Study Progress
Pilot studies, recruitment and follow-up
Prior to starting the main study, pilot studies involving around 6,000 women were conducted between 1994 and 1996. These preliminary studies showed that the questionnaire was acceptable to women and that receiving the questionnaire did not affect whether or not they went to screening. The pilot studies also showed that around one third of women attending the National Health Service Breast Screening Programme were using hormone replacement therapy (HRT), and that if a large scale study of hormone replacement therapy and women’s health were to go ahead, the vast majority of those attending screening would take part. The Million Women Study (MWS) was officially launched in 1997, involving 66 National Health Service Breast Screening Centres nationwide. Thanks to staff working on the study and the enthusiasm of women throughout the UK, the study finished recruiting in 2001 with 1.3 million women taking part. We started collecting blood samples for genetic studies – the Disease Susceptibility in Women part of the study – in 2005 with the help of GP practices throughout England and Scotland, and this continues, along with follow-up of all women in the study through NHS medical record linkage and through follow-up questionnaires (see Methods).
Most women in the study were aged 50-64 at recruitment, with an average age of 56 years. By June 2009 nearly 8 years’ follow-up information on cancer had been collected for each woman – a total of 10 million woman-years for the whole study, and including information on nearly 90,000 incident cancers (cancers first diagnosed since recruitment), of which nearly 35,000 are breast cancers.
The results from the study are being published in peer-reviewed journals and all MWS publications can be found on the Publications page.
Some early findings about women in the study
Analysis of responses received to the recruitment questionnaire showed that among women participating in the study:
- 1 in 2 women had taken the oral contraceptive pill
- 1 in 2 women had tried HRT
- 1 in 3 women was currently using HRT
- 1 in 4 had had a hysterectomy
- 1 in 11 had a close female relative with breast cancer
- 1 in 70 had had breast cancer in the past
Whether or not a woman was currently using HRT did not depend much or at all on where she lived, when she entered the study or on socio-economic or “lifestyle” factors (such as number if children, smoking or exercise), but was strongly influenced by her age and by her medical history. For example, among women who had had a hysterectomy, 48% were current users, but among women with a history of breast cancer only 6% used HRT. These findings are being taken into account in analyses so that we can be sure we are looking at the effects of HRT, and not the effects of factors influencing HRT use. More generally, the large amount of detailed information we have collected on many disease risk factors (eg smoking, alcohol, physical activity, diet) means that when we look at the effects of any one factor, we can take the effects of the other factors into account.
HRT and breast cancer
Results from the Million Women Study published in 2003 showed that women currently using HRT are more likely to develop breast cancer than those who are not using HRT. Past users are not at increased risk. The Million Women Study was able to show that this effect is substantially greater for combined (oestrogen-progestagen) HRT than for oestrogen-only HRT; and that the effects were similar for all specific types and doses of oestrogen and progestagen, including pills (oral HRT), skin patches and gels (transdermal HRT), and HRT implants. Current users of oestrogen-progestagen HRT were at 2 fold increased risk of developing breast cancer, and current users of oestrogen-only HRT at 1.3 fold risk. Use of HRT by women aged 50-64 in the UK in the decade from 1993-2003 resulted in an estimated 20,000 extra breast cancers. More recently we have found that the effects of HRT on breast cancer risk vary depending on the histological (cell) type of tumour, with greater increases in risk for lobular and tubular than for ductal types (Reeves et al, 2006). We have also shown that breast cancers detected by screening in women with a family history of the disease are similar in size and type to those in women with no family history of breast cancer (Couto et al, 2008); and that current users of hormone replacement therapy are more likely to be recalled for further assessment after mammography (Banks et al, 2004 and 2005).
HRT and endometrial (womb) cancer
It is well known that post-menopausal women who have not had a hysterectomy are at increased risk of cancer of the endometrium (the lining of the womb) if they take oestrogen-only HRT. Follow up of over 700 000 women in the Million Women Study confirmed this and showed that the risk of endometrial cancer is also increased in women who take tibolone; but is not altered, or may even be reduced, in women taking combined oestrogen-progestagen HRT (MWS 2005). These effects depend also on a woman’s body mass index (BMI, a measure of obesity) such that adverse effects of tibolone and oestrogen-only HRT are greatest in thinner women, and the beneficial effects of combined HRT are greatest in fatter women.
