IBIS-I The International Breast Cancer Intervention Study - MR710

Queen Mary University of London (QMUL) requires access to NHS England data for the purpose of the following research project: the International Breast Cancer Intervention (IBIS-I) Study.

Established in 1992, the IBIS-I Study investigated the efficacy of tamoxifen (a hormonal drug used to prevent breast cancer) versus a placebo drug (taken daily for five years) in terms of reduction of breast cancer incidence in pre and post-menopausal women at high risk of developing breast cancer (e.g. through family history of breast cancer). It was a double-blind, randomised placebo-controlled trial that recruited 7,154 women internationally (of which 4,277 were UK participants and 2,877 from Australia, New Zealand, Spain and Ireland), aged 35-70 years. The primary outcome measure was the incidence of breast cancer, including ductal carcinoma in situ (cancer cells in the lining of the breast milk duct) and side effects present in the patients were also investigated.

Recruitment to the study completed in 2001 and the intervention (placebo/tamoxifen) ended in 2007. In early 2008 the Research Ethics Committee (REC) approved the conversion of IBIS-I to an epidemiological cohort study. During 2007–2016 participants were followed-up via an annual postal questionnaire.

In 2002, initial results found that tamoxifen reduced the risk of invasive breast cancer by 31%. Mortality from non-breast-cancer causes was not increased by tamoxifen. However, the analysis concluded that the overall risk/benefit ratio for the use of tamoxifen in prevention remained unclear and that continued follow-up of trial participants was essential. A 2007 analysis on long-term tamoxifen prophylaxis for breast cancer confirmed the preventive effect of tamoxifen in terms of breast cancer incidence and that this was constant for the entire follow-up period. No reduction in size of benefit was observed for up to ten years following participant randomisation. Additionally, tamoxifen-related side effects such as thrombo-embolism were not increased anymore after the 5-year treatment period. These results therefore demonstrate that the benefit-to-risk ratio of tamoxifen improves with increasing duration of follow-up. Thus, how much additional benefit will be seen long-term remains an important question.

Based on these above-mentioned results, the Central Coordinating Office (CCO) at the Centre for Cancer Prevention (CCP) at QMUL seek to continue to passively collect cancer registration, mortality data and Hospital Episode Statistics (HES) products provided by NHS England. The identifiable data sets returned by NHS England will provide vital information on side effects, survival and breast cancer incidence.

The international centres that participated in the study would be co-ordinated through the IBCSG (International Breast Cancer Study Group). Where possible except for Australia and New Zealand, all foreign centres would be randomised through the central London coordinating office but data collection and cholesterol assays will be carried out nationally. Data forms and blood sample aliquots will be transferred to the central office on a regular basis. The cohort has now decreased from 4,277 to approximately 3,603 due to either patients passing away or the study losing contact with the patients.

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

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

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

The processing is in the public interest as these data are essential in enabling the CCO to determine whether tamoxifen continues to have a long-term beneficial impact in terms of breast cancer incidence, survival and side effects after the initial 5-year treatment period. The CCO will be able to perform a thorough risk-benefit assessment of tamoxifen and a 30-year median follow-up analysis. These analyses will enable the research community to make more informed decisions on tamoxifen vis-a-vis patient safety and both short- and long-term effectiveness. The results so far have been very important for breast cancer in the preventive setting.

QMUL is the controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above.

The first results of the IBIS-I have already been published (Cuzick J, et al. The Lancet. 2002;360: 817-24; Cuzick J, et al. J Natl Cancer Inst. 2004;96:621-628; Cuzick J, et al. J Natl Cancer Ins. 2007;99:272-82; Cuzick J, et al. San Antonio Breast Cancer Symposium. 2014, Dec 9-13; Cuzick J, et al. Lancet Oncol. 2015;16(1):67-75).

Further outputs and analyses of the IBIS-I trials will be published in peer-reviewed medical journals such as The Lancet, The Lancet Oncology, Breast Cancer Research and Treatment and the British Journal of Cancer with at least a publication date in 2025.

Outputs were anticipated in 2019 when there is 20 years of median follow-up data available. This output is still anticipated when current data is collected from devolved nations. It is further anticipated that Queen Mary University of London will run an updated analysis in 2024 (25 years median follow-up).

The public will be made aware of the research progress through two web pages (http://www.ibis-trials.org/thetrials/yourstories/press-articles and https://www.qmul.ac.uk/wolfson/research-/current-projects/projects/ibis-1.html). The anticipated audiences of the above outputs are researchers, scientists, stakeholders for the wider project and research participants.

Policy makers - such as NICE will also be targeted with the outputs of the study. NICE will be informed on the safety and efficacy of tamoxifen as a chemopreventive agent, allowing more information available to women at risk of developing breast cancer on the options available to them. An estimated 15% of women in the UK could benefit from preventive tamoxifen therapy and therefore results from the IBIS-I study are of great relevance to these women.

