Million Women Study
The Million Women Study: Original Protocol (1996)
The principal aim of this research is to obtain reliable information on the risk of breast cancer associated with the use of different types of hormone replacement therapy (HRT). Evidence suggests that HRT use increases the risk of breast cancer, but insufficient data are available to determine whether HRT preparations containing oestrogen alone or oestrogen and progestogen have different effects (Collaborative Group on Hormonal Factors in Breast Cancer 1997). The results of that study also suggested that the breast cancers diagnosed in women who used HRT were more likely to be localised to the breast than the cancers in never users. Large numbers of women, i.e. around 5,000 with breast cancer, need to be studied to examine the effects of different types of HRT and to look at the extent of tumour spread in women who have used HRT, and the NHSBSP offers a unique opportunity to do so. Indeed it would probably be impossible to carry out a study of the scale required anywhere else in the world. An additional consideration is that the age range of women who use HRT corresponds with the age when screening is offered, and a subsidiary question that would be answered by the proposed study is whether HRT use affects the sensitivity and specificity of mammography.
Summary of the study
The proposed study would involve sending a brief questionnaire to women when they are invited for screening. (A copy of the questionnaire is attached). The questionnaire asks about factors known to affect breast cancer risk and about the use of hormone replacement therapy and other hormones. It also asks women for permission to obtain follow-up information about their health, and to provide personal details. Follow-up for cancers detected at mammography would be initially via the screening clinics and for other cancers and deaths, via the NHS Central Registers. The risk of cancer and death from various causes in women who had used HRT will then be compared to the risks in women who had not used HRT.
Results from pilot studies
Extensive piloting of the study has already been carried out in Oxford and West London. These have demonstrated that the questionnaire is acceptable to women: a sample of women who were sent the questionnaire were interviewed by telephone and none expressed concern about any of the questions asked. By far the most common questions were about the effects of HRT; and many women said how pleased they were that this research was being done. Pilot studies have also shown that attendance rates did not differ significantly in women who were and were not sent a questionnaire. Furthermore, among the women who attended for screening, 78% completed the questionnaire, and 95% of these women gave permission for follow-up. The results from pilot studies therefore demonstrate that the enclosed questionnaire is acceptable and sending it out to women does not alter attendance rates for screening. The response rate is high and women seem keen to take part in this type of research. Additionally, the prevalence of use of HRT is relatively high, with 41% having used HRT at some time and 28% being current users of HRT.
Details of the study
Eligibility: All screening centres in the NHSBSP will be eligible to collaborate in this research and all women invited for screening will be eligible to take part. Participation is entirely voluntary.
Approach to clinics: Each breast screening centre will be approached and asked if it wishes to collaborate in this research. If so, the study team will discuss how best to arrange the sending out and collection of questionnaires and seek appropriate ethical committee approval for the study. The study is already underway in about 50 screening centres in the UK, and the experience so far is that each centre has its own particular routine: an important principle of the study is that it should interfere as little as possible with the normal running of the screening programme. Therefore, there will be regular communication between the study team and staff at each participating centre to ensure that involvement in the study causes as little extra work as possible and that problems are dealt with swiftly.
Approach to subjects: Women will be sent the attached questionnaire at the time they are invited for screening and asked to bring it with them when they attend for screening. A freephone number will be provided if the women have any questions.
Follow-up: Once each year routine information about the breast cancers diagnosed at screening will be sought from each screening clinic. In addition, the study team will seek information about cancer incidence and deaths from the NHS Central Registers.
Logistics: Staff for the Cancer Epidemiology Unit, Oxford, will be responsible for the preparation and delivery of the questionnaires to the screening centres, for the collection of the questionnaires and for the follow-up. The screening clinics will be responsible for despatching the questionnaire to the women and for providing, once each year, routine details about the cancers diagnosed in study participants.
Numbers: At least 5,000 women with breast cancer area needed to detect a 25% difference in breast cancer risk in long term users of oestrogen alone compared with users of combinations of oestrogen and progestogen. In addition at least 500 interval cancers are needed in the first year after screening to see whether HRT use affects sensitivity and specificity of screening. To obtain such numbers about 1,000,000 women will have been recruited by then.
Confidentiality and ethics: Ethical committee approval will be sought separately for each centre. Participation in the study will be entirely voluntary. It will be made clear to women that they do not have to take part in the study if they do not want to and that their decision does not affect their management. All information provided will be stored in accordance with the Data Protection Act (registration number with the Office of the Data Protection Registrar: K3039784). The data will be treated with utmost confidentiality and used only for medical research. Only the study team will have access to computerised data, via passwords. Any publication resulting from this work will not identify the individual women who took part.
Publication of results: This is a joint research project of the NHS Breast Screening Programme, the Medical Research Council and the Imperial Cancer Research Fund. Publication of the main results will be in the name of “The Million Women Study”, and all centres that have collaborated will be named.
Reference: Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 1047-1059.