HRT and ovarian cancer
In 2007 we published results showing a small increase in risk of ovarian cancer in women taking HRT (see Publications). Such an increased risk had been suspected from some previous studies, and has now been confirmed with the larger numbers available in the MWS. The findings come from analyses on 948,576 post-menopausal women in the study, followed up for about 5 years. Women currently taking HRT were at higher risk of developing and of dying from ovarian cancer than women not using HRT. Past users were not at increased risk. The risk in current users was increased about 1.2 fold; for every 1000 women using HRT, 2.6 developed ovarian cancer over 5 years, compared with 2.2 in those not taking HRT. The risk was the same for oestrogen-only, combined oestrogen-progestagen and other types of HRT (including tibolone) and did not vary by specific type of oestrogen or progestagen, or between oral and transdermal (patch) administration. These results are equivalent to one extra case of ovarian cancer for every 2500 women taking HRT, and one extra death from ovarian cancer per 3300 women taking HRT, over 5 years.
HRT and the overall risks of breast, endometrial and ovarian cancers
We can now estimate the overall effect of HRT use on three common cancers in women: breast cancer, endometrial (womb) cancer and ovarian cancer. Together, these cancers account for about 4 in 10 cancers in women in the UK. In women aged 50-69, about 19 of these cancers will develop over 5 years in every 1000 women not taking HRT. In women taking HRT we estimate the number of cancers to be increased to about 31. The overall increased risk is higher in women using combined oestrogen-progestagen HRT (an increase from 19 to 34 cancers over 5 years) than in women using oestrogen-only HRT (an increase from 19 to 26 cancers over 5 years) because most of the overall increase is due to an increase in breast cancer, and users of combined HRT have a higher risk of breast cancer than users of oestrogen-only HRT.
Our results on cancer need to be looked at in the context of the other risks and benefits of HRT. Advice on HRT prescribing remains to use HRT for as short a time as possible to treat menopausal symptoms.
HRT and other cancers
The Million Women Study, because of its large size and the reliable and complete follow-up for cancer, offers the opportunity to study HRT-related risks for a wide range of cancers, including some which are relatively rare. For these cancers, any effect– positive or negative- of HRT use on cancer risk will not affect many people, but may be interesting in helping us to understand better how cancers develop. For example, we have recently found a small (about 40%) increased risk of brain tumours (of all common types) in women using HRT compared to women not using HRT (Benson et al, 2010), but these cancers remain rare whether or not HRT is used.
HRT and other conditions: bones, joints, and gallbladder
One of the benefits of HRT use is in reducing risk of fractures, particularly those linked to osteoporosis. In the MWS we have confirmed that all types of hormone therapy studied confer substantial protection against fracture while they are being used; and have shown that this protection appears rapidly after use commences, increases the longer a woman uses HRT, but wears off rapidly after use ceases (Banks et al, 2004). Risk of fracture in current users of HRT is about 40% lower than in non-users (relative risk 0.62, 95% confidence interval 0.40-0.94). Fractures become much more common with age, so the older women are, the greater is their absolute reduction in fracture incidence while using hormone therapy. For example, among 1000 women aged 50-54, about 0.8 hip fractures would be expected to occur over 5 years; if the women were taking HRT for 5 years, about 0.3 fractures would be prevented. Starting at age 60-64, 2.5 hip fractures would be expected to occur among 1000 women over 5 years, and 1 fracture would be prevented if the women took HRT; and so on – the number of fractures prevented at older ages would be much higher. However, most women take HRT around the time of the menopause, when fracture risks are low, and the benefits for bone health do not persist after HRT use stops. Overall the increased risks of breast cancer and of stroke associated with HRT use outweigh the reduced risks of fracture, and HRT is no longer recommended as a first-line treatment for osteoporosis.
In contrast to the benefits for bone health associated with using HRT, we have found that women using HRT are more likely than women not taking HRT to be admitted to hospital for hip or knee replacement surgery (Liu et al, 2008). HRT users are about 50% more likely than non-users to have joint replacements (with relative risks for hip replacement of 1.4 and for knee replacement of about 1.6); the reasons for this association are not clear.
Gallbladder disease is common in postmenopausal women, and it is well known that use of hormone replacement therapy increases the risk. We have found that this increase in risk is much smaller in women using transdermal HRT (in which the hormones are absorbed through the skin: patches, gels) than in women using oral HRT (pills). This is thought to be because the hormones in oral HRT are processed by the liver and gallbladder before they can be circulated around the body: HRT given through skin gels or patches is absorbed directly into the blood stream and so levels of hormones in the liver and gallbladder system are much lower. In women in the MWS, we found that over a 5 year period 1.1 in 100 women who had never used HRT were admitted to hospital for removal of the gallbladder, compared with 1.3 per 100 taking transdermal HRT and 2.0 per 100 taking oral HRT.
