflicting approaches in the clinical management of these women. The results suggest that risk reducing surgeries may not be appropriate in women who are relatives of BRCA1/BRCA2 mutation carriers.
Results across the EMBRACE studies have been incorporated into the genetic testing and counselling protocols or recommendations for prevention in several countries. For example:
• In the UK by NICE (https://www.nice.org.uk/guidance/cg164) and the UK Cancer Genetics Group;
• In the USA by the US National Comprehensive Cancer Network (https://www.nccn.org/guidelines/guidelines-detail?category=2&id=1503) and the US Preventive Services Task Force (https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/breast-cancer-medications-for-risk-reduction);
• In Australia through the eviQ clinical guidelines: Prostate cancer panel testing (https://www.eviq.org.au/cancer-genetics/adult/genetic-testing-using-cancer-gene-panels/3648-prostate-cancer-panel-testing); BRCA1 or BRCA2 risk management;( https://www.eviq.org.au/cancer-genetics/adult/risk-management/3814-brca1-or-brca2-risk-management-female); BRCA1 or BRCA2 risk management (males) ( https://www.eviq.org.au/cancer-genetics/adult/risk-management/656-brca1-or-brca2-risk-management-male#references);
• The European Association of Urology (https://uroweb.org/guidelines/prostate-cancer#3).
Estimates generated by the EMBRACE study have been critical in developing the BRCA1/2 component of the BOADICEA model and CanRisk (https://www.canrisk.org/) tool which is recommended in guidelines including, for example, the Ontario Breast Screening program - https://www.cancercareontario.ca/en/guidelines-advice/cancer-continuum/screening/breast-cancer-high-risk-women) for Breast Cancer (BC) and Epithelial Ovarian Cancer (EOC) risk assessment.
Datasets on the current version
Legal basis for provision: Health and Social Care Act 2012 - s261(5)(d); Health and Social Care Act 2012 – s261(2)(c); National Health Service Act 2006 - s251 - 'Control of patient information'.
| Dataset | Type of data | Sensitivity | Frequency | Confidential data |
|---|---|---|---|---|
| Cancer Registration Data | Identifiable | Sensitive | Ongoing | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 |
| Civil Registrations of Death | Identifiable | Sensitive | Ongoing | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 |
| MRIS - Cause of Death Report | Identifiable | Sensitive | Ongoing | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 |
| MRIS - Cohort Event Notification Report | Identifiable | Sensitive | Ongoing | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 |
| MRIS - Flagging Current Status Report | Identifiable | Sensitive | One-Off | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 |
| MRIS - Members and Postings Report | Identifiable | Sensitive | One-Off | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 |
Files released
Files released counts only files released externally by DARS. Access granted in NHS England's own systems, such as its Secure Data Environment, is not included.
Patient opt-outs were applied to all 36 files released under this agreement, across every version. About opt-outs
Files released against version 8.5 of this agreement, summarised by dataset.
| Dataset | Files | First released | Last released | Opt-outs applied |
|---|---|---|---|---|
| Cancer Registration Data | 1 | July 2026 | July 2026 | Yes |
| Civil Registrations of Death | 1 | July 2026 | July 2026 | Yes |
Version history
The register lists each renewal of this agreement as a separate row. This site has 6 versions — earlier versions existed before this site's records begin.
DARS-NIC-302473-K6R0Z-v8.5 17 June 2026 to 16 June 2029
- Title
- Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers
- Commercial
- No
- Sublicensing
- No
- Datasets
- 6
- Files released
- 2
Datasets: Cancer Registration Data; Civil Registrations of Death; MRIS - Cause of Death Report; MRIS - Cohort Event Notification Report; MRIS - Flagging Current Status Report; MRIS - Members and Postings Report
What changed from DARS-NIC-302473-K6R0Z-v7.2
Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.
| Field | Was | Became |
|---|---|---|
| Start date | 2026-06-17 | |
| End date | 2029-06-16 |
Processing activities
[2 paragraphs unchanged]
The linked data is supplied to the University of Cambridge via NHS
[5 words unchanged]
(SEFT) service and uploaded to the University of Cambridge Clinical School’s Secure
Research Computing Platform (SRCP) (previous the Secure
Data Hosting Site
(SDHS).
- SDHS).
Using the unique Study ID the University of Cambridge then link the linked NHS England data to the information already stored there.
The
SDHS
SRCP
is a distinct area set up to ensure the security of personal
[80 words unchanged]
employees of the University of Cambridge. Internet traffic to and from the
SDHS
SRCP
is
severely limited - for example, an exception had to be applied for to allow access to the NHS England site from within the SDHS.
removed.
The downloaded data is stored in a separate folder to the main study database within the
SDHS.
SRCP.
Cancer data is linked and compared to the information already held using
[48 words unchanged]
patients are not contacted by the EMBRACE study team for follow up.
[2 paragraphs unchanged]
Changed only in punctuation, spacing or capitalisation: Benefits reported.
Unchanged: Objective for processing, Expected output, Expected measurable benefits.
DARS-NIC-302473-K6R0Z-v7.2 30 June 2023 to 14 July 2026
- Title
- Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers
- Commercial
- No
- Sublicensing
- No
- Datasets
- 6
- Files released
- 10
Datasets: Cancer Registration Data; Civil Registrations of Death; MRIS - Cause of Death Report; MRIS - Cohort Event Notification Report; MRIS - Flagging Current Status Report; MRIS - Members and Postings Report
What changed from DARS-NIC-302473-K6R0Z-v6.13
Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.
| Field | Was | Became |
|---|---|---|
| Start date | 2023-06-30 | |
| End date | 2026-07-14 | |
| MRIS - Cause of Death Report: legal basis | Health and Social Care Act 2012 - s261(5)(d); Health and Social Care Act 2012 – s261(2)(c); National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| MRIS - Cohort Event Notification Report: legal basis | Health and Social Care Act 2012 - s261(5)(d); Health and Social Care Act 2012 – s261(2)(c); National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| MRIS - Flagging Current Status Report: legal basis | Health and Social Care Act 2012 - s261(5)(d); Health and Social Care Act 2012 – s261(2)(c); National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| MRIS - Members and Postings Report: legal basis | Health and Social Care Act 2012 - s261(5)(d); Health and Social Care Act 2012 – s261(2)(c); National Health Service Act 2006 - s251 - 'Control of patient information'. |
Unchanged: Objective for processing, Processing activities, Expected output, Expected measurable benefits, Benefits reported.
Objective for processing
BACKGROUND
Germline mutations (a gene change in a body's reproductive cell (egg or sperm) that can be passed down to offspring) in at least thirteen genes are now known to predispose to an increased susceptibility to breast or ovarian cancer. In the context of high-risk families the genes BRCA1 and BRCA2 are by far the most important. Germline BRCA1 mutations confer a high lifetime risk of breast cancer as well as a high risk of ovarian cancer. BRCA2 mutations confer a similarly high risk of breast cancer together with a smaller risk of ovarian cancer. BRCA2 mutation carriers also suffer significantly increased risks of pancreatic and prostate cancer. BRCA2 mutations (and, to a lesser extent, BRCA1 mutations) also cause a smaller increased risk of breast cancer in men. Since the identification of these genes in the mid-1990s, genetic testing for mutations in the genes has been become a major component of clinical cancer genetics.
Management of mutation carriers in families due to BRCA1 and BRCA2 is critically dependent on information derived from epidemiological studies: the age and site-specific risks of cancer for different mutations, the extent of risk modification available through lifestyle changes and/or chemo preventive action and the extent of cancer risk reduction associated with prophylactic surgery (removals of breasts/ovary to prevent risk of cancer). Other areas of major uncertainty are the efficacy of mammographic (breast) and ultrasound screening in gene 4 carriers and the prognosis of breast and ovarian cancer occurring in affected mutation carriers.
The EMBRACE study (http://ccge.medschl.cam.ac.uk/embrace/), led by the University of Cambridge, was established in 1998. It is the largest national prospective study of BRCA1/2 carriers and their relatives, having recruited more than 15,000 individuals, of whom ~5,000 are known female carriers.
The primary aims of this study are:
1. to define a cohort of breast/ovarian cancer gene mutation carriers, and their relatives, identified through clinical genetics centres in the UK, who can be followed prospectively to determine cancer risks and to examine the efficacy of different interventions;
2. to obtain simple epidemiological information, by questionnaire, on affected and unaffected mutation carriers in order to determine lifestyle factors which may modify risk;
3. To collect serial blood samples from participants to evaluate:
a. genetic variants that may modify the risk of cancer
b. blood markers that may be able to detect cancer earlier
A secondary aim is to establish the feasibility of serial cervical sampling to evaluate markers for early detection of ovarian cancer.
The University of Cambridge aims to: (1) continue its register of BRCA1 and BRCA2 families and (2) create a register of families who have a fault in other genes to find out more about their associated cancer type and risk. Participants will be asked to fill in a questionnaire and provide blood samples. Blood samples will be analysed in a laboratory as part of this research. Some of the recruits will be followed up through further questionnaires and for blood samples. Carriers and Non-Carrier members of these families can take part in this study as can those members affected or not affected with cancer.
DATA CONTROLLERSHIP/FUNDING
The University of Cambridge is the sole data controller that also processes the NHS England data disseminated under this Agreement.
EMBRACE is collaborating with the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) (https://cimba.ccge.medschl.cam.ac.uk/) and the International BRCA1/2 Carrier Cohort Study (IBCCS) (http://www.ibccs.nl/) consortia. CIMBA and IBCCS are international consortia of studies with similar designs to the EMBRACE study.
The EMBRACE study team at the University of Cambridge also collaborate in the CRUK funded BrOvEd (Breast and Ovarian Cancer Early Detection) project with the with the CRUK Cambridge Institute (CI) Rosenfeld Group (https://www.cruk.cam.ac.uk/research-groups/rosenfeld-group). This is an internal collaborative project within the University of Cambridge and involves analysis of tumour blood samples. The NHS England data disseminated under this Agreement will not be and has not been used for the purposes of the BrOvEd study.
Collaborating teams, funding organisations and sponsors have not and will not access or process the NHS England data received as part of the EMBRACE study and will not have decision-making responsibility regarding how NHS England data is processed.
The EMBRACE study is funded by Cancer Research UK (CRUK) And has been awarded another grant from Cancer Research UK to continue until at least January 2027. NHS Cambridge University Hospitals (CUH) and the University of Cambridge are joint sponsors.
LEGAL BASIS FOR PROCESSING PERSONAL DATA AND SPECIAL CATEGORIES OF PERSONAL DATA
The University of Cambridge has a legal basis to process personal data and special categories of personal data under the following provisions of the UK General Data Protection Regulation (UK GDPR):
- 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’.
- Article 9 (2)(j) – ‘processing is necessary for achieving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89 (1)’.
This research is in public interest given the large proportion of people who suffer from breast and ovarian cancer. To this end it meets the conditions outlined in Schedule 1 Part 1 (4) of the Data Protection Act 2018.
COHORT
The EMBRACE study is comprised of two cohorts – a retrospective and prospective cohort. The University of Cambridge received section 251 support under the NHS Act 2006 to permit access to NHS number, name, date of birth and address including postcode for the retrospective cohort (approximately 10,300 participants).
Informed patient consent to supply NHS England with individuals’ confidential patient information (NHS number, name, address and date of birth) for linkage with cancer registration and mortality date has been sought as the legal basis to meet the common law duty of confidentiality in respect of the prospective cohort (approximately 5,200 participants).
EMBRACE study participants are: (1) carriers of mutations in the breast and ovarian cancer susceptibility genes identified through clinical genetics centres in the UK; (2) family members from families with mutations who themselves do not carry the mutation (treated as “controls” in certain analyses).
Study participants are recruited via clinics across the UK that identify eligible patients based on the study’s criteria. As these clinics are involved in following up the participants for their own respective purposes, the EMBRACE study team will inform them if a participant has passed away to avoid causing upset to relatives when attempting to make contact. The EMBRACE study team do not pass on the cause of death or the actual date of death. However, the clinics will have access to these data themselves via the NHS tracking system, often before the EMBRACE study team does. When communicating a death, both parties use encrypted identifiers and date of birth.
Prospective Cohort specifically:
Information packs will be sent out by the clinics to those patients identified as eligible (meeting study criteria) by their Genetics Counsellor/Nurse. These potential recruits will also have had the study introduced to them in their clinic consultation. The pack will contain a cover invitation letter, detailed patient information sheet which contains information pertaining to the UK General Data Protection Regulation (UK GDPR) and a consent form.
