MR589 - UKCCCR TRIAL OF BREAST SCREENING IN YOUNG WOMEN

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

Objective for processing

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling Queen Mary University of London to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance). This Data Sharing Agreement permits Queen Mary University of London to retain and process data supplied by NHS Digital and predecessor organisations between 2012 and 2017 for the purpose of the UK Breast Screening Age Trial. The broad objective for processing the data from the UK Breast Screening Age Trial is to determine the effect on mortality from breast cancer of mammographic screening in women starting ages 40-41, compared with starting at age 50 as in the current national programme, and to understand mechanisms of both the effect on mortality and differences in this with respect to age. Policy makers are continually pressured to expand the age range for breast cancer screening and need information from this trial to make their decisions. Thus, under Article 6 of the Data Protection Act, the justification for processing is public interest, as there is substantial public benefit in the results. As regards GDPR Article 9, this comes under article 9(2) (j) scientific research purposes. The major objective of estimation of the effect on breast cancer mortality has been achieved (Duffy et al, Lancet Oncology 2020; 21: 1165-72). The tasks which remain are to understand the mechanism of the mortality reduction in terms of the cancers diagnosed, and to examine the reason why the mortality benefit seems to be of shorter duration than that of screening in older women. Understanding of this may inform measures to rectify it, and thus alter the cost-benefit balance of mammography screening in women aged 40-49. It should be reemphasised that this is a perennially recurring issue for public health policy, and therefore it is in the public interest that analysis continues. The processing will involve analysis of the data on cancers diagnosed in the trial, particularly survival analysis, estimating the effect of screening on survival, and the extent to which it can be shown to be mediated through stage of cancer at diagnosis. To further understand the duration of benefit, it will be necessary to analyse if the survival effect is modified by the histological grade of the cancer. That is, is the reduced duration of effect explained by biological aspects of the cancers diagnosed and how these vary by age? The following analyses will take place: 1. Description of the distributions of cancers diagnosed with respect to invasive status, size, node status, grade, histological type and TNM stage, stratified by detection mode (see 5a above). Comparison of these with corresponding published results for ages 50-70. 2. Estimation of effects on survival of invasive status, size, node status, grade, histological type, TNM stage, and detection mode. Estimation of the effect of detection mode on survival adjusted for invasive status, size, node status, grade, histological type and TNM stage. 3. Testing of heterogeneity of the effect of screening on survival by histological grade and type of cancers. Is this consistent with the effect on chronological factors such as size and node status? 4. Repeat of analyses 2 and 3 for different epochs of time (0-5 years after diagnosis; 5.1-10 years; 10.1-15 years, 15 years or more). 5. Repeat of analyses 3 and 4 above with respect to population mortality rather than case survival. That is, analyse number of deaths relative to the entire population randomised rather than the population of women actually diagnosed with cancer and with respect to the time origin of time of randomisation rather than diagnosis. The processing will only involve analysis of data which Queen Mary University of London supplied up to March 2017 and which has had explicit identifiers already removed by Queen Mary University of London data management team. No new data is requested. The data are held securely firewall and password protected. Thus risks to confidentiality have been reduced, since even the analysis team do not have access to explicitly identifiable data. The following MRIS products were previously provided to QMUL: Cause of Death, Cohort Even Notification, Members and Postings, Flagging Current Status The data items required for analysis within these products are: cancer site cancer type cancer registration date histology QMUL also obtain the following cancer data, including pathology data, which comes directly from registration data linked with information from screening centres: - invasive status, - size - node status - grade - histological type - TNM stage and detection mode (screening, interval between screens, symptomatically in non-participants, symptomatically in control group members), - survival time (already calculated, so the analysis team do not need explicit dates of diagnosis and death) - cause of death (if applicable) The Data Controller is Queen Mary University of London.