Other factors, including childbearing, smoking, alcohol body size and diet
As well as HRT, we are examining a wide range of other factors in relation to cancer and to other conditions.
A woman’s reproductive history includes the age when she started her periods (menarche); the number of children she has, how old she was when they were born, and whether or not she breastfed; and her age at menopause, when her periods stop. These factors are related to the natural levels of female hormones in the body, such as oestrogen and progesterone; and so are often found to be linked to risk of diseases such as breast cancer, which are also affected by use of female sex hormones for contraception or for hormone replacement therapy. We have recently described the detailed relationships between reproductive factors and risk of different types of breast cancer (Reeves et al, 2009), and we have examined risk of pancreatic cancer (Stevens et al, 2009) and of brain tumours (Benson et al, 2008) but found no links with reproductive factors. Risk of gallbladder disease was found to be higher, the more children a woman has had; but set against this was a reduction in risk in women who breastfed (Liu et al, 2008). Risk of having hip or knee replacement surgery was also higher in women with more children, taking into account related factors such as activity and body weight (Liu et al, 2008). It is well known that risk of fracture increases after the menopause, and we have been able to use the detailed information in the MWS to separate out the effects of age itself, age at menopause and menopausal status on hip fracture risk (Banks et al, 2009). While for women of similar age, postmenopausal women have twice the risk of hip fracture compared to women before the menopause, in older women it is age itself, and not age at or since menopause, which determines most of the fracture risk.
We have confirmed that smoking increases the risk of pancreatic cancer (Stevens et al, 2008), but found that it was not linked to risk of glioma or meningioma tumours of the brain (Benson et al, 2008). We found no association between passive smoking and risk of breast cancer (Pirie et al, 2008), and showed that previous reports of a link were likely to be due to biased (unbalanced) reporting in studies in which smoking information was collected after cancers were diagnosed (women who already had cancer being more likely than women without cancer to report being exposed to passive smoking in the past).
Women in the Million Women Study drink on average low to moderate amounts of alcohol, and this provided the opportunity to study the effects of relatively low alcohol intake on risk of a wide range of cancers (Allen et al, 2009). Overall, cancer risk increased with increasing levels of drinking, with a rise of 6% for every drink (10g of alcohol, about 1 unit) per day – equivalent to an extra 15 cancers (in addition to the average expected 118) developing in every 1000 women up to the age of 75 for each additional drink per day. Risk is increased most (by 30-40%) for cancers of the mouth and throat in women who also smoke; but because breast cancer is by far the most common cancer in middle aged women, the increase of about 12% per daily drink for breast cancer (regardless of smoking) makes the biggest contribution to the overall increased risk. For a few cancers, such as non-Hodgkin lymphoma, risk is lower in women who drink alcohol than in non-drinkers.
For cirrhosis of the liver and for gallbladder disease, we found that both smoking and alcohol affect the risks of the 2 conditions in different ways (Liu et al, 2009). For cirrhosis, alcohol and smoking separately increase risk, and their joint effects are particularly hazardous. For gallbladder disease, alcohol reduces risk and smoking results in a small risk increase.
Body size, for example height and obesity (body mass index) influences risk of many cancers and other conditions. Our results suggest that about 6000 cancers annually, 5% of all cancers in postmenopausal women in the UK, may be due to being overweight (a body mass index (BMI)of 25-29) or obese (BMI of 30 or more) (Reeves et al, 2007), with obesity being a major factor particularly for endometrial (womb) cancer and for adenocarcinoma of the oesophagus. In our papers on breast and endometrial (womb) cancers, we have also described the way in which body mass index affects the way that HRT use influences cancer risk – the effects of HRT are greater in thinner women. This is thought to be because fatter women have higher levels of natural oestrogens, so the added hormones from HRT have less effect. We have also studied in detail the links between overweight and obesity and risk of cancer of the pancreas (Stevens et al, 2008) and of glioma and meningioma tumours of the brain (Benson et al, 2008): risk of these brain tumours is also independently linked to height, with risk for the tallest women in the study being about 30% higher than for the smallest women.
In a series of studies (Liu et al, 2007, 2008 and 2010) we have examined the links between body mass index and conditions other than cancer. Overweight and obesity are associated with increased risk of hospitalisation for hip and knee replacements, gallbladder disease, and cirrhosis of the liver. We estimate that 17% of cases of cirrhosis in UK middle aged women may be due to overweight and obesity (compared with 42% due to alcohol drinking); and that a quarter of all hospital stays for gallbladder disease are related to obesity.