New publications, attendance of conference and meetings will be shared with international partners. Data contained in any outputs will be aggregated with small numbers suppressed in line with the HES analysis guide. There will be no onward sharing of data. Data received at the Centre for Cancer Prevention is only used to meet the objectives as stated in the trial protocol and will not be shared with any other third party or organisation. Individual patient data is never shared.

Publications with significant findings may be accompanied by press releases and subsequent news stories. Two recent papers (Tamoxifen related side effects and their impact on breast cancer incidence. ‘A retrospective analysis of the randomised IBIS-I trial. The Breast vol 54 Dec. 2020’ and ‘The impact of body mass index on breast cancer incidence among women with increased risk: an observational study from the International Breast Intervention Studies. Breast Cancer Res Treat Mar. 2021)’ have been published continuing to prove the benefits of being able to obtain long term follow up data through NHS England. These 2 papers were expected to be released in 2019 (as above), however were subject to delays. Additionally, the study held a PPI event in January 2020 whereby discussion took place about the work carried out in the CCP covering breast cancer research. This proved to be a useful way to disseminate outputs and discuss the future of following up patients in the long term follow up method.

Registry data provided to date has identified numerous cases of breast cancers, other cancers and side-effects in participants with whom the Centre for Cancer Prevention at Queen Mary University London have no direct contact and therefore not already known by the study team. Collection of this data has contributed directly to the primary endpoints of the trial and will continue to provide valuable information on the long-term risk/benefit status of the trial intervention. This long term data is essential for informing bodies such as NICE to inform the prescribing utility of these drugs as chemopreventive agents. The CCP use registry reported events as a prompt for further investigation by asking participants' current GP practice to confirm the event and also provide any further information e.g. cancer grade, size, receptor status that is required to meet secondary and exploratory objectives.

So far the long-term follow-up has shown that tamoxifen significantly reduces breast cancer incidence in women at risk of developing the disease (see for example Cuzick J, et al. J Natl Cancer Ins. 2007; 99: 272-82). The thromboembolic side effects and increase in gynaecological problems (including endometrial cancer) disappear after the active treatment phase has ended. The trial has also provided further information on the impact of tamoxifen on breast density: mammographic density appears to be a prognostic marker for improved long-term survival in participants receiving adjuvant tamoxifen.

Notably, the IBIS-I study won the Cancer Research UK Prize for Translational Cancer Research at the 2014 NCRI Cancer Conference for its improvements in cancer research (http://www.ibis-trials.org/thetrials/ibistrials/ibis-i-award). Moreover, NICE updated its guidelines on prescription of tamoxifen to women at high risk of developing breast cancer, a decision partly based on results of the IBIS-I Study (first published June 2013, update August 2015; https://www.nice.org.uk/guidance/CG164 and https://www.nice.org.uk/guidance/cg164/evidence/surveillance-review-decision-november-2015-pdf-2178797581).

Established in 1992, the IBIS-I Study investigated the efficacy of tamoxifen (a hormonal drug used to prevent breast cancer) versus a placebo drug (taken daily for five years) in terms of reduction of breast cancer incidence in pre and post-menopausal women at high risk of developing breast cancer (e.g. through family history of breast cancer: full details in protocol). It was a double-blind, randomised placebo-controlled trial that recruited 7,154 women internationally (of which 4,277 were UK participants and 2,877 from Australia, New Zealand, Spain and Ireland), aged 35-70 years. The primary outcome measure was the incidence of breast cancer, including ductal carcinoma in situ (cancer cells in the lining of the breast milk duct) and side effects present in the patients were also investigated.

Recruitment to the study completed in 2001 and the intervention (placebo/tamoxifen) ended in 2007. In early 2008 the Research Ethics Committee (REC) approved the conversion of IBIS-I to an epidemiological cohort study. During 2007–2016 participants were followed-up via an annual postal questionnaire.

In 2002, initial results found that tamoxifen reduced the risk of invasive breast cancer by 31%. Mortality from non-breast-cancer causes was not increased by tamoxifen. However, the analysis concluded that the overall risk/benefit ratio for the use of tamoxifen in prevention remained unclear and that continued follow-up of trial participants was essential. A 2007 analysis on long-term tamoxifen prophylaxis for breast cancer confirmed the preventive effect of tamoxifen in terms of breast cancer incidence and that this was constant for the entire follow-up period. No reduction in size of benefit was observed for up to ten years following participant randomisation. Additionally, tamoxifen-related side effects such as thrombo-embolism were not increased anymore after the 5-year treatment period. These results therefore demonstrate that the benefit-to-risk ratio of tamoxifen improves with increasing duration of follow-up. Thus, how much additional benefit will be seen long-term remains an important question.

Based on these above-mentioned results, the Central Coordinating Office (CCO) at the Centre for Cancer Prevention (CCP) at Queen Mary University London (QMUL) seek to continue to passively collect cancer registration and mortality data via MRIS and HES products provided by NHS Digital. The identifiable data sets returned by NHS Digital will provide vital information on side effects, survival and breast cancer incidence.