The informed consent of participants follows Good Clinical Practice (GCP) guidelines (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/good-clinical-practice/).
Consent documentation is completed, signed and returned in the post to the EMBRACE study team. Patients are entitled to withdraw at any point if they no longer want to take part in the study without it affecting the care they receive through the NHS. The local coordinators at each site are responsible for checking the addresses and status of these recruits when the EMBRACE study team at the University of Cambridge want to approach them for follow up.
DATA SUMMARY
The University of Cambridge holds Demographics, Cancer Registration and Civil Registration mortality data. These datasets have been and will continue to be essential to the validity of the study.
The University of Cambridge require the data to be disseminated annually.
Data on cancer occurrence are collected by the EMBRACE study team, at the University of Cambridge, using questionnaires. However, the study design only allows for three follow up questionnaires. The data provided by NHS England allows the University of Cambridge to address the gaps between questionnaires and is the only source of data for the study once a participant has completed their final questionnaire or if a participant does not return follow-up questionnaires (for example if they move and cannot be traced). Without these data, the analysis of the study will be invalid as, for example, individuals may die before being able to return a follow-up questionnaire. In addition, the data from NHS England provides accurate confirmation of the cancer type and diagnosis date, which a participant may not know or remember exactly. Identifiable cancer data is required (cancer registry number) in order to check whether the data is consistent with cancers self-reported by a patient.
The mortality data is necessary in order to evaluate the survival after cancer in carriers, and mortality from other causes of death, both of which are important aims of the study. The University of Cambridge require both date and cause of death. The mortality data also, to a large extent, reduces the risk of the EMBRACE study team attempting to contact deceased participants, which could cause upset to family members. No identifiable fields are required from the Mortality dataset.
Although the main cancers of interest are breast and ovarian, analyses need to take account of other cancers (either prior to the start of the study or after recruitment). Other types of cancers have been shown to have a link with BRCA1/2 mutations, including prostate and pancreatic cancer. The increasing recruitment base combined with additional years of follow up may reveal more associations. As the project aims to evaluate the full spectrum of cancer risks in carriers, it is necessary to analyse the data on all cancers that occur in the cohort - a filter on a particular type of cancer would remove this valuable information.
The study is UK wide although NHS England data is only requested in relation to English and Welsh patients. The genetic mutations in these genes are uncommon and it is therefore necessary to recruit patients from the whole country to provide an adequately powered study. In addition, without using national data, it would not be possible to guarantee that the dataset would be accurately representative of the mutation carriers and hence the results may not be broadly applicable. The data are required for a long period as the project is monitoring cancers that may take many years to manifest.
PATIENT AND PUBLIC INVOLVEMENT
The EMBRACE study used National Institute for Health Research (NIHR) INVOLVE (https://www.invo.org.uk/) to identify people with a history of breast cancer who would be able to review patient leaflets for content, ease of understanding and sensitivity. In total 5 people came forward to read and review the documents; their comments have been incorporated into the EMBRACE study consent documentation. A patient representative has also been involved in the writing of the grant proposal. As the EMBRACE study is an experimental study, a patient delegate will also be invited for feedback on the outputs and outcomes for the study newsletters, once these are available. All participants are always able to communicate with the EMBRACE study team at any time by email and phone if they have any questions they would like to be answered - contact details are available on the EMBRACE study website.
Expected output
Results from the EMBRACE study have been and are anticipated to continue to be published in peer-reviewed journals such as the BMJ (British Medical Journal) or the Journal of Clinical Oncology, depending on each journal’s requirements. Multiple publications are expected over the next 1-5 years and beyond subject to funding.
The EMBRACE study has contributed data to 130 publications in high-impact journals, including publications developed through the study team’s collaboration with the IBCCS prospective cohort study and the CIMBA. Due to the continuous nature of the study there will be no final results paper: results will be published once sufficient data have been accrued to allow robust statistical analysis. These analyses include: (1) estimating cancer risks for mutation carriers; (2) estimating risks of second cancers; (3) evaluating the effects of different risk factors on cancer risk in carriers, including genetic modifiers and the role of lifestyle/hormonal risk factors; (4) evaluating the effects of risk-reducing surgery and other interventions on cancer risks and other outcomes; (5) evaluating the role of mammographic density of breast cancer risk; (6) assessing the associations between molecular tumour characteristics of BRCA1/2-associated tumours and prognosis.
All outputs have included and will continue to only include tables in the form of aggregated data with small numbers suppressed in line with the HES Analysis Guide. No record-level data has been or will be disclosed.
Interim reports have been and will continue to be made available to the main funding body (CRUK) on an annual basis. CRUK has a clear interest in the outputs of the study and is able to assist in promoting key papers in the media. Important publications are also highlighted on social media. CRUK cannot influence the outputs of the research or restrict their dissemination.
Results from the EMBRACE study are regularly presented at the UK Cancer Genetics Group (CGG) meetings, which is the national forum to assess and implement new findings of clinical relevance - http://www.ukcgg.org. These meetings have a membership of 350 individuals who comprise clinicians, counsellors and scientists, including all the clinics already involved in the study. The purpose of the CGG is to improve the quality of care patients and their families receive in respect of any condition resulting in hereditary tumours. Having frontline clinicians involved in the study and discussing progress with them directly in this fashion helps ensure findings are communicated effectively within the relevant groups - i.e. the genetic counsellors and by extension their patients. The EMBRACE study results are also presented in other national and international meetings e.g. the biannual BRCA symposium (https://brcasymposium.ca), the key international meeting in the field of hereditary breast and ovarian cancer, which attracts clinicians, researchers, policy makers and public and patient representatives.
The University of Cambridge lists publications on the EMBRACE study website (https://ccge.medschl.cam.ac.uk/embrace/embrace-study-news/) and produce simplified summaries of the findings for key papers. The University of Cambridge is committed to open access publications and to this end publications are available free of charge. No restrictions are placed on publications and the dissemination of results. The investigators also present the latest findings from the EMBRACE study at open days, held by regional clinical genetics centres across the UK, for BRCA1/2 carriers. The investigators will also work with the EMBRACE study patient and public partners to provide regular updates to EMBRACE study participants through newsletters, and the PPI delegates will be invited for comments and suggestions on the outputs and outcomes once these are available. All participants are always welcome to communicate with the EMBRACE study team by email and phone - details are available on the EMBRACE study website.
The University of Cambridge also disseminate the study at the Cambridge Science Festival, which is a celebration showcasing the leading edge in science, and can attract huge amount visitors every year.
Benefits reported
It is hoped the results from the following papers published in accessible journals will guide clinical geneticists and other health professionals in determining the appropriate provision of cancer screening (for example using mammography or MRI), prophylactic surgery or risk reducing medication.
The EMBRACE study team at the University of Cambridge has made major contributions to several published papers with implications for the clinical management of BRCA1/2 carriers:
A JAMA paper (https://jamanetwork.com/journals/jama/fullarticle/2632503) provides the most reliable estimates on cancer risks to women with BRCA1/2 mutations to date.
Two manuscripts in European Urology provided the first prospective estimates of prostate cancer risk for men with mutations (https://pubmed.ncbi.nlm.nih.gov/31495749/; https://www.europeanurology.com/article/S0302-2838(20)30345-6/fulltext) -
A recent retrospective family-based study in the Journal of Clinical Oncology has evaluated the associations of BRCA1/2 mutations with 22 different cancers (other than breast and ovarian) and provided evidence that BRCA1/2 mutations are associated also with male breast cancer, pancreatic cancer and possibly stomach cancers. No evidence of association was found with the other cancers (https://pubmed.ncbi.nlm.nih.gov/35077220/). These cancer risk estimates have been incorporated into the genetic testing and counselling protocols or recommendations for prevention in several countries.
Another paper evaluated the effect of oophorectomy on breast cancer risk in carriers of BRCA1/2 mutations which has impacted clinical practice by altering the advice to women on the uptake and timing of risk reducing oophorectomy (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966793/).
Two parallel papers examined the effect of oral contraceptive use on breast and ovarian cancer risks in carriers (https://pubmed.ncbi.nlm.nih.gov/33493488/; https://pubmed.ncbi.nlm.nih.gov/31360853/). Based on these results a separate paper assessed that the risks and benefits of Oral Contraceptive use in carriers may impact the advice given to women with mutations (https://pubmed.ncbi.nlm.nih.gov/35048954/).
Another important piece of recent work looked at the effect of Single nucleotide polymorphisms (SNPs) (or polygenic risk scores) on the risk of cancer in BRCA1/2 carriers (https://pubmed.ncbi.nlm.nih.gov/28376175/; https://pubmed.ncbi.nlm.nih.gov/32665703/; https://pubmed.ncbi.nlm.nih.gov/34320204/). These may also influence clinical practice as clinicians incorporate SNP testing into genetic counselling. Based on these results, two randomised controlled trials assessing the impact of incorporating SNP testing for carriers on patient and clinical decision making have been set up and are currently ongoing (in the UK, USA and Australia). Results from these trials will allow risk reducing surgery or other interventions to be targeted more effectively at those women at the highest risk.
Finally, the EMBRACE study examined breast and ovarian cancer risks for BRCA1/BRCA2 predictive test negatives (proven non-carriers of the BRCA mutation segregating in their family) and found that they are not at an elevated risk of breast or ovarian cancer (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033314/). There have been conflicting approaches in the clinical management of these women. The results suggest that risk reducing surgeries may not be appropriate in women who are relatives of BRCA1/BRCA2 mutation carriers.
Results across the EMBRACE studies have been incorporated into the genetic testing and counselling protocols or recommendations for prevention in several countries. For example:
• In the UK by NICE (https://www.nice.org.uk/guidance/cg164) and the UK Cancer Genetics Group;
• In the USA by the US National Comprehensive Cancer Network (https://www.nccn.org/guidelines/guidelines-detail?category=2&id=1503) and the US Preventive Services Task Force (https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/breast-cancer-medications-for-risk-reduction);
• In Australia through the eviQ clinical guidelines: Prostate cancer panel testing (https://www.eviq.org.au/cancer-genetics/adult/genetic-testing-using-cancer-gene-panels/3648-prostate-cancer-panel-testing); BRCA1 or BRCA2 risk management;( https://www.eviq.org.au/cancer-genetics/adult/risk-management/3814-brca1-or-brca2-risk-management-female); BRCA1 or BRCA2 risk management (males) ( https://www.eviq.org.au/cancer-genetics/adult/risk-management/656-brca1-or-brca2-risk-management-male#references);
• The European Association of Urology (https://uroweb.org/guidelines/prostate-cancer#3).
Estimates generated by the EMBRACE study have been critical in developing the BRCA1/2 component of the BOADICEA model and CanRisk (https://www.canrisk.org/) tool which is recommended in guidelines including, for example, the Ontario Breast Screening program - https://www.cancercareontario.ca/en/guidelines-advice/cancer-continuum/screening/breast-cancer-high-risk-women) for Breast Cancer (BC) and Epithelial Ovarian Cancer (EOC) risk assessment.
DARS-NIC-302473-K6R0Z-v6.13 20 February 2023 to 19 February 2026
- Title
- Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers
- Commercial
- No
- Sublicensing
- No
- Datasets
- 6
- Files released
- 2
Datasets: Cancer Registration Data; Civil Registrations of Death; MRIS - Cause of Death Report; MRIS - Cohort Event Notification Report; MRIS - Flagging Current Status Report; MRIS - Members and Postings Report
What changed from DARS-NIC-302473-K6R0Z-v5.1
Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.
| Field | Was | Became |
|---|---|---|
| Start date | 2023-02-20 | |
| End date | 2026-02-19 | |
| Cancer Registration Data: legal basis | Health and Social Care Act 2012 - s261(5)(d); Health and Social Care Act 2012 – s261(2)(c); National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| Cancer Registration Data: common law duty of confidentiality | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 | |
| Civil Registrations of Death: legal basis | Health and Social Care Act 2012 - s261(5)(d); Health and Social Care Act 2012 – s261(2)(c); National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| Civil Registrations of Death: common law duty of confidentiality | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 | |
| MRIS - Cause of Death Report: legal basis | Health and Social Care Act 2012 - s261 - 'Other dissemination of information'; National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| MRIS - Cause of Death Report: common law duty of confidentiality | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 | |
| MRIS - Cohort Event Notification Report: legal basis | Health and Social Care Act 2012 - s261 - 'Other dissemination of information'; National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| MRIS - Cohort Event Notification Report: common law duty of confidentiality | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 | |
| MRIS - Flagging Current Status Report: legal basis | Health and Social Care Act 2012 - s261 - 'Other dissemination of information'; National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| MRIS - Flagging Current Status Report: common law duty of confidentiality | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 | |
| MRIS - Members and Postings Report: legal basis | Health and Social Care Act 2012 - s261 - 'Other dissemination of information'; National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| MRIS - Members and Postings Report: common law duty of confidentiality | Mixture of confidential data flow(s) with consent and flow(s) with support under section 251 NHS Act 2006 |
Datasets:
− Demographics
Objective for processing
The University of Cambridge requires a patient tracking service providing follow up data on cancer incidence and mortality for use in the Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers (EMBRACE).
