Metastatic breast cancer cells in pleural fluid. Photo by Ed Uthman, CC BY 2.0.
The effect of combined hormone replacement therapy (HRT) in increasing a woman’s risk of breast cancer is likely to have been underestimated by a number of previous studies, according to a new prospective study published in the British Journal of Cancer.
HRT is used to treat uncomfortable symptoms of the menopause – such as hot flushes, migraines, disrupted sleep, mood changes and depression — by topping up the decreased levels of oestrogen being produced by the body. Around one in ten women use HRT during their fifties, with use lessening in older age groups as menopausal symptoms reduce.
There are two main types of HRT, one containing just oestrogen (‘oestrogen-only HRT’) and the other a combination of oestrogen and a progestogen (‘combined HRT’) and it can be taken in four ways: through tablets, skin patches, a cream or a gel. A third less commonly used type of HRT known as ‘tibolone’ contains a steroid that acts like oestrogen and progestogen.
The Generations Study
The new research was part of the Breast Cancer Now Generations Study — a major prospective study led by scientists at The Institute of Cancer Research, London, following more than 100,000 women for 40 years to investigate the causes of breast cancer.
Some 39,000 women with a known age at menopause were identified and monitored for six years, with follow-up questionnaires gathering comprehensive data on any HRT use (type and duration) as well as their general health and lifestyle.
During this time, 775 of these women developed breast cancer, with the researchers finding that women using combined HRT (for a median duration of 5.4 years) were 2.7 times more likely to develop breast cancer during the period of HRT use than women who had never used HRT.
This risk increased with duration of use, with women who had used combined HRT for over 15 years being 3.3 times more likely to develop breast cancer than non-users. However in women using oestrogen-only HRT there was no overall increase seen in breast cancer risk compared with women who had never used HRT.
Importantly, this increased risk level has been found to return to about normal once HRT use ends: after a year or two had gone by since women stopped taking combined HRT, the scientists did not find a significantly increased risk of breast cancer, confirming the findings of previous studies.
A more accurate estimate of breast cancer risk
It is widely acknowledged that combined HRT is linked to an increased risk of breast cancer and this could be explained by an increased exposure to hormones affecting the development and growth of some breast cancers; however scientists have debated exactly how great this increase in risk is.
Unlike many studies in this area, the researchers updated information on women’s use of HRT over time through follow-up questionnaires. This avoids the biases created when women who have stopped using HRT after entering a study are still counted as “current users”, or women who have started using HRT after entering the study are still counted as “never users”. In the Generations Study, 65% of women who were using HRT when they entered the study later stopped.
The study also updated menopausal status through follow-up, ensuring the study could accurately identify post-menopausal women and did not include as post-menopausal those who had undergone a hysterectomy (without ovary removal) before the natural menopause, who have been included in past studies and can introduce further bias in risk estimates.
By adjusting for actual age at menopause and updating information on HRT use, the study authors believe the findings provide a more accurate estimate of the increased risk of breast cancer for HRT users and that several previously published estimates of risk for combined HRT use are likely to be underestimates.
To test this hypothesis, the researchers also analysed their data without adjusting for changes in HRT use or women’s known menopause age. This led to an estimate of a 1.7 fold increase in risk for combined HRT use compared with non-users, meaning this method underestimated the more accurate (2.7-fold) risk estimate by about 60%.
Allowing women to make informed decisions
Study leader Professor Anthony Swerdlow, Professor of Epidemiology at the ICR said: “Our research shows that some previous studies are likely to have underestimated the risk of breast cancer with combined oestrogen-progestogen HRT. We found that current use of combined HRT increases the risk of breast cancer by up to three fold, depending on how long HRT has been used.
“Our findings provide further information to allow women to make informed decisions about the potential risks and benefits of HRT use. This research was only possible because of the detailed information provided over many years by the dedicated participants in the Generations Study.”
Baroness Delyth Morgan, Chief Executive at Breast Cancer Now, said:“Whether to use HRT is an entirely personal choice, which is why it’s so important that women fully understand the risks and benefits and discuss them with their GP. We hope these findings will help anyone considering the treatment to make an even more informed decision.
“On balance, some women will feel HRT to be a necessity. But in order to minimise the risk of breast cancer during treatment, it is recommended that the lowest effective dose is used for the shortest possible time.
“The good news is that the increased risk of breast cancer begins to fall once you stop using HRT.
“If anyone is at all worried about either HRT or breast cancer, we’d highly encourage you to speak to your GP.”
The Breast Cancer Now Generations Study participants will continue to complete further questionnaires as the study progresses, enabling the researchers to investigate — with even more detail and precision — the risk of breast cancer in relation to duration of HRT use and to the types of HRT used.
The Breast Cancer Now Generations Study was launched in 2003 to help understand the causes of breast cancer. While it is known that one in eight women will be diagnosed with the disease in their lifetime, a clearer understanding of the causes of the disease is needed in order to identify those women who are most likely to develop it, and find the most effective ways to reduce their risk.
Breast Cancer Now thanks M&S for their generous support of the Breast Cancer Now Generations Study.
For more on this story, read our companion Science Talk blog post by Claire Bithell: What should women know about the new HRT and breast cancer study?
 At recruitment to the Breast Cancer Now Generations Study, 1719 post-menopausal women were using oestrogen-only HRT, 1612 were using combined HRT and 398 were using other or unspecified HRT.