Processing activities

Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement. The study data, including data provided by NHS Digital under previous iterations of this Agreement, are currently held by Queen Mary University of London. The study data, including data provided by NHS Digital under previous agreements, are currently held by Queen Mary University of London. No flow of data is requested or anticipated either to or from NHS Digital. The trial has closed and the aim is now to complete analysis of data already held at Queen Mary University of London. The only organisation processing the data is Queen Mary University of London. All data management and linkage to enable this analysis has already taken place, for purposes previously agreed in successive DSA’s. There will be no further linkage or matching to other data. There will be no attempt to reidentify individuals. Data processing will only be carried out by a statistical team at Queen Mary University of London. All members undergo compulsory annual training in GDPR and data security. All data will be stored in a restricted section of a UNIX server kept in a secure server room within the Wolfson Institute in QMUL and also at the site of QMUL's data centre facility provider, Interxion, who store the data and run QMUL's IT infrastructure. Access to the database will be controlled using a username and password login. No users other than the Senior Data Manager shall have access to the full, identifiable dataset. All other users will have access to pseudonymised data that contains no identifiable data, but a unique study identifier to link the record to the complete dataset. Backup tapes are all stored off site with Iron Mountain. All tapes are fully encrypted to the university's agreed standard (AES 256). Tapes are delivered and collected directly from the datacentre and all tapes are electronically tracked via their barcode. The data is stored at Interxion with the back up tapes held by Iron Mountain. Neither organisations are able to access the data or servers holding the data. No new data will be provided by NHS Digital under this Agreement.

Expected output

This Agreement permits the secure retention of the data only and no other processing. The main objective of the study estimating the effect of the screening in women aged 40-49 on breast cancer mortality, has already been achieved. It remains to carry out the analyses to understand the reasons for the mortality results. The analyses, with their corresponding outputs are: No new outputs will be produced under this Data Sharing Agreement. 1. Understanding of the difference in effect of screening between ages 40-49 and 50-70 in terms of stage shift and propensity of detection of cancer by stage and histology. Will identify gaps in the capability of mammography for early detection in women aged 40-49. Expected date of completion 28th July 2022. 2. Understanding of the mechanism whereby screening in this age group confers a reduced mortality. It will answer the question is the appropriate target for quality monitoring the size, node status or the combination of the two in TNM-stage? Expected date of completion 28th July 2022. 3. Establishment of targets for improvement of mammography protocols to detect earlier those cancers for which smaller effects on survival are seen. It is important to design screening programmes to have the best chance of early detection of those cancers which are most life-threatening. Expected date of completion 31st May 2022. 4. Diagnosis of the reason for the apparent shorter duration of the relative mortality benefit in women aged 40-49 (see Duffy et al, Lancet Oncology 2020; 21: 1165-72). Expected date of completion 30th June 2022. 5. Knowledge of the public health policy implications of screening in this age group in relation to tumour type, in addition to the effect on individual case fatality. Understanding of the extent to which such observations are qualified by the lead time, length bias and overdiagnosis which can affect case survival from diagnosis. Expected date of completion 30th September 2022. Reporting and dissemination is expected to be complete (including response to post-publication queries by 30th June 2022. In addition to the conventional publication in peer-reviewed medical journals, results will be communicated to stakeholders in Public Health England and NHS England in case they have immediate implications for screening policy and practice. These outputs will deliver considerable insight into the effect of mammography screening in women under age 50, and will assist in informing policy in this area. The reasons for the reduction in the relative benefit but maintenance of the absolute benefit will indicate potential changes to screening protocols to improve upon this, and to obtain an absolute benefit which grows over 2-3 decades, as happens in screening women at older ages. There are between 7000 and 8000 cases of female breast cancer per year at ages 40-49 in the UK, so there is a large potential patient population which may benefit from the results. (1)The finding of a reduction in breast cancer mortality which is diluted in relative terms after ten years (Moss SM, Wale C, Smith R, Evans A, Cuckle H, Duffy SW. Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17 years' follow-up: a randomised controlled trial. The Lancet Oncology. 2015;16:1123-32). (2) Confirmation that although the relative benefit loses its significance, the absolute benefit of around 1 life saved per thousand women remains constant in the long term, and there is a significant reduction due to screening in years of life lost in both the short and the long term (Duffy SW, Vulkan D, Cuckle H, Parmar D, Sheikh S, Smith RA, Evans A, Blyuss O, Johns L, Ellis IO, Myles J, Sasieni PD, Moss SM. Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial. Lancet Oncol. 2020; 21: 1165-72). Queen Mary University of London is completing a diagnostic to explain published observations in terms of cancer type and grade which is expected to be complete by December 2022. (3) The finding that there is little or no overdiagnosis beyond that which would occur in the National Programme, with screening at ages 50-70 (Moss SM, Wale C, Smith R, Evans A, Cuckle H, Duffy SW. Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17 years' follow-up: a randomised controlled trial. The Lancet Oncology. 2015;16:1123-32). (4) The finding that the rates of false-positive mammography at first and subsequent routine screens in women aged 40-49 were 4.9% and 3.2%, respectively (Johns LE, Moss SM; Age Trial Management Group. False-positive results in the randomized controlled trial of mammographic screening from age 40 ("Age" trial).Cancer Epidemiol Biomarkers Prev. 2010 Nov;19(11):2758-64). (5) Screening in this age group reduces the incidence of late stage disease (Moss S, Waller M, Anderson TJ, Cuckle H; Trial Management Group. Randomised controlled trial of mammographic screening in women from age 40: predicted mortality based on surrogate outcome measures.Br J Cancer. 2005 Mar 14;92(5):955-60.)