BACKGROUND
Embrace is a long-running study that initially received MREC approval in 1998 and has been awarded another grant from Cancer Research UK to continue for at least five more years until January 2022. The study’s objectives have increased in scope a little over this time, but the major aim has always been to evaluate the long term cancer incidence and mortality in BRCA1/2 carriers and to examine associations with other risk factors, both environmental and genetic.
Germline mutations (a gene change in a body's reproductive cell (egg or sperm) that can be passed down to offspring) in at least thirteen genes are now known to predispose to an increased susceptibility to breast or ovarian cancer. In the context of high-risk families the genes BRCA1 and BRCA2 are by far the most important. Germline BRCA1 mutations confer a high lifetime risk of breast cancer as well as a high risk of ovarian cancer. BRCA2 mutations confer a similarly high risk of breast cancer together with a smaller risk of ovarian cancer. BRCA2 mutation carriers also suffer significantly increased risks of pancreatic and prostate cancer. BRCA2 mutations (and, to a lesser extent, BRCA1 mutations) also cause a smaller increased risk of breast cancer in men. Since the identification of these genes in the mid-1990s, genetic testing for mutations in the genes has been become a major component of clinical cancer genetics.
Only participants belonging to the retrospective cohort as defined by the study’s section 251 support will be covered by this Agreement.
Management of mutation carriers in families due to BRCA1 and BRCA2 is critically dependent on information derived from epidemiological studies: the age and site-specific risks of cancer for different mutations, the extent of risk modification available through lifestyle changes and/or chemo preventive action and the extent of cancer risk reduction associated with prophylactic surgery (removals of breasts/ovary to prevent risk of cancer). Other areas of major uncertainty are the efficacy of mammographic (breast) and ultrasound screening in gene 4 carriers and the prognosis of breast and ovarian cancer occurring in affected mutation carriers.
Cancer Research UK cannot influence the outputs of the research or restrict their dissemination.
The EMBRACE study (http://ccge.medschl.cam.ac.uk/embrace/), led by the University of Cambridge, was established in 1998. It is the largest national prospective study of BRCA1/2 carriers and their relatives, having recruited more than 15,000 individuals, of whom ~5,000 are known female carriers.
The data on cancer incidence and mortality from NHS Digital has been and will continue to be essential to the validity of the study.
The primary aims of this study are:
• Data on cancer occurrence are collected by the Embrace study team, at the University of Cambridge, using questionnaires. However the study design only allows for three follow up questionnaires. NHS Digital provides information in the long gaps between questionnaires and is the only source of data for the study once a participant has completed their final questionnaire. Without this, the analysis of the study may be invalid as, for example, individuals may die before being able to return a follow-up questionnaire. In addition, the data from NHS Digital provide accurate confirmation of the cancer type and diagnosis date, which a participant may not remember exactly.
1. to define a cohort of breast/ovarian cancer gene mutation carriers, and their relatives, identified through clinical genetics centres in the UK, who can be followed prospectively to determine cancer risks and to examine the efficacy of different interventions;
• The mortality data are necessary in order to evaluate the survival after cancer in carriers, and mortality from other causes of death, both of which are important aims of the study. These require both the date and causes of death (from the death certificate and coded consistently) to be provided. The mortality data also, to a large extent, reduces the risk of the Embrace study team attempting to contact deceased participants, which could cause upset to their family members.
2. to obtain simple epidemiological information, by questionnaire, on affected and unaffected mutation carriers in order to determine lifestyle factors which may modify risk;
The data will not be used for any commercial purposes.
3. To collect serial blood samples from participants to evaluate:
Study participants are recruited via clinics across the UK that identify eligible patients based on the studies criteria. As these clinics are involved in following up with the participants for their own purposes, the Embrace study team will inform them (as they inform the Embrace team) if a participant has passed away to avoid causing upset to relatives when attempting contact. The Embrace team do not pass on the cause of death or the actual date of death. However the clinics will have access to these data themselves via the NHS tracking system, often before the Embrace study team does. When communicating a death both parties use artificial identifiers and Date of Birth.
a. genetic variants that may modify the risk of cancer
The data are required for a long period as the project is monitoring cancers that may take many years to manifest. Additionally the study aims to analyse the long-term survival from cancer and other diseases, and requires continued access to mortality data.
b. blood markers that may be able to detect cancer earlier
The study is UK wide. The genetic mutations in these genes are uncommon and it is therefore necessary to recruit patients from the whole country to provide an adequately powered study. In addition, without using national data, it would not be possible to guarantee that the dataset would be accurately representative of the mutation carriers and hence the results may not be broadly applicable.
A secondary aim is to establish the feasibility of serial cervical sampling to evaluate markers for early detection of ovarian cancer.
Although the main cancers of interest are breast and ovarian certain, analyses need to take account of other cancers (either prior to the start of the study or after recruitment). Other types of cancers have been shown to have a link with BRCA1/2, including prostate and pancreatic cancer. The increasing recruitment base combined with additional years of follow up may reveal more associations. As the project aims to evaluate the full spectrum of cancer risk in carriers, it is necessary to analyse the data on all cancers that occur in the cohort: a filter would remove this valuable information.
The University of Cambridge aims to: (1) continue its register of BRCA1 and BRCA2 families and (2) create a register of families who have a fault in other genes to find out more about their associated cancer type and risk. Participants will be asked to fill in a questionnaire and provide blood samples. Blood samples will be analysed in a laboratory as part of this research. Some of the recruits will be followed up through further questionnaires and for blood samples. Carriers and Non-Carrier members of these families can take part in this study as can those members affected or not affected with cancer.
DATA CONTROLLERSHIP/FUNDING
The University of Cambridge is the sole data controller that also processes the NHS England data disseminated under this Agreement.
EMBRACE is collaborating with the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) (https://cimba.ccge.medschl.cam.ac.uk/) and the International BRCA1/2 Carrier Cohort Study (IBCCS) (http://www.ibccs.nl/) consortia. CIMBA and IBCCS are international consortia of studies with similar designs to the EMBRACE study.
The EMBRACE study team at the University of Cambridge also collaborate in the CRUK funded BrOvEd (Breast and Ovarian Cancer Early Detection) project with the with the CRUK Cambridge Institute (CI) Rosenfeld Group (https://www.cruk.cam.ac.uk/research-groups/rosenfeld-group). This is an internal collaborative project within the University of Cambridge and involves analysis of tumour blood samples. The NHS England data disseminated under this Agreement will not be and has not been used for the purposes of the BrOvEd study.
Collaborating teams, funding organisations and sponsors have not and will not access or process the NHS England data received as part of the EMBRACE study and will not have decision-making responsibility regarding how NHS England data is processed.
The EMBRACE study is funded by Cancer Research UK (CRUK) And has been awarded another grant from Cancer Research UK to continue until at least January 2027. NHS Cambridge University Hospitals (CUH) and the University of Cambridge are joint sponsors.
LEGAL BASIS FOR PROCESSING PERSONAL DATA AND SPECIAL CATEGORIES OF PERSONAL DATA
The University of Cambridge has a legal basis to process personal data and special categories of personal data under the following provisions of the UK General Data Protection Regulation (UK GDPR):
- 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’.
- Article 9 (2)(j) – ‘processing is necessary for achieving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89 (1)’.
This research is in public interest given the large proportion of people who suffer from breast and ovarian cancer. To this end it meets the conditions outlined in Schedule 1 Part 1 (4) of the Data Protection Act 2018.
COHORT
The EMBRACE study is comprised of two cohorts – a retrospective and prospective cohort. The University of Cambridge received section 251 support under the NHS Act 2006 to permit access to NHS number, name, date of birth and address including postcode for the retrospective cohort (approximately 10,300 participants).
Informed patient consent to supply NHS England with individuals’ confidential patient information (NHS number, name, address and date of birth) for linkage with cancer registration and mortality date has been sought as the legal basis to meet the common law duty of confidentiality in respect of the prospective cohort (approximately 5,200 participants).
EMBRACE study participants are: (1) carriers of mutations in the breast and ovarian cancer susceptibility genes identified through clinical genetics centres in the UK; (2) family members from families with mutations who themselves do not carry the mutation (treated as “controls” in certain analyses).
Study participants are recruited via clinics across the UK that identify eligible patients based on the study’s criteria. As these clinics are involved in following up the participants for their own respective purposes, the EMBRACE study team will inform them if a participant has passed away to avoid causing upset to relatives when attempting to make contact. The EMBRACE study team do not pass on the cause of death or the actual date of death. However, the clinics will have access to these data themselves via the NHS tracking system, often before the EMBRACE study team does. When communicating a death, both parties use encrypted identifiers and date of birth.
Prospective Cohort specifically:
Information packs will be sent out by the clinics to those patients identified as eligible (meeting study criteria) by their Genetics Counsellor/Nurse. These potential recruits will also have had the study introduced to them in their clinic consultation. The pack will contain a cover invitation letter, detailed patient information sheet which contains information pertaining to the UK General Data Protection Regulation (UK GDPR) and a consent form.
The informed consent of participants follows Good Clinical Practice (GCP) guidelines (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/good-clinical-practice/).
Consent documentation is completed, signed and returned in the post to the EMBRACE study team. Patients are entitled to withdraw at any point if they no longer want to take part in the study without it affecting the care they receive through the NHS. The local coordinators at each site are responsible for checking the addresses and status of these recruits when the EMBRACE study team at the University of Cambridge want to approach them for follow up.
DATA SUMMARY
The University of Cambridge holds Demographics, Cancer Registration and Civil Registration mortality data. These datasets have been and will continue to be essential to the validity of the study.
The University of Cambridge require the data to be disseminated annually.
Data on cancer occurrence are collected by the EMBRACE study team, at the University of Cambridge, using questionnaires. However, the study design only allows for three follow up questionnaires. The data provided by NHS England allows the University of Cambridge to address the gaps between questionnaires and is the only source of data for the study once a participant has completed their final questionnaire or if a participant does not return follow-up questionnaires (for example if they move and cannot be traced). Without these data, the analysis of the study will be invalid as, for example, individuals may die before being able to return a follow-up questionnaire. In addition, the data from NHS England provides accurate confirmation of the cancer type and diagnosis date, which a participant may not know or remember exactly. Identifiable cancer data is required (cancer registry number) in order to check whether the data is consistent with cancers self-reported by a patient.
The mortality data is necessary in order to evaluate the survival after cancer in carriers, and mortality from other causes of death, both of which are important aims of the study. The University of Cambridge require both date and cause of death. The mortality data also, to a large extent, reduces the risk of the EMBRACE study team attempting to contact deceased participants, which could cause upset to family members. No identifiable fields are required from the Mortality dataset.
Although the main cancers of interest are breast and ovarian, analyses need to take account of other cancers (either prior to the start of the study or after recruitment). Other types of cancers have been shown to have a link with BRCA1/2 mutations, including prostate and pancreatic cancer. The increasing recruitment base combined with additional years of follow up may reveal more associations. As the project aims to evaluate the full spectrum of cancer risks in carriers, it is necessary to analyse the data on all cancers that occur in the cohort - a filter on a particular type of cancer would remove this valuable information.
The study is UK wide although NHS England data is only requested in relation to English and Welsh patients. The genetic mutations in these genes are uncommon and it is therefore necessary to recruit patients from the whole country to provide an adequately powered study. In addition, without using national data, it would not be possible to guarantee that the dataset would be accurately representative of the mutation carriers and hence the results may not be broadly applicable. The data are required for a long period as the project is monitoring cancers that may take many years to manifest.
