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Women considering hormone replacement therapy (HRT) can be reassured about the risk of breast cancer. New research suggests that HRT is generally linked to only small increased risks. Different types of HRT were linked to different risks of breast cancer. The details of this study should help guide discussions between doctors and women considering HRT. 

Symptoms of the menopause can be severe in many women. HRT alleviates these symptoms and can be life-changing. However, a recent study reported a bigger than expected risk of breast cancer with HRT. This renewed the concerns that many women have. 

The new large study, which included more than half a million women, provides reassurance. It found that – in line with other evidence – the risks of HRT are generally low. Breast cancer risks were extremely low with oestrogen-only HRT, but this can only be taken by women who have had their womb removed (hysterectomy). Most women take combined HRT which contains oestrogen and progestogen. 

There was no increase in risk of breast cancer for HRT taken for less than a year.  Risks increased with the duration of HRT treatment and were noticeably higher if taken for longer than five years. But the risks then declined once the HRT was stopped. Five years after stopping, there was no increase in breast cancer risk for women who had taken combined HRT for less than five years.

A woman’s age also made a difference, with women in their 50s at lower risk than those in their 60s and 70s. The type of progestogen in combined HRT made a difference: norethisterone was linked to the highest increases in risk of breast cancer, and dydrogesterone to the lowest risk.

This research supports the UK’s current prescribing guidance, which recommends taking HRT for no more than five years.

Further information on HRT for symptoms of the menopause is available on the NHS website.  

What’s the issue?

Women usually go through the menopause when they are between 45 and 55 years old. A reduction in their oestrogen levels is associated with unpleasant effects that can be severe. They include concentration loss, sleep disturbances, hot flushes, mood swings, vaginal dryness and reduced sex drive.

HRT is widely used by women to relieve symptoms of the menopause. The treatment can also help to prevent osteoporosis (weakening of bones) that commonly develops after the menopause. Sometimes HRT is taken for several years. 

A type of oestrogen called estradiol is commonly prescribed. Given alone, it raises the risk of womb cancer. It can therefore be given only to women who have had a hysterectomy. For most women, therefore, oestrogen is combined with another hormone, progestogen, which protects the womb. 

HRT is available as tablets, gel, implants or skin patches. Effectiveness and side effects differ between the available treatments. 

Women's use of HRT has declined over the past two decades since research showed an increased risk of breast cancer among women taking it. This risk was found in a more recent review of research, which has renewed the concerns felt by many women. 

However, before this study, there was little information about the detailed risks of breast cancer with different hormone combinations and durations of treatment. This new study was large enough to explore whether risks differ between the different HRT drugs and treatment durations.

What’s new?

The researchers looked at data from 99,000 women with breast cancer who were aged between 50 and 79. Each was matched to five other women (457,000 controls) who did not have breast cancer. This was so researchers could look at the association between taking HRT and having a diagnosis of breast cancer.

The study showed that about one in three women had taken HRT at some stage. Most (70%) had taken combined oestrogen-progestogen. Fewer (30%) had taken oestrogen-only, which is only suitable for women who have had a hysterectomy. The study showed oestrogen-only HRT increased breast cancer risk only marginally and this extra risk disappeared after treatment stopped. 

Most women took combined HRT, which was linked to a small increase in risk of breast cancer. The risk increased with: 

    • a woman’s age, with lower increases in risk for women in their 50s, compared to those in their 60s and 70s
    • the duration of treatment, with lower increases in risk with HRT taken short-term (less than 5 years) than long-term (more than 5 years)
    • current or more recent HRT treatment, which came with higher risks than past-use (more than 5 years ago)
    • the type of progestogen in combined HRT; with the highest risks with norethisterone and the lowest with dydrogesterone.

The researchers stressed that some women who had never taken HRT would still get breast cancer. For example, if a group of 10,000 women in their 50s had never taken HRT, 26 women would still get breast cancer in a year. If all 10,000 women had recently taken combined HRT for less than 5 years, 35 would get breast cancer. So, in this large group of women, the HRT is linked to 9 extra cases of breast cancer in a year. That is less than one in a thousand women.