Expected measurable benefits

This Agreement permits the secure retention of the data only and no other processing. The major benefit will be the understanding of how mammographic screening works in women aged under 50, which will in turn indicate avenues to explore to make it work better. The principal favourable effect of screening is the reduction in breast cancer mortality, which this study has already established (Duffy et al, Lancet Oncology 2020; 21: 1165-72). This work indicated that the relative benefit of screening is attenuated after 10 years in women under age 50, although importantly the absolute mortality reduction is maintained more than 20 years after beginning screening. However, in older women the reduction in relative benefit in later years is not seen, so that additional lives saved continue to accrue as a result of screening up to and possible more than 20 years later. The most likely hypothesis to explain the absence of this long-term benefit in younger women is a differential effect on tumours by histological grade. Grade 1 tumours have longer term survival, grade 2 shorter, and grade 3 shorter still. The results will clarify whether the screening is performing more poorly in the last category in this age group. If this hypothesis is correct it will yield a very tangible benefit In the form of indicated changes to radiological protocols to achieve more effective early detection of grade 3 cancers.

Benefits reported

Not stated in the previous version; added here.

The UK Age Trial has added to QMUL's understanding that breast cancer does not respect a woman’s 50th birthday. The trial has shown that there is a benefit in terms of reduced breast cancer mortality from early detection before age 50. Consequently, the results in (2) below were the subject of considerable media attention.

The current policy in the UK is to screen from age 50. Due to the hiatus in screening activity in 2020 as a result of the COVID-19 pandemic, and the backlog of screening which this has engendered, now is not the time to expand the eligible age range. The immediate priority for the NHS Breast Screening Programme is to recover services and in so far as possible catch up on the backlog. In future years, however, there will very likely be a need to revisit the eligible age range for mammography screening and the results of the UK Age Trial are a unique resource to inform this.

Individual benefits include the following specific additions to QMUL's knowledge with respect to early detection of breast cancer in women aged under 50.

(1)The finding of a reduction in breast cancer mortality which is diluted in relative terms after ten years (Moss SM, Wale C, Smith R, Evans A, Cuckle H, Duffy SW. Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17 years' follow-up: a randomised controlled trial. The Lancet Oncology. 2015;16:1123-32).

(2) Confirmation that although the relative benefit loses its significance, the absolute benefit of around 1 life saved per thousand women remains constant in the long term, and there is a significant reduction due to screening in years of life lost in both the short and the long term (Duffy SW, Vulkan D, Cuckle H, Parmar D, Sheikh S, Smith RA, Evans A, Blyuss O, Johns L, Ellis IO, Myles J, Sasieni PD, Moss SM. Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial. Lancet Oncol. 2020; 21: 1165-72). The explanation for these observations in terms of cancer type and grade is the subject of this application to extend the DSA.

(3) The finding that there is little or no overdiagnosis beyond that which would occur in the National Programme, with screening at ages 50-70 (Moss SM, Wale C, Smith R, Evans A, Cuckle H, Duffy SW. Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17 years' follow-up: a randomised controlled trial. The Lancet Oncology. 2015;16:1123-32).

(4) The finding that the rates of false-positive mammography at first and subsequent routine screens in women aged 40-49 were 4.9% and 3.2%, respectively (Johns LE, Moss SM; Age Trial Management Group. False-positive results in the randomized controlled trial of mammographic screening from age 40 ("Age" trial).Cancer Epidemiol Biomarkers Prev. 2010 Nov;19(11):2758-64).

(5) Screening in this age group reduces the incidence of late stage disease (Moss S, Waller M, Anderson TJ, Cuckle H; Trial Management Group. Randomised controlled trial of mammographic screening in women from age 40: predicted mortality based on surrogate outcome measures.Br J Cancer. 2005 Mar 14;92(5):955-60.)