PATIENT AND PUBLIC INVOLVEMENT
The EMBRACE study used National Institute for Health Research (NIHR) INVOLVE (https://www.invo.org.uk/) to identify people with a history of breast cancer who would be able to review patient leaflets for content, ease of understanding and sensitivity. In total 5 people came forward to read and review the documents; their comments have been incorporated into the EMBRACE study consent documentation. A patient representative has also been involved in the writing of the grant proposal. As the EMBRACE study is an experimental study, a patient delegate will also be invited for feedback on the outputs and outcomes for the study newsletters, once these are available. All participants are always able to communicate with the EMBRACE study team at any time by email and phone if they have any questions they would like to be answered - contact details are available on the EMBRACE study website.
Processing activities
Data are provided to NHS Digital for the purposes of correctly identifying study participants, which allows their incidence and mortality data to be sent to the Embrace study team at the University of Cambridge.
In respect of the retrospective cohort, no additional confidential patient information will be supplied to NHS England under this iteration of the Agreement. In relation to the prospective cohort, as the EMBRACE study team are still recruiting participants to the study, the University of Cambridge will flow NHS number and date of birth plus a unique Study ID assigned to each participant to NHS England for linkage to cancer registration and mortality data. Approximately 5,200 participants have consented to participate in the study so far (for the prospective cohort) and a further ~750 participants are recruited to the EMBRACE study each year. Consent is ongoing and is expected to run until February 2027 inline with funding.
Only participants belonging to the retrospective cohort as defined by the study’s section 251 support will be covered by this Agreement, and as such, no further participant details will need to flow to NHS Digital for this cohort. The University of Cambridge is responsible for ensuring that details of participants recruited subsequently who are not part of the retrospective cohort will not be shared with NHS Digital unless covered by a separate Agreement.
The University of Cambridge requires that NHS England provide an updated file of mortality and cancer registration data for the retrospective cohort of approximately 10,300 participants (for which identifying information has already been supplied) on an annual basis plus a file of linked cancer registration and mortality data on an annual basis for the approx. 5,200 participants already consented to the study and those participants recruited to the study over the previous year.
The data from NHS Digital was downloaded into the Secure Data Hosting System (SDHS) based at the clinical school at the University of Cambridge. This is a distinct area set up to ensure the security of personal identifiable data for studies like Embrace. Only the Embrace study team can access the Embrace data, and only when onsite, using their own two passwords and their physical ‘Signify’ key, which generates a unique third password every minute. Data will only be accessed by individuals within the Embrace study team who have authorisation from the Data Manager and Study Principal Investigator to access the data for the purpose(s) described, all of whom are substantive employees of the University of Cambridge. Internet traffic to and from the SDHS is severely limited, for example, an exception had to be applied for to allow access to the NHS Digital site from within the SDHS.
The linked data is supplied to the University of Cambridge via NHS England’s Secure Electronic File Transfer (SEFT) service and uploaded to the University of Cambridge Clinical School’s Secure Data Hosting Site (SDHS). Using the unique Study ID the University of Cambridge then link the linked NHS England data to the information already stored there.
The downloaded data are linked to the study data using the artificial identifier supplied to NHS Digital. Cancer incidence data are compared to and stored alongside the information already held based on self-reporting, if present. Mortality data are stored separately, but require linking periodically to ensure deceased patients are not contacted by Embrace for follow up.
The SDHS is a distinct area set up to ensure the security of personal identifiable data for studies like the EMBRACE study. Only the EMBRACE study team at the University of Cambridge can access NHS England data and only when onsite, using their own two passwords and their physical ‘Signify’ key, which generates a unique third password every minute. Data is only accessed by individuals within the EMBRACE study team who have authorisation from the Data Manager and Study Principal Investigator to access the data for the purpose(s) described, all of whom are substantive employees of the University of Cambridge. Internet traffic to and from the SDHS is severely limited - for example, an exception had to be applied for to allow access to the NHS England site from within the SDHS.
The downloaded data is stored in a separate folder to the main study database within the SDHS. Cancer data is linked and compared to the information already held using the Study ID supplied to NHS England if corresponding questionnaires are present. This will augment the data collected by the study and increase the number of people in the cancer group, hence reducing analysis bias caused by missing data. Mortality data will be linked periodically to ensure deceased patients are not contacted by the EMBRACE study team for follow up.
None of the collaborating teams or funders listed in this application will have access to or process the NHS England data disseminated. Identifiable cancer registration data can be only accessed by the study data manager. Pseudonymised study data will be available only to EMBRACE study researchers who are substantive employees of the University of Cambridge.
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All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract i.e.: employees, agents and contractors of the Data Recipient who may have access to that data).
Expected output
Results from the Embrace study will be published in peer-reviewed journals. Multiple publications are expected over the next four years, and beyond subject to funding (the study is currently funded until 2022 but further funding will be sought to continue follow-up beyond that date). More than 70 publications to date have used Embrace data. Due to the continuous nature of the study there will be no “final” results paper: results will be published once sufficient data have been accrued to allow robust statistical analysis. In particular, multiple papers are planned over the next 1-3 years that examine the effects of different risk factors on cancer risk in carriers. Later analyses, however, will require a larger dataset with longer follow-up.
Results from the EMBRACE study have been and are anticipated to continue to be published in peer-reviewed journals such as the BMJ (British Medical Journal) or the Journal of Clinical Oncology, depending on each journal’s requirements. Multiple publications are expected over the next 1-5 years and beyond subject to funding.
Interim reports will be made to the main funding body (Cancer Research UK) on an annual basis. Cancer Research UK has a clear interest in the outputs of the study, and is able to assist in promoting key papers in the media. Important publications are also highlighted on social media.
The EMBRACE study has contributed data to 130 publications in high-impact journals, including publications developed through the study team’s collaboration with the IBCCS prospective cohort study and the CIMBA. Due to the continuous nature of the study there will be no final results paper: results will be published once sufficient data have been accrued to allow robust statistical analysis. These analyses include: (1) estimating cancer risks for mutation carriers; (2) estimating risks of second cancers; (3) evaluating the effects of different risk factors on cancer risk in carriers, including genetic modifiers and the role of lifestyle/hormonal risk factors; (4) evaluating the effects of risk-reducing surgery and other interventions on cancer risks and other outcomes; (5) evaluating the role of mammographic density of breast cancer risk; (6) assessing the associations between molecular tumour characteristics of BRCA1/2-associated tumours and prognosis.
Results from the EMBRACE study are regularly presented at the UK Cancer Genetics Group (CGG) meetings, which is the national forum to assess and implement new findings of clinical relevance - http://www.ukcgg.org. These meetings have a membership of 350 made up of clinicians, counsellors and scientists, including all the clinics already involved in the study. New results and future plans are discussed. The purpose of the CGG is to improve the quality of care of patients and their families with any condition resulting in hereditary tumours. Having frontline clinicians involved in the study and discussing progress with them directly in this fashion helps ensure our findings are communicated to the relevant groups i.e. the genetic counsellors and by extension their patients.
All outputs have included and will continue to only include tables in the form of aggregated data with small numbers suppressed in line with the HES Analysis Guide. No record-level data has been or will be disclosed.
The University of Cambridge currently lists some publications on its Embrace study website and will produce simplified summaries of the findings for key papers. The University of Cambridge is committed to open access publications and our publications will be available free of charge. No restrictions are placed on publications and dissemination of results.
Interim reports have been and will continue to be made available to the main funding body (CRUK) on an annual basis. CRUK has a clear interest in the outputs of the study and is able to assist in promoting key papers in the media. Important publications are also highlighted on social media. CRUK cannot influence the outputs of the research or restrict their dissemination.
All outputs will contain only data that are aggregated with small numbers suppressed in line with the HES Analysis Guide.
Results from the EMBRACE study are regularly presented at the UK Cancer Genetics Group (CGG) meetings, which is the national forum to assess and implement new findings of clinical relevance - http://www.ukcgg.org. These meetings have a membership of 350 individuals who comprise clinicians, counsellors and scientists, including all the clinics already involved in the study. The purpose of the CGG is to improve the quality of care patients and their families receive in respect of any condition resulting in hereditary tumours. Having frontline clinicians involved in the study and discussing progress with them directly in this fashion helps ensure findings are communicated effectively within the relevant groups - i.e. the genetic counsellors and by extension their patients. The EMBRACE study results are also presented in other national and international meetings e.g. the biannual BRCA symposium (https://brcasymposium.ca), the key international meeting in the field of hereditary breast and ovarian cancer, which attracts clinicians, researchers, policy makers and public and patient representatives.
The University of Cambridge lists publications on the EMBRACE study website (https://ccge.medschl.cam.ac.uk/embrace/embrace-study-news/) and produce simplified summaries of the findings for key papers. The University of Cambridge is committed to open access publications and to this end publications are available free of charge. No restrictions are placed on publications and the dissemination of results. The investigators also present the latest findings from the EMBRACE study at open days, held by regional clinical genetics centres across the UK, for BRCA1/2 carriers. The investigators will also work with the EMBRACE study patient and public partners to provide regular updates to EMBRACE study participants through newsletters, and the PPI delegates will be invited for comments and suggestions on the outputs and outcomes once these are available. All participants are always welcome to communicate with the EMBRACE study team by email and phone - details are available on the EMBRACE study website.
The University of Cambridge also disseminate the study at the Cambridge Science Festival, which is a celebration showcasing the leading edge in science, and can attract huge amount visitors every year.
Expected measurable benefits
The results from this study underpin counselling and management of women with a family history of cancer. Management of individuals with a family history of cancer is a major part of the workload of NHS clinical genetics services.
1. Benefit to the people who have inherited faulty cancer genes
The results of the research will guide clinical geneticists and other health professionals in determining the appropriate provision of cancer screening (for example using mammography or MRI), prophylactic surgery or risk reducing medication.
A small number of men and women have inherited faulty genes which means they are at an increased risk of developing certain cancers. Two of these genes are called BRCA1 and BRCA2 and when someone has a fault in these genes they are more likely to develop cancers of the breast, ovary or prostate. Testing for mutations in these genes has been part of clinical genetics practice for a number of years and as such National Institute for Health and Care Excellence (NICE) guidelines include specific screening programmes and some interventional procedures to lower risks for those that have these mutations. The EMBRACE study collects information about people who have inherited faulty cancer genes and the findings may help these people to understand the cancer and disease risk so they can make informed medical decisions about living a healthier lifestyle. The EMBRACE study may also help people to educate other family members about the potential risk.
In the last 2 years, Embrace has made major contributions to five recently published or soon to be published, papers. The first is a JAMA paper (Kuchenbaecker KB et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 2017:317(23):2402-2416) that provides the most reliable estimates on cancer risks to women with BRCA1/2 mutations to date.
2. Impact on wider society
The second paper (in preparation) evaluates the effect of oophorectomy on breast cancer risk in carriers of BRCA1/2 mutations. This could change clinical practice by altering the advice to women on the uptake and timing of risk reducing oophorectomy. A parallel paper examines the effect of oral contraceptive use on breast cancer risk in carriers (Schrijver L et al. JNCI Cancer Spectrum). The fourth important piece of recent work looked at the effect of SNPS on the risk of cancer in BRCA1/2 carriers (Kuchenbaecker KB et al. Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers.
The impact of knowing cancer risk at an earlier stage and subsequently making proper risk reduction decisions could filter down to the wider family. Spouses and partners would be reassured, minimising the disruption to family life caused by lengthy treatments and operations. Potentially, it could reduce the strain on the family's finances and the time out for rehabilitation.
JNCI 2017:109(7):djw302). This may also influence clinical practice as clinicians incorporate SNP testing into genetic counselling. Clinical implementation studies to evaluate such testing are currently ongoing. This would allow risk reducing surgery or other interventions to be targeted more effectively at those women at the highest risk. Finally, in the largest study of its kind to date, Embrace examined breast and ovarian cancer risks for BRCA1/BRCA2 predictive test negatives (proven non-carriers of the BRCA mutation segregating in their family) and found that they are not at elevated risk of breast or ovarian cancer. There have been conflicting approaches in the clinical management of these women. The results suggest that risk reducing surgeries may not be appropriate in women who are relatives of BRCA1/BRCA2 mutation carriers.
