The Million Women Study: Disease Susceptibility

Disease Susceptibilty Study

The Million Women Study: Detailed Investigation into Susceptibility of Disease

Protocol (2004)

Aim

To investigate in detail factors affecting susceptibility to disease within the Million Women Study, including the separate and joint effects of exposure to environmental factors, such as hormone replacement therapy, and of the individual’s genetic constitution. The main focus will be on susceptibility to breast cancer and to cardiovascular disease.

Background

The Million Women Study (Eastern MREC 97/5/01) is a nationwide prospective cohort study set up primarily to investigate the effects of different types of hormone replacement therapy (HRT) on the risk of breast cancer. Over 1.3 million women aged 50-64 (1 in 4 of UK women in this age group) were recruited through NHS breast screening centres between 1996 and 2001. Prevalent and incident disease is monitored through self-reporting on recruitment and follow-up questionnaires and by linkage to the National Health Service Breast Screening Programme, Cancer Registries and the Office of National Statistics. The large scale of the Million Women Study and the detailed prospective information collected on environmental risk factors such as the use of HRT mean that it offers an unprecedented opportunity to study the separate and joint effects of both environmental and genetic risk factors for disease.

Rationale

Breast Cancer

Breast cancer is the commonest cancer among women in the UK and is an important cause of morbidity and mortality. There is considerable public and scientific interest in the role of genetic factors in susceptibility to breast cancer. While there is mounting evidence on the substantial risk of breast cancer associated with rare high-risk gene mutations such as BRCA1 and BRCA2, much less is known about the possible effect on breast cancer risk of more common lower-risk variations (polymorphisms) in genes such as those (eg CYP17, CYP19, HSD17B1) involved in the metabolism of sex hormones like oestrogen. Although the risks of breast cancer associated with these lower-risk gene variants are likely to be relatively modest, they are potentially of considerable public health importance as the genetic variations involved are very common (present, on average, in about 20-60% of the population in the UK). Particularly important are the possible joint effects on breast cancer risk of these common genetic variants and equally common environmental risk factors such as the use of hormone replacement therapy (at recruitment a third of women in the Million Women Study were current users of HRT). These joint effects can only be adequately investigated in very large studies. Initial studies in this field have been limited by small study size, overemphasis on marginal findings and failure to replicate positive results; however it is hoped that relevant polymorphisms will be more reliably identified in larger-scale studies currently under way. The Million Women Study has accrued 10 000 incident cases of breast cancer within the first three years of follow-up and over 35 000 incident cases are expected by 2008. We plan to focus our breast cancer susceptibility studies on the investigation of strong candidate polymorphisms once these have been identified, and, unlike previous studies, we will be able to take into account detailed information on tumour histology and on oestrogen and progesterone receptor status as well as prospective data on reproductive factors and HRT use.

all information will be treated with absolute confidentiality in accordance with the Data Protection Act, used for medical research purposes only and will never be used in a way which could identify them personally
they will not receive individual feedback about the results of genetic or other tests
the study is important for future research and many of the tests and analyses which will be conducted in the future cannot be specified at present
the study has been approved by the appropriate Multi- Research Ethics Committee.

Participants will be asked to give written consent for the storage of their blood or buccal cell/saliva sample and for the use of the sample for unspecified biochemical and genetic tests now and in the future.

Participants will be encouraged to ask about or comment on any aspect of the study either in writing or by telephoning a study Freephone number.

Pilot studies

Pilot studies will be carried out on a small sample (about 200 – 400 women with disease and a similar number of control women). The results, including comments from participants, will be used to test methods of collection, storage, processing and analysis of biological samples and to confirm acceptability and usefulness of the study methods for the questionnaires. A major feature of the pilot study will be to compare the feasibility of collection and analysis of blood samples and of buccal smears. As part of the pilot studies information from the hospital records of a sample of women reporting incident cardiovascular disease will be compared with self-reported information from questionnaires to assess diagnostic validity of questionnaire reports.

Publication of results

The Million Women Study is a joint research project of the NHS Breast Screening Programme, the Medical Research Council and Cancer Research UK. Results from the study will be published in peer-reviewed journals and appropriate authorities (eg the Department of Health and the Medicines Control Agency) will be notified of relevant results where necessary.

A number of minor amendments to this protocol have been approved. Details are available on request.

Further information can be fund in the Disease Susceptibility Study section of this website.