The increased risk was mostly linked to combined HRT, and the type of progestogen made a difference. Risk increased similarly when preparations containing some types of progestogen (norethisterone, levonorgestrel, or medroxyprogesterone) were taken for more than a year. The lowest increase in risk was with dydrogesterone (another type of progestogen).

Even if women took combined HRT long-term (more than 5 years), risks reduced after therapy was stopped. For women in their 50s, there was no extra risk of breast cancer with combined HRT that was stopped more than 5 years previously. There was little extra risk among women in their 60s and 70s.

There was no increased risk of breast cancer:

    • with any current HRT taken for one year or less
    • with past use of oestrogen-only HRT, even if taken long-term
    • with past use of combined HRT taken short-term.

Why is this important?

The results support those found in earlier observational studies. They provide reassurance that HRT is linked to only a small increased risk of breast cancer. 

The study contradicts a recent analysis, which pooled the results of 58 other studies and found higher than expected risk of breast cancer with HRT. That study could not make direct comparisons between types of HRT, or different durations of treatment.  

The current research clarifies the types of HRT with the lowest risk and could guide the HRT of choice for many women. Oestrogen-only HRT has the lowest risk, but can only be taken by women who have had a hysterectomy. This work supports the current UK guidance around menopause, which says that there is little increased risk of breast cancer with oestrogen-only HRT. 

Different types of combined HRT had different risks. The lowest was with dydrogesterone, which is not prescribed as often as other progestogens with higher risks (norethisterone, medroxyprogesterone and levonorgestrel).

An alternative to HRT, tibolone, was also associated with low risk. But the authors say it may not be as effective as HRT in managing menopausal symptoms and it is rarely prescribed.

What’s next?

It is important that GPs discuss the benefits and risks of HRT with women troubled by symptoms of the menopause. HRT can have a dramatic effect on these symptoms, and this research suggests that risks of breast cancer are low. The results could guide the choice of HRT, and the length of time women take it. 

The researchers organised formal and informal conversations with women to understand behaviour around taking HRT. They found that women were highly likely to take the HRT they were prescribed. Some, who travelled abroad and missed a prescription, kept up with their treatment by finding another source of HRT. 

More research could examine further the link between HRT and breast cancer. Questions include whether HRT use has an impact on survival rates among women with breast cancer. It would also be interesting to explore whether certain tumour types are more linked with HRT than others.

You may be interested to read

This NIHR Alert is based on: Vinogradova Y, and others. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ 2020;371:m3873 

The recent meta-analysis showing very high increased risk: Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. The Lancet 2019;394:10204

A large-scale study of HRT and the risk of breast cancer: Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. The Lancet 2003;362:9382 

Menopause: diagnosis and managementNational Institute for Health and Care Excellence (NICE) guidance on diagnosing and managing menopause. 

HRT and breast cancer risk: a blog post from the ICR discussing what research about HRT and breast cancer means for women.

Effect of combined HRT on breast cancer risk likely to have been underestimated, new study finds: a news piece from the ICR discussing research from the Breast Cancer Now Generations Study.

Further information on the Breast Cancer Now Generations Study.

 

Funding: This work is partially funded by the NIHR School for Primary Care Research and by Cancer Research UK through its Oxford Centre.

Conflicts of Interest: The study authors declare no conflicts of interest.

Disclaimer: NIHR Alerts are not a substitute for professional medical advice. They provide information about research which is funded or supported by the NIHR. Please note that views expressed in NIHR Alerts are those of the author(s) and reviewer(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.