Many women choose to continue to work through cancer treatment due to financial reasons or the need to continue with as normal a life as possible. Employers must be flexible and adaptable in accommodating the needs of these employees. However, this does not come without a cost for employers. Productivity may be down due to the need to attend hospital for treatment or for monitoring the disease. Side effects of treatment may also result in a reduction in the number of hours/days worked each week.
In some cases the effects on healthcare are likely to be rapid. In the case of the 2nd and 5th paper for example, dissemination of these findings to clinical practitioners will likely have an immediate effect on practice, though surveys would be required to monitor the extent of the change in behaviour. These findings are also likely to alter guidelines on risk management, namely NICE guidelines e.g. CG164 which form the basis of clinical management of familial cancer risk in the UK (and are also used by many other countries). CG164 is used to direct surveillance protocols in the UK. In the case of the 4th paper, further studies will be required to evaluate the acceptability and impact of SNP testing in carriers, so the impact on healthcare is likely to take longer.
Most patients with cancer will also take with them a family member, friend or carer to hospital appointments thus doubling productive workdays lost.
In other cases, for example considering the risks of other cancers, any impact is likely to be long term and will require consideration of data from multiple studies. Similarly, the effect of lifestyle or genetic factors on cancer, or non-cancer, mortality, in carriers, will take many years to evaluate. Examples of this are the long-term effects of risk-reducing oophorectomy and of risk reducing medication such as tamoxifen. The outcomes of these analyses could have major implications to health provision in this population.
3. Service implications for the NHS and other healthcare providers
The Mortality data has also been vital to ensure the Embrace study team does not inadvertently contact deceased participants for follow up questionnaires.
The EMBRACE study may help to identify the role of genetic factors in disease occurrence in populations and families and evaluate the effectiveness of health programs and services in improving the population's health generally.
The results from this study may underpin counselling and the management of women with a family history of cancer. The management of individuals with a family history of cancer is a major part of the workload for NHS clinical genetics services. The cancer risk estimates generated by the EMBRACE study may be incorporated into the genetic testing and counselling protocols or recommendations for prevention in the UK and other countries.
The study results hope to guide clinical geneticists and other health professionals in determining the appropriate provision of cancer screening (for example using mammography or MRI), prophylactic surgery or risk reducing medication. For example, the evidence from the study shows that risk reducing surgeries may not be appropriate in women who are relatives of BRCA1/BRCA2 mutation carriers, which conflicts with the approaches in the clinical management of these women. Paper details are available in section 5.d.iii.
As noted in section 5.d.iii, the study results may influence management guidelines such as the NICE guidelines and clinical practice through the counselling offered to carriers. For many areas of interest however (for example providing reliable prospective estimates on the risk of cancers other than breast and ovarian cancer, second cancer risks, the survival from cancer in carriers, long-term health outcomes), longer term follow-up of carriers to study incidence and mortality will be required. Individuals are identified and recruited at a relatively young age but cancer cases and deaths accrue over many years and it is only with long term follow-up that reliable estimates can be obtained.
In some cases the effects on healthcare are likely to be rapid (as indicated in section 5.d.iii) where dissemination of the findings to clinical practitioners will have an immediate effect on practice, though surveys would be required to monitor the extent of the change in behaviour. In the case of SNPs and Polygenic Risk Score (PRS) modifiers, ongoing studies are evaluating the acceptability and impact of SNP testing in carriers, so the impact on healthcare is likely to take longer. SNPs are the most common type of genetic variation among people, most commonly they can act as biological markers, helping to locate genes that are associated with disease.
In other cases, for example considering the risks of other cancers, any impact is likely to be long term and will require consideration of data from multiple studies. Similarly, the effect of lifestyle or genetic factors on cancer or non-cancer and mortality in carriers will take many years to evaluate. Examples of this are the long-term effects of risk-reducing oophorectomy (surgical procedure to remove one or both ovaries) and risk reducing medication such as tamoxifen. The outcomes of these analyses could have major implications to health provision in this population.
Benefits reported
Some of the publications that have arisen from the Embrace study are indicated above. The Embrace study is helping to provide the most reliable information on the cancer risks in BRCA1 and BRCA2 carriers, and the effects of both genetic and lifestyle factors on these risks. Some of these have been clearly established already, in part using EMBRACE study data. These include the effects of SNPs on cancer risk in carriers (Antoniou et al. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008 Apr;82(4):937-48, Kuchenbaecker KB et al. Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers. JNCI 2017:109(7):djw302) and the effects of oral contraceptive use on ovarian cancer risk in carriers (Antoniou et al, Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study. CEBP 2009:18(2):601-10).
It is hoped the results from the following papers published in accessible journals will guide clinical geneticists and other health professionals in determining the appropriate provision of cancer screening (for example using mammography or MRI), prophylactic surgery or risk reducing medication.
As noted above, these results influence management guidelines such as the NICE guidelines, and clinical practice through the counselling offer to carriers. For many questions, however (for example providing reliable estimates on the risk of cancers other than breast and ovarian cancer, and the survival from cancer in carriers), much longer term follow-up of carriers to study incidence and mortality will be required. Individuals are identified and recruited at a relative young age but cancer cases and deaths accrue over many years, and it is only with long term follow-up that reliable estimates can be obtained.
The EMBRACE study team at the University of Cambridge has made major contributions to several published papers with implications for the clinical management of BRCA1/2 carriers:
A JAMA paper (https://jamanetwork.com/journals/jama/fullarticle/2632503) provides the most reliable estimates on cancer risks to women with BRCA1/2 mutations to date.
Two manuscripts in European Urology provided the first prospective estimates of prostate cancer risk for men with mutations (https://pubmed.ncbi.nlm.nih.gov/31495749/; https://www.europeanurology.com/article/S0302-2838(20)30345-6/fulltext) -
A recent retrospective family-based study in the Journal of Clinical Oncology has evaluated the associations of BRCA1/2 mutations with 22 different cancers (other than breast and ovarian) and provided evidence that BRCA1/2 mutations are associated also with male breast cancer, pancreatic cancer and possibly stomach cancers. No evidence of association was found with the other cancers (https://pubmed.ncbi.nlm.nih.gov/35077220/). These cancer risk estimates have been incorporated into the genetic testing and counselling protocols or recommendations for prevention in several countries.
Another paper evaluated the effect of oophorectomy on breast cancer risk in carriers of BRCA1/2 mutations which has impacted clinical practice by altering the advice to women on the uptake and timing of risk reducing oophorectomy (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966793/).
Two parallel papers examined the effect of oral contraceptive use on breast and ovarian cancer risks in carriers (https://pubmed.ncbi.nlm.nih.gov/33493488/; https://pubmed.ncbi.nlm.nih.gov/31360853/). Based on these results a separate paper assessed that the risks and benefits of Oral Contraceptive use in carriers may impact the advice given to women with mutations (https://pubmed.ncbi.nlm.nih.gov/35048954/).
Another important piece of recent work looked at the effect of Single nucleotide polymorphisms (SNPs) (or polygenic risk scores) on the risk of cancer in BRCA1/2 carriers (https://pubmed.ncbi.nlm.nih.gov/28376175/; https://pubmed.ncbi.nlm.nih.gov/32665703/; https://pubmed.ncbi.nlm.nih.gov/34320204/). These may also influence clinical practice as clinicians incorporate SNP testing into genetic counselling. Based on these results, two randomised controlled trials assessing the impact of incorporating SNP testing for carriers on patient and clinical decision making have been set up and are currently ongoing (in the UK, USA and Australia). Results from these trials will allow risk reducing surgery or other interventions to be targeted more effectively at those women at the highest risk.
Finally, the EMBRACE study examined breast and ovarian cancer risks for BRCA1/BRCA2 predictive test negatives (proven non-carriers of the BRCA mutation segregating in their family) and found that they are not at an elevated risk of breast or ovarian cancer (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033314/). There have been conflicting approaches in the clinical management of these women. The results suggest that risk reducing surgeries may not be appropriate in women who are relatives of BRCA1/BRCA2 mutation carriers.
Results across the EMBRACE studies have been incorporated into the genetic testing and counselling protocols or recommendations for prevention in several countries. For example:
• In the UK by NICE (https://www.nice.org.uk/guidance/cg164) and the UK Cancer Genetics Group;
• In the USA by the US National Comprehensive Cancer Network (https://www.nccn.org/guidelines/guidelines-detail?category=2&id=1503) and the US Preventive Services Task Force (https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/breast-cancer-medications-for-risk-reduction);
• In Australia through the eviQ clinical guidelines: Prostate cancer panel testing (https://www.eviq.org.au/cancer-genetics/adult/genetic-testing-using-cancer-gene-panels/3648-prostate-cancer-panel-testing); BRCA1 or BRCA2 risk management;( https://www.eviq.org.au/cancer-genetics/adult/risk-management/3814-brca1-or-brca2-risk-management-female); BRCA1 or BRCA2 risk management (males) ( https://www.eviq.org.au/cancer-genetics/adult/risk-management/656-brca1-or-brca2-risk-management-male#references);
• The European Association of Urology (https://uroweb.org/guidelines/prostate-cancer#3).
Estimates generated by the EMBRACE study have been critical in developing the BRCA1/2 component of the BOADICEA model and CanRisk (https://www.canrisk.org/) tool which is recommended in guidelines including, for example, the Ontario Breast Screening program - https://www.cancercareontario.ca/en/guidelines-advice/cancer-continuum/screening/breast-cancer-high-risk-women) for Breast Cancer (BC) and Epithelial Ovarian Cancer (EOC) risk assessment.
Objective for processing
BACKGROUND
Germline mutations (a gene change in a body's reproductive cell (egg or sperm) that can be passed down to offspring) in at least thirteen genes are now known to predispose to an increased susceptibility to breast or ovarian cancer. In the context of high-risk families the genes BRCA1 and BRCA2 are by far the most important. Germline BRCA1 mutations confer a high lifetime risk of breast cancer as well as a high risk of ovarian cancer. BRCA2 mutations confer a similarly high risk of breast cancer together with a smaller risk of ovarian cancer. BRCA2 mutation carriers also suffer significantly increased risks of pancreatic and prostate cancer. BRCA2 mutations (and, to a lesser extent, BRCA1 mutations) also cause a smaller increased risk of breast cancer in men. Since the identification of these genes in the mid-1990s, genetic testing for mutations in the genes has been become a major component of clinical cancer genetics.
Management of mutation carriers in families due to BRCA1 and BRCA2 is critically dependent on information derived from epidemiological studies: the age and site-specific risks of cancer for different mutations, the extent of risk modification available through lifestyle changes and/or chemo preventive action and the extent of cancer risk reduction associated with prophylactic surgery (removals of breasts/ovary to prevent risk of cancer). Other areas of major uncertainty are the efficacy of mammographic (breast) and ultrasound screening in gene 4 carriers and the prognosis of breast and ovarian cancer occurring in affected mutation carriers.
The EMBRACE study (http://ccge.medschl.cam.ac.uk/embrace/), led by the University of Cambridge, was established in 1998. It is the largest national prospective study of BRCA1/2 carriers and their relatives, having recruited more than 15,000 individuals, of whom ~5,000 are known female carriers.
The primary aims of this study are:
1. to define a cohort of breast/ovarian cancer gene mutation carriers, and their relatives, identified through clinical genetics centres in the UK, who can be followed prospectively to determine cancer risks and to examine the efficacy of different interventions;
2. to obtain simple epidemiological information, by questionnaire, on affected and unaffected mutation carriers in order to determine lifestyle factors which may modify risk;
3. To collect serial blood samples from participants to evaluate:
a. genetic variants that may modify the risk of cancer
b. blood markers that may be able to detect cancer earlier
A secondary aim is to establish the feasibility of serial cervical sampling to evaluate markers for early detection of ovarian cancer.
The University of Cambridge aims to: (1) continue its register of BRCA1 and BRCA2 families and (2) create a register of families who have a fault in other genes to find out more about their associated cancer type and risk. Participants will be asked to fill in a questionnaire and provide blood samples. Blood samples will be analysed in a laboratory as part of this research. Some of the recruits will be followed up through further questionnaires and for blood samples. Carriers and Non-Carrier members of these families can take part in this study as can those members affected or not affected with cancer.
DATA CONTROLLERSHIP/FUNDING
The University of Cambridge is the sole data controller that also processes the NHS England data disseminated under this Agreement.