We have collected a large amount of detailed information on women’s body size throughout life, including birth weight, weight and height at recruitment and as follow-up continues, and waist and hip measurements. In order to make reliable use of values reported to us, we have obtained height, weight, waist and hip measurements from a sample of women in the study to compare with self-reported values (thanks to these women and the staff of their General Practices). We are also comparing reported birth weights with those in medical records. We plan extensive analyses in the future to study the details of how body size, and related aspects of lifestyle such as diet and physical activity, relate to disease risk, and we plan further collection of information on diet and on physical activity through a newly designed web-based questionnaire.
Genetic studies
Since 2006 we have collected more than 40,000 blood samples from women in the study. Because of the large size of the study, and the details we have about non-genetic (‘environmental’) risk factors, such as HRT use, smoking and body size, we will be able to examine how genetic and non-genetic factors act both separately and together to affect disease risk.
June 2010
New results: lifestyle and genes pose separate risks for breast cancer.
The first Million Women Study paper on genetic risk for breast cancer has now been published Travis et al. We looked at the small risk of breast cancer linked to several common genes, and found that this risk was the same regardless of lifestyle factors such as obesity, alcohol, or use of HRT.
This is the first time this aspect of breast cancer has been studied in detail, and we were able to do so thanks to the generosity of tens of thousands of women who gave us blood, and of their GPs and practice nurses who helped us by taking the blood samples. Knowing how genes and lifestyle act together on risk of cancer is important because it may help us understand better how cancers develop.
Several common genes have recently been identified, which each carry a small increased risk of breast cancer (these are different from the rare, higher-risk breast cancer genes such as BRCA1 and 2, which we did not study). We have looked at the risk of breast cancer with several of these genes, in relation to the known ‘lifestyle’ (environmental) factors such as childbearing, HRT, obesity and alcohol. We found that the genetic risks were the same whether or not the lifestyle risks were also present. In other words, while both genes and lifestyle separately affect breast cancer risk, they do so independently.
This means that overall it is still the lifestyle factors which have most effect on breast cancer risk. Genetic factors (including family history, even where no specific genes are identified) account for only about 20% of breast cancers (and about a quarter of these, 5% overall, are linked to the high risk genes BRCA1 and 2). Fortunately many of the main lifestyle risk factors are modifiable, so breast cancer risk can to some extent be altered.
Validation and methodological studies
Throughout the study, we have been conducting studies to compare the information we have collected from questionnaires with similar information recorded elsewhere, so we can be sure we are interpreting the self-reported data reliably. These studies include the ones mentioned above on body size, as well as others on HRT use (Banks et al, 2001), diet (Roddam et al, 2005), cervical smear records (Canfell et al,2006) and hospital admissions for joint replacements and gallbladder disease (Liu et al, 2007) and for blood clots (venous thromboembolism) (Sweetland et al, 2009). Validation studies in progress are comparing diagnosis information for heart attacks, stroke and blood clots from questionnaires with both general practice medical records and hospital admissions records. We are also exploring the best statistical methods to use in analysing information from such a long-term study, where, for example, use of HRT or body size changes over time.
The Million Women Study and other studies: collaborations
We have been able to include information from the Million Women Study in several international collaborative studies which we are conducting. For these collaborations, data from many studies worldwide are re-analysed in a standard way so that the information they provide can be pooled to give as complete and reliable a picture of disease risk as possible. For example, MWS information on breast cancer was included in collaborative studies on breastfeeding, family history and alcohol and tobacco; and information on cervical cancer, in studies on oral contraceptives (the pill), smoking and reproductive factors. These publications can be found in the other publications section of this website.
Public Health Implications: impact of the Million Women Study
Results from the Million Women Study, together with those from other studies such as the Women’s Health Initiative trial from the USA, have influenced national policy, including recent recommendations on the prescribing and use of hormone replacement therapy from the Royal College of Obstetricians and Gynaecologists and from the Commission on Human Medicines. Because HRT use is linked to higher rates of breast and other cancers, and of stroke, it is now recommended that HRT should be generally used for a few years only to relieve menopausal symptoms such as hot flushes (although of course the balance of risks and benefits of HRT still needs to be considered for each woman individually). Greater knowledge of the risks of HRT use is not without problems: in particular, women who were taking, or might want to take, HRT for bone health now face a more difficult decision.
In terms of direct impact on women’s health, use of HRT has fallen by about half over the past few years, both in the UK and across the world. It is very encouraging to see that fewer breast cancers are now developing in women in their 50s and 60s – the age group most likely to use HRT. While other factors have also to be considered, it is thought that the fall in numbers of breast cancer cases and the fall in use of HRT are linked, and that as a result of the changes in HRT prescribing, many thousands of breast cancers have been prevented.