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Commentaries

Study author

Some women experience debilitating, occasionally life-changing effects from the menopause, and they need access to safe and effective treatment. Existing evidence has tended to highlight the risks without being able to provide good estimates of actual breast cancer numbers.The risks found in this study were lower than expected, especially compared with some recently published work that might have put women off taking HRT. Our work looked at different combinations, different preparations and different durations of HRT. It is critical that these results are shared, as is a thorough discussion between GP and patient about the risks and benefits of different combinations of HRT.Yana Vinogradova, Senior Research Fellow, University of Nottingham 

British Menopause Society

This paper provides further observational evidence about the risk of breast cancer diagnosis associated with HRT exposure based on 2 large databases providing a representative primary care population.Overall, the key findings do not differ significantly from previously published evidence with respect to patterns of risk and the degree of risk conferred. The risk of breast cancer diagnosis was duration dependent, greatest with combined HRT and fell following cessation. Risk was not increased with topical oestrogen and there was no evidence of a dosage effect with unopposed systemic therapy, in keeping with the recent Collaborative Group for Hormonal Factors in Breast cancer (2019).Lean women appear to be at greater risk with more exposure than those who are overweight or obese. Whilst risk appeared to increase after relatively short exposure times (i.e. within three years) this is probably due to the promotion of pre-existing, impalpable, hormone sensitive cancers, present at the time of initiation. In the placebo-controlled, randomised WHI study the time for increased risk of diagnosis to emerge was longer and almost certainly due to such cancers being 'screened' out prior to randomisation by baseline mammography in all participants.Probably the most important finding is that compared to the synthetic progestogens medroxyprogesterone acetate, norethisterone and levonorgestrel, combined preparations containing dydrogesterone were associated with a lower risk of diagnosis, which supports a growing body of observational evidence with similar findings.Jo Marsden and Hugo Pedder on behalf of the Medical Advisory Council of the British Menopause Society  

The Institute of Cancer Research

The study in question is very large and uses GP medical records from over 98,000 women with breast cancer, and over 450,000 women without, so the strong statistical associations are unlikely to be due to chance.The results of this study generally confirm what has been seen before and is well established – that the use of combined oestrogen plus progestogen HRT is associated with increased risk of breast cancer, and this risk increases with duration of use. But reassuringly, after stopping HRT, the raised risk of breast cancer mostly returns to that seen in non-users of HRT.The study also found a small risk associated with oestrogen only HRT use.It’s important to note that no one study should be considered in isolation. Even though some risks were found to be slightly smaller than those reported in another meta-analysis of the worldwide epidemiological evidence recently published in 2019, women considering use of HRT should still follow advice given to them by their GPs.Michael Jones, Senior Staff Scientist in Genetics and Epidemiology at The Institute of Cancer Research 

Member of the public

The research is relevant in a personal capacity as I fall into the age group covered by the study. I also have friends and family members who have struggled with the dilemma of taking HRT to relieve extreme symptoms of the menopause balanced against the possible risk of breast cancer. This paper provides detailed evidence about the risk of breast cancer with HRT and can help with decision making prior to agreeing to take HRT. It is important to update literature around HRT and make it accessible for people.Marie McHugh, Public Contributor, Newcastle Upon Tyne 

Nurse

I provide nursing care for breast cancer patients daily and many are on HRT therapy. This paper highlights the particular combinations of HRT that are linked with the highest breast cancer risk. I expect this paper to impact prescribing guidelines for HRT, so that they include the risks of breast cancer associated with each hormone type/combination.The findings support previous observational studies. I would expect them to have an impact on the decision-making of healthcare professionals in what HRT is suitable for each individual and what should be prescribed. This decision should include weighing up the pros and cons of each type of HRT and taking into account which types have the greatest risk of breast cancer.Sophie Craig, Senior Staff Nurse, The Royal Marsden NHS Foundation Trust  

Clinician

This evidence is mostly consistent with what is already known. However, it is unique because it uses databases that are largely representative of the general population in the UK.In addition, it explored age-specific estimates of excess breast cancer risk with the different types of HRT. This could lead to more informed decisions about HRT use. This work will help me when discussing HRT with my patients. This study has potential to make evidence more easily / intuitively accessible for clinicians and patients alike.Mangesh Thorat, Honorary Senior Lecturer, Queen Mary University of London  
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