EMBRACE is collaborating with the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) (https://cimba.ccge.medschl.cam.ac.uk/) and the International BRCA1/2 Carrier Cohort Study (IBCCS) (http://www.ibccs.nl/) consortia. CIMBA and IBCCS are international consortia of studies with similar designs to the EMBRACE study.
The EMBRACE study team at the University of Cambridge also collaborate in the CRUK funded BrOvEd (Breast and Ovarian Cancer Early Detection) project with the with the CRUK Cambridge Institute (CI) Rosenfeld Group (https://www.cruk.cam.ac.uk/research-groups/rosenfeld-group). This is an internal collaborative project within the University of Cambridge and involves analysis of tumour blood samples. The NHS England data disseminated under this Agreement will not be and has not been used for the purposes of the BrOvEd study.
Collaborating teams, funding organisations and sponsors have not and will not access or process the NHS England data received as part of the EMBRACE study and will not have decision-making responsibility regarding how NHS England data is processed.
The EMBRACE study is funded by Cancer Research UK (CRUK) And has been awarded another grant from Cancer Research UK to continue until at least January 2027. NHS Cambridge University Hospitals (CUH) and the University of Cambridge are joint sponsors.
LEGAL BASIS FOR PROCESSING PERSONAL DATA AND SPECIAL CATEGORIES OF PERSONAL DATA
The University of Cambridge has a legal basis to process personal data and special categories of personal data under the following provisions of the UK General Data Protection Regulation (UK GDPR):
- 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’.
- Article 9 (2)(j) – ‘processing is necessary for achieving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89 (1)’.
This research is in public interest given the large proportion of people who suffer from breast and ovarian cancer. To this end it meets the conditions outlined in Schedule 1 Part 1 (4) of the Data Protection Act 2018.
COHORT
The EMBRACE study is comprised of two cohorts – a retrospective and prospective cohort. The University of Cambridge received section 251 support under the NHS Act 2006 to permit access to NHS number, name, date of birth and address including postcode for the retrospective cohort (approximately 10,300 participants).
Informed patient consent to supply NHS England with individuals’ confidential patient information (NHS number, name, address and date of birth) for linkage with cancer registration and mortality date has been sought as the legal basis to meet the common law duty of confidentiality in respect of the prospective cohort (approximately 5,200 participants).
EMBRACE study participants are: (1) carriers of mutations in the breast and ovarian cancer susceptibility genes identified through clinical genetics centres in the UK; (2) family members from families with mutations who themselves do not carry the mutation (treated as “controls” in certain analyses).
Study participants are recruited via clinics across the UK that identify eligible patients based on the study’s criteria. As these clinics are involved in following up the participants for their own respective purposes, the EMBRACE study team will inform them if a participant has passed away to avoid causing upset to relatives when attempting to make contact. The EMBRACE study team do not pass on the cause of death or the actual date of death. However, the clinics will have access to these data themselves via the NHS tracking system, often before the EMBRACE study team does. When communicating a death, both parties use encrypted identifiers and date of birth.
Prospective Cohort specifically:
Information packs will be sent out by the clinics to those patients identified as eligible (meeting study criteria) by their Genetics Counsellor/Nurse. These potential recruits will also have had the study introduced to them in their clinic consultation. The pack will contain a cover invitation letter, detailed patient information sheet which contains information pertaining to the UK General Data Protection Regulation (UK GDPR) and a consent form.
The informed consent of participants follows Good Clinical Practice (GCP) guidelines (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/good-clinical-practice/).
Consent documentation is completed, signed and returned in the post to the EMBRACE study team. Patients are entitled to withdraw at any point if they no longer want to take part in the study without it affecting the care they receive through the NHS. The local coordinators at each site are responsible for checking the addresses and status of these recruits when the EMBRACE study team at the University of Cambridge want to approach them for follow up.
DATA SUMMARY
The University of Cambridge holds Demographics, Cancer Registration and Civil Registration mortality data. These datasets have been and will continue to be essential to the validity of the study.
The University of Cambridge require the data to be disseminated annually.
Data on cancer occurrence are collected by the EMBRACE study team, at the University of Cambridge, using questionnaires. However, the study design only allows for three follow up questionnaires. The data provided by NHS England allows the University of Cambridge to address the gaps between questionnaires and is the only source of data for the study once a participant has completed their final questionnaire or if a participant does not return follow-up questionnaires (for example if they move and cannot be traced). Without these data, the analysis of the study will be invalid as, for example, individuals may die before being able to return a follow-up questionnaire. In addition, the data from NHS England provides accurate confirmation of the cancer type and diagnosis date, which a participant may not know or remember exactly. Identifiable cancer data is required (cancer registry number) in order to check whether the data is consistent with cancers self-reported by a patient.
The mortality data is necessary in order to evaluate the survival after cancer in carriers, and mortality from other causes of death, both of which are important aims of the study. The University of Cambridge require both date and cause of death. The mortality data also, to a large extent, reduces the risk of the EMBRACE study team attempting to contact deceased participants, which could cause upset to family members. No identifiable fields are required from the Mortality dataset.
Although the main cancers of interest are breast and ovarian, analyses need to take account of other cancers (either prior to the start of the study or after recruitment). Other types of cancers have been shown to have a link with BRCA1/2 mutations, including prostate and pancreatic cancer. The increasing recruitment base combined with additional years of follow up may reveal more associations. As the project aims to evaluate the full spectrum of cancer risks in carriers, it is necessary to analyse the data on all cancers that occur in the cohort - a filter on a particular type of cancer would remove this valuable information.
The study is UK wide although NHS England data is only requested in relation to English and Welsh patients. The genetic mutations in these genes are uncommon and it is therefore necessary to recruit patients from the whole country to provide an adequately powered study. In addition, without using national data, it would not be possible to guarantee that the dataset would be accurately representative of the mutation carriers and hence the results may not be broadly applicable. The data are required for a long period as the project is monitoring cancers that may take many years to manifest.
PATIENT AND PUBLIC INVOLVEMENT
The EMBRACE study used National Institute for Health Research (NIHR) INVOLVE (https://www.invo.org.uk/) to identify people with a history of breast cancer who would be able to review patient leaflets for content, ease of understanding and sensitivity. In total 5 people came forward to read and review the documents; their comments have been incorporated into the EMBRACE study consent documentation. A patient representative has also been involved in the writing of the grant proposal. As the EMBRACE study is an experimental study, a patient delegate will also be invited for feedback on the outputs and outcomes for the study newsletters, once these are available. All participants are always able to communicate with the EMBRACE study team at any time by email and phone if they have any questions they would like to be answered - contact details are available on the EMBRACE study website.
Expected output
Results from the EMBRACE study have been and are anticipated to continue to be published in peer-reviewed journals such as the BMJ (British Medical Journal) or the Journal of Clinical Oncology, depending on each journal’s requirements. Multiple publications are expected over the next 1-5 years and beyond subject to funding.
The EMBRACE study has contributed data to 130 publications in high-impact journals, including publications developed through the study team’s collaboration with the IBCCS prospective cohort study and the CIMBA. Due to the continuous nature of the study there will be no final results paper: results will be published once sufficient data have been accrued to allow robust statistical analysis. These analyses include: (1) estimating cancer risks for mutation carriers; (2) estimating risks of second cancers; (3) evaluating the effects of different risk factors on cancer risk in carriers, including genetic modifiers and the role of lifestyle/hormonal risk factors; (4) evaluating the effects of risk-reducing surgery and other interventions on cancer risks and other outcomes; (5) evaluating the role of mammographic density of breast cancer risk; (6) assessing the associations between molecular tumour characteristics of BRCA1/2-associated tumours and prognosis.
All outputs have included and will continue to only include tables in the form of aggregated data with small numbers suppressed in line with the HES Analysis Guide. No record-level data has been or will be disclosed.
Interim reports have been and will continue to be made available to the main funding body (CRUK) on an annual basis. CRUK has a clear interest in the outputs of the study and is able to assist in promoting key papers in the media. Important publications are also highlighted on social media. CRUK cannot influence the outputs of the research or restrict their dissemination.
Results from the EMBRACE study are regularly presented at the UK Cancer Genetics Group (CGG) meetings, which is the national forum to assess and implement new findings of clinical relevance - http://www.ukcgg.org. These meetings have a membership of 350 individuals who comprise clinicians, counsellors and scientists, including all the clinics already involved in the study. The purpose of the CGG is to improve the quality of care patients and their families receive in respect of any condition resulting in hereditary tumours. Having frontline clinicians involved in the study and discussing progress with them directly in this fashion helps ensure findings are communicated effectively within the relevant groups - i.e. the genetic counsellors and by extension their patients. The EMBRACE study results are also presented in other national and international meetings e.g. the biannual BRCA symposium (https://brcasymposium.ca), the key international meeting in the field of hereditary breast and ovarian cancer, which attracts clinicians, researchers, policy makers and public and patient representatives.
The University of Cambridge lists publications on the EMBRACE study website (https://ccge.medschl.cam.ac.uk/embrace/embrace-study-news/) and produce simplified summaries of the findings for key papers. The University of Cambridge is committed to open access publications and to this end publications are available free of charge. No restrictions are placed on publications and the dissemination of results. The investigators also present the latest findings from the EMBRACE study at open days, held by regional clinical genetics centres across the UK, for BRCA1/2 carriers. The investigators will also work with the EMBRACE study patient and public partners to provide regular updates to EMBRACE study participants through newsletters, and the PPI delegates will be invited for comments and suggestions on the outputs and outcomes once these are available. All participants are always welcome to communicate with the EMBRACE study team by email and phone - details are available on the EMBRACE study website.
The University of Cambridge also disseminate the study at the Cambridge Science Festival, which is a celebration showcasing the leading edge in science, and can attract huge amount visitors every year.
Benefits reported
It is hoped the results from the following papers published in accessible journals will guide clinical geneticists and other health professionals in determining the appropriate provision of cancer screening (for example using mammography or MRI), prophylactic surgery or risk reducing medication.
The EMBRACE study team at the University of Cambridge has made major contributions to several published papers with implications for the clinical management of BRCA1/2 carriers:
A JAMA paper (https://jamanetwork.com/journals/jama/fullarticle/2632503) provides the most reliable estimates on cancer risks to women with BRCA1/2 mutations to date.
Two manuscripts in European Urology provided the first prospective estimates of prostate cancer risk for men with mutations (https://pubmed.ncbi.nlm.nih.gov/31495749/; https://www.europeanurology.com/article/S0302-2838(20)30345-6/fulltext) -
A recent retrospective family-based study in the Journal of Clinical Oncology has evaluated the associations of BRCA1/2 mutations with 22 different cancers (other than breast and ovarian) and provided evidence that BRCA1/2 mutations are associated also with male breast cancer, pancreatic cancer and possibly stomach cancers. No evidence of association was found with the other cancers (https://pubmed.ncbi.nlm.nih.gov/35077220/). These cancer risk estimates have been incorporated into the genetic testing and counselling protocols or recommendations for prevention in several countries.
Another paper evaluated the effect of oophorectomy on breast cancer risk in carriers of BRCA1/2 mutations which has impacted clinical practice by altering the advice to women on the uptake and timing of risk reducing oophorectomy (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966793/).
Two parallel papers examined the effect of oral contraceptive use on breast and ovarian cancer risks in carriers (https://pubmed.ncbi.nlm.nih.gov/33493488/; https://pubmed.ncbi.nlm.nih.gov/31360853/). Based on these results a separate paper assessed that the risks and benefits of Oral Contraceptive use in carriers may impact the advice given to women with mutations (https://pubmed.ncbi.nlm.nih.gov/35048954/).
Another important piece of recent work looked at the effect of Single nucleotide polymorphisms (SNPs) (or polygenic risk scores) on the risk of cancer in BRCA1/2 carriers (https://pubmed.ncbi.nlm.nih.gov/28376175/; https://pubmed.ncbi.nlm.nih.gov/32665703/; https://pubmed.ncbi.nlm.nih.gov/34320204/). These may also influence clinical practice as clinicians incorporate SNP testing into genetic counselling. Based on these results, two randomised controlled trials assessing the impact of incorporating SNP testing for carriers on patient and clinical decision making have been set up and are currently ongoing (in the UK, USA and Australia). Results from these trials will allow risk reducing surgery or other interventions to be targeted more effectively at those women at the highest risk.