The international centres that participated in the study would be co-ordinated through the IBCSG (International Breast Cancer Study Group). Where possible except for Australia and New Zealand, all foreign centres would be randomised through the central London coordinating office but data collection and cholesterol assays will be carried out nationally. Data forms and blood sample aliquots will be transferred to the central office on a regular basis. The cohort has now decreased from 4,277 to approximately 3,603 due to either patients passing away or the study losing contact with the patients.

These data are essential in enabling the CCO to determine whether tamoxifen continues to have a long-term beneficial impact in terms of breast cancer incidence, survival and side effects after the initial 5-year treatment period. The CCO will be able to perform a thorough risk-benefit assessment of tamoxifen and a 30-year median follow-up analysis. These analyses will enable the research community to make more informed decisions on tamoxifen vis-a-vis patient safety and both short- and long-term effectiveness. The results so far have been very important for breast cancer in the preventive setting.

GDPR Legal Basis:

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 archiving purposes in the public interest, scientific or historical research purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

The first results of the IBIS-I have already been published (Cuzick J, et al. The Lancet. 2002;360: 817-24; Cuzick J, et al. J Natl Cancer Inst. 2004;96:621-628; Cuzick J, et al. J Natl Cancer Ins. 2007;99:272-82; Cuzick J, et al. San Antonio Breast Cancer Symposium. 2014, Dec 9-13; Cuzick J, et al. Lancet Oncol. 2015;16(1):67-75).

Further outputs and analyses of the IBIS-I trials will be published in peer-reviewed medical journals such as The Lancet, The Lancet Oncology, Breast Cancer Research and Treatment and the British Journal of Cancer with at least two anticipated publication dates in 2020 and 2025

Outputs were anticipated in 2019 when there is 20 years of median follow-up data available. This output is still anticipated when current data is collected from devolved nations. It is further anticipated that Queen Mary University of London will run an updated analysis in 2024 (25 years median follow-up).

The public will be made aware of the research progress through two web pages (http://www.ibis-trials.org/thetrials/yourstories/press-articles and https://www.qmul.ac.uk/wolfson/research-/current-projects/projects/ibis-1.html). The anticipated audiences of the above outputs are researchers, scientists, stakeholders for the wider project and research participants.

Publications with significant findings may be accompanied by press releases and subsequent news stories. Additionally, the study is planning on holding a PPI event in January 2020 whereby discussion will take place about the work carried out in the CCP covering breast cancer research. This will be a useful way to disseminate outputs and discuss the future of following up patients in the long term follow up method.

Policy makers - such as NICE will also be targeted with the outputs of the study. NICE will be informed on the safety and efficacy of tamoxifen as a chemopreventive agent, allowing more information available to women at risk of developing breast cancer on the options available to them. An estimated 15% of women in the UK could benefit from preventive tamoxifen therapy and therefore results from the IBIS-I study are of great relevance to these women.

New publications, attendance of conference and meetings will be shared with international partners. Data contained in any outputs will be aggregated with small numbers suppressed in line with the HES analysis guide. There will be no onward sharing of data. Data received at the Centre for Cancer Prevention is only used to meet the objectives as stated in the trial protocol and will not be shared with any other third party or organisation. Individual patient data is never shared.

Registry data provided to date has identified numerous cases of breast cancers, other cancers and side-effects in participants with whom the Centre for Cancer Prevention at Queen Mary University London have no direct contact and therefore not already known by the study team. Collection of this data has contributed directly to the primary endpoints of the trial and will continue to provide valuable information on the long-term risk/benefit status of the trial intervention. This long term data is essential for informing bodies such as NICE to inform the prescribing utility of these drugs as chemopreventive agents. The CCP use registry reported events as a prompt for further investigation by asking participants' current GP practice to confirm the event and also provide any further information e.g. cancer grade, size, receptor status that is required to meet secondary and exploratory objectives.

So far the long-term follow-up has shown that tamoxifen significantly reduces breast cancer incidence in women at risk of developing the disease (see for example Cuzick J, et al. J Natl Cancer Ins. 2007; 99: 272-82). The thromboembolic side effects and increase in gynaecological problems (including endometrial cancer) disappear after the active treatment phase has ended. The trial has also provided further information on the impact of tamoxifen on breast density: mammographic density appears to be a prognostic marker for improved long-term survival in participants receiving adjuvant tamoxifen.

Notably, the IBIS-I study won the Cancer Research UK Prize for Translational Cancer Research at the 2014 NCRI Cancer Conference for its improvements in cancer research (http://www.ibis-trials.org/thetrials/ibistrials/ibis-i-award). Moreover, NICE updated its guidelines on prescription of tamoxifen to women at high risk of developing breast cancer, a decision partly based on results of the IBIS-I Study (first published June 2013, update August 2015; https://www.nice.org.uk/guidance/CG164 and https://www.nice.org.uk/guidance/cg164/evidence/surveillance-review-decision-november-2015-pdf-2178797581).