Finally, the EMBRACE study examined breast and ovarian cancer risks for BRCA1/BRCA2 predictive test negatives (proven non-carriers of the BRCA mutation segregating in their family) and found that they are not at an elevated risk of breast or ovarian cancer (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033314/). There have been conflicting approaches in the clinical management of these women. The results suggest that risk reducing surgeries may not be appropriate in women who are relatives of BRCA1/BRCA2 mutation carriers.
Results across the EMBRACE studies have been incorporated into the genetic testing and counselling protocols or recommendations for prevention in several countries. For example:
• In the UK by NICE (https://www.nice.org.uk/guidance/cg164) and the UK Cancer Genetics Group;
• In the USA by the US National Comprehensive Cancer Network (https://www.nccn.org/guidelines/guidelines-detail?category=2&id=1503) and the US Preventive Services Task Force (https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/breast-cancer-medications-for-risk-reduction);
• In Australia through the eviQ clinical guidelines: Prostate cancer panel testing (https://www.eviq.org.au/cancer-genetics/adult/genetic-testing-using-cancer-gene-panels/3648-prostate-cancer-panel-testing); BRCA1 or BRCA2 risk management;( https://www.eviq.org.au/cancer-genetics/adult/risk-management/3814-brca1-or-brca2-risk-management-female); BRCA1 or BRCA2 risk management (males) ( https://www.eviq.org.au/cancer-genetics/adult/risk-management/656-brca1-or-brca2-risk-management-male#references);
• The European Association of Urology (https://uroweb.org/guidelines/prostate-cancer#3).
Estimates generated by the EMBRACE study have been critical in developing the BRCA1/2 component of the BOADICEA model and CanRisk (https://www.canrisk.org/) tool which is recommended in guidelines including, for example, the Ontario Breast Screening program - https://www.cancercareontario.ca/en/guidelines-advice/cancer-continuum/screening/breast-cancer-high-risk-women) for Breast Cancer (BC) and Epithelial Ovarian Cancer (EOC) risk assessment.
DARS-NIC-302473-K6R0Z-v5.1 1 October 2021 to 30 September 2022
- Title
- Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers
- Commercial
- No
- Sublicensing
- No
- Datasets
- 7
- Files released
- 0
Datasets: Cancer Registration Data; Civil Registrations of Death; Demographics; MRIS - Cause of Death Report; MRIS - Cohort Event Notification Report; MRIS - Flagging Current Status Report; MRIS - Members and Postings Report
What changed from DARS-NIC-302473-K6R0Z-v4.5
Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.
| Field | Was | Became |
|---|---|---|
| Title | Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers | |
| Start date | 2021-10-01 | |
| End date | 2022-09-30 | |
| Cancer Registration Data: legal basis | National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| Civil Registrations of Death: legal basis | National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| Demographics: legal basis | National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| MRIS - Cause of Death Report: legal basis | National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| MRIS - Cohort Event Notification Report: legal basis | National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| MRIS - Flagging Current Status Report: legal basis | National Health Service Act 2006 - s251 - 'Control of patient information'. | |
| MRIS - Members and Postings Report: legal basis | National Health Service Act 2006 - s251 - 'Control of patient information'. |
Objective for processing
[1 paragraph unchanged]
Embrace is a long-running study that initially received MREC approval in
1998,
1998
and has been awarded another grant from Cancer Research UK to continue
[40 words unchanged]
and to examine associations with other risk factors, both environmental and genetic.
[1 paragraph unchanged]
The funding organisation
Cancer Research UK
cannot influence the outputs of the research or restrict their dissemination.
[2 paragraphs unchanged]
• The mortality data are necessary in order to evaluate the survival
[35 words unchanged]
consistently) to be provided. The mortality data also, to a large extent,
prevents
reduces the risk of
the Embrace study team
from
attempting to contact deceased participants, which could cause upset to their family members.
[2 paragraphs unchanged]
The data are required for a long period as the project is monitoring cancers that may take many years to manifest. Additionally the study aims to analyse the long-term survival from cancer and other diseases, and requires continued access to mortality data.
The study is UK wide. The genetic mutations in these genes are uncommon and it is therefore necessary to recruit patients from the whole country to provide an adequately powered study. In addition, without using national data, it would not be possible to guarantee that the dataset would be accurately representative of the mutation carriers and hence the results may not be broadly applicable.
Although the main cancers of interest are breast and ovarian certain, analyses need to take account of other cancers (either prior to the start of the study or after recruitment). Other types of cancers have been shown to have a link with BRCA1/2, including prostate and pancreatic cancer. The increasing recruitment base combined with additional years of follow up may reveal more associations. As the project aims to evaluate the full spectrum of cancer risk in carriers, it is necessary to analyse the data on all cancers that occur in the cohort: a filter would remove this valuable information.
Processing activities
[1 paragraph unchanged]
Only participants belonging to the retrospective cohort as defined by the study’s section 251 support will be covered by this
agreement,
Agreement,
and as
such
such,
no further participant details will need to flow to NHS Digital for
[24 words unchanged]
will not be shared with NHS Digital unless covered by a separate
agreement.
Agreement.
The data from NHS Digital
is
was
downloaded into the Secure Data Hosting System (SDHS) based at the clinical
[98 words unchanged]
Cambridge. Internet traffic to and from the SDHS is severely limited, for
example
example,
an exception had to be applied for to allow access to the NHS Digital site from within the SDHS.
The downloaded data are linked to the study data using the artificial identifier supplied to NHS Digital. Cancer incidence data are compared to and stored alongside the information
we
already
hold
held
based on self-reporting, if present. Mortality data are stored separately, but require linking periodically to ensure deceased patients are not contacted by Embrace for follow up.
The data are required for a long period as the project is monitoring cancers that may take many years to manifest. Additionally the study aims to analyse the long-term survival from cancer and other diseases, and requires continued access to mortality data.
The study is UK wide. The genetic mutations in these genes are uncommon and it is therefore necessary to recruit patients from the whole country to provide an adequately powered study. In addition, without using national data, it would not be possible to guarantee that the dataset would be accurately representative of the mutation carriers and hence the results may not be broadly applicable.
Although the main cancers of interest are breast and ovarian certain, analyses need to take account of other cancers (either prior to the start of the study or after recruitment). Other types of cancers have been shown to have a link with BRCA1/2, including prostate and pancreatic cancer. The increasing recruitment base combined with additional years of follow up may reveal more associations. As the project aims to evaluate the full spectrum of cancer risk in carriers, it is necessary to analyse the data on all cancers that occur in the cohort: a filter would remove this valuable information.
[1 paragraph unchanged]
All organisations party to this agreement must comply with the Data Sharing
[11 words unchanged]
that use) by “Personnel” (as defined within the Data Sharing Framework Contract
ie:
i.e.:
employees, agents and contractors of the Data Recipient who may have access to that data).
Expected output
[1 paragraph unchanged]
Interim reports will be made to
our
the
main funding body (Cancer Research UK) on an annual basis. Cancer Research
[19 words unchanged]
papers in the media. Important publications are also highlighted on social media.
[3 paragraphs unchanged]
Unchanged: Expected measurable benefits, Benefits reported.
Objective for processing
The University of Cambridge requires a patient tracking service providing follow up data on cancer incidence and mortality for use in the Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers (EMBRACE).
Embrace is a long-running study that initially received MREC approval in 1998 and has been awarded another grant from Cancer Research UK to continue for at least five more years until January 2022. The study’s objectives have increased in scope a little over this time, but the major aim has always been to evaluate the long term cancer incidence and mortality in BRCA1/2 carriers and to examine associations with other risk factors, both environmental and genetic.
Only participants belonging to the retrospective cohort as defined by the study’s section 251 support will be covered by this Agreement.
Cancer Research UK cannot influence the outputs of the research or restrict their dissemination.
The data on cancer incidence and mortality from NHS Digital has been and will continue to be essential to the validity of the study.
• Data on cancer occurrence are collected by the Embrace study team, at the University of Cambridge, using questionnaires. However the study design only allows for three follow up questionnaires. NHS Digital provides information in the long gaps between questionnaires and is the only source of data for the study once a participant has completed their final questionnaire. Without this, the analysis of the study may be invalid as, for example, individuals may die before being able to return a follow-up questionnaire. In addition, the data from NHS Digital provide accurate confirmation of the cancer type and diagnosis date, which a participant may not remember exactly.
• The mortality data are necessary in order to evaluate the survival after cancer in carriers, and mortality from other causes of death, both of which are important aims of the study. These require both the date and causes of death (from the death certificate and coded consistently) to be provided. The mortality data also, to a large extent, reduces the risk of the Embrace study team attempting to contact deceased participants, which could cause upset to their family members.
The data will not be used for any commercial purposes.
Study participants are recruited via clinics across the UK that identify eligible patients based on the studies criteria. As these clinics are involved in following up with the participants for their own purposes, the Embrace study team will inform them (as they inform the Embrace team) if a participant has passed away to avoid causing upset to relatives when attempting contact. The Embrace team do not pass on the cause of death or the actual date of death. However the clinics will have access to these data themselves via the NHS tracking system, often before the Embrace study team does. When communicating a death both parties use artificial identifiers and Date of Birth.
The data are required for a long period as the project is monitoring cancers that may take many years to manifest. Additionally the study aims to analyse the long-term survival from cancer and other diseases, and requires continued access to mortality data.
The study is UK wide. The genetic mutations in these genes are uncommon and it is therefore necessary to recruit patients from the whole country to provide an adequately powered study. In addition, without using national data, it would not be possible to guarantee that the dataset would be accurately representative of the mutation carriers and hence the results may not be broadly applicable.
Although the main cancers of interest are breast and ovarian certain, analyses need to take account of other cancers (either prior to the start of the study or after recruitment). Other types of cancers have been shown to have a link with BRCA1/2, including prostate and pancreatic cancer. The increasing recruitment base combined with additional years of follow up may reveal more associations. As the project aims to evaluate the full spectrum of cancer risk in carriers, it is necessary to analyse the data on all cancers that occur in the cohort: a filter would remove this valuable information.
Expected output
Results from the Embrace study will be published in peer-reviewed journals. Multiple publications are expected over the next four years, and beyond subject to funding (the study is currently funded until 2022 but further funding will be sought to continue follow-up beyond that date). More than 70 publications to date have used Embrace data. Due to the continuous nature of the study there will be no “final” results paper: results will be published once sufficient data have been accrued to allow robust statistical analysis. In particular, multiple papers are planned over the next 1-3 years that examine the effects of different risk factors on cancer risk in carriers. Later analyses, however, will require a larger dataset with longer follow-up.
Interim reports will be made to the main funding body (Cancer Research UK) on an annual basis. Cancer Research UK has a clear interest in the outputs of the study, and is able to assist in promoting key papers in the media. Important publications are also highlighted on social media.
Results from the EMBRACE study are regularly presented at the UK Cancer Genetics Group (CGG) meetings, which is the national forum to assess and implement new findings of clinical relevance - http://www.ukcgg.org. These meetings have a membership of 350 made up of clinicians, counsellors and scientists, including all the clinics already involved in the study. New results and future plans are discussed. The purpose of the CGG is to improve the quality of care of patients and their families with any condition resulting in hereditary tumours. Having frontline clinicians involved in the study and discussing progress with them directly in this fashion helps ensure our findings are communicated to the relevant groups i.e. the genetic counsellors and by extension their patients.
The University of Cambridge currently lists some publications on its Embrace study website and will produce simplified summaries of the findings for key papers. The University of Cambridge is committed to open access publications and our publications will be available free of charge. No restrictions are placed on publications and dissemination of results.
All outputs will contain only data that are aggregated with small numbers suppressed in line with the HES Analysis Guide.
Benefits reported
Some of the publications that have arisen from the Embrace study are indicated above. The Embrace study is helping to provide the most reliable information on the cancer risks in BRCA1 and BRCA2 carriers, and the effects of both genetic and lifestyle factors on these risks. Some of these have been clearly established already, in part using EMBRACE study data. These include the effects of SNPs on cancer risk in carriers (Antoniou et al. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008 Apr;82(4):937-48, Kuchenbaecker KB et al. Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers. JNCI 2017:109(7):djw302) and the effects of oral contraceptive use on ovarian cancer risk in carriers (Antoniou et al, Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study. CEBP 2009:18(2):601-10).
As noted above, these results influence management guidelines such as the NICE guidelines, and clinical practice through the counselling offer to carriers. For many questions, however (for example providing reliable estimates on the risk of cancers other than breast and ovarian cancer, and the survival from cancer in carriers), much longer term follow-up of carriers to study incidence and mortality will be required. Individuals are identified and recruited at a relative young age but cancer cases and deaths accrue over many years, and it is only with long term follow-up that reliable estimates can be obtained.
DARS-NIC-302473-K6R0Z-v4.5 21 May 2020 to 30 September 2021
- Title
- MR699 - Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers
- Commercial
- No
- Sublicensing
- No
- Datasets
- 7
- Files released
- 12
Datasets: Cancer Registration Data; Civil Registrations of Death; Demographics; MRIS - Cause of Death Report; MRIS - Cohort Event Notification Report; MRIS - Flagging Current Status Report; MRIS - Members and Postings Report
What changed from DARS-NIC-302473-K6R0Z-v3.5
Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.
| Field | Was | Became |
|---|---|---|
| Start date | 2020-05-21 |
Datasets: + Cancer Registration Data; + Civil Registrations of Death; + Demographics
Unchanged: Objective for processing, Processing activities, Expected output, Expected measurable benefits, Benefits reported.
Objective for processing
The University of Cambridge requires a patient tracking service providing follow up data on cancer incidence and mortality for use in the Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers (EMBRACE).
Embrace is a long-running study that initially received MREC approval in 1998, and has been awarded another grant from Cancer Research UK to continue for at least five more years until January 2022. The study’s objectives have increased in scope a little over this time, but the major aim has always been to evaluate the long term cancer incidence and mortality in BRCA1/2 carriers and to examine associations with other risk factors, both environmental and genetic.
Only participants belonging to the retrospective cohort as defined by the study’s section 251 support will be covered by this agreement.
The funding organisation cannot influence the outputs of the research or restrict their dissemination.
The data on cancer incidence and mortality from NHS Digital has been and will continue to be essential to the validity of the study.
• Data on cancer occurrence are collected by the Embrace study team, at the University of Cambridge, using questionnaires. However the study design only allows for three follow up questionnaires. NHS Digital provides information in the long gaps between questionnaires and is the only source of data for the study once a participant has completed their final questionnaire. Without this, the analysis of the study may be invalid as, for example, individuals may die before being able to return a follow-up questionnaire. In addition, the data from NHS Digital provide accurate confirmation of the cancer type and diagnosis date, which a participant may not remember exactly.
• The mortality data are necessary in order to evaluate the survival after cancer in carriers, and mortality from other causes of death, both of which are important aims of the study. These require both the date and causes of death (from the death certificate and coded consistently) to be provided. The mortality data also, to a large extent, prevents the Embrace study team from attempting to contact deceased participants, which could cause upset to their family members.
The data will not be used for any commercial purposes.
Study participants are recruited via clinics across the UK that identify eligible patients based on the studies criteria. As these clinics are involved in following up with the participants for their own purposes, the Embrace study team will inform them (as they inform the Embrace team) if a participant has passed away to avoid causing upset to relatives when attempting contact. The Embrace team do not pass on the cause of death or the actual date of death. However the clinics will have access to these data themselves via the NHS tracking system, often before the Embrace study team does. When communicating a death both parties use artificial identifiers and Date of Birth.
Expected output
Results from the Embrace study will be published in peer-reviewed journals. Multiple publications are expected over the next four years, and beyond subject to funding (the study is currently funded until 2022 but further funding will be sought to continue follow-up beyond that date). More than 70 publications to date have used Embrace data. Due to the continuous nature of the study there will be no “final” results paper: results will be published once sufficient data have been accrued to allow robust statistical analysis. In particular, multiple papers are planned over the next 1-3 years that examine the effects of different risk factors on cancer risk in carriers. Later analyses, however, will require a larger dataset with longer follow-up.
Interim reports will be made to our main funding body (Cancer Research UK) on an annual basis. Cancer Research UK has a clear interest in the outputs of the study, and is able to assist in promoting key papers in the media. Important publications are also highlighted on social media.
Results from the EMBRACE study are regularly presented at the UK Cancer Genetics Group (CGG) meetings, which is the national forum to assess and implement new findings of clinical relevance - http://www.ukcgg.org. These meetings have a membership of 350 made up of clinicians, counsellors and scientists, including all the clinics already involved in the study. New results and future plans are discussed. The purpose of the CGG is to improve the quality of care of patients and their families with any condition resulting in hereditary tumours. Having frontline clinicians involved in the study and discussing progress with them directly in this fashion helps ensure our findings are communicated to the relevant groups i.e. the genetic counsellors and by extension their patients.
The University of Cambridge currently lists some publications on its Embrace study website and will produce simplified summaries of the findings for key papers. The University of Cambridge is committed to open access publications and our publications will be available free of charge. No restrictions are placed on publications and dissemination of results.
All outputs will contain only data that are aggregated with small numbers suppressed in line with the HES Analysis Guide.
Benefits reported
Some of the publications that have arisen from the Embrace study are indicated above. The Embrace study is helping to provide the most reliable information on the cancer risks in BRCA1 and BRCA2 carriers, and the effects of both genetic and lifestyle factors on these risks. Some of these have been clearly established already, in part using EMBRACE study data. These include the effects of SNPs on cancer risk in carriers (Antoniou et al. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008 Apr;82(4):937-48, Kuchenbaecker KB et al. Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers. JNCI 2017:109(7):djw302) and the effects of oral contraceptive use on ovarian cancer risk in carriers (Antoniou et al, Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study. CEBP 2009:18(2):601-10).
As noted above, these results influence management guidelines such as the NICE guidelines, and clinical practice through the counselling offer to carriers. For many questions, however (for example providing reliable estimates on the risk of cancers other than breast and ovarian cancer, and the survival from cancer in carriers), much longer term follow-up of carriers to study incidence and mortality will be required. Individuals are identified and recruited at a relative young age but cancer cases and deaths accrue over many years, and it is only with long term follow-up that reliable estimates can be obtained.
DARS-NIC-302473-K6R0Z-v3.5 1 October 2018 to 30 September 2021
- Title
- MR699 - Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers
- Commercial
- No
- Sublicensing
- No
- Datasets
- 4
- Files released
- 10
Datasets: MRIS - Cause of Death Report; MRIS - Cohort Event Notification Report; MRIS - Flagging Current Status Report; MRIS - Members and Postings Report
Objective for processing
The University of Cambridge requires a patient tracking service providing follow up data on cancer incidence and mortality for use in the Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers (EMBRACE).
Embrace is a long-running study that initially received MREC approval in 1998, and has been awarded another grant from Cancer Research UK to continue for at least five more years until January 2022. The study’s objectives have increased in scope a little over this time, but the major aim has always been to evaluate the long term cancer incidence and mortality in BRCA1/2 carriers and to examine associations with other risk factors, both environmental and genetic.
Only participants belonging to the retrospective cohort as defined by the study’s section 251 support will be covered by this agreement.
The funding organisation cannot influence the outputs of the research or restrict their dissemination.
The data on cancer incidence and mortality from NHS Digital has been and will continue to be essential to the validity of the study.
• Data on cancer occurrence are collected by the Embrace study team, at the University of Cambridge, using questionnaires. However the study design only allows for three follow up questionnaires. NHS Digital provides information in the long gaps between questionnaires and is the only source of data for the study once a participant has completed their final questionnaire. Without this, the analysis of the study may be invalid as, for example, individuals may die before being able to return a follow-up questionnaire. In addition, the data from NHS Digital provide accurate confirmation of the cancer type and diagnosis date, which a participant may not remember exactly.
• The mortality data are necessary in order to evaluate the survival after cancer in carriers, and mortality from other causes of death, both of which are important aims of the study. These require both the date and causes of death (from the death certificate and coded consistently) to be provided. The mortality data also, to a large extent, prevents the Embrace study team from attempting to contact deceased participants, which could cause upset to their family members.
The data will not be used for any commercial purposes.
Study participants are recruited via clinics across the UK that identify eligible patients based on the studies criteria. As these clinics are involved in following up with the participants for their own purposes, the Embrace study team will inform them (as they inform the Embrace team) if a participant has passed away to avoid causing upset to relatives when attempting contact. The Embrace team do not pass on the cause of death or the actual date of death. However the clinics will have access to these data themselves via the NHS tracking system, often before the Embrace study team does. When communicating a death both parties use artificial identifiers and Date of Birth.
Expected output
Results from the Embrace study will be published in peer-reviewed journals. Multiple publications are expected over the next four years, and beyond subject to funding (the study is currently funded until 2022 but further funding will be sought to continue follow-up beyond that date). More than 70 publications to date have used Embrace data. Due to the continuous nature of the study there will be no “final” results paper: results will be published once sufficient data have been accrued to allow robust statistical analysis. In particular, multiple papers are planned over the next 1-3 years that examine the effects of different risk factors on cancer risk in carriers. Later analyses, however, will require a larger dataset with longer follow-up.
Interim reports will be made to our main funding body (Cancer Research UK) on an annual basis. Cancer Research UK has a clear interest in the outputs of the study, and is able to assist in promoting key papers in the media. Important publications are also highlighted on social media.
Results from the EMBRACE study are regularly presented at the UK Cancer Genetics Group (CGG) meetings, which is the national forum to assess and implement new findings of clinical relevance - http://www.ukcgg.org. These meetings have a membership of 350 made up of clinicians, counsellors and scientists, including all the clinics already involved in the study. New results and future plans are discussed. The purpose of the CGG is to improve the quality of care of patients and their families with any condition resulting in hereditary tumours. Having frontline clinicians involved in the study and discussing progress with them directly in this fashion helps ensure our findings are communicated to the relevant groups i.e. the genetic counsellors and by extension their patients.
The University of Cambridge currently lists some publications on its Embrace study website and will produce simplified summaries of the findings for key papers. The University of Cambridge is committed to open access publications and our publications will be available free of charge. No restrictions are placed on publications and dissemination of results.
All outputs will contain only data that are aggregated with small numbers suppressed in line with the HES Analysis Guide.
Benefits reported
Some of the publications that have arisen from the Embrace study are indicated above. The Embrace study is helping to provide the most reliable information on the cancer risks in BRCA1 and BRCA2 carriers, and the effects of both genetic and lifestyle factors on these risks. Some of these have been clearly established already, in part using EMBRACE study data. These include the effects of SNPs on cancer risk in carriers (Antoniou et al. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008 Apr;82(4):937-48, Kuchenbaecker KB et al. Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers. JNCI 2017:109(7):djw302) and the effects of oral contraceptive use on ovarian cancer risk in carriers (Antoniou et al, Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study. CEBP 2009:18(2):601-10).
As noted above, these results influence management guidelines such as the NICE guidelines, and clinical practice through the counselling offer to carriers. For many questions, however (for example providing reliable estimates on the risk of cancers other than breast and ovarian cancer, and the survival from cancer in carriers), much longer term follow-up of carriers to study incidence and mortality will be required. Individuals are identified and recruited at a relative young age but cancer cases and deaths accrue over many years, and it is only with long term follow-up that reliable estimates can be obtained.
Register history
When this agreement appeared in, or was edited in, each monthly edition of the register. Built by comparing every edition this site holds, the earliest of which is July 2021.
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July 2021 —
already listed in the earliest edition this site holds, so it may be older. 2 versions: DARS-NIC-302473-K6R0Z-v3.5, DARS-NIC-302473-K6R0Z-v4.5
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October 2021
1 version added: DARS-NIC-302473-K6R0Z-v5.1
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April 2023
1 version added: DARS-NIC-302473-K6R0Z-v6.13
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July 2023
1 version added: DARS-NIC-302473-K6R0Z-v7.2
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July 2026
1 version added: DARS-NIC-302473-K6R0Z-v8.5
Cite this page
NHS England (2026) Data Uses Register, September 2026 edition, agreement DARS-NIC-302473-K6R0Z, “Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers”. Read via NHS Data Access Explorer (unofficial), https://healthdatauses.uk/agreements/dars-nic-302473-k6r0z/ (accessed [date]).
This address stays the same, but the page is rebuilt with each monthly edition, so the citation names the edition it shows. Every edition's data is kept in the facts store.
Source: datausesregister_september2026.xlsx, September 2026 edition of the NHS England Data Uses Register. Search that workbook for DARS-NIC-302473-K6R0Z to